ISSN 1883-9606

2018

Vol.137

ANNUAL REPORT OF
THE GRADUATE SCHOOL OF MEDICINEAND
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2017 ---- March 2018

Introduction
This is volume 137(the edition of year 2018) of the annual report by the University of Tokyo’s
Graduate School of Medicine and Faculty of Medicine.
In it are recorded the past year’s research, educational, clinical, and other activities of the
Graduate School of Medicine and Faculty of Medicine and the Tokyo Society of Medical Sciences.
It reports our accomplishments, and each year we make such a document freely available bypublishing it on compact disk and on the Internet, expecting it to be used for internal and external
evaluations.
The University of Tokyo’s Faculty of Medicine was founded 160 years ago. Since then we haveconsistently driven Japan’s progress in medical research, medical education, and clinical care, andin some fields we have become world leaders.
We have more than 1000 students in the Graduate School of Medicine, and with as many as 150
foreign researchers and students we are an international center for medical research and education.
Pursuing excellence in our research, educational, and clinical activities, we will continue meetingthe needs for tomorrow’s pioneers in medical sciences and clinical care.

Kohei Miyazono, Dean
Graduate School of Medicine and Faculty of Medicine
The University of Tokyo
October, 2018

i

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

1

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

2

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

4

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

6

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

8

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

9

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

13

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

16

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

19

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

20

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

23

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

26

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

29

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

30

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

33

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

37

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

38

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

44

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

48

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

49

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

52

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

55

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

56

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

60

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

61

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

69

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

70

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

73

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

76

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

79

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

80

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

83

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

88

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

90

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

91

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

93

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

94

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

98

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

103

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

109

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

110

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

112

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

117

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

118

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

121

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

124

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

125

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

131

iii

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

135

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

140

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

141

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

146

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

152

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

156

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

159

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

162

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

164

Department of Clinical Laboratory Medicine (See Department of Clinical Laboratory [P.448] )Department of Transfusion Medicine ·········································································

165

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

168

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

169

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

171

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

174

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

177

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

179

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

180

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

185

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

188

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

189

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

193

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

194

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

198

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

202

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

206

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

210

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

215

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

222

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

225

iv

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

227

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

228

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

232

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

235

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

239

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

247

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

251

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

257

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

260

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

261

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

264

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

268

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

269

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

273

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

277

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

280

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

281

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

284

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

287

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

290

Department of Gerontological Home Care and Long-term Care Nursing/Palliative Care Nursing ···291

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

294

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

297

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

301

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

308

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

309

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

314

v

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

317

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

318

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

321

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

324

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

327

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

329

Department of Biostatistics(See Department of Biostatistics / Epidemiology and Preventive Health Sciences [P.273] )Department of Social and Preventive Epidemiology ························································

330

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

333

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

338

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

341

Department of Mental Health(See Department of Mental Health [P.269] )Department of Health Sociology and Health Education(See Departments of Health and Social Behavior & Health Education and Health Sociology [P.342] )Departments of Health and Social Behavior & Health Education and Health Sociology ···············

342

Department of Biomedical Ethics & Department of Health Promotion Sciences(See Department of Biomedical Ethics & Department of Health Promotion Sciences [P.277] )3. Health Services Sciences ·························································································

346

Department of Health Policy (See Department of Public Health / Department of Health Policy [P.112] )Department of Healthcare Informatics (See Department of Biomedical Informatics [ P.121] )Department of Clinical Information Engineering ····························································

347

Department of Forensic Medicine and Medical Law (See Department of Forensic Medicine [P.118] )Endowed Department ···································································································

349

Department of Bone & Cartilage Regenerative Medicine(See Central Clinical Facilities Division of Tissue Engineering [P.496] )Department of Cartilage & Bone Regeneration (Fujisoft)(See Central Clinical Facilities Division of Tissue Engineering [P.496] )Department of Ubiquitous Preventive Medicine ·····························································

350

Science for joint reconstruction ( See Department of Orthopaedic Surgery [P.239] )Division of Chronic Kidney Disease (CKD) Pathophysiology ············································

352

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

355

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

357

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

359

vi

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

362

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

365

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

367

Department of medical research and the management of musculoskeletal pain ························369

AXA Chair on Health and Human Security ( See Department of Global Health Policy [P.309] )Department of Advanced Nephrology and Regenerative Medicine(See Central Clinical Facilities Division of Tissue Engineering [P.496] )Department of Molecular Sciences on Diabetes·······························································

373

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

375

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

377

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

380

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

384

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

386

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

389

Laboratory for New Generation Drug Discovery ( See Laboratory of Molecular Biomedicine
for Pathogenesis[P.534] )Department of Molecular Neurology ···········································································

391

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

394

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

396

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

397

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

400

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

403

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

406

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

408

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

412

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

416

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

417

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

420

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

422

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

425

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

428(See Department of Gerontological Nursing /Wound Care Management [P.301] )Department of Imaging nursing Science ·······································································

430

Department of Innovative Dementia Prevention ······························································

433

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

436

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

437

vii

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

440

University Hospital
Clinical Divisions ····································································································
Internal Medicine
Cardiovascular Medicine (See Department of Cardiovascular Medicine [P.125] )Respiratory Medicine (See Department of Respiratory Medicine [P.131] )Gastroenterology (See Department of Gastroenterology [P.135] )Nephrology and Endocrinology(See Department of Nephrology and Endocrinology [P.141] )Diabetes and Metabolic Diseases (See Department of Diabetes and Metabolic Diseases [P.146] )Hematology and Oncology (See Department of Hematology and Oncology [P.152] )Allergy and Rheumatology (See Department of Allergy and Rheumatology [P.156] )Infectious Diseases (See Department of Infectious Diseases (Internal Medicine) [P.159] )Neurology (See Department of Neurology [P.98] )Geriatric Medicine(See Department of Geriatric Medicine, Department of Aging Research [P.189] )Psychosomatic Medicine(See Department of Stress Science and Psychosomatic Medicine [P.162] )Surgery
Stomach and Esophageal Surgery (See Department of Gastrointestinal Surgery [P.202] )Colon and Rectal Surgery (See Department of Surgical Oncology [P.215] )Hepatobiliary Pancreatic Surgery(See Hepato-biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation
Division [P.206] )Vascular Surgery (See Department of Vascular Surgery [P.222] )Breast and Endocrine Surgery(See Department of Metabolic Care and Endocrine Surgery [P.225] )Artificial Organ and Transplantation Surgery(See Hepato-biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation
Division [P.206] )Cardiovascular Surgery (See Department of Cardiac Surgery [P.198] )Thoracic Surgery (See Department of Thoracic Surgery [P.194] )Neurosurgery (See Department of Neurosurgery [P.103] )Anesthesiology and Pain Relief Center (See Department of Anesthesiology [P.261] )Urology and Andrology (See Department of Urology [P.210] )Gynecologic Surgery (See Obstetrics and Gynecology [P.168] )

446

viii

Sensory and Motor System Medicine
Dermatology (See Department of Dermatology [P.228] )Ophthalmology (See Department of Ophthalmology [P.247] )Orthopaedic Surgery and Spinal Surgery(See Department of Orthopaedic Surgery [P.239] )Otorhinolaryngology and Head and Neck Surgery(See Department of Otorhinolaryngology and Head & Neck Surgery [P.251] )Rehabilitation Medicine (See Department of Rehabilitation Medicine [P.257] )Plastic, Reconstructive and Aesthetic Surgery(See Department of Plastic and Reconstructive Surgery [P.232] )Oral-Maxillofacial Surgery and Orhtodontics(See Department of Oral-Maxillofacial Surgery [P.235] )Pediatrics,Perinatal and Women’s Medicine
Pediatrics(See Department of Pediatrics, Department of Developmental Pediatrics [P.180] )Pediatrics Surgery (See Department of Pediatric Surgery [P.185] )Obstetrics and Gynecology(See Department of Reproductive Endocrinology / Department of Gynecologic Oncology / Departmentof Perinatal Medicine [P.169, 171, 174] )Neuropsychiatry
Neuropsychiatry (See Department of Neuropsychiatry [P.94] )Radiology
Radiology (See Department of Radiology [P.61] )Central Clinical Facilities ···························································································

447

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

448

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

452

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

455

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

457

Department of Transfusion Medicine and Immunohematology(See Department of Transfusion Medicine [P.165] )Rehabilitation Center ····························································································

461

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

464

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

466

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

470

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

472

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

474

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

477

ix

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

480

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

482

Department of Infection Control and Prevention(See Department of Infection Control and Prevention [P.52] )Department of Planning, Information, and Management(See Department of Biomedical Informatics [P.121] )University Hospital Medical Information Network (UMIN) Center ······································

489

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

492

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

496

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

501

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

504

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

507

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

510

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

512

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

514

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

516

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

518

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

526

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

528

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

529

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

533

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

534

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

537

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

540

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

542

Laboratory of Microenvironmental and Metarboric Health Sciences ······································

547

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

551

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

554

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

557

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

560

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

561

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

562

x

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

566

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

569

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

572

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

574

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

576

The Tokyo Journal of Medical Sciences. Vol. 137, October 2018xi

History
1858

May

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

Nov.

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

1859

Sep.

Shutojo was reconstructed at Shitaya Izumibashi Dohri.

1860

Oct.

Shutojo became an official medical institution of the Shogunate Government.

1861

Oct.

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

1863

Feb.

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

1868

Jul.

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

1869
1871

Feb.

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

Dec.

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

Jul.

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

1872

Aug.

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

1874

May

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

1876

Nov.

Tokyo-Igakko was moved to Hongo.

1877

Apr.

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

1886

Mar.

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

1897

Jun.

The Imperial University was renamed as Tokyo Imperial University.

1917

Aug.

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

1919

Apr.

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

1931

Feb.

The first building of the Faculty of Medicine was constructed.

1936

Jan.

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

Nov.

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

1947

Oct.

Tokyo Imperial University was renamed as The University of Tokyo.

1950

Apr.

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

1953

Apr.

The School of Health Care and Nursing was founded.

The Tokyo Journal of Medical Sciences. Vol. 137, October 2018

xii

Jul.

The Graduate School was founded, and the Division of Medical Doctor Biological Science wasestablished. The Brain Research Laboratory became the Brain Research Institute of the Facultyof Medicine.

1956

Apr.

The Midwives School was established.

1958

Apr.

The Division of Pharmaceutical Sciences became an independent faculty.

May

The University of Tokyo Faculty of Medicine celebrated its centennial anniversary.

Mar.

The Medical Library was built in commemoration of the centenary.

Apr.

The Institute of Medical Electronics was established.

Apr.

The Research Institute of Logopedics and Pediatrics was established. The School of Health Care

1961
1965

and Nursing was reorganized as the School of Health Sciences. The Graduate School of The
University of Tokyo was reorganized and the Division of Medical Doctor Biological Science
became the Faculty of Medicine. The Health science Course was established in the Medical
Science Division.
1966

Sep.

The third building of the Faculty of Medicine was constructed.

1971

Apr.

The Laboratory of Animal Experiments was established.

1973

Mar.

The Animal Center for Biomedical Research was constructed.

1983

Jan.

An annex of the third building of the Faculty of Medicine was constructed.

1985

Sep.

The office of International Academic Affairs was established.

1987

Apr.

Specialized courses were introduced to the Graduate School of Medicine.

1992

Apr.

The School of Health Sciences became the School of Health Science and Nursing. The School ofInternational Health was established in the Medical Science Division.

1995

Jul.

The Radiation Research Institute was established.

Apr.

As a result of the shift to the chair system of the Graduate School of Medicine, four divisions,Third Basic Medicine, Social Medicine, Third and Fourth Clinical Medicine, were replaced with
Pathology, Immunology and Microbiology, Social Medicine, Reproduction and Development,
and Aging Science and Surgery.

1996

Apr.

As a result of the shift to the chair system of the Graduate School of Medicine, three divisions,First Clinical Medicine, Health Science, and International Health, were replaced with Internal
Medicine, Health Science and Nursing, and International Health.

1997

Apr.

As a result of the shift to the chair system of the Graduate School of Medicine, three divisions,First and Second Basic Medicine, and Second Clinical Medicine, were replaced with Molecular
Cell Biology, Functional Biology, Radiology and Biomedical Engineering, and Neuroscience.
As a result of the above-mentioned reorganization, three institutes, the Institute of Brain
Research, the Institute of Medical Electronics, and the Institute of Logopedics and Phoniatrics
were made redundant.

1999

Apr.

The Master course of Medical Science was established in the Graduate School of Medicine. This
course accepts graduates of all faculties except those from Schools of Medicine, Dentistry, andVeterinary Medicine.

The Tokyo Journal of Medical Sciences. Vol. 137, October 2018

2000

Apr.

xiii

The International Research Center for Medical Education was established (A shared facility foreducation and research).

2001

Apr.

The University Branch Hospital was united with the University Hospital.

2002

Mar.

Nursing School and Midwives School was Closed.

2002

Mar.

Experimental Building (First Stage) was constructed.

2003

Apr.

The Center for Disease Biology and Integrative Medicine was established.
The Radiation Research Institute and the Laboratory of Animal Experiments were integrated into
the Center for Disease Biology and Integrative Medicine.

2004

Apr.

All the National Universities owned by the Japanese Government became National University
Corporations and the University of Corporation.

2005

Mar.

Experimental Building (Second Stage) was constructed.

2007

Apr.

The School of Public Health was established. This school offers programs for Master of Public
Health.

2008

May.

The University of Tokyo Faculty of Medicine and the University of Tokyo Hospital celebrated
their 150th anniversary.

2010

Apr.

The School of Health Science and Nursing became the School of Integrated Health Sciences.

2011

Jan.

The Museum of Health and Medicine was established.

2012

Apr.

The Office for research Ethics Support was established.

2013

Apr.

The International Research Center for Medical Education became a facility of the Graduate
School of medicine.

2013

Oct.

The Life Sciences Core facility was established.

2015

Apr.

The Office for Clinical Practice and Medical Education was established.

2018

Apr.

The Advisory office for Conflicts of interest was established.

2017

Apr.

The Global Nursing Research Center was established.

2017

Apr.

The Institute for Life Science Research and Education was established.

2017

Apr.

The Research Institute for Biomedical Science and Engineering was established.

xiv

The Tokyo Journal of Medical Sciences. Vol. 137, October 2018

Organization Chart
Cell Biology and Anatomy

Cell Biology
Structural Biology
Structural Cell Biology
Cellular Neurobiology

Molecular Cell Biology

Molecular Biology
Biochemistry and Molecular Biology

Cellular Signaling
Physiological Chemistry and Metabolism

Collaborative Department

Clinical Genome Informatics
Lipid Science
Integrative Physiology

Physiology

Cellular and Molecular Physiology
Neurophysiology

Functional Biology
Pharmacology

Cellular and Molecular Pharmacology
Systems Pharmacology
Human Pathology and Diagnostic Pathology

Pathology

Molecular Pathology
Surgical Pathology

Microbiology
Pathology, Immunology
and Microbiology

Microbiology
Infection Control and Prevention

Immunology

Immunology
Clinical Immunology
Infection Pathology

Collaborative Department

Tumor Pathology
Molecular Oncology
Diagnoatic Radiology

Radiology

Radiotherapy
Nuclear Medicine

Radiology and Biomedical
Engineering

System Physiology
Biomedical Engineering

Chemical Biology and Molecular Imaging
Biosystem Construction and Control
Neuropathology

Basic Neuroscience

Neurochemistry
Neurobiology

Graduate School of
Medicine

Developmental Neuroscience
Neuroscience

Integrativ Medical Neurosciences

Cognitive Neuroscience
Systems Medical Neuroscience
Child Neuropsychiatry
Neuropsychiatry

Clinical Neuroscience

Neurology
Neurosurgery
Molecular Preventive Medicine

Social Medicine

Occupational, Environmental andPreventive Medicine

Public HealthForensic Medicine, and Medical
Informatics and Economics

Forensic Medicine

Collaborative Department

Cancer Health Services ResearchRadiological Health

Medical Informatics

The Tokyo Journal of Medical Sciences. Vol. 137, October 2018

xv

Cardiovascular Medicine
Vascular Biology
Medicine I

Respiratory Medicine
Gastroenterology
Nephrology
Endocrinology

Internal Medicine

Diabetes and Metabolic Diseases
Medicine II

Hematology and Oncology
Allergy and Rheumatology
Infectious Diseases

Clinical Laboratory Medicine
and Pathology

Stress Sciences and Psychosomatic
Medicine
Clinical Laboratory Medicine
Transfusion Medicine

Collaborative Department

Molecular Diabetology
Reproductive Endocrinology

Obstetrics and Gynecology

Gynecological Oncology
Perinatal Medicine
Molecular Reproductive Endocrinology
Pediatrics

Reproductive,
Developmental andAging Sciences

Pediatric Sciences

Developmental Pediatrics
Pediatric Surgery
Pediatric Oncology

Aging Sciences

Geriatrics
Aging Research

Collaborative Department

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

Surgery

Urology
Artificial Organ and Transplantation
Division
Surgical Oncology

Surgical Sciences

Vascular Surgery
Breast and Endocrine Surgery
Dermatology
Plastic and Reconstructive Surgery
Oral and Maxillofacial Surgery
Sensory and Motor System
Medicine

Orthopaedic Surgery
Ophthalmology
Otolaryngology and Head and Neck
Surgery
Rehabilitation Medicine

Vital Care Medicine

Anesthesiology
Acute Medicine

xvi

The Tokyo Journal of Medical Sciences. Vol. 137, October 2018
Health Sociology
Mental Health
Epidemiology and Preventive Health
Sciences
Health Sciences

Social Gerontology
Health Promotion Sciences
Biostatistics
Biomedical Ethics

Health Sciences andNursing

Advanced Clinical Nursing
Preventive and Administrative
NursingNursing Administration
Family Nursing
Community Health Nursing
Public Health Nursing
Gerontological Home Care andLong-term Care Nursing
Palliative Care Nursing

Clinical Nursing

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

Collaborative Department

Public Mental Health Policy

International Social Medicine

Global Health Policy
Community and Global HealthInternational HealthInternational Biomedical
Sciences

Human Genetics
Developmental Medical Sciences
Human Ecology
Biomedical Chemistry

Medical Science (Master’s Program)

Biostatistics

Epidemiology and Health Sciences

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

School of Public HealthBehavioral Health Sciences

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

Health Services Sciences

Healthcare Informatics
Clinical Information Engineering
Forensic Medicine and Medical Law

Collaborative Department

Public Health Science

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

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

International ResearchCenter for Medical Education

Laboratory of Molecular Radiology

Section of Animal Research

Division of Research Resources and Support

Section of Radiation Biology

Department of Medical Education Studies

Section of Bioinformatics

Department of International Cooperation for
Medical Education

The Tokyo Journal of Medical Sciences. Vol. 137, October 2018

Global Nursing ResearchCenterxvii

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

Institution

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

Endowed Department

Department of Life Support Technology (Molten)
Youth Mental Health
Department of Advanced Translational Research and Medicine in Management of Pulmonary Hypertension
Department of Immunotherapy Management
Chronic Kidney Disease Pathophysiology
Department of medical research and management for musculoskeletal pain
Department of Molecular Science on Diabetes
Department of Integrated Molecular Sciences on Metabolic Diseases
Department of Osteoimmunology
Department of medical and pharmaceutical community healthcare
Health Economy and Society Policy
Departmento of Biostatics and Bioinformatics
Department of Preventive Medicine for Locomotive Organ Disorders
Laboratory for New Generation Drug Discovery
Laboratory for Advanced Research on Pathophysiology of Metabolic Diseases
Department of Ubiquitous Health Informatics
Department of Lipidomics
Advanced Nursing Technology
Verbal analysis of pathophysiology

Social Cooperation Program

Department of Health Services Research
Skincare Science
Imaging Nursing Science
Department of Healthcare Quality Assessment

General Affairs Office

Bariatric & Metabolic Care

Personnel Office

Department of Innovative Dementia Prevention

Research Support Office
Educational Affairs
Graduate Student Affairs

xviiiThe Tokyo Journal of Medical Sciences. Vol. 137, October 2018

Finance Office

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

Finance Office
Facilities Office

Administrative Division

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

Administrative Office

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

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

Faculty of
Medicine

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

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

The Tokyo Journal of Medical Sciences. Vol. 137, October 2018

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

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

ClinicalDivisions

Neurology
Geriatric Medicine
Psychosomatic Medicine
General Surgery
Stomach and Esophageal Surgery

University
Hospital

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

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

Sensory and Motor System
Medicine

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

Pediatrics, Perinatal and
Women's Medicine

Pediatrics
Pediatric Surgery
Obstetrics and Gynecology

Neuropsychiatry

NeuropsychiatryRadiology

Radiology
Pharmaceutical Department
Nursing Department

Office of General Administration

Administration Office

Office of Procurement andFacility Management

Clinical Laboratory
Operation Center
Imaging Center
Central Clinical Facilities

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

Office of Management Planning
Office of Medical Accounting

xix

xx

The Tokyo Journal of Medical Sciences. Vol. 137, October 2018
Intensive Care Unit
Pathology
Corneal Transplantation
Department of Cell a Therapy and Transplantation Medicine
Department of Endoscopy and Endoscopic Surgery
Department of Hemodialysis and Apheresis
Medical Community Network and Discharge Planning
Infection Control and Prevention Service
Department of Planning, Information, and Management
University Hospital Medical Information Network Center
Organ Transplantation Service
Labor Safety and Health Management Office
Department of Child Psychiatry
Tissue Bank
Epidemiology and Preventive Medicine
Cancer Resource Center
Center for Liaison and Public Relations
Database Center of the National University Hospitals
Department of Chemotherapy
Department of Health Record Management
Critical Care Center
Department of Palliative Medicine
Children's Medical Center
Department of Disaster Medical Management
International Medical Center
Department of Clinical Nutrition Therapy
Department of Pediatric and Neonatal Intensive Care
Clinical Research Support Center
22nd Century Medical and Research Center
Tissue Engineering
Clinical Research Division

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

Organization of ClinicalManagement Support

Department of Performance
Monitoring and Risk
Management

Department of Education andStaff Development

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

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

Outpatient Services
Administration
Central Clinical Services
Administration

Department of Clinical Research
Governance
Cancer Board
Inpatient Center
Vascular Board
Perioperative Assessment Center
Epilepsy Center
Immunotherapy Center

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

xxi

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

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

Yutaka Matsuyama

Director, Medical Library

Hideo Yasunaga

Director General, University Hospital

Nobuhito Saito

Director, Center for Disease Biology and Integrative Medicine

Shigeo Okabe

Director, International Research Center for Medical Education

Tatsuya Yamasoba

Director, Global Nursing Research Center

Hiromi Sanada

Graduate School of Medicine
Molecular Cell Biology
Professor

Masahide Kikkawa

Professor

Shigeo Okabe

Professor

Noboru Mizushima

Professor

Hiroyuki Mano

Professor

Hiroki Kurihara

Professor

Kenichi Ohki

Professor

Masanori Matsuzaki

Professor

Masanobu Kano

Professor

Kenzo Hirose

Professor

Hiroki Ueda

Professor

Masashi Fukayama

Professor

Kohei Miyazono

Professor

Masanori Hatakeyama

Professor

Kyoji Moriya

Professor

Hiroshi Takayanagi

Department of Radiology

Professor

Osamu Abe

Department of Biomedical Engineering

Professor

Yasuteru Urano

Department of Cell Biology and Anatomy
Department of Biochemistry and Molecular Biology

Functional Biology
Department of Physiology

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

xxii

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

Neuroscience
Department of Basic Neuroscience

Professor

Takeshi Iwatsubo

Professor

Haruhiko Bito

Professor

Kenzo Hirose

Professor

Kiyoto Kasai

Professor

Tatsushi Toda

Professor

Nobuhito Saito

Department of Occupational, Environmental and Preventive

Professor

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

Keishi Fujio

Professor

Kyoji Moriya

Professor

Yutaka Yatomi

Professor

Hitoshi Okazaki

Professor

Tomoyuki Fujii

Professor

Yutaka Osuga

Department of Pediatric Science

Professor

Akira Oka

Department of Aging Science

Professor

Masahiro Akishita

Professor

Jun Nakajima

Professor

Minoru Ono

Professor

Yasuyuki Seto

Professor

Kiyoshi Hasegawa

Professor

Haruki Kume

Professor

Shinichi Sato

Professor

Mutsumi Okazaki

Professor

Kazuto Hoshi

Professor

Sakae Tanaka

Department of Integrative Medical Neuroscience
Department of Clinical Neuroscience

Social Medicine

Internal Medicine
Department of Medicine I

Department of Medicine II

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

Surgical Sciences
Department of Surgery

Department of Sensory and Motor System Medicine

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

xxiii

Professor

Makoto Aihara

Professor

Tatsuya Yamasoba

Professor

Nobuhiko Haga

Professor

Yoshitsugu Yamada

Professor

Naoto Morimura

Professor

Norito Kawakami

Professor

Yutaka Matsuyama

Professor

Hideki Hashimoto

Professor

Akira Akabayashi

Department of Preventive and Administrative Nursing

Professor

Kiyoko Kamibeppu

Department of Clinical Nursing

Professor

Noriko Yamamoto

Professor

Norito Kawakami

Professor

Hiromi Sanada

Professor

Kenji Shibuya

Professor

Masamine Jinba

Professor

Katsushi Tokunaga

Professor

Masashi Mizuguchi

Professor

Masahiro Umezaki

Professor

Tomoyoshi Nozaki

Professor

Yutaka Matsuyama

Professor

Satoshi Sasaki

Professor

Hideo Yasunaga

Professor

Takahiro Kiuchi

Professor

Norito Kawakami

Professor

Hideki Hashimoto

Professor

Akira Akabayashi

Professor

Yasuki Kobayashi

Professor

Kazuhiko Ohe

Professor

Hiroshi Oyama

Professor

Hirotaro Iwase

Department of Vital Care Medicine
Health Sciences and Nursing
Department of Health Sciences

International Health
Department of International Social Medicine
Department of International Biomedical Sciences

School of Public Health
Department of Epidemiology and Health Sciences

Department of Behavioral Health Sciences

Department of Health Services Sciences

xxiv

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

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

Professor

Toru Miyazaki

Laboratory of Structural Physiology

Professor

Haruo Kasai

Laboratory of Regenerative Medical Engineering

Professor

Takashi Azuma

Laboratory of Clinical Biotechnology

Professor

Ungil Chung

Laboratory of Environmental and Metabolic Health Sciences

Professor

Makoto MurakamiLaboratory of Animal Resources

Professor

Atsu Aiba

Laboratory of Molecular Radiology

Professor

Kiyoshi Miyagawa

International Research Center for Medical Education

Professor

Tatsuya Yamasoba

Global Nursing Research Center

Professor

Hiromi Sanada

Medical LibraryProfessor

Hideo Yasunaga

International Academic Affairs

Professor

Yasuyuki Seto

Medical Scientist Training Program

Professor

Haruhiko Bito

Museum of Health and Medicine

Professor

Kazuhiko Ohe

Office for Human Research Studies

Professor

Yutaka Yatomi

Life Sciences Core Facility

Associate Professor

Yoshihiro Kita

Office for Clinical Practice and Medical Education

Professor

Tatsuya Yamasoba

Department of Bone & Cartilage Regenerative Medicine

Project Associate professor

Takumi Matsumoto

Cell & Tissue Engineering(Fujisoft)

Project Associate professor

Atsuhiko Hikita

Immunotherapeutics

Project Professor

Kazuhiro Kakimi

Project Professor

Naoto Hayashi

Project Associate professor

Masaki Anraku

Ubiquitous Preventive Medicine

Project Associate professor

Yuichi Ikeda

Science for joint reconstruction

Project Associate professor

Toru Moro

Therapeutic Strategy for Heart Failure

Project Associate professor

Masaru Hatano

Department of Molecular Structure and Dynamics

Project Professor

Nobutaka Hirokawa

Department of Medical Genomics

Project Associate professor

Masato Kawazu

Continence medicine

Project Professor

Yasuhiko Igawa

Department of Life Support Technology (Molten)

Project professor

Taketoshi Mori

Project Associate professor

Hiroko Kanda

Division of Research Resources and Support

Endowed Departments

Department of Advanced Clinical Science andTherapeutics
Computational Diagnostic Radiology and Preventive
Medicine
Healthcare Safety Management (Tokio Marine &Nichido)Clinical Trial Data Management

Department of Advanced Translational Research andMedicine in Management of Pulmonary Hypertension
Department of Immunotherapy Management

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

xxv

Chronic kidney disease pathophysiology

Project Associate professor

Reiko Inagi

Department of medical research and management for

Project Professor

Koh Matsudaira

Department of Molecular Science on Diabetes

Project Associate professor

Hironori Waki

Department of Integrated Molecular Sciences on

Project Associate professor

Masato Iwabu

Department of Osteoimmunology

Project Associate professor

Kazuo Okamoto

Department of medical and pharmaceutical community

Project Professor

Hirohisa Imai

Health Economy and Society Policy

Project Professor

Tomoyuki Takura

Department of Biostatistics and Bioinformatics

Project Professor

Daisuke Koide

Department of Preventive Medicine for Locomotive

Project Professor

Noriko Yoshimura

Laboratory for New Generation Drug Discovery

Project Associate Professor

Shigeru Matsuoka

Department of Molecular Neurology

Project Professor

Syoji Tsuji

Laboratory for Advanced Research on Pathophysiology

Project Associate Professor

Miki Iwabu

Department of Ubiquitous Health Informatics

Project Associate professor

Kayo Waki

Department of Lipidomics

Project Professor

Takao Shimizu

Project Associate professor

Fuyuki Tokumasu

Advanced Nursing Technology

Project Associate professor

Ryoko Murayama

Verbal analysis of pathophysiology

Project Associate professor

Shinichi Tokuno

Department of Health Services Research

Project Associate professor

Taisuke Jo

Skincare Science

Project Associate professor

Takeo Minematsu

Imaging Nursing Science

Project Associate professor

Koichi Yabunaka

Department of Healthcare Quality Assessment

Project Professor

Hiroaki Miyata

Bariatric & Metabolic Care

Project Associate professor

Susumu Aiko

Department of Innovative Dementia Prevention

Project Associate professor

Tadafumi Hashimotomusculoskeletal pain

Metabolic Diseases

healthcare

Organ Disordersof Metabolic Diseases
Social Cooperation Program

University Hospital
Clinical Divisions
General Medicine

Head

Masaomi Nangaku

Cardiovascular Medicine

Head

Issei Komuro

Respiratory Medicine

Head

Takahide Nagase

Gastroenterology

Head

Kazuhiko Koike

Nephrology and Endocrinology

Head

Masaomi Nangaku

Diabetes and Metabolic Medicine

Head

Takashi Kadowaki

xxvi

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

Hematology and Oncology

Head

Mineo Kurokawa

Allergy and Rheumatology

Head

Keishi Fujio

Infectious Diseases

Head

Kyoji Moriya

Neurology

Head

Tatsushi Toda

Geriatric Medicine

Head

Masahiro Akishita

Psychosomatic Medicine

Head

Kazuhiro Yoshiuchi

General Surgery

Head

Yasuyuki Seto

Stomach and Esophagus Surgery

Head

Yasuyuki Seto

Colon and Rectal Surgery

Head

Hiroaki Nozawa

Hepatobiliary Pancreatic Surgery

HeadKiyoshi Hasegawa

Vascular Surgery

Head

Katsuyuki Hoshina

Breast and Endocrine Surgery

Head

Masahiko Tanabe

Artificial organ and Transplantation Surgery

HeadKiyoshi Hasegawa

Cardiovascular Surgery

HeadMinoru Ono

Thoracic Surgery

Head

Jun Nakajima

Neurosurgery

Head

Nobuhito Saito

Anesthesiology and Pain Relief Center

Head

Yoshitsugu Yamada

Urology and Andrology

Head

Haruki Kume

Gynecologic Surgery

Head

Yutaka Ohsuga

Dermatology

HeadShinichi Sato

Ophthalmology

Head

Makoto Aihara

Orthopaedic Surgery and Spinal Surgery

Head

Sakae Tanaka

Otorhinolaryngology and Head and Neck Surgery

Head

Tatsuya Yamasoba

Rehabilitation Medicine

Head

Nobuhiko Haga

Plastic, Reconstructive and Aesthetic Surgery

Head

Mutsumi Okazaki

Oral-Maxillofacial Surgery and Orthodontics

Head

Kazuto Hoshi

Pediatrics

Head

Akira Oka

Pediatric Surgery

Head

Jun Fujishiro

Obstetrics and Gynecology

HeadTomoyuki Fujii

Neuropsychiatry

Head

Kiyoto Kasai

Radiology

Head

Osamu Abe

Pharmaceutical Department

Head

Hiroshi Suzuki

Department of Clinical Laboratory

Head

Yutaka Yatomi

Surgical Center

Head

Hiroshi Yasuhara

Imaging Center

Head

Osamu Abe

Emergency Service

Head

Naoto Morimura

Department of Blood Transfusion

Head

Hitoshi Okazaki

Perinatal Center

Head

Tomoyuki Fujii

Central Clinical Facilites

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

xxvii

Rehabilitation Center

Head

Nobuhiko Haga

Department of Medical Engineering

Head

Kyouhiro ChouCentral Supply Service

Head

Kazuhiko Fukatsu

Intensive Care Unit

Head

Naoto Morimura

Pathology

Head

Tetsuo Ushiku

Department of Corneal Transplantation

Head

Tomohiko Usui

Department of Cell Therapy and Transplantation Medicine

Head

Mineo Kurokawa

Department of Endoscopy and Endoscopic Surgery

Head

Mitsuhiro FujisiroDepartment of Hemodialysis and Apheresis

Head

Masaomi Nangaku

Medical Community Network and Discharge Planning

Head

Kiyoto Kasai

Infection Control and Prevention Service

Head

Kyoji Moriya

Department of Planning, Information and Management

Head

Kazuhiko Ohe

University Hospital Medical Information Network Center

Head

Takahiro Kiuchi

Organ Transplantation Service

Head

Kiyoshi Hasegawa

Labor Safety and Health Management Office

HeadTomotaka Yamamoto

Child Psychiatry

Head

Yukiko Kano

Tissue Bank

Head

Sumihito Tamura

Epidemiology and Preventive Medicine

Head

Tsutomu Yamazaki

Cancer Resource Center

Head

Sachiyo Nomura

Center for Liaison and Public Relations

Head

Kazuhiko Ohe

Department of Chemotherapy

Head

Mineo Kurokawa

Department of Medical Record Management

Head

Kazuhiko Ohe

Critical Care Center

Head

Naoto Morimura

Department of Palliative Medicine

Head

Masahiko SumitaniChildren’s Medical Center

Head

Akira Oka

Department of Disaster Medical Management

Head

Naoto MorimuraInternational Medical Center

Head

Sumihito Tamura

Department of Clinical Nutrition Therapy

Head

Naoto Kubota

Department of Pediatric and Neonatal Intensive Care

Head

Naoto Takahashi

Clinical Research Support Center

Head

Tsutomu Yamazaki

22nd Century Medical and Research Center

Head

Masaomi Nangaku

Department of Tissue Engineering

Head

Kazuto Hoshi

Cooperative Unit of Medicine and Engineering Research

Head

Minoru Ono

Translational Research Center

Head

Mineo Kurokawa

Center for Genome Medicine

Head

Masaomi Nangaku

Unit for Early and Exploratory Clinical Development

Head

Takeshi Iwatsubo

The University of Tokyo,
Graduate School of Medicine

Molecular Cell Biology
1. Cell Biology and Anatomy

2

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

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

Noriko Homma, Ph. D.,

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

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

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

cryoelectron microscopy at atomic resolution, andcryoultramicrotomy,
biochemistry,
immunocytochemistry, molecular biology, molecular genetics suchas gene targeting and transgenic mouse approaches,molecular biophysics and structure biology including
X ray crystallography and cryoelectron microscopy.
In this way we can study structure, dynamics andfunctions of cytoskeleton from gene to cell, tissue andwhole body.
Nerve cells as units of complicated neuronal
networks in the brain develop very polarizedmorphology composed of dendrites, cell body and along axon along the direction of impulse propagation.
The neuronal cytoskeleton plays three major importantroles.
1) It provides dynamic frameworks for neurite
extension and maintenance.
2) It provides structural bases for organelle transports
in the cells. Namely it works as rails and motor
molecules to transport materials from cell center toperiphery and from periphery to cell center.
3) It very importantly regulates release processes oftransmitters and also contributes to anchor receptors at
the postsynaptic sites.
Our laboratory studies molecular architecture,dynamics and function of the cytoskeleton focusing onthese three major roles.
To study these molecular mechanisms we use newmolecular cell biological approaches including
electron microscopy of molecular resolution,
biochemistry, biophysics, molecular biology and3molecular genetics and X-ray crystallography.

References
1. Ogawa, T., S. Saijo, N. Shimizu, X. Jiang and N.
Hirokawa. Mechanism of Catalytic Microtubule
Depolymerization via KIF2-tubulin Transitional
Conformation.. Cell Rep. 20: 2626–2638, 2017.
2. Ogawa, T., and N. Hirokawa. Multiple analysesof protein dynamics in solution. Biophy. Rev..
https://doi.org/10.1007/s12551-017-0354-7 2017
3. Homma, N. R., Zhou, M. I. Naseer, A. G.
Chaudhary, M. H. Al-Qahtani, and N. Hirokawa.
KIF2A regulates the development of dentate
granule cells and postnatal hippocampal wiring.
eLife 7: e30935. DOI: https://doi.org/10.7554/
eLife. 30935, 2018
4. Morikawa, Mo., Y. Tanaka, H. –S. Cho, M.
Yoshihara, and N. Hirokawa. The molecularmotor KIF21B mediates synaptic plasticity andfear extinction by terminating Rac1 activation.
Cell Rep. 23: 3864-3877, 2018.
5. Xu, F., H. Takahashi, Y. Tanaka, S. Ichinose, S.
Niwa, M. P. Wicklund, and N. Hirokawa. KIF1B
beta mutations detected in hereditary neuropathy
impair IGF1R transport and axon growth. J. Cell
Biol. 217:3480-3496. 2018.
6. Wang, L., Y. Tanaka, D. Wang, R. Zhou, N. Homma,
Y. Miyamoto and N. Hirokawa. The atypicalkinesin KIF26A facilitates termination of noticeptive
responses by sequestering focal adhesion kinase.
Cell Rep. 24:2894-2907. 2018
7. Shima, T., M. Morikawa, J. Kaneshiro, T. Kambara,
S. Kamimura, T. Yagi, H. Iwamoto, S. Uemura, H.
Shigematsu, M. Shiromizu, T. Ichimura, T.
Watanabe, R. Nitta, Y. Okada, N. Hirokawa.
Kinesin-binding triggered conformation switchingof microtubules contributes to polarized transport.
J. Cell Biol. 2018 https://doi.org/10.1083/jcb.
201711178.

4

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

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

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

Research activities

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

Our lab focuses on the structure and function of
eukaryotic flagella/cilia. Flagella/cilia is both“propeller” and “antenna” of cells, whose diameter isabout 250 nm. From the recent studies, it is becoming
clear that flagella/cilia are involved in various
important cell functions.

Currently the lab members include: Masahide
Kikkawa (professor), Haruaki Yanagisawa (Lecturer),
Tsukasa Makino, Hiroshi Yamaguchi (research
associates), Akihisa Tsutsumi (project research
associate), (project researcher), Motohiro Morikawa,Yuta Komori, and Shuohang Gao (MSTP students),
Akiko Oosakaya, Ayako Ogasawara, Koshi Chiba(technical assistant), Kazuhiro Nakamura (Advanced
Academic Specialist), and Mikako Yanagiuchi and
Aiko Shibata(assistant clerk).

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

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

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

5available to many biological/medical researchers. New
state-of-the-art cryo-electron microscopes will be
installed and available to Japanese researchers.
Model Organism
Our lab currently uses Chlamydomonas, zebrafish, andmice as a model organism for studying cilia/flagella.
To identify molecules that are involved in regulating
dynein, we use various genetic tools, includingclassical mutagenesis, siRNA.
In addition, we are also developing 3D-tracking
microscopy in collaboration with Dr. Oku in
Department of Engineering. We are trying to track
Chlamydomonas cells and simultaneously record
flagella movement to elucidate the mechanism offlagella regulation.

References
1. Kuroki K., K. Mio, A. Takahashi, H. Matsubara, Y.
Kasai, S. Manaka, M. Kikkawa, D. Hamada, C.
Sato, K. Maenaka
Class II-like Structural Features and Strong
Receptor Binding of the Nonclassical HLA-G2
Isoform Homodimer.
J Immunology 198:3399, 2017

6

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

Lecturer
Hirohide Iwasaki, Ph.D

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

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 29 members.

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

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

7

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

Publications
1. Chen S, Weitemier AZ, Zeng X, He L, Wang X,
Tao Y, Huang AJY, Hashimotodani Y, Kano M,
Iwasaki H, Parajuli LK, Okabe S, Teh DBL, All
AH, Tsutsui-Kimura I, Tanaka KF, Liu X,
McHugh TJ. Near-infrared deep brain stimulation
via upconversion nanoparticle-mediated optogenetics. Science. 2018, 359, 679- 684. doi: 10.11
26/science.aaq1144.
2. Morimoto MM, Tanaka S, Mizutani S, Urata S,
Kobayashi K, Okabe S. In Vivo observation of
structural changes in neocortical catecholaminergic projections in response to drugs ofabuse. eNeuro. 2018, 5. doi: 0.1523/ENEUR O.
0071-17.2018.
3. Higashi T, Tanaka S, Iida T, Okabe S. Synapse
Elimination Triggered by BMP4 Exocytosis andPresynaptic BMP Receptor Activation. Cell Rep.
2018, 22, 919-929. doi: 10.10 16/j.celrep.2017.12.
101.
4. Cornelia Koeberle S, Tanaka S, Kuriu T, Iwasaki
H, Koeberle A, Schulz A, Helbing DL, Yamagata
Y, Morrison H, Okabe S. Developmental
stage-dependent regulation of spine formation by
calcium-calmodulin- dependent protein kinase
IIα and Rap1. Sci Rep. 2017 7, 13409. doi: 10.
1038/ s41598-017-13728-y.
5. Yokoyama T, Lee JK, Miwa K, Opthof T,
Tomoyama S, Nakanishi H, Yoshida A, Yasui H,
Iida T, Miyagawa S, Okabe S, Sawa Y, Sakata Y,
Komuro I. Quantification of sympathetic hyperinnervation and denervation after myocardial
infarction by three-dimensional assessment of the

cardiac sympathetic network in clearedtransparent murine hearts. PLoS One. 2017 12,
e0182072. doi:10.1371/ journal.pone.0182072.
6. Hirai S, Hotta K, Kubo Y, Nishino A, Okabe S,
Okamura Y, Okado H. AMPA glutamate receptors
are required for sensory-organ formation andmorpho- genesis in the basal chordate. Proc Natl
Acad Sci U S A. 2017, 114, 3939-3944. doi:10.
1073/pnas.1612943114.
7. Parajuli LK, Tanaka S, Okabe S. Insights into
age-old questions of new dendritic spines: From
form to function. Brain Res Bull. 2017, 129, 3-11.
doi: 10.1016/j.brainresbull.2016.07.014.
8. Okabe S. Fluorescence imaging of synapse
dynamics in normal circuit maturation and indevelopmental disorders. Proc Jpn Acad Ser B
Phys Biol Sci. 2017, 93, 483-497. doi: 10.2183/
pjab.93.029.

Molecular Cell Biology
2. Biochemistry and Molecular Biology

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

Lecturer
Hayashi Yamamoto, Ph.D.

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

Homepage

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

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) closure, fusion, anddegradation of the autophagosome (5) recognitionof selective substrates. In 2017, we reported thefollowing novel findings.
We
analyzed
autophagosome-related
membranes at the initiation stage of autophagy
using atg knockout (KO) cells and demonstrated
that the ULK complex is recruited to two distinct
membranes: the endoplasmic reticulum (ER)membrane and ATG9A-positive autophagosome
precursors. We also identified phosphatidylinositol synthase (PIS)-enriched ER subdomains
as the initiation site of autophagosome formation.
Based on these findings, we proposed that the
ULK complex, the PIS-enriched ER subdomain,and ATG9A vesicles together initiate autophagosome formation.
ATG2 localizes to isolation membranes andlipid droplets in mammalian cells. We
investigated the requirement of regions in ATG2A
for its organellar localization and function. We
found that the N-terminal and C-terminal regions
are required for the localization to isolation
membranes and lipid droplets, respectively.
However, the C-terminal region is not required forthe localization to isolation membranes and for
autophagy. We also identified an amphipathic
helix in ATG2A that is required for both its
localization to organelles and autophagosome
formation. These data suggest that the dual
localization of ATG2A is regulated by different
regions.
We developed a simple method toaccumulate undigested autophagosomes byoverexpression of dominant negative forms of the
autophagosomal Qa-SNARE syntaxin 17, whichlack the N-terminal domain or N-terminallytagged with GFP.

11

2. Physiological and pathological roles of
autophagy
Using autophagosome-indicator GFP-LC3 miceand various autophagy-deficient mouse models,
we have shown that autophagy is important for
maintenance of the amino acid pool during
starvation and neonatal periods, preimplantation
development as an amino acid supplying system,
and for intracellular protein quality control toprevent neurodegeneration and tumorigenesis.
Damaged mitochondria can also be eliminated by
autophagy (called "mitophagy") and this function
is linked to pathogenesis of Parkinson disease.
In 2017, we reported an essential role for
autophagy in inner ear by collaboration with Drs.
Chisato Fujimoto and Tatsuya Yamasoba of
Department of Otolaryngology. We also generated
ATG gene knockout resources using zebrafish.
3. Methods for monitoring autophagic activity
Measuring autophagic activity is critical to dissect
molecular mechanisms and functions ofautophagy but remains challenging due to the lackof a definitive method. We have recently
developed a new fluorescent reporter, GFP-LC3RFP-LC3ΔG, to assess autophagic flux. In 2017,
we generated a new mouse model ubiquitously
expressing this autophagy flux reporter.

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

Publication
1. Tamura, N., Nishimura, T., Sakamaki, Y.,
Koyama-Honda, I., Yamamoto, H., Mizushima, N.
Differential requirement for ATG2A domains for
localization to autophagic membranes and lipid
droplets. FEBS Lett. 591:3819-3830 (2017)
2. Fujimoto, C., Iwasaki, S., Urata, S., Morishita, H.,

Sakamaki, Y., Fujioka, M., Kondo, K., Mizushima,N., Yamasoba, T. Autophagy is essential forhearing in mice. Cell Death Dis. 8(5):e2780(2017).
3. Nishimura, T., Tamura, N., Kono, N., Shimanaka,
Y., Arai, H., Yamamoto, H., Mizushima, N.
Autophagosome

formation

phosphatidylinositol

isinitiatedsynthase-enrichedatER

subdomains. EMBO J. 36:1719-1735 (2017).
4. Uematsu, M., Nishimura, T., Sakamaki, Y.,
Yamamoto, H., Mizushima, N. Accumulation ofundegraded autophagosomes by expression of
dominant-negativesyntaxin

17

mutants.

Autophagy 9:1-13 (2017).
5. Kimura, H., Eguchi, S., Sasaki, J., Kuba, K.,
Nakanishi, H., Takasuga, S., Yamazaki, M., Goto,
A., Watanabe, H., Itoh, H., Imai, Y., Suzuki, A.,
Mizushima, N., Sasaki, T. Vps34 regulates
myofibril proteostasis to prevent hypertrophic
cardiomyopathy. JCI Insight 2(1):e89462 (2017).
6. Fujita, N., Huang, W., Lin, T.H., Groulx, J.F., Jean,

S., Kuchitsu, Y., Koyama-Honda, I., Mizushima,N., Fukuda, M., Kiger, A.A. Genetic screen in
Drosophila muscle identifies autophagy-mediatedT-tubule remodeling and a Rab2 role in autophagy.
Elife 10.7554/eLife.23367 (2017).
7. Yoshii, S.R., Mizushima, N. Monitoring andmeasuring autophagy. Int. J. Mol. Sci. 18(9). pii:
E1865 (2017).
8. Kuma,A.,

Komatsu,M.,

Mizushima,

N.

Autophagy-monitoring and autophagy-deficientmice. Autophagy. 13:1619-1628 (2017).
9. Nishimura,T.,

Mizushima,

N.

The

ULK

complex initiates autophagosome formation at
phosphatidylinositol

synthase-enrichedER

subdomains. Autophagy 13:1795-1796 (2017).
10. Knorr, R.L., Mizushima, N., Dimova, R. Fusionand scission of membranes: ubiquitous topological transformations in cells. Traffic 18:758761 (2017).
11. Galluzzi, L. et al. Molecular definitions ofautophagy and related processes. EMBO J. 36:
1811-1836 (2017).

12

12. Koyama-Honda, I., Tsuboyama, K., Mizushima, N.
ATG conjugation-dependent degradation of theinner autophagosomal membrane is a key step for
autophagosome maturation Autophagy 13:12521253 (2017).
13. Mizushima, N. The exponential growth of
autophagy-related research: from the humble
yeast to the Nobel Prize. FEBS Lett. 591:681-689(2017).
14. Yoshii, S.R., Kuma, A. Mizushima, N. Transgenic
rescue of Atg5-null mice from neonatal lethality
withneuron-specificexpression

of

ATG5:

Systemic analysis of adult Atg5-deficient mice.
Autophagy 13:763-764 (2017).
15. Morishita, H., Kaizuka, T., Hama, Y., Mizushima,
N. A new probe to measure autophagic flux invitro and in vivo. Autophagy. 13:757-758 (2017).

13

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

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

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, one
research fellow, one visiting fellow, five graduates,
one undergraduate, four research technicians and one
secretary belong to our department. We are also in atight collaboration with Department of Medical
Genomics.

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

Research activities
Department of Cellular Signaling tries to fulfill ourgoals mainly through two approaches.
(1) Functional screening with the use of retroviral

cDNA expression libraries.
The focus formation assay had been widely usedin 1980s and 1990s to identify oncogenes from humancancer. However, since this technology directly usescancer genome to transfer oncogenes into recipient
cells, expression of each gene is regulated by its own
promoter/enhancer fragments. Therefore, such technology is theoretically unable to capture oncogenes
whose promoter/enhancer is silent in recipient cells.
To make every gene expressed sufficiently in recipient
cells, we here developed a highly efficient
retrovirus–mediated cDNA expression library system.
Our system enables to make a library with highcomplexity (containing millions of independent cDNA
clones) even from < 104 of cells.
(2) Cancer genome resequencing
In addition to the functional screening shown
above, we also tried to search for somatically mutatedgenes in human cancers with the use of “the next
generation sequencers (NGS)”. While development of
NGS has enabled us to determine the full genome
sequence of a cancer specimen even in private
laboratories, it is still a demanding task to conduct
full-genome sequencing for a large number of samples.
Therefore, many laboratories now purify exonic
fragments from a sample genome, and determine theirsequences. However, since gene fusions usually takeplace at intronic regions, such sequencing approachwith captured exons fails to discover fusion genes.
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

14(Cancer Sci 103:131). We mainly use HiSeq2500 and
HiSeq2000 systems for NGS, and have developed
in-house computational pipelines for detecting
somatic single nucleotide variations, insertions/deletions, and chromosomal rearrangements.
(3) High-throughput functional evaluation method
Numerous variants of unknown significance(VUS) have been identified through large-scale cancer
genome projects, although their functional relevanceremains uninvestigated. The L858R substitution orexon 19 deletions are, for instance, known to confer
activation of epidermal growth factor receptor (EGFR)
kinase, but there are more than one thousand of
nonsynonymous mutations within EGFR reported in
the COSMIC database. It is still obscure whether suchmutations have some relevance to EGFR kinase
activity or are merely passenger mutations. To
drastically increase the speed of functional annotation,
here
we
have
developedamixed-all-nominated-mutants-in-one(MANO)
method to evaluate the transforming potential anddrug sensitivity of oncogene VUS in ahigh-throughput manner. To validate its usefulness, weapplied this method to 101 nonsynonymous EGFR
mutants, and successfully evaluated clinical relevanceof each mutations.

References
1. Takamochi K, Takahashi F, Suehara Y, Sato E,
Kohsaka S, Hayashi T, Kitano S, Uneno T,
Kojima S, Takeuchi K, Mano H & Suzuki K.
DNA mismatch repair deficiency in surgicallyresected lung adenocarcinoma: Microsatellite
instability analysis using the Promega panel.
Lung Cancer 110, 26-31, 2017.
2. Soh SX, Siddiqui FJ, Allen JC, Kim GW, Lee JC,
Yatabe Y, Soda M, Mano H, Soo RA, Chin TM,
Ebi H, Yano S, Matsuo K, Niu X, Lu S, Isobe K,
Lee JH, Yang JC, Zhao M, Zhou C, Lee JK, Lee
SH, Lee JY, Ahn MJ, Tan TJ, Tan DS, Tan EH,
Ong ST & Lim WT. A systematic review andmeta-analysis of individual patient data on theimpact of the BIM deletion polymorphism on
treatment outcomes in epidermal growth factor
receptor mutant lung cancer. Oncotarget 8,41474-41486, 2017.

3. Seki M, Kimura S, Isobe T, Yoshida K, Ueno H,
Nakajima-Takagi Y, Wang C, Lin L, Kon A,
Suzuki H, Shiozawa Y, Kataoka K, Fujii Y,
Shiraishi Y, Chiba K, Tanaka H, Shimamura T,
Masuda K, Kawamoto H, Ohki K, Kato M,
Arakawa Y, Koh K, Hanada R, Moritake H,
Akiyama M, Kobayashi R, Deguchi T, Hashii Y,
Imamura T, Sato A, Kiyokawa N, Oka A, Hayashi
Y, Takagi M, Manabe A, Ohara A, Horibe K,
Sanada M, Iwama A, Mano H, Miyano S, Ogawa
S & Takita J. Recurrent SPI1 (PU.1) fusions inhigh-risk pediatric T cell acute lymphoblastic
leukemia. Nat Genet 49, 1274-1281, 2017.
4. Nakamura T, Yamashita S, Fukumura K,
Nakabayashi J, Tanaka K, Tamura K, Tateishi K,
Kinoshita M, Fukushima S, Takami H, Fukuoka K,
Yamazaki K, Matsushita Y, Ohno M, Miyakita Y,
Shibui S, Kubo A, Shuto T, Kocialkowski S,
Yamanaka S, Mukasa A, Sasayama T, Mishima K,
Maehara T, Kawahara N, Nagane M, Narita Y,
Mano H, Ushijima T & Ichimura K. Genomewide DNA methylation profiling identifies
primary central nervous system lymphoma as a
distinct entity different from systemic diffuse
large B-cell lymphoma. Acta Neuropathol 133,
321-324, 2017.
5. Matsubara D, Soda M, Yoshimoto T, Amano Y,
Sakuma Y, Yamato A, Ueno T, Kojima S,
Shibano T, Hosono Y, Kawazu M, Yamashita Y,
Endo S, Hagiwara K, Fukayama M, Takahashi T,
Mano H & Niki T. Inactivating mutations andhypermethylation of the NKX2-1/TTF-1 gene in
non-terminal
respiratory
unit-typelungadenocarcinomas. Cancer Sci 108, 1888-1896,
2017.
6. Kohsaka S, Nagano M, Ueno T, Suehara Y,
Hayashi T, Shimada N, Takahashi K, Suzuki K,
Takamochi K, Takahashi F & Mano H. A methodof high-throughput functional evaluation of EGFR
gene variants of unknown significance in cancer.
Sci Transl Med 9, eaan6556, 2017.
7. Kawazu M, Kojima S, Ueno T, Totoki Y,
Nakamura H, Kunita A, Qu W, Yoshimura J,
Soda M, Yasuda T, Hama N, Saito-Adachi M,
Sato K, Kohsaka S, Sai E, Ikemura M, Yamamoto
S, Ogawa T, Fukayama M, Tada K, Seto Y,
Morishita S, Hazama S, Shibata T, Yamashita Y

15& Mano H. Integrative analysis of genomic
alterations in triple-negative breast cancer inassociation with homologous recombination
deficiency. PLoS Genet 13, e1006853, 2017.

16

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

Lecturer
Yukiko Kurihara, M.D.

Research Associate
Kazuo Tonami, M.D.

Associate
Yasunobu Uchijima, Ph.D.

URL http://bio.m.u-tokyo.ac.jp/home-j.html
Introduction and Organization
The Department of Physiological Chemistry andNutrition, the predecessor of the present department,
was founded in 1952. Upon the restructuring of theuniversity system in 1997, the department was
renamed ‘Department of Physiological Chemistry andMetabolism’ as one unit of the Specialty of Molecular
Cell Biology. The present members include the above
stuffs, 1 postdoctoral fellow, 7 graduate students(doctor course 5, master course 2), 1 technical staff
and 1 secretary. Professor Tomoichiro Asano(Hiroshima University) is invited as a part-time
lecturer to instruct graduate students and give lecturesto undergraduate students.

Teaching Activities
We give a series of lectures and laboratory courses
on biochemistry and molecular biology forundergraduate students from Faculty of Medicine andFaculty of Science. We also accept undergraduate
students taking “Free Quarter” and “Early-Exposureto-Medicine” courses every year. Several students arestaying in our lab beyond the term to join our
research.
For graduate students, we hold progress-reportmeeting and journal club every week, and sometimes
invite established scientists for seminar to encourage
scientific discussion. We also provide a monthly
training course of theoretical biology for young
researchers and students in cooperation with themembers of Institute for Biology and Mathematics ofDynamical Cell Processes (iBMath), The Universityof Tokyo (lead by Professor Yasuo Ihara) and Core
Research for Evolutional Science and Technology(CREST), Japan Science and Technology Agency.

Research Activities
1. Developmental Biology and Medicine
Our research is aimed at understanding molecularmechanisms underlying morphogenesis of the craniofacial and cardiovascular structures.
(1) Craniofacial development
The branchial (pharyngeal) arches are a segmental
series of bulging structures common and characteristic
for all vertebrate embryos. They are mainly formed bymigratory cranial neural crests, which give rise tovarious skeletal components including the jaw andmiddle ear structures. We have revealed that
endothelin-1 (ET-1), first identified as an17endothelium-derived vasoconstrictor peptide, and its
receptor ETAR signaling acts as a molecular switchthat determines the lower jaw identity by using mouse
genetics. Recently, human ETAR gene mutations
causing craniofacial abnormalities and alopecia wereidentified, and the causal relationship was confirmed
by our experiments recapitulating the same mutations
in mice. In another work, we clarified that the
tympanic membranes of mammals and reptiles/birds
are independently acquired as a product of convergent
evolution by showing that lower-to-upper jaw
transformation induced by inactivation of ET-1/ETAR
signaling results in loss of the tympanic membrane inmouse, but causes duplication of the tympanic
membrane in chicken.
Furthermore, we verified that Hoxa2, a member ofthe Hox gene clusters, is sufficient for endowing
Hox-free pharyngeal arch tissues with the second
pharyngeal arch identity by introducing ectopic Hoxa2
expression. Hoxa2 gene manipulation also identified
the dorso-ventral boundary in the pharyngeal region,
together with experiments using mice carrying
mutations in ET-1/ETAR and its downstream genes
Dlx5 and Dlx6.
(2) Cardiac development
Recently, we found that the cranial neural crest
from the preotic region, rather than post-otic ‘cardiac’
neural crest cells, migrate into the heart anddifferentiate into coronary artery smooth muscle cells
in the proximal region. Ablation of the preotic neuralcrest in chick embryos causes abnormalities incoronary septal branch and orifice formation.
Appropriate migration and deployment of neural crest
cells and subsequent smooth muscle differentiation
require multicellular interactions involving ET-1/
ETAR signaling possibly through G12/13-mediated,
Dlx5/Dlx6-independet mechanisms, whereas ET-1/
ETAR signaling is involved in ventral identification of
the pharyngeal arches through Gq/11-mediated, Dlx5/
Dlx6-dependet mechanisms. These findings indicatethat the ET-1/ETAR signaling pathway is involved incraniofacial and cardiac development throughdifferent trimeric G-proteins.
(3) Angiogenesis
Angiogenesis is a morphogenetic process that

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

References
1. Asai R, Haneda Y, Seya D, Arima Y, Fukuda K,
Kurihara Y, Miyagawa-Tomita S, Kurihara H.
Amniogenic somatopleure: a novel origin of
multiple cell lineages contributing to thecardiovascular system. Sci. Rep. 7(1):8955, 2017.
2. Furutera T, Takechi M, Kitazawa T, Takei J,
Yamada T, Vu Hoang T, Rijli FM, Kurihara H,
Kuratani S, Iseki S. Differing contributions of thefirst and second pharyngeal arches to tympanic
membrane formation in the mouse and chick.
Development. 144(18):3315-3324, 2017.
3. Shinohara K, Watabe AM, Nagase M, Okutsu Y,
Takahashi Y, Kurihara H, Kato F. Essential role ofendogenous calcitonin gene-related peptide in
pain-associated plasticity in the central amygdala.
Eur. J. Neurosci. 46(6):2149-2160, 2017.
4. Hayashi T, Tokihiro T, Kurihara H, Yasuda K.
Community effect of cardiomyocytes in beating
rhythms is determined by stable cells. Sci. Rep.

187(1):15450, 2017.
5. Isono W, Wada-Hiraike O, Kawamura Y, Fujii T,
Osuga Y, Kurihara H. Administration of oral
contraceptives could alleviate age-related fertility
decline possibly by preventing ovarian damage ina mouse model. Reprod. Sci. 25(9):1413-1423,
2018.
6. Hayashi T, Tokihiro T, Kurihara H, Nomura F,
Yasuda K. Integrate and fire model with refractory
period for synchronization of two cardiomyocytes.
J. Theor. Biol. 437:141-148, 2018.

Functional Biology
1. Physiology

20

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

Homepage

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

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

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

Research activities
Most of our research is focused on the higher brain
function of the mammalian central nervous system.
(1) Functional columns in the cerebral cortex are
believed to be essential to process sensory informationsuch as orientation selectivity. However, neurons inrodent visual cortex are organized in a mixedsalt-and-pepper fashion for orientation selectivity. If
the connections between neurons are random,
information from different orientations would bemixed, and orientation selectivity would be largely
lost. Sharp orientation tuning without functional
clustering suggests the existence of specific21

connections among similarly tuned excitatory neurons.
Indeed, networks of specifically connectedsubpopulation of excitatory neurons — subnetworks— have been found in rodent visual cortex, and they
are related to the orientation selectivity of theseneurons. In our lab, we examine whether adevelopmental basis exists for such subnetworks.
It has been long debated to what extent neuronal
functions are determined genetically or by postnatal
experience or neuronal activity. However, how thefunction of neurons in the cortex is influenced byprenatal development is not well understood. In theembryonic stage of cortical development, progenitor
cells in the ventricular zone produce excitatoryneurons that migrate into the cortical plate using radial
glial fibers as a scaffold. Interestingly, in the rodent
cortex, clonally related sister neurons are not tightly
packed. Instead, they are sparsely distributed throughlayers 2–6, spanning several radial minicolumns, insuch a way that sister neurons derived from a given
progenitor are separated from each other by neurons
derived from other progenitors. We wonder whether
there is any relation between the scattered progeny ofsingle progenitors and the scattered salt-and-pepper
orientation map in rodent visual cortex.
Recent studies reported that the progeny of single
progenitor cells are preferentially connected to eachother. These results suggest that clonally related
neurons may participate in specific subnetworks inadult cortex. Since cells with similar response
selectivity also have high probabilities of synaptic
connection, we hypothesize that sister cells may sharesimilar response selectivity.
We image a mouse in which all cells derived from asingle cortical progenitor are labeled. By imaging all
the upper layer cells of a single cortical clone, we
obtain a near-complete picture of the functional
properties of the cells in a cortical clone. We observethat more than half of, but not all, clonally related
cells share response selectivity, indicating that celllineage is partly responsible for the functional
properties of mature neurons.
We find that the orientation preference of sister
cells is not totally determined by clonal identity, assome sister cells show orientation preference different
from the majority of sister cells. We hypothesize thatthe preferential connectivity between sister cells

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

22

dependent on retinal activity, has been proposed to be
involved in the formation and maturation oforientation selectivity. This synchronous spontaneous
activity appears approximately 1 week before eye
opening and becomes sparse afterwards. The initialformation and maturation of orientation selectivity isthought to occur during the same period, and this
temporal coincidence may imply that the synchronous
spontaneous activity is involved in the formation
and/or maturation of orientation selectivity. Indeed, aprevious report showed that suppressing spontaneous
activity by infusing tetrodotoxin (a sodium channel
blocker) into the developing visual cortex of ferrets
impairs the maturation of orientation selectivity.
However, as it is technically challenging to suppress
spontaneous activity earlier than the initial formation,
its role in the initial formation of orientation
selectivity remained untested.
Recently, a genetically specified mechanism has
been proposed: cell lineage–derived microcircuit
formation is critically involved in the formation oforientation selectivity in the mouse primary visualcortex (V1). Thus, it is still unknown which of the two
mechanisms — the activity-dependent or theactivity-independent one — is more important for thedevelopment of orientation selectivity.
We use a genetic method to suppress neuronal
activity starting prenatally, which allow us, for the
first time, to investigate the contribution of neuronal
activity to the initial formation of orientation
selectivity. We observe almost normally tuned
orientation selectivity in visual cortical neurons inadults despite a strong suppression of bothspontaneous and visually evoked activity throughout
development. This finding suggests that the initialformation and maturation of orientation selectivity islargely activity independent (Hagihara et al., 2015).
(3) It has been debated whether orientation selectivity
in mouse primary visual cortex (V1) is derived fromtuned lateral geniculate nucleus (LGN) inputs orcomputed from untuned LGN inputs. However, few
studies have measured orientation tuning of LGN
axons projecting to V1. We measure the response
properties of mouse LGN axons terminating in V1 andfind that LGN axons projecting to layer 4 are
generally less tuned for orientation than axons

projecting to more superficial layers of V1. We alsofind several differences in response properties
between LGN axons and V1 neurons in layer 4. These
results suggest that orientation selectivity of mouse
V1 may not simply be inherited from LGN inputs, but
could also depend on thalamocortical or V1 circuits(Kondo and Ohki, 2016).

References(1) Murakami T, Matsui T, Ohki K. Matsui T,
Murakami T, Ohki K. Functional Segregation andDevelopment of Mouse Higher Visual Areas. J
Neurosci. (2017) 37:9424-9437.
(2) Matsui T, Murakami T, Ohki K. Neuronal Originof the Temporal Dynamics of Spontaneous BOLD
Activity Correlation. Cereb Cortex. (2018) doi:
10.1093/cercor/bhy045.

23

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

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

Homepage

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

Introduction and Organization

Research activities

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

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

Teaching activities
The department provides lectures and practice inphysiology for undergraduate students. We teachimaging, electrophysiology and cellular and molecularphysiology methods for free quarter students. The
department provides also lectures and instructions forlaboratory research for graduate and undergraduate
students in the fields of neurophysiology andmolecular and cellular imaging. Seminars, progress
reports, and journal club for graduate students areroutinely provided. Monthly joint seminars(Functional Biology Seminars) are also provided for
graduate students.

(1) Thalamocortical dynamics mediate learning andexecution of self-initiated movement.
Through motor learning, animals acquire the skilled
movements to efficiently accomplish their basic goals
in everyday life. Within the primary motor cortex, therepresentation of well-learned movement is stabilized24

through motor learning. The thalamus is the hub
through which signals are transmitted from the basal
ganglia and cerebellum, which play pivotal roles inmotor learning, to the neocortex. However, thetemporal dynamics of thalamocortical axonal
activities during motor learning and execution remain
largely unknown. Here we conducted two-photon
calcium imaging of thalamocortical axons in themouse motor cortex during learning of a self-initiatedlever-pull task (Hira et al., 2013; Masamizu et al.,2014). We demonstrate that thalamocortical activities
evolve their specific representation for movements
through the learning and employ various temporal
dynamics depending on their projecting layers.
Furthermore, we show that from anatomical andphysiological experiments mouse layer 1 and layer 3
thalamocortical axons carry information from thebasal ganglia and cerebellum, respectively, and lesionof either the dorsal striatum or deep cerebellar nuclei
impair motor learning. Thus, origin- and targetspecific thalamocortical signals for execution ofskilled movement emerge throughout learning.
(2) Development of in vivo wide-field calcium
imaging of axonal boutons in the mouse neocortex atsynaptic resolution.
In vivo wide-field imaging of neural activity with ahigh spatio-temporal resolution is a challenge inmodern neuroscience. Although two-photon imaging
is very powerful, high-speed imaging of the activity of
individual synapses is limited to a field ofapproximately 200 μm on a side because theexcitation laser should be sequentially scanned within
an imaging field. Wide-field one-photon epifluorescence imaging can reveal neuronal activity over a
field of ≥ 1 mm2 at a high speed, but is not able toresolve a single synapse. Here, to achieve a highspatio-temporal
resolution,
wecombineanultra-high-definition (UHD) camera with spinningdisk one-photon confocal laser microscopy (SDCLM).
In SDCLM, a rotating Nipkow disk divides an
excitation laser beam into a thousand of light sources
via a series of pinholes, and parallel scan by the lightsources enables to image a wide field at high speed. In
addition, SDCLM has a three-dimensional resolution
because the pinholes reject out-of-focus fluorescence.
The combination of the UHD camera and SDCLM

allowed us to image a 1 mm2 field with a pixel
resolution of ~0.2 μm at 60 fps. When we imaged
motor cortical layer 1 in a behaving head-restrainedmouse, calcium transients were detected in thousandsof presynaptic boutons of thalamocortical axons
expressing a genetically-encoded calcium indicator.
The effects of out-of-focus fluorescence changes on
calcium transients in individual boutons appeared
minimal. Axonal boutons with highly correlated
activity were detected over the 1 mm2 field, and were
probably distributed on multiple axonal arbors
originating from the same thalamic neuron. This new
microscopy with the UHD camera should serve toclarify the activity and plasticity of widely distributed
cortical synapses.
(3) Establishment of two-photon calcium imaging of
the medial frontal cortex and hippocampus without
cortical invasion.
Two-photon calcium imaging reveals the in vivo
activity of multiple neurons at cellular and subcellular
resolution. Recent work demonstrates that by exciting
red-fluorescent calcium indicators with a laser atwavelengths of 1000–1100 nm through a cranial
window, it is possible to image neural activity in themouse sensory cortex at depths of 800–900 µm fromthe cortical surface (corresponding to layers 5 and 6).
However, for functional imaging of deeper regions
such as the medial prefrontal cortex, hippocampus,
and basal ganglia, invasive penetration is unavoidable;
it is necessary to insert a microlens or a microprism
into the cortical tissue, or to remove the cortical tissue
above the target region. The difficulty of deep imaging
is mainly caused by refractive index mismatch andlight scattering within the tissue. These can be
weakened when objectives with low numericalaperture (NA) are used because the angle of lightemitted from the objective is smaller and thelight-path length within the tissue is shorter than whenhigh NA objectives are used. However, when low NA
objectives are used, the spatial resolution andcollection efficiency of emitted fluorescent signals areworse than when high NA objectives are used. If ahigh NA objective is used in conjunction with
underfilling of the back aperture by the excitation
laser, the collection efficiency of the fluorescent signal
remains high. If the effective NA for the excitation

25

light is small but sufficient to resolve single neurons(10–15 μm along the Z axis), this technique may
increase the maximal depth for two-photon calcium
imaging of neuronal somata. Although this technique
has been theoretically predicted and partiallydemonstrated in the skin (Helmchen and Denk 2005;
Tung et al., 2005), it has not been applied to deep
imaging of neural activity in behaving animals. In
addition, long-wavelength excitation light andred-fluorescent genetically encoded calcium indicators(red GECIs) are suitable for deep imaging becauselight scattering is weaker at longer wavelengths. We
used an 1100 nm laser that underfilled the backaperture of the objective together with red GECIs toestablish two-photon calcium imaging of the intact
mouse brain and detect neural activity up to 1200 μm
from the cortical surface. This imaging was obtained
from the medial prefrontal cortex (the prelimbic area)
and the hippocampal CA1 region. Deep imaging ofneural activity required a relatively high-power laser.
However, we confirmed that 15- and 30-min imaging
did not produce any apparent morphological orfunctional damage to the brain tissue. We found thatneural activity before water delivery repeated at aconstant interval was higher in the prelimbic area thanin layer 2/3 of the secondary motor area. Reducing theinvasiveness of imaging is an important strategy toreveal the intact brain processes active in cognition
and memory.
(4) Two-photon calcium imaging in the motor cortex
of common marmosets during upper-limb movement
tasks
Recent advances in calcium imaging have revealed
cellular and subcellular mechanisms underlying avariety of brain functions in rodents, fishes, andinvertebrates. However, the calcium imaging
technique is still difficult to apply to awake
non-human primates, especially during forelimb
movement tasks, which are very useful forinvestigating the mechanisms underlying cognitive
behaviors, decision making, motor planning/execution
and motor skill learning. We have extended thetechnique of two-photon calcium imaging, which weestablished in a non-human primate, the common
marmoset, in an anesthetized state (Sadakane et al.,2015), to record neuronal activity in the cerebral

cortex of behaving marmosets. We developed
protocols to train head-fixed common marmosets(Callithrix jacchus) to perform upper-limb movementtasks. Until this study, the only behavioral tasks thathave previously been reported for the head-fixedmarmosets are saccade and licking tasks, and training
head-fixed marmosets to perform upper-limb
movement tasks is considered to be difficult. We
therefore developed new step-by-step training
protocols. After 2-5 months of training sessions,head-fixed marmosets could control a pole with an
upper limb to move a cursor to a target on a screen.
These animals could also learn to appropriately movethe pole when either of two targets was randomly
presented in each trial. We conducted two-photon
calcium imaging of layer 2/3 neurons in the motor
cortex during this motor task performance, anddetected task-relevant activity from neuronal somata,dendrites and axons. In terms of imaging, themarmoset, a New-World monkey with the essential
features of primate cortical organization, has anadvantage over other monkeys because it has arelatively small and flat cerebral cortex with athickness of approximately 1.5-2.0 mm. Two-photon
calcium imaging in behaving marmosets could
become a fundamental technique for determining the
spatial organization of the cortical dynamics
underlying action and cognition.
(From abstracts in the 41th Annual Meeting of theJapan Neuroscience Meeting)

References
1. Kondo M, Kobayashi K, Ohkura M, Nakai J,
Matsuzaki M. Two-photon calcium imaging of themedial prefrontal cortex and hippocampus without
cortical invasion. eLife 6, e26839 (2017).
2. Endo K., Ishigaki S., Masamizu Y., Fujioka Y.,
Watakabe A., Yamamori T., Hatanaka N., Nambu
A., Okado H., Katsuno M., Watanabe H.,
Matsuzaki M., and Sobue G. Silencing of FUS in
the common marmoset (Callithrix jacchus) brain
via stereotaxic injection of an adeno-associatedvirus encoding shRNA. Neuroscience Research,
AOP (2018).

26

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

Research Associate
Naofumi Uesaka, Ph.D.
Yuki Hashimotodani, Ph.D.

Homepage

http://plaza.umin.ac.jp/~neurophy/

Introduction and Organization
This laboratory was founded in 1953 as Departmentof Neurophysiology, Institute for Brain Research. In
1996, it was integrated into Graduate School of
Medicine. The current members of this laboratory are
5 faculty members (professor, 3 research associate,
project research associate), 3 postdoctoral fellows, 13
graduate students, 2 undergraduate students and 5
technicians. We teach neurophysiology for medical
undergraduates and for students in the Master andPh.D. courses. Our research aims at elucidating
cellular and molecular mechanisms underlying
regulation of synaptic transmission and postnatal
development of neuronal circuits.

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

record electromyogram (EMG) from humangastrocnemius muscles and learn how the stretch
reflex works.
We accept Free-Quarter students. Students areencouraged to experience patch-clamp recordings
from neurons either in brain slices or in dissociatedculture, or to experience recordings of neuronal
activities from living animals.
For the training of Master and Ph.D. course students,
we have a weekly conference for discussing current
research activities. A laboratory member summarizes
his/her recent experimental data or presents papers
closely related to his/her research. Moreover, formutual communication between the laboratories withsimilar interests in neuroscience, we have a weekly
joint seminar with Department of Cellular
Neurobiology, Division of Structural Physiology,
Department of Cellular and Molecular Physiology,
Department of Integrative Physiology, and Division ofAnimal Resources.

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

27particularly focus on observing neuronal activities inreal time in intact neurons. We use whole-cell patch
clamp recording, calcium imaging, two-photon
imaging and their combinations in various
preparations (cultured neurons, brain slices and intact
animals) and investigate molecular mechanisms ofsynaptic transmission and plasticity.
The main subjects of our research are as follows(1) Refinement of synaptic organization during
cerebellar development:
In early postnatal days, all Purkinje cells in the
cerebellum are innervated by multiple climbing fibers.
These surplus climbing fibers are eliminatedeventually with the progress of postnatal development,
and most Purkinje cells become innervated by single
climbing fibers by the end of the third postnatal weekin mice. We investigate the mechanisms how single
climbing fibers are selected and how the surplus
climbing fibers are eliminated.
(2) Retrograde synaptic modulation mediated byendogenous cannabinoids:
We reported in 2001 that endogenous cannabinoids
are released from postsynaptic neurons in an
activity-dependent manner, act retrogradely onto
presynaptic cannabinoid receptors and suppress
transmitter release. Since then, we have been
investigating the mechanisms of this retrograde
modulation. We are also interested in elucidating thephysiological significance of this phenomenon
including learning and memory, addiction, andanxiety.
(3) Synaptic integration in intact animals:
To understand the physiological function ofsynapses in vivo, we analyze synaptic transmission
and integration in single neurons in the intact brain byusing in vivo two-photon imaging and whole-cellrecording. We also develop new methods toimplement these experiments.

References(1) Kano M, Watanabe T. Type-1 metabotropic
glutamate receptor signaling in cerebellar
Purkinje cells in health and disease. F1000Res.

2017 Apr 4;6:416. doi: 10.12688/f1000research.
10485.1.eCollection 2017. Review.
(2) Aikawa T, Watanabe T, Miyazaki T, Mikuni T,
Wakamori M, Sakurai M, Aizawa H, Ishizu N,
Watanabe M, Kano M, Mizusawa H, Watase K.
Alternative splicing in the C-terminal tail of
Cav2.1 is essential for preventing a neurologicaldisease in mice. Hum Mol Genet. 2017 Aug 15;
26(16):3094-3104. doi: 10.1093/hmg/ddx193.
(3) Miyazaki T, Yamasaki M, Hashimoto K, Kohda K,
Yuzaki M, Shimamoto K, Tanaka K, Kano M,
Watanabe M. Glutamate transporter GLAST
controls synaptic wrapping by Bergmann glia andensures proper wiring of Purkinje cells. Proc Natl
Acad Sci U S A. 2017 Jul 11;114(28):7438-7443.
doi:10.1073/pnas.1617330114. Epub 2017 Jun 27.
(4) Nakai N, Nagano M, Saitow F, Watanabe Y,
Kawamura Y, Kawamoto A, Tamada K, Mizuma
H, Onoe H, Watanabe Y, Monai H, Hirase H,
Nakatani J, Inagaki H, Kawada T, Miyazaki T,
Watanabe M, Sato Y, Okabe S, Kitamura K, Kano
M, Hashimoto K, Suzuki H, Takumi T. Serotoninrebalances cortical tuning and behavior linked to
autism symptoms in 15q11-13 CNV mice. Sci Adv.
2017 Jun 21;3(6):e1603001. doi:10.1126/sciadv.
1603001. eCollection 2017 Jun.
(5) Choo M, Miyazaki T, Yamazaki M, Kawamura M,
Nakazawa T, Zhang J, Tanimura A, Uesaka N,
Watanabe M, Sakimura K, Kano M. Retrograde
BDNF to TrkB signaling promotes synapse
elimination in the developing cerebellum. Nat
Commun. 2017 Aug4; 8(1):195. doi: 10.1038/
s41467-017-00260-w.
(6) Good JM, Mahoney M, Miyazaki T, Tanaka KF,
Sakimura K, Watanabe M, Kitamura K, Kano M.
Maturation of Cerebellar Purkinje Cell Population
Activity during Postnatal Refinement of Climbing
Fiber Network. Cell Rep. 2017 Nov 21;21(8):2066-2073. doi: 10.1016/j.celrep.2017.10.101.
(7) Uesaka N, Kano M. Presynaptic Mechanisms
Mediating Retrograde Semaphorin Signals for
Climbing Fiber Synapse Elimination During
Postnatal Cerebellar Development. Cerebellum.
2018 Feb; 17(1):17-22. doi: 10.1007/s12311-0170888-z. Review.
(8) Jung D, Hwang YJ, Ryu H, Kano M, Sakimura K,
Cho J. Corrigendum: Conditional Knockout of

28

Cav2.1 Disrupts the Accuracy of Spatial
Recognition of CA1 Place Cells and Spatial/
Contextual Recognition Behavior. Front Behav
Neurosci. 2017 Dec 8;11:242. doi: 10.3389/fnbeh.
2017.00242.
(9) Yokoyama R, Kinoshita K, Hata Y, Abe M,
Matsuoka K, Hirono K, Kano M, Nakazawa M,
Ichida F, Nishida N, Tabata T. A mutant HCN4
channel in a family with bradycardia, left bundle
branch block, and left ventricular noncompaction.
Heart Vessels. 2018 Jul;33(7):802-819. doi: 10.
1007/s00380-018-1116-6. Epub 2018 Jan(10) Uesaka N, Abe M, Konno K, Yamazaki M,
Sakoori K, Watanabe T, Kao TH, Mikuni T,
Watanabe M, Sakimura K, Kano M. Retrograde
Signaling from Progranulin to Sort1 Counteracts
Synapse Elimination in the Developing
Cerebellum. Neuron. 2018 Feb 21;97(4):796-805.
e5. doi: 10.1016/j.neuron.2018.01.018. Epub 2018
Feb 1.
(11) Chen S, Weitemier AZ, Zeng X, He L, Wang X,
Tao Y, Huang AJY, Hashimotodani Y, Kano M,
Iwasaki H, Parajuli LK, Okabe S, Teh DBL, All
AH, Tsutsui-Kimura I, Tanaka KF, Liu X,
McHugh TJ. Near-infrared deep brain stimulation
via upconversion nanoparticle-mediated optogenetics. Science. 2018 Feb 9;359(6376):679-684.
doi: 10.1126/science.aaq1144.
(12) Hirai H, Kano M. Type 1 metabotropic glutamate
receptor and its signaling molecules as therapeutictargets for the treatment of cerebellar disorders.
Curr Opin Pharmacol. 2018 Feb;38:51-58. doi:
10.1016/j.coph.2018.02.002. Epub 2018 Mar 8.

Functional Biology
2. Pharmacology

30

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

Lecturer
Yohei Okubo, Ph. D.

Research Associate
Kazunori Kanemaru, Ph. D.,

Homepage

Hiroshi Sekiya, M.D.

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

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

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

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

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

31

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

Imaging of signalling molecules
Our study on Ca2+ signalling made us realize theimportance of visualization of signalling molecules within living cells. Thus, our laboratory has
been involved in the generation of new indicatorsof signalling molecules upstream and downstream
Ca2+ signals. We have succeeded in imaging IP3
signalling in various cells including intact neurons
within cerebellar slice preparations. We also
developed an indicator to detect the phosphorylation of myosin regulatory light chain. The
indicator allowed us to image phosphorylation
state of myosin light chain in living cells.
Furthermore, we generated a nitric oxide (NO)indicator based on the heme-binding domain ofsoluble guanylyl cyclase. This indicator was
successfully used in cerebellar slice preparations
to image NO signals in response to parallel fiber(PF) stimulation. We found that the NO signal
intensity decreases steeply with distance form theactivated synapse and generate synapse-specificlong-term potentiation (LTP) of PF-Purkinje cell
synapses. We also showed that the NO signal
intensity depends biphasically on the frequency of
PF stimulation. Importantly, the LTP depends
similarly on the frequency of PF stimulation. Thus,
our NO indicator provided us with valuable
information regarding the role of NO signals in thecentral nervous system.
Glutamate is the most important excitatory
synaptic transmitter in the brain. We havegenerated a glutamate indicator based on theglutamate-binding domain of the AMPA-typeglutamate receptor. Using this fluorescentglutamate indicator, we have succeeded in imaging
spatiotemporal dynamics of glutamate in theextrasynaptic space in brain slices. This study
demonstrated that bursting synaptic activities
cause glutamate spillover from the synaptic cleft
to activate perisynaptic metabotropic glutamate
receptors, and will provide a basis for the researchof extrasynaptic glutamate transmission that is
involved in many important brain functions.
3) Exploration of previously unrecognized cellularfunctions that are regulated by Ca2+ signals
Although many important cell functions havebeen found to be regulated by Ca2+ signals, not all
the Ca2+-dependent cell functions have been32

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 synapses in the cerebral cortex andthe cerebellar cortex. We have found that there is aretrograde signaling mechanism downstream of
metabotropic
glutamate
receptor-mediated
IP3-Ca2+ signaling in pyramidal neurons andPurkinje neurons, which then generates BDNF
(brain-derived neurotrophic factor) that maintains
the glutamate-release function of the presynaptic
terminal. This presents a new form of activitydependent synaptic maintenance mechanism.
We have studied the role of IP3-Ca2+ signaling
in astrocytes (the most abundant glial cells) andfound that it regulates the expression of moleculeson the surface of astrocytes that regulate thegrowth of neurons. Our results indicate thatN-cadherin is involved in the regulation of neural
growth in vitro. Furthermore, we recently showedthat IP3-Ca2+ signaling in cerebellar astrocytes(Bergmann glia) regulates glutamate transporter
levels in Bergman glial cells to maintain glutamate
clearance in the mature cerebellum.
In response to brain injury, astrocytes undergo
structural and functional changes (reactive
astrogliosis). We showed that injury-induced Ca2+
responses in astrocytes are important for reactive
astrogliosis and also for neuroprotection. We
studied the molecular mechanism involved in thisreaction, and found that a translational repressor
Pum2 is downregulated in a Ca2+-dependent
manner. We also identified that N-cadherin
mRNA is one of the target mRNAs of Pum2. Thus,
Pum2 down-regulation induces reciprocal upregulation of N-cadherin after brain injury. When
the N-cadherin gene is disrupted in astrocytes,
injury-induced astrogliosis and neuroprotection
were attenuated. These results clarified themolecular events that are responsible for the
astrogliosis and neuroprotection following brain
injury.
We have identified a new NO-dependent Ca2+
signaling mechanism in central neurons. We foundthat synaptically released NO S-nitrosylates theryanodine receptor (RyR) to activate Ca2+ releasethrough the Ca2+ release channel, which we referto as NO-induced Ca2+ release (NICR). NICR isrequired for the NO-dependent LTP at the parallel
fiber-Purkinje cell synapse described above.
Furthermore, NICR has a pathophysiological role,and seems to play an important role in NOdependent neuronal cell death after brain ischemia.
This finding suggests that NICR can be a therapeutic target in certain forms of ischemic brain
diseases.
We have made it possible to image Ca2+ signals
in the fine processes of individual astrocytes invivo using transgenic mice that express anultrasensitive genetically encoded Ca2+ indicator,
YC-Nano50, in an astrocyte-specific manner. Thismethod allowed us to find a previously
unidentified mode of spontaneous astrocytic Ca2+
signals, Ca2+ twinkles, which are preferentiallydisplayed in fine astrocytic processes in living
mice brain. Moreover, a highly sensitive nature ofastrocytic fine processes as a sensitive detector ofneuronal activity was also revealed.

References
1. Sakamoto H., Ariyoshi T., Kimpara N., Sugao K.,
Taiko I., Takikawa K., Asanuma D., Namiki S.,
Hirose K. Synaptic weight set by Munc13-1
supramolecular assemblies. Nat. Neurosci. 21,
41-49, 2018

33

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

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

Associate
Koji L. Ode, Ph.D.
Shoi Shi, Ph.D.

Homepage

http://sys-pharm.m.u-tokyo.ac.jp/

Teaching activities
Our department, in collaboration with the department of cellular and molecular pharmacology, takes
responsibility for lectures and laboratory courses on
pharmacology for the undergraduate students of thefaculty. There are some 39 lectures per year including
those given by six invited lectures to cover specialized
and currently highlighted fields in pharmacology. We
offer several laboratory courses, and all the membersof the Department participate in the courses to provide
close consultation for the students.
For the graduate students, there are series ofseminars on physiology and neuroscience. We also
have research seminars to discuss and stimulate theresearch activities of the graduate students in the
Department.

Research activities
With our members from different backgrounds, wewould like to realize experimental systems biology at
the organism level, leading to greater understanding
and even control of organismal pathophysiology. To
this end, we specifically focus on the cellular circuits
controlling the sleep/wake cycle and address thehourglass mechanism of sleep, a homeostatic- andcircadian-dependent regulation of sleep amount andtiming. We are also planning on multi-scale research
activities covering a series of length scales;
molecule-to-cell, cell-to-tissue, and tissue-to-organism
to envision such complicated underlying mechanism.
We are currently devoting our research to twotechnological challenges; 1) next-generation mammalian reverse genetics, where we can produce
genetically modified mice in a high-throughput
fashion, 2) system-level identification and analysis ofcellular circuits in the whole-organ (especially, thewhole-brain) and whole-body, where we can identify
individual cells or cellular circuits in the whole-organ
and whole-body. Combined with these techniques, weinvestigate how the average (diurnality or
nocturnality), the dispersion (the length of sleepingtime), and the amount (insomniac or hypersomniac
responses) of sleep during circadian time aredetermined by environments and history of activities.
Additionally, we execute a comprehensive study to
examine dynamic properties of the biological system
inside cell-to-tissue scale, and their relations toorganism-level phenotypes.
1) Next-generation mammalian reverse genetics
In the conventional method for production ofgenetically-modified mice, a single line ofgene-targeted ES cells is injected into host embryos

34(typically use blastocysts) to generate chimera micecomprising a mixture of ES- and host-derived cells. In
addition, multiple mating procedures are needed togenerate the desired genetically modified mouse strain,
which typically takes from 9 months to several years.
Such multiple rounds of mating procedures arenecessary to produce gene knockout / knock-in micein the conventional method, which was usually abottleneck to promote organism-level system biology.
Therefore, we propose the concept of "next-generation
mouse genetics" which creates genetically modified
mice without mating and uses it for analysis, and aredeveloping technology for the research scheme. In
order to produce bi-allelic gene knockout mice
without crossing, we improved the design of guide
RNAs (gRNAs) used in CRISPR-Cas9 technology anddeveloped the "triple CRISPR method" which
simultaneously cuts 3 places in a single targeted gene
(Sunagawa et al., Cell Reports 2016). When thistechnique was applied, it succeeded in producing
various kinds of gene knockout mice with extremely
high production rate (almost 100%) in the first
generation. Furthermore, in order to directly produce
knock-in mice without crossing, ~100% ES
cell-derived mice (ES mice) were directly preparedfrom the genome-modified ES cells and used for thefollowing experiments. Using this method, multiple
rescue experiments on a circadian clock geneknockout mice (Cry1, Cry2 double-KO mice) were
performed regarding over 20 strains, leading to thediscovery of important phosphorylation sites andprotein structures of the molecule (Ode et al.,
Molecular Cell 2017). Through these experiments, we
showed the efficiency and throughput of theestablished method which facilitates to create
genetically modified mice in just about three months
and use them for subsequent analyses (Susaki et al.
npj Systems Biology and Applications, 2017; Ukai etal. Nature Protocols 2017).
2) System-level identification and analysis of cellular
circuits in the whole-organ and whole-body
The comprehensive identification of molecular
circuits at the organism level also requires accurate(>90%) phenotype analysis. In neuroscience,
sleep/wake behavior is an intriguing phenotype,because sleep disorders (e.g., insomnia or

hypersomnia) are sensitive and informative symptomsof almost all psychological disorders. Sleep/wakestates have been characterized in humans byelectroencephalography (EEG) and electromyography(EMG). Characteristic EEG/EMG patterns during
sleep and waking are preserved in mammals and canbe measured by electrodes surgically implanted in thebrain and muscles. However, such recording requires
special surgical skills, and the surgery is highlyinvasive, requiring a long recovery period (more than
10 days) after implantation before sleep/wakerecording. Furthermore, the EEG/EMG data are often
manually annotated and classified into sleep/wakephenotypes by visual assessment, which can be time
consuming and somewhat subjective. Therefore,
sleep/wake phenotyping has been a low-throughput
method; for comprehensive studies, a scalable,
non-invasive, fully automated sleep/wake recording
method was needed. For accurate phenotype analysis,
we developed a respiration-based, non-invasive, fully
automated system, the Snappy Sleep Stager (SSS),
which enabled the high-performance analysis (95.3%
accuracy) of sleep/wake phenotypes (Sunagawa et al.,Cell Reports, 2016).
To highlight the regulatory cellular networks in thesleep/wake rhythm, we facilitate an identification of
sleep/wake generating cells in the whole-brain in ahighly-parallelized manner. A concerted effort has
been made especially in the brain, as scientists areaiming to clarify how neural activity is translated into
consciousness and other complex brain activities. One
example of the technologies needed is whole-brain
imaging at single-cell resolution. This imaging
normally involves preparing a highly transparent
sample that minimizes light scattering and thenimaging neurons tagged with fluorescent probes atdifferent slices to produce a 3D representation.
However, limitations in current methods prevent
comprehensive study of the relationship. A new
high-throughput method, CUBIC (Clear, Unobstructed
Brain Imaging Cocktails and Computational Analysis),published in Cell, is a great leap forward, as it offers
unprecedented rapid whole-brain imaging at single
cell resolution and a simple protocol to clear andtransparentize the brain sample based on the use ofaminoalcohols (Susaki et al., Cell, 2014; Tainaka et al.,Cell 2014; Susaki et al., 2015; Kubota et al. Cell

35

Reports 2017; Nojima et al. Scientific Reports 2017).
We recently integrated the latest light-sheet
microscopy with swelling-based clearing protocol(CUBIC-X) and succeeded in generating a single-cellresolution whole mouse brain atlas (CUBIC-Atlas)(Murakami et al. Nature Neuroscience 2018). CUBIC
provides information on previously unattainable 3D
gene expression profiles and neural networks at thesystems level. Because of its rapid imaging capabilityof whole organ/body, CUBIC offers extraordinary
opportunity of novel discoveries in life science andmedical researches (Kubota et al. Cell Reports 2017;
Nojima et al. Scientific Reports 2017; Yamamoto et al.,Nature Communications 2018; Watanabe et al.,Developmental Biology 2018). It is also expected tohelp analyzing localized effects of genomic editing
and identifying neural connections at the whole brain
level.
3) Mechanism of dynamic homeostasis in sleep/wakecycle
Sleep amount during a day is under homeostatic
control, in which sleep pressure accumulates during
awake time and gradually decreases during sleep.
Sleep deprivation further promotes the accumulationof sleep pressure, resulting in the longer/deeper sleepin the next cycle. The required sleep duration in a day
is mostly determined genetically as evident from thefact that each animal spices shows characteristic
different sleep duration. However, detailed molecularmechanisms underlying the control of sleep durationin mammals are still elusive. Using triple-target
CRISPR, SSS, and CUBIC techniques together with acomputational model that simulates the membranepotential of cortex neuron regulated by a group of ionchannels, we discovered and proposed that
Ca2+-dependent neuronal hyperpolarization pathway
affects sleep duration in mammals (Sunagawa et al.,Cell Reports 2016; Tatsuki et al., Neuron 2016;
Tatsuki et al., Neurosci. Res. 2017; Ode et al., Curr.
Opin. Neurobiol. 2017; Ode and Ueda. Cold Spring
Harb. Perspect. Biol. 2017; Shi and Ueda. BioEssays
2018).
Given these results showing the role of Ca2+ forsleep control, our next challenge is to investigate
molecules that regulate the transition between sleep
and awake phases. We focused on CaMKII(calcium/calmodulin-dependent protein kinase II),protein kinases important for the post-translational
regulation of several neuronal channels. We found thatCamk2a or Camk2b knock-out mice exhibit abnormal
sleep phenotype. These kinases may play an importantrole for the transition between neural activities, whichhappen during milliseconds to seconds, and exchangeof sleep/awake states, which occurs in a time scale ofminutes to hours (Tatsuki et al., Neurosci. Res. 2017;
Ode et al., Curr. Opin. Neurobiol. 2017; Ode and Ueda.
Cold Spring Harb. Perspect. Biol. 2017; Shi and Ueda.
BioEssays 2018).
We further revealed the mechanism of temperaturecompensation in circadian clock. The biological clock
regulates 24h animal behavior including sleep andwake. We investigate biochemical mechanisms
underlying
temperature-compensated,
CKIδdependent multi-site phosphorylation in mammals. We
identify two mechanisms for temperature-insensitive
phosphorylation at higher temperature: lower substrateaffinity to CKIδ-ATP complex and higher productaffinity to CKIδ-ADP complex. Our findings suggest
thetemperature-sensitive
substrateandproduct-binding mechanisms underlie temperaturecompensation of circadian clock (Shinohara et al.,
Molecular Cell 2017).
Considering that numbers of researches encompass
model mice for sleep, circadian rhythm and relateddisorders, we envisage that our technologies andresearch outcomes will contribute the understandingof such disorders including psychiatric disorders andneurodegenerative disorders.

References
1. Watanabe T., Nakamura R., Takase Y., Susaki EA.,
Ueda HR., Tadokoro R., Takahashi Y. Comparisonof the 3-D patterns of the parasympathetic
nervous system in the lung at late developmental
stages between mouse and chicken. Dev. Biol.
2018:S0012-1606:30096-4.
2. Murakami T.C., Mano T., Saikawa S., Horiguchi
S.A., Shigeta D., Baba K., Sekiya H., Shimizu Y.,
Tanaka K.F., Kiyonari H., Iino M., Mochizuki H.,
Tainaka K., Ueda H.R. A three-dimensional
single-cell-resolution whole-brain atlas using
CUBIC-X expansion microscopy and tissue

36

clearing. Nat. Neurosci. 2018: 21, 625-637.
3. Udagawa T., Harita Y., Miura K., Mitsui J., Ode
K.L., Morishita S., Urae S., Kanda S., Kajiho Y.,
Tsurumi H., Ueda H.R., Tsuji S., Saito A. Oka A.
Amnionless-mediated glycosylation is crucial forcell surface targeting of cubilin in renal andintestinal cells. Sci. Rep. 2018:8:2351.
4. Shi S., Ueda H.R. Ca2+-Dependent Hyperpolarization Pathways in Sleep Homeostasis andMental Disorders. BioEssays 2018:40:1700105.
5. Yamamoto J., Imai J., Izumi T., Takahashi H.,
Kawana Y., Takahashi K., Kodama S., Kaneko K.,
Gao J., Uno K., Sawada S., Asano T.,
Kalinichenko V.V., Susaki E.A., Kanzaki M.,
Ueda H.R., Ishigaki Y., Yamada T., Katagiri H.
Neuronal signals regulate obesity induced β-cellproliferation by FoxM1 dependent mechanism.
Nat. Commun. 2017:8:1930.
6. Ukai H., Kiyonari H., Ueda H.R. Production ofknock-in mice in a single generation fromembryonic stem cells. Nat. Protoc. 2017:12:25132530.
7. Ode K.L., Ueda H.R. Design Principles of
Phosphorylation-Dependent
TimekeepinginEukaryotic Circadian Clocks. Cold Spring Harb.
Perspect. Biol. 2017:pii:a028357.
8. Shinohara Y., Koyama Y.M., Ukai-Tadenuma M.,
Hirokawa T., Kikuchi M., Yamada R.G., Ukai H.,
Fujishima H., Umehara T., Tainaka K., Ueda H.R.
Temperature-Sensitive Substrate and ProductBinding Underlie Temperature- CompensatedPhosphorylation in the Clock. Mol. Cell 2017:67:
783–798.
9. Nojima S., Susaki E.A., Yoshida K., Takemoto H.,
Tsujimura N., Iijima S., Takachi K., Nakahara Y.,
Tahara S., Ohshima K., Kurashige M., Hori Y.,
Wada N., Ikeda J., Kumanogoh A., Morii E.,
Ueda H.R. CUBIC pathology: three-dimensional
imaging for pathological diagnosis. Sci. Rep.
2017:7:9269.
10. Kubota S.I., Takahashi K., Nishida J., MorishitaY., Ehata S., Tainaka K., Miyazono K., Ueda H.R.
Whole-Body Profiling of Cancer Metastasis with
Single-Cell Resolution. Cell Rep. 2017:20:
236-250.
11. Susaki E.A., Ukai H., Ueda H.R. Next-generation
mammalian genetics toward organism-levelsystems biology. npj Syst. Biol. Appl. 2017:3:15.
12. Ode K.L., Katsumata T., Tone D., Ueda H.R. Fastand slow Ca2+-dependent hyperpolarization
mechanisms connect membrane potential andsleep homeostasis. Curr. Opin. Neurobiol. 2017:44:212-221.
13. Sugai S.S., Ode K.L., Ueda H.R. A designprinciple for an autonomous post-translational
pattern formation. Cell Rep. 2017:19:863-874.
14. Tatsuki F., Ode K.L., Ueda H.R. Ca2+-dependent
Hyperpolarization Hypothesis for Mammalian
Sleep. Neurosci. Res. 2017:118:48-55.

Pathology, Immunology andMicrobiology
1. Pathology

38

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

Associate Professor
Tetsuo Ushiku, M.D., Ph.D.
Teppei Morikawa, M.D., Ph.D.
Takeshi Sasaki, M.D., Ph.D. (Chief, Telepathology & Remote Diagnosis Promotion Center)*

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

Associates
Naoko Yamauchi, M.D., Ph.D.
Akiko Kunita, Ph.D.,
Mariko Tanaka, M.D., Ph.D.
Yukako Shintani-Domoto, M.D., Ph.D.* (Hospital Lecturer)
Hiroyuki Abe, M.D., Ph.D.* (Hospital Lecturer),
Zen-ichi Tanei, M.D., Ph.D. *Atsushi Tanaka, M.D., Ph.D.*
Munetoshi Hinata, M.D., Ph.D. *Ryu Miyagawa, Ph.D.* (Research, Investigation of Health Hazard by Radiation)

Technical Support Specialist
Kei Sakuma, Yasuyuki Morishita, M.T., Kimiko Takeshita, M.T.

Homepage

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

Introduction and Organization
Department of Pathology and Diagnostic Pathology is
responsible for the practice of diagnostic pathology,
education, and research in conjunction with Divisionof Diagnostic Pathology of the University Hospital*.
Our aim is the construction of “pathology as clinicalmedicine” as well as “next-generation pathology
incorporating cutting-edge science and technology”.
Associate Dr. Morita moved as the chief toDepartment of Pathology, Mitsui Memorial Hospital.
Lecturer Dr. Tanei has moved to Division of
Diagnostic Pathology. Dr. Naoko Yamauchi and Dr.
Munetoshi Hinata are now Associates.

39

Four postgraduate students (Hosoi, Makise,
Misumi, and Yamazawa) finished the course andreceived Ph.D. In the new fiscal year, 2018, seven newstudents will enter the postgraduate course, and there
will be 23 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 of the medical students, we takecharge of the following courses; General Pathology
Course for the 1st grade students in collaboration with
Department of Molecular Pathology, Systemic
Pathology for the 2nd grade, Elective ClinicalClerkship for the 3rd grade, and Clinical Clerkship forthe 4th grade students. Programs for postgraduates andjunior residents are also included in our education
activities.
"Tsunagu"Fukushima-Kanto
PathologyForensic Pathology Cooperation Program was plannedin collaboration with Fukushima Medical University
and Juntendo University, headed by Prof. Miyazono,
the dean of Graduate School. The program has been
adopted as one of Activation Program of Basic
Researcher Training of the Ministry of Education,
Culture, Sports, Science and Technology. For the four
years since FY2018, in graduate school education, weplan to train pathologists, who are specialized in"death investigation, distant pathology diagnosis, andgenomic medicine" with the training system oriented
to region support by circulating them among
universities.
Clinical Genome Conference started in the
University of Tokyo Hospital for the application ofcancer clinical sequencing to medical practice as a
research project of genome medicine (Project
organizer: Prof. Hiroyuki Mano). At the end of the
fiscal year, the University of Tokyo Hospital isselected as a core cancer hospital for cancer genomics.
Clinical sequence will be incorporated into actual
medical practice as advanced medical care from thenext fiscal year.
We registered 1000 cases of whole slide images(WSI) in the research project of Japanese Society of
Pathology “Database of Pathology-WSI for Development of Artificial Intelligence (AI) Technique andAI-based Support System for Pathology Diagnosis” in2017. We also examined the problems in image

registration in the hospital with the Departments ofRadiology and Neurosurgery.

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) (see the corresponding section of Divisionof Diagnostic Pathology).
Surgical pathology conferences are regularly heldwith each clinical division, and the cases of various
tumors are discussed, including thoracic organs, liverand pancreato-biliary tract, urology, gynecology,
breast, and orthopedics, as well as biopsy cases ofkidney, and skin.
Clinico-pathological conferences (CPCs) for two
autopsy cases are held every month in the hospital.
Both CPCs and weekly autopsy conferences are usefulfor the education of clinical residents. Digest versionsof CPC slides are now open in the hospital (Drs.
Shintani and Hinata), 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.

Teaching activities
We take on General Pathology Course for the 1st gradeof undergraduate students, especially in its morphological field.
Each class of Systemic Pathology Course andexercises are held in parallel with that of Systemic
Medicine Course. Handouts are available in every halfcourse of the pathological exercises, and all slides
used in the course are accessible on our website as
virtual slides (digital images of the slides).
In Clinical Clerkship for 4th grade medical
students, following courses are included; autopsy
pathologic practices with a case presentation forpaired students, surgical pathologic practices using
various tumor sections, and a tour of the pathology
laboratory.
Four students chose the clinical clerkship coursefor 3rd grade medical students. As for the free quarter40

program, we received three students of M1 in thisfiscal year.
We also set up the lecture series of “Infection/
Immunology/Cancer II” and “Tumor Pathology. We
also provided two intensive exercise courses,“Integration of Neuropathology/Raiology/Clinics” and“Histochemistry/Immuno-histochemistry/ClinicalElectron Microscopy”.

Research activities
The first major theme is “chronic inflammation andneoplasms”, especially Epstein-Barr virus (EBV)
associated gastric carcinoma (GC) (Drs. Kunita,
Shinozaki-Ushiku and Abe). In collaboration with
Department of Molecular Oncology, Chiba University
School of Medicine, we investigated molecularmechanism of epigenetic abnormalities in this specific
type of gastric cancer (ref.1, 14, 24).
The second major theme is ‘translational researchpathology’. We (Drs. Ushiku and Morikawa) areengaged in search of target molecules for cancer
therapy by global analysis of various cancers, incollaboration with Research Center for Advanced
Science and Technology (RCAST) and Department of
Molecular Pathology, Tokyo Medical and Dental
University (TMDU). Prof. Ishikawa and Dr. Katoh(TMDU) profiled immunoglobulin repertoires oftumor-infiltrating B cells, identifying sulfatedglycosaminoglycan as a major functional B cell
antigen in tumors. We succeeded in generating ofantibodies with anti-tumor activity through genomic
information (ref.7).
The third theme is to re-evaluate the disease
entities and tumor entities from the standpoint ofhistopathology. Dr. Ushiku identified the subgroup of
gastric cancer with worse prognosis, which ischaracterized by the expression of fetal marker
proteins among intestinal-type adenocarcinomas(ref.35). We also performed investigation of urothelial
carcinoma (ref.11, 18), breast cancer (ref.26),
malignant mesothelioma (ref.29), pancreatic cancer(ref.33), intrahepatic cholangiocarcinoma (ref.17), soft
tissue tumor (ref.12) and lymphoma (ref.16). In
non-neoplastic disease, we investigated pathogenesisof desmin cardiomyopathy applying proteomics to thetissue sections (ref.30).

References(including those of Diagnostic Pathology Division)
Case reports are listed in the section of Diagnostic
Pathology Division.
(1) Funata S, Matsusaka K, Yamanaka R, Yamamoto
S, Okabe A, Fukuyo M, Aburatani H, Fukayama
M, Kaneda A. Histone modification alteration
coordinated with acquisition of promoter DNA
methylation during Epstein-Barr virus infection.
Oncotarget. 2017, 8(33), 55265-79.
(2) Inaki R, Abe M, Zong L, Abe T,
Shinozaki-Ushiku A, Ushiku T, Hoshi K.
Secretory carcinoma - impact of translocation andgene fusions on salivary gland tumor. Chin J
Cancer Res. 2017, 29(5), 379-84.
(3) Ishihara S, Kawai K, Tanaka T, Kiyomatsu T,
Hata K, Nozawa H, Morikawa T, Watanabe T.
Oncological outcomes of lateral pelvic lymph
node metastasis in rectal cancer treated withpreoperative chemoradiotherapy. Dis Colon
Rectum. 2017;60(5):469-476.
(4) Kaneko MK, Yamada S, Nakamura T, Abe S,
Nishioka Y, Kunita A, Fukayama M, Fujii Y,
Ogasawara S, Kato Y. Antitumor activity of
chLpMab-2, a human-mouse chimeric cancerspecific antihuman podoplanin antibody, via
antibody- dependent cellular cytotoxicity. Cancer
Med. 2017, 6(4), 768-77.
(5) Kaneko MK, Kunita A, Yamada S, Nakamura T,
Yanaka M, Saidoh N, Chang YW, Handa S,
Ogasawara S, Ohishi T, Abe S, Itai S, Harada H,
Kawada M, Nishioka Y, Fukayama M, Kato Y.
Antipodocalyxin antibody chPcMab-47 exerts
antitumor activity in mouse xenograft models ofcolorectal adenocarcinomas. Monoclon AntibImmunodiagn Immunother. 2017, 36(4), 157-162.
(6) Kaneko MK, Nakamura T, Kunita A, Fukayama
M, Abe S, Nishioka Y, Yamada S, Yanaka M,
Saidoh N, Yoshida K, Fujii Y, Ogasawara S, Kato
Y. ChLpMab-23: cancer-specific human-mousechimeric anti-podoplanin antibody exhibits antitumor activity via antibody- Dependent cellularcytotoxicity. Monoclon Antib Immunodiagn
Immunother. 2017, 36(3), 104-112.
(7) Katoh H, Komura D, Konishi H, Suzuki R,
Yamamoto A, Kakiuchi M, Sato R, Ushiku T,

41

Yamamoto S, Tatsuno K, Oshima T, Nomura S,
Seto Y, Fukayama M, Aburatani H, Ishikawa S.
Immunogenetic profiling for gastric cancers
identifies sulfated glycosaminoglycans as major
and functional B cell antigens in humanmalignancies. Cell Rep. 2017, 20(5), 1073-1087.
(8) Kawai K, Ishihara S, Nozawa H, Hata K,
Kiyomatsu T, Morikawa T, Fukayama M,
Watanabe T. Prediction of pathological complete
response using endoscopic findings and outcomesof patients who underwent watchful waiting after
chemoradiotherapy for rectal cancer. Dis Colon
Rectum. 2017;60(4):368-375.
(9) Kawazu M, Kojima S, Ueno T, Totoki Y,
Nakamura H, Kunita A, Qu W, Yoshimura J,
Soda M, Yasuda T, Hama N, Saito-Adachi M,
Sato K, Kohsaka S, Sai E, Ikemura M, Yamamoto
S, Ogawa T, Fukayama M, Tada K, Seto Y,
Morishita S, Hazama S, Shibata T, Yamashita Y,
Mano H. Integrative analysis of genomic
alterations in triple-negative breast cancer inassociation with homologous recombination
deficiency. PLoS Genet. 2017, 13(6), e1006853.
(10) Ishibashi Y, Ohtsu H, Ikemura M, Kikuchi Y,
Niwa T, Nishioka K, Uchida Y, Miura H, Aikou S,
Gunji T, Matsuhashi N, Ohmoto Y, Sasaki T, Seto
Y, Ogawa T, Tada K, Nomura S. Serum TFF1 andTFF3 but not TFF2 are higher in women withbreast cancer than in women without breast cancer.
Sci Rep. 2017;7(1):4846.
(11) Koyama Y, Morikawa T, Miyakawa J, Miyama Y,
Nakagawa T, Homma Y, Fukayama M.
Diagnostic utility of Ki-67 immunohistochemistryin small endoscopic biopsies of the ureter andrenal pelvis. Pathol Res Pract. 2017;213(7):737741.
(12) Makise N, Yoshida A, Komiyama M, Nakatani F,
Yonemori K, Kawai A, Fukayama M, Hiraoka N.
Dedifferentiated Liposarcoma With Epithelioid/
Epithelial Features. Am J Surg Pathol. 2017,41(11), 1523-1531.
(13) Manley BJ, Zabor EC, Casuscelli J, Tennenbaum
DM, Redzematovic A, Becerra MF, Benfante N,
Sato Y, Morikawa T, Kume H, Fukayama M,
Homma Y, Ogawa S, Arcila ME, Voss MH,
Feldman DR, Coleman JA, Reuter VE, Motzer RJ,
Russo P, Hsieh JJ, Hakimi AA. Integration of

Recurrent Somatic Mutations with Clinical
Outcomes: A Pooled Analysis of 1049 Patientswith Clear Cell Renal Cell Carcinoma. Eur Urol
Focus. 2017;3(4-5):421-427.
(14) Matsusaka K, Funata S, Fukuyo M, Seto Y,
Aburatani H, Fukayama M, Kaneda A.
Epstein-Barr virus infection induces genome-wide
de novo DNA methylation in non-neoplastic
gastric epithelial cells. J Pathol. 2017, 242(4),391-399.
(15) Matsubara D, Soda M, Yoshimoto T, Amano Y,
Sakuma Y, Yamato A, Ueno T, Kojima S,
Shibano T, Hosono Y, Kawazu M, Yamashita Y,
Endo S, Hagiwara K, Fukayama M, Takahashi T,
Mano H, Niki T. Inactivating mutations andhypermethylation of the NKX2-1/TTF-1 gene in
non-terminal
respiratory
unit-typelungadenocarcinomas. Cancer Sci. 2017, 108(9),1888-1896.
(16) Mine S, Hishima T, Suganuma A, Fukumoto H,
Sato Y, Kataoka M, Sekizuka T, Kuroda M,
Suzuki T, Hasegawa H, Fukayama M, Katano H.
Interleukin-6- dependent growth in a newly
established plasmablastic lymphoma cell line andits therapeutic targets. Sci Rep. 2017, 7(1), 10188.
(17) Misumi K, Hayashi A, Shibahara J, Arita J,
Sakamoto Y, Hasegawa K, Kokudo N, Fukayama
M. Intrahepatic cholangio- carcinoma frequently
shows loss of BAP1 and PBRM1 expression, anddemonstrates specific clinicopathological andgenetic characteristics with BAP1 loss.
Histopathology. 2017, 70(5), 766-774.
(18) Miyakawa J, Morikawa T, Miyama Y, Nakagawa
T, Kawai T, Homma Y, Fukayama M. Loss ofstromal antigen 2 (STAG2) expression in upper
urinary tract carcinoma: Differential prognostic
effect according to the Ki-67 proliferating Index.
Ann Surg Oncol. 2017, 24(13), 4059-66.
(19) Miyata Y, Ishizawa T, Kamiya M, Yamashita S,
Hasegawa K, Ushiku A, Shibahara J, Fukayama
M, Urano Y, Kokudo N. Intraoperative imaging of
hepatic cancers using γ-glutamyl- transpeptidasespecific fluorophore enabling real-time identification and estimation of recurrence. Sci Rep. 2017,
7(1), 3542.
(20) Nakano T, Kanai Y, Amano Y, Yoshimoto T,
Matsubara D, Shibano T, Tamura T, Oguni S,

42

Katashiba S, Ito T, Murakami Y, Fukayama M,
Murakami T, Endo S, Niki T. Establishment ofhighly metastatic KRAS mutant lung cancer cellsublines in long-term three-dimensional low
attachment cultures. PLoS One. 2017, 12(8),e0181342.
(21) Nakaoka HJ, Tanei Z, Hara T, Weng JS,
Kanamori A, Hayashi T, Sato H, Orimo A, Otsuji
K, Tada K, Morikawa T, Sasaki T, Fukayama M,
Seiki M, Murakami Y, Sakamoto T.
Mint3-mediated L1CAM expression in fibroblasts
promotes cancer cell proliferation via integrin
α5β1 and tumour growth. Oncogenesis. 2017, 6(5),e334.
(22) Nishioka Y, Shindoh J, Yoshioka R, Gonoi W,
Abe H, Okura N, Yoshida S, Sakamoto Y,
Hasegawa K, Fukayama M, Kokudo N. Clinicalimpact of preoperative chemo- therapy on
microscopic cancer spread surrounding colorectal
liver metastases. Ann Surg Oncol. 2017;24(8):2326-2333.
(23) Okabe A, Funata S, Matsusaka K, Namba H,
Fukuyo M, Rahmutulla B, Oshima M, Iwama A,
Fukayama M, Kaneda A. Regulation of tumour
related genes by dynamic epigenetic alteration atenhancer regions in gastric epithelial cells
infected by Epstein-Barr virus. Sci Rep. 2017,
7(1), 7924.
(24) Oki S, Sone K, Oda K, Hamamoto R, Ikemura M,
Maeda D, Takeuchi M, Tanikawa M,
Mori-Uchino M, Nagasaka K, Miyasaka A,
Kashiyama T, Ikeda Y, Arimoto T, Kuramoto H,
Wada-Hiraike O, Kawana K, Fukayama M, Osuga
Y, Fujii T. Oncogenic histone methyltransferase
EZH2: A novel prognostic marker withtherapeutic potential in endometrial cancer.
Oncotarget. 2017, 8(25), 40402-40411.
(25) Okuma H, Gonoi W, Ishida M, Shirota G, Kanno
S, Shintani Y, Abe H, Fukayama M, Ohtomo K.
Comparison of the cardiothoracic ratio between
postmortem
andantemortem
computed
tomography. Leg Med (Tokyo). 2017, 24, 86-91.
(26) Otsuji K, Sasaki T, Tanaka A, Kunita A, Ikemura
M, Matsusaka K, Tada K, Fukayama M, Seto Y.
Use of droplet digital PCR for quantitative andautomatic analysis of the HER2 status in breast

cancer patients. Breast Cancer Res Treat. 2017,
162(1), 11-18.
(27) Saito R, Abe H, Kunita A, Yamashita H, Seto Y,
Fukayama M. Overexpression and gene
amplification of PD-L1 in cancer cells andPD-L1(+) immune cells in Epstein-Barrvirus-associated gastric cancer: the prognostic
implications. Mod Pathol. 2017, 30(3), 427-439.
(28) Sakuramachi M, Igaki H, Ikemura M, Yamashita
H, Okuma K, Sekiya N, Hayakawa Y, Sakumi A,
Takahashi W, Hasegawa H, Fukayama M,
Nakagawa K. Detection of residual metastatic
tumor in the brain following Gamma Knife
radiosurgery using a single or a series of magnetic
resonance imaging scans: An autopsy study.
Oncol Lett. 2017, 14(2), 2033-40.
(29) Shinozaki-Ushiku A, Ushiku T, Morita S, Anraku
M, Nakajima J, Fukayama M. Diagnostic utilityof BAP1 and EZH2 expression in malignant
mesothelioma. Histopathology. 2017, 70(5), 722733.
(30) Shintani-Domoto Y, Hayasaka T, Maeda D,
Masaki N, Ito TK, Sakuma K, Tanaka M,
Kabashima K, Takei S, Setou M, Fukayama M.
Different desmin peptides are distinctly depositedin cytoplasmic aggregations and cytoplasm ofdesmin-related cardiomyopathy patients. Biochim
Biophys Acta. 2017, 1865(7), 828-36.
(31) Shirota G, Gonoi W, Ikemura M, Ishida M,
Shintani Y, Abe H, Fukayama M, Higashida T,
Okuma H, Abe O. The pseudo-SAH sign: an
imaging pitfall in postmortem computed
tomography. Int J Legal Med. 2017, 131(6), 16471653.
(32) Tabata K, Mori I, Sasaki T, Itoh T, Shiraishi T,
Yoshimi N, Maeda I, Harada O, Taniyama K,
Taniyama D, Watanabe M, Mikami Y, Sato S,
Kashima Y, Fujimura S, Fukuoka J. Whole-slide
imaging at primary pathological diagnosis:
Validation of whole-slide imaging-based primarypathological diagnosis at twelve Japanese
academic institutes. Pathol Int. 2017, 67(11), 54754.
(33) Tanaka M, Ishikawa S, Ushiku T, Morikawa T,
Isagawa T, Yamagishi M, Yamamoto H, Katoh H,
Takeshita K, Arita J, Sakamoto Y, Hasegawa K,
Kokudo N, Fukayama M. EVI1 modulates

43

oncogenic role of GPC1 in pancreatic carcinogenesis. Oncotarget. 2017, 8(59), 99552-66.
(34) Yamamoto M, Akamatsu N, Hayashi A, Togashi J,
Sakamoto Y, Tamura S, Hasegawa K, Fukayama
M, Makuuchi M, Kokudo N. Safety and efficacy
of venous reconstruction in liver resection using
cryopreserved homologous veins. J Hepatobiliary
Pancreat Sci. 2017, 24(9), 511-19.
(35) Yamazawa S, Ushiku T, Shinozaki-Ushiku A,
Hayashi A, Iwasaki A, Abe H, Tagashira A,
Yamashita H, Seto Y, Aburatani H, Fukayama M.
Gastric cancer with primitive enterocyte phenotype: An aggressive subgroup of intestinal-typeadenocarcinoma. Am J Surg Pathol. 2017, 41(7),989-97.
(36) Yasaka K, Akai H, Nojima M, Shinozaki-Ushiku
A, Fukayama M, Nakajima J, Ohtomo K, Kiryu S.
Quantitative computed tomography texture
analysis for estimating histological subtypes ofthymic epithelial tumors. Eur J Radiol. 2017, 92,
84-92.
(37) Yoshida Y, Nitadori JI, Shinozaki-Ushiku A, SatoJ, Miyaji T, Yamaguchi T, Fukayama M,
Nakajima J. Micropapillary histological subtype
in lung adenocarcinoma of 2 cm or less: impact onrecurrence and clinical predictors. Gen Thorac
Cardiovasc Surg. 2017, 65(5), 273-9.

44

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

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

Project Associate Professor
Shogo Ehata, M.D., Ph.D.

Assistant Professors
Masato Morikawa, M.D., Ph.D.
Yoko Katsuno, 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 March
2018, the Department consists of a professor, anassociate professor, a project associate professor, two
assistant professors, technical assistants, and someresearch fellows, including 5 graduate students, amaster course student, and five 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 we believe itvery important for medical students to study basic
oncology, we teach a basic tumor biology course in
our lectures of General Pathology. In addition, weoffer several laboratory courses for students frommolecular pathological points of view.

We also supervise research activities of the graduate
students of the Department. Our laboratory is locatedat the 11th floor at the Research Building of Graduate
School of Medicine. The laboratory is very convenientfor doing research, because most of the experiments
can be done at this floor. We have “Progress Meeting”
twice a month and “Monday Seminar” once a month.
We have been doing collaboration with the Ludwig
Institute for Cancer Research, Uppsala, Sweden for
more than 20 years (http://c2ctgfb.umin.jp/). We haveannual TGF-β meeting in Sweden or in the
Netherlands every year, and four graduate students
participated in the TGF-β meeting in Uppsala in 2017.
Three of our graduate students are supported by the
GPLLI Graduate Program for Leaders in Life
Innovation at the University of Tokyo from the
Ministry of Education, Culture, Sports, Science andTechnology, Japan (MEXT). GPLLI was designed forthe purpose of guiding outstanding students to be
globally active leaders in industry, academia andgovernment. This program also stimulates interaction
between students and scientists in the program as wellas those from other laboratories (http://square.umin.
ac.jp/gplli/).

45

Research activities
Our major research interest is to elucidate how
members of the TGF-β (transforming growth factor-β)family transduce signals, and how they regulate
growth, differentiation, and apoptosis of various cells.
From 2015, our research is mainly supported by aGrant-in-Aid for Scientific Research (S) on“Transcriptional regulation by TGF-β signaling and its
relation to progression of cancer” (15H05774) fromthe Japanese Society for the Promotion of Science(JSPS). From 2017, our research is also supported by
a Grant-in-Aid for Scientific Research on Innovative
Area on Integrated Analysis and Regulation of
Cellular Diversity (17H06326) from MEXT.
In collaboration with Rik Derynck at University ofCalifornia, San Francisco (UCSF), Kohei Miyazonoedited and published a book “The Biology of the
TGF-β Family” (35 chapters) as Cold Spring Harbor
Perspectives in Biology.
Dynamics of chromatin accessibility during
TGF-β-induced EMT of Ras-transformed mammary
epithelial cells: TGF-β regulates various cellularresponses, including growth arrest, cell differentiation,
apoptosis, cell motility, and extracellular matrix
production. Abnormalities of TGF-β signaling isrelated to various diseases. Epithelial-mesenchymaltransition (EMT) is a crucial cell differentiation
process in which epithelial cells functionally andmorphologically differentiate into mesenchymal cells.
EMT is induced by TGF-β as well as by othercytokines, and it facilitates tumor progression. EMT is
accompanied by reduced expression of epithelial
markers, including E-cadherin and epithelial splicing
regulatory protein 2 (ESRP2), and upregulation of theexpression of mesenchymal markers, including
N-cadherin, fibronectin, and α-smooth muscle actin(α-SMA). Cells become spindle-shaped with increased
motility and actin stress fiber formation.
We performed global mapping of accessible
chromatin regions in the mouse mammary glandepithelial cell line (EpH4) and its Ras-transformedderivative cell line (EpRas) using formaldehydeassisted isolation of regulatory element (FAIRE)sequencing. It allowed us to analyze the mechanismsof transcriptional regulation during TGF-β-induced

EMT. TGF-β and Ras altered chromatin accessibility
either cooperatively or independently, and sometranscription factor binding motifs, such as AP1, ETS,
and RUNX binding motifs, were enriched in theaccessible chromatin regions of EpH4 and EpRas cells.
Etv4, an ETS family oncogenic transcription factor,
was strongly expressed and bound to more than 30%of the accessible chromatin regions in EpRas cells
treated with TGF-β. Our findings suggested amechanism of transcriptional regulation during Rasand TGF-β-induced EMT that involves alterations ofaccessible chromatin regions, which are partly
regulated by Etv4 and its related protein, Etv5 incancer cells (Arase et al. Scientific Reports 2017).
Bone morphogenetic protein signaling mediated by
ALK-2 and DLX2 regulates apoptosis in gliomainitiating cells: Glioblastoma multiforme is the mostmalignant form of adult brain tumor. A major sourceof recurrence is glioma-initiating cells (GICs), which
are neural stem-like cells expressing markers such as
Olig2, Sox2 and Nestin. Bone morphogenetic proteins(BMPs) are members of the TGF-β family, which
control various biological processes. Recent findings
revealed that BMP signaling has crucial roles in the
progression of multiple cancers. Since BMPs induce
differentiation and apoptosis of GICs, BMP signaling
has been considered as a potential therapeutic target inglioblastoma.
We have shown that of the three different BMP type
I receptors expressed in GICs, ALK-2 (encoded by the
ACVR1 gene) has crucial roles in apoptosis inductionof patient-derived GICs. We also searched for some
BMP target genes; of those, Distal-less homeobox 2(DLX2), promoted apoptosis and neural differentiation of GICs. The tumor-suppressive effects of ALK-2
and DLX2 were further confirmed in an orthotopic
transplantation model using nude mice. Interestingly,
valproic acid (VPA), an anti-epileptic compound,induced BMP2, BMP4, ACVR1 and DLX2 mRNA
expression with increased phosphorylation of
Smad1/5, which are signaling molecules downstreamof the BMP signaling pathway. Accordingly, wedemonstrated that VPA treatment induced apoptosis of
GICs, whereas knockdown of ALK-2 or DLX2
expression partially suppressed it. Our study thus
indicated potential roles of BMP signaling via ALK-2

46

and DLX2 in VPA-induced apoptosis of GICs (Raja etal. Oncogene 2017).
Autocrine BMP-4 signaling is a potential
therapeutic target in colorectal cancer: Colorectal
cancer is the third most common cancer and the fourthmost common cause of cancer-related death worldwide. Although colorectal cancer prognoses havesteadily improved, the 5-year survival rate remains
low, especially in patients with metastatic lesions.
We demonstrate that expression of BMP-4 isupregulated in human colorectal cancer cells andtissues through aberrant activation of the Wnt/βcatenin pathway, leading to activation of the BMP
signaling pathways. Colorectal cancer cells undergo
apoptosis following the inhibition of autocrine BMP-4
signaling by the BMP type I receptor inhibitor
LDN-193189. LDN-193189 induces apoptosis ofcolorectal cancer cells through the elevated expressionof the phosphatase DUSP5 and dephosphorylation of
Erk MAPK. Administration of LDN-193189 to mice
suppressed tumor formation of colorectal cancer cells
in vivo. Our findings suggested that inhibition of
autocrine BMP-4 is a candidate treatment strategy forcolorectal cancer (Yokoyama et al. Cancer Research2017).
ZEB1-regulated inflammatory phenotype in breast
cancer cells: Zinc finger E-box binding protein 1(ZEB1) and ZEB2 are well-known transcriptional
regulators that induce EMT in various epithelial cells.
However, the global view of transcriptional regulation
by ZEB1 and ZEB2 have not been fully elucidated.
We identified a ZEB1-regulated inflammatory phenotype in several basal-type breast cancer cell lines
using chromatin immunoprecipitation sequencing(ChIP-seq) and RNA sequencing (RNA-seq), followed
by gene set enrichment analysis (GSEA) of ZEB1bound genes.
We found that ZEB1 upregulated the production of
inflammatory cytokines, including IL-6 and IL-8, inthe basal-type breast cancer cell lines MDA-231-D
and Hs578T. ZEB2 has similar functions with ZEB1
in terms of the regulation of production of
inflammatory cytokines. Antibody array and ELISA
experiments confirmed that ZEB1 controlled the
production of the IL-6 and IL-8 proteins. The

secretory proteins regulated by ZEB1 enhanced breast
cancer cell proliferation and tumor growth. ZEB1
expression in breast cancer cells also affected thegrowth of fibroblasts in vitro, and the accumulation of
myeloid-derived suppressor cells (MDSCs) in tumors
in vivo. Our findings suggested that ZEB1 promotes
the proliferation of cancer cells and contributes to theformation of the tumor microenvironment byregulating the expression of inflammatory cytokines.
The ZEB1-regulated inflammatory phenotype
identified in this study provides insights into amechanism that is critical for cancer progression(Katsura, Tamura et al. Molecular Oncology 2017).

References
1. Akatsu, Y., Yoshimatsu, Y., Tomizawa, T.,
Takahashi, K., Katsura, A., Miyazono, K., and
Watabe, T. (2017) Dual targeting of vascularendothelial growth factor and bone morphogenetic
protein-9/10 impairs tumor growth throughinhibition of angiogenesis. Cancer Science 108(1), 151-155.
2. Arase, M., Tamura, Y., Kawasaki, N., Isogaya, K.,
Nakaki, R., Mizutani, A., Tsutsumi, S., Aburatani,
H., Miyazono, K., and Koinuma, D. (2017)
Dynamics of chromatin accessibility during
TGF--induced
EMTof
Ras-transformed
mammary gland epithelial cells. Scientific Reports
7 (1), 1166.
3. Suzuki, H. I., Katsura, A., Mihira, H., Horie, M.,
Saito, A., and Miyazono, K. (2017) Regulation of
TGF--mediated endothelial-mesenchymal transition by microRNA-27. Journal of Biochemistry
161 (5), 417-420.
4. Raja, E., Komuro, A., Tanabe, R., Sakai, S., Ino,
Y., Saito, N., Todo, T., Morikawa, M., Aburatani,
H., Koinuma, D., Iwata, C., and Miyazono, K.
(2017) Bone morphogenetic protein signaling
mediated by ALK-2 and DLX2 regulates
apoptosis in glioma-initiating cells. Oncogene 36(35), 4963-4974.
5. Yokoyama, Y., Watanabe, T., Tamura, Y.,
Hashizume, Y., Miyazono, K., and Ehata, S.
(2017) Autocrine BMP-4 signaling is atherapeutic target in colorectal cancer. Cancer
Research 77 (15), 4026-4038.

47

6. Katsura, A., Tamura, Y., Hokari, S., Harada, M.,
Morikawa, M., Sakurai, T., Takahashi, K.,
Mizutani, A., Nishida, J., Yokoyama, Y., Morishita,Y., Murakami, T., Ehata, S., Miyazono, K., andKoinuma, D. (2017) ZEB1-regulated inflammatory phenotype in breast cancer cells.
Molecular Oncology 11 (9), 1241-1262.
7. Kubota, S.I., Takahashi, K., Nishida, J., Morishita,Y., Ehata, S., Tainaka, K., Miyazono, K., andUeda, H.R. (2017) Whole-body profiling ofcancer metastasis with single-cell resolution. Cell
Reports 20 (1), 236-250.
8. Kamiyama, M., Shirai, T., Tamura, S., SuzukiInoue, K., Ehata, S., Takahashi, K., Miyazono, K.,
Hayakawa, Y., Sato, T., Takeda, K., Naguro, I.,
and Ichijo, H. (2017) ASK1 facilitates tumor
metastasis through phosphorylation of an ADP
receptor P2Y12 in platelets. Cell Death andDifferentiation 24 (12), 2066-2076.
9. Derynck, R. and Miyazono, K., editors. (2017)
The Biology of the TGF-β Family. Cold Spring
Harbor Perspectives in Biology. pp. 1-1164.

Pathology, Immunology andMicrobiology
2. Microbiology

49

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

Lecturer
Naoko Kamiya, Ph.D.

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

Homepage

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

Introduction and Organization

Research

Professor emeritus Akio Nomoto who had been thechief of the Department retired in 2008 and moved to
Microbial Chemistry Research Foundation as the
Chairman of Board. From 2009, new Department ofMicrobiology started with Professor Masanori
Hatakeyama as the new chief. The present Department
consists of 25 members; 1 professor (Dr. Hatakeyama),
1 senior lecturer (Dr. Kamiya), 2 research associates(Drs. Takahashi and Hayashi), 1 project research
associate (Dr. Fujii), 4 post-doctoral fellows (Drs.
Nishikawa, Kikuchi, Tang, and Hashi), 2 academic
assistants (Ms. Shimada and Komatsu), 9 graduate
school students (Ms. and Mrs. Ooki, Nojima, Ben, Lu,
Knight, Inoue, Wada, Imai, Suzuki), and 5 research
students (Ms. and Mrs. Tahmina, Marrero, Wu, Wu,
He).

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

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

50

1. Structural basis for carcinogenic activity of
Helicobacter pylori
Most if not all human gastric cancers are caused bychronic infection of the stomach lining with H. pylori
strains that possess the cagA gene. Intriguingly,
epidemiological studies have indicated that East
Asian CagA, a subtype of the CagA protein producedby H. pylori isolated in East Asia, is more involved in
the development of stomach cancer compared toWestern CagA, the standard CagA produced by H.
pylori found around the world except East Asia.
However, the molecular structural mechanisms
responsible for evoking the distinct carcinogenic
activities of these two CagA subtypes remained
unknown.
Upon delivery into gastric epithelial cells via typeIV secretion, CagA undergoes tyrosine phosphorylation by Src family kinases (SFKs) or c-Abl kinase at
the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif. Tyrosinephosphorylated CagA acquires the ability to
specifically bind to and aberrantly activate SHP2
tyrosine phosphatase, causing aberrant activation of
the Ras-Erk MAP kinase signaling pathway. SHP2 hasbeen recognized as a pro-oncogenic phosphatase, andactivating mutations of SHP2 have been found in avariety of human malignancies.
In the present study, we determined the threedimensional atomic structures of CagA complexedwith SHP using a method called X-ray crystal
structure analysis. We determined by comparing thecomplex structures of the East Asian and Western
CagA proteins that a variation in a single amino acidgreatly influences CagA's capability to bind to SHP2.
Furthermore, we found that the more robust SHP2binding of East Asian CagA, compared to that ofWestern CagA, significantly augments the enzymatic
activity of SHP2 and thereby strongly inducesaberrant cellular signals that promote gastric cells to
become cancerous. This work revealed the molecular
structural mechanisms of how East Asian CagA exerts
stronger carcinogenic activity amounting to the higher
risk in Japan for developing gastric cancer.

2. Impact of structural polymorphism for the
Helicobacter pylori CagA on binding topolarity-regulating kinase PAR1b
Once inside the host cells, H. pylori CagA also binds
to partitioning-defective 1b (PAR1b)/microtubule
affinity-regulating kinase 2 (MARK2) via the CagA
multimerization (CM) motif in a tyrosine
phosphorylation-independent
manner.
Throughcomplex formation, CagA inhibits kinase activity ofPAR1b, resulting in induction of junctional andpolarity defects. Notably, the polymorphism in the
CM motif has been identified among geographic
variants of CagA, differing in either the copy number
or the sequence composition.
Through quantitative analysis of the complex
formation between CagA and PAR1b, we found thatseveral CagA species have acquired elevatedPAR1b-binding activity via duplication of the CM
motifs, while others have lost their PAR1b-binding
activity. We also found that strength of CagA-PAR1b
interaction is proportional to the degrees of stressfiber formation and tight junctional disruption by
CagA in gastric epithelial cells. These results indicatethat the CM polymorphism is a determinant for themagnitude of pathophysiological actions of H. pylori
CagA. Therefore, the CM diversity may contribute to
the different disease manifestations caused by cagApositive H. pylori infection.
3. Parafibromin is a transcriptional coactivator of
the Wnt/Hedgehog/Notch pathways
The Wnt, Hedgehog (Hh) and Notch signaling
pathways are among only a handful of evolutionallyconserved morphogen pathways mediating embryonicdevelopment as well as homeostasis of adult tissues.
Nevertheless, mechanisms that intracellularly
coordinate these signal inputs remain poorly
understood.
Parafibromin is the human (mammalian) orthologueof budding yeast Cdc73, a component of the RNAPolymerase II (Pol II)-associated factor (PAF)
complex. Absence of, or mutation in, the PAF
components results in alterations in gene expressionthat can lead to deregulation of developmental
programs and loss of control of cell growth anddifferentiation, thereby predisposing to various
diseases including cancer. Here we found that

51

parafibromin competitively interacts with β-catenin
and Gli1, thereby potentiating transactivation of Wntand Hh-target genes in a mutually exclusive manner.
Parafibromin also binds to the Notch intracellulardomain (NICD), enabling concerted activation of
Wnt- and Notch-target genes. The transcriptional
platform function of parafibromin is potentiated bytyrosine dephosphorylation, mediated by SHP2
phosphatase, while it is attenuated by tyrosine
phosphorylation, mediated by PTK6 kinase.
Consequently, acute loss of parafibromin in micedisorganizes the normal epithelial architecture of theintestine, which requires coordinated activation/
inactivation of Wnt, Hh and/or Notch signaling. This
work revealed that multiple independent morphogen
signaling pathways converge on the transcriptional
platform parafibromin.

Publications
1. Shiroki, T., Yokoyama, M., Tanuma, N., Maejima,R., Tamai, K., Yamaguchi, K., Oikawa, T.,
Noguchi, T., Miura, K., Fujiya, T., Shima, H.,
Sato, I., Murata-Kamiya, N., Hatakeyama, M.,
Iijima, K., Shimosegawa, T., Satoh, K. The
enhanced expression of PKM2 is involved in thegastric cancer development via regulating cancer
specific metabolism. Cancer Sci, 108(5): 931-940(2017)
2. Nishikawa, H., Hatakeyama, M. Sequence
Polymorphism and Intrinsic Structural Disorder
as Related to Pathobiological Performance of the
Helicobacter pylori CagA Oncoprotein. Toxins
9(4), pii: E136 (2017)
3. Hatakeyama, M. Structure and function of
Helicobacter pylori CagA, the first-identified
bacterial protein involved in human cancer. Proc
Jpn Acad Ser B Phys Biol Sci 93(4): 196-219(2017)
4. Hayashi, T., Senda, M., Suzuki, N., Nishikawa, H.,
Ben, C., Tang, C., Nagase, L., Inoue, K., Senda, T.,
Hatakeyama, M. Differential mechanisms for
SHP2 binding and activation are exploited bygeographically distinct Helicobacter pylori CagA
oncoproteins. Cell Reports 20(12): 2879-90(2017)

52

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

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

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

Homepage

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

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

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

Education
We have been charged for education of undergraduate
students on the course of medicine (lectures andpractical exercises on the infection control for the 4th
grade students). These lectures and exercises contain
subjects not only on the hospital infection but also on
clinical microbiology. We are also engaged in the
education of graduate students as well as hospital
staff.
For postgraduate education, we have been committed
to the guidance for new postgraduates and residents on

53

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

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

Publications
1.

2.

3.

Tsutsumi T, Okushin K, Enooku K, Fujinaga H,
Moriya K, Yotsuyanagi H, Aizaki H, Suzuki T,
Matsuura Y, Koike K. Nonstructural 5A Proteinof Hepatitis C Virus Interferes with Toll-Like
Receptor Signaling and Suppresses the Interferon
Response in Mouse Liver. PLoS One. 2017 Jan
20;12(1): e0170461.
Satoh N, Suzuki M, Nakamura M, Suzuki A,
Horita S, Seki G, Moriya K. Functional couplingof V-ATPase and CLC-5. World J Nephrol. 2017
Jan 6;6(1):14-20.
Ota Y, Yamada A, Kobayashi Y, Niikura R,
Shimpoh T, Narita A, Yoshida S, Suzuki N,
Watabe H, Hirata Y, Ishihara S, Sunami E,
Watanabe T, Koike K. Diagnostic capability ofcolon capsule endoscopy for advanced colorectal
cancer: A pilot study. Dig Endosc. 2017 Mar 10.

4.

Hatakeyama S, Ohama Y, Okazaki M, Nukui Y,
Moriya K. Antimicrobial susceptibility testing of
rapidly growing mycobacteria isolated in Japan.
BMC Infect Dis. 2017 Mar 7;17(1):197.
5. Kawaai K, Ando H, Satoh N, Yamada H, Ogawa
N, Hirose M, Mizutani A, Bonneau B, Seki G,
Mikoshiba K. Splicing variation of Long-IRBIT
determines the target selectivity of IRBIT family
proteins. Proc Natl Acad Sci U S A. 2017 Apr
11;114(15):3921-3926.
6. Kamei J, Yagihara Y, Kume H, Horiuchi T, Sato T,
Nakagawa T, Fujimura T, Fukuhara H, Moriya K,
Homma Y. Prevalence and characteristics of fecal
antimicrobial-resistant Escherichia coli in acohort of Japanese men undergoing prostatebiopsy. Int J Urol. 2017 Apr;24(4):295-300.
7. Tabuchi F, Matsumoto Y, Ishii M, Tatsuno K,
Okazaki M, Sato T, Moriya K, Sekimizu K.
D-cycloserine increases the effectiveness ofvancomycin against vancomycin-highly resistant
Staphylococcus aureus. J Antibiot (Tokyo). 2017
Jul;70(8):907-910.
8. Kanno Y, Wakabayashi Y, Ikeda M, Tatsuno K,
Misawa Y, Sato T, Yanagimoto S, Okugawa S,
Moriya K, Yotsuyanagi H. Catheter-related
bloodstream infection caused by Kodamaea
ohmeri: A case report and literature review. J
Infect Chemother. 2017 Jun;23(6):410-414.
9. Tabuchi F, Matsumoto Y, Ishii M, Tatsuno K,
Okazaki M, Sato T, Moriya K, Sekimizu K.
Synergistic effects of vancomycin and β-lactams
against vancomycin highly resistant Staphylococcus aureus. J Antibiot (Tokyo). 2017 Jun;70(6):771-774.
10. Yamaguchi D, Kodashima S, Fujishiro M, Ono S,
Niimi K, Mochizuki S, Tsuji Y, Asada-Hirayama
I, Sakaguchi Y, Shichijo S, Minatsuki C,
Yamamichi N, Koike K. Evaluation of imageenhanced endoscopic technology using advanced
diagnostic endoscopy for the detection of earlygastric cancer: a pilot study. Endosc Int Open.
2017 Sep;5(9):E825-E833.
11. Ota Y, Yamada A, Kobayashi Y, Niikura R,
Shimpoh T, Narita A, Yoshida S, Suzuki N,
Watabe H, Hirata Y, Ishihara S, Sunami E,
Watanabe T, Koike K. Diagnostic capability ofcolon capsule endoscopy for advanced colorectal

54

12.

13.

14.

15.

16.

17.

18.

cancer: A pilot study. Dig Endosc. 2017 Sep;
29(6):695-701.
Yamaguchi D, Kodashima S, Fujishiro M, Ono S,
Niimi K, Mochizuki S, Tsuji Y, Asada-Hirayama
I, Sakaguchi Y, Shichijo S, Minatsuki C,
Yamamichi N, Koike K. Erratum: Evaluation ofimage-enhanced endoscopic technology using
advanced diagnostic endoscopy for the detectionof early gastric cancer: a pilot study. Endosc Int
Open. 2017 Sep;5(9):C2.
Satoh N, Nakamura M, Suzuki A, Tsukada H,
Horita S, Suzuki M, Moriya K, Seki G.Effects of
Nitric Oxide on Renal Proximal Tubular Na+
Transport. Biomed Res Int. 2017:687 1081.
Mizutani H, Ono S, Ohki D, Takeuchi C, Yakabi
S, Kataoka Y, Saito I, Sakaguchi Y, Minatsuki C,
Tsuji Y, Niimi K, Kodashima S, Yamamichi N,
Fujishiro M, Koike K. Recent Development ofTechniques and Devices in Colorectal Endoscopic Submucosal Dissection. Clin Endosc.
2017 Nov;50(6):562-568.
Matsuda K, Koya J, Toyama K, Ikeda M, Arai S,
Nakamura F, Okugawa S, Moriya K, Kurokawa
M. A therapeutic benefit of daptomycin against
glycopeptide-resistant gram-positive cocci bloodstream infections under neutropenia. J InfectChemother. 2017 Nov;23(11):788-790.
Kawaguchi Y, Sakamoto Y, Ito D, Ito K, Arita J,
Akamatsu N, Kaneko J, Hasegawa K, Moriya K,
Kokudo N. Statin use is associated with areduced risk of hepatocellular carcinoma recurrence after initial liver resection. Biosci Trends.
2017 Nov 20;11(5):574-580.
Hirano J, Okamoto T, Sugiyama Y, Suzuki T,
Kusakabe S, Tokunaga M, Fukuhara T, Sasai M,
Tougan T, Matsunaga Y, Yamashita K, Sakai Y,
Yamamoto M, Horii T, Standley DM, Moriishi K,
Moriya K, Koike K, Matsuura Y. Characterization of SPP inhibitors suppressing propagationof HCV and protozoa. Proc Natl Acad Sci U S A.
2017 Dec 12;114(50):E10782-E10791.
Morita K, Honda A, Koya J, Toyama K, Ikeda M,
Misawa Y, Okugawa S, Nakamura F, Moriya K,
Kurokawa M. Three cases of Candida fermentati
fungemia following hematopoietic stem celltransplantation. J Infect Chemother. 2018 Jan 19.
pii: S1341-321X(17)30316-1.

19. Aoki K, Harada S, Yahara K, Ishii Y, Motooka D,
Nakamura S, Akeda Y, Iida T, Tomono K, Iwata S,
Moriya K, Tateda K. Molecular Characterizationof IMP-1-Producing Enterobacter cloacae
Complex Isolates in Tokyo. Antimicrob Agents
Chemother. 2018 Feb 23;62(3). pii: e02091-17.
20. Araoka H, Baba M, Okada C, Kimura M, Sato T,
Yatomi Y, Moriya K, Yoneyama A. First evidenceof bacterial translocation from the intestinal tract
as a route of Helicobacter cinaedi bacteremia.
Helicobacter. 2018 Feb;23(1).
21. Araoka H, Baba M, Okada C, Kimura M, Sato T,
Yatomi Y, Moriya K, Yoneyama A. Risk factors
for recurrent Helicobacter cinaedi bacteremia andthe efficacy of selective digestive decontamination with kanamycin to prevent recurrence. Clin
Infect Dis. 2018 Feb 15.
22. Ohki D, Tsuji Y, Shinozaki T, Sakaguchi Y,
Minatsuki C, Kinoshita H, Niimi K, Ono S,
Hayakawa Y, Yoshida S, Yamada A, Kodashima S,
Yamamichi N, Hirata Y, Ushiku T, Fujishiro M,
Fukayama M, Koike K. Sessile serrated adenoma
detection rate is correlated with adenoma
detection rate. World J Gastrointest Oncol. 2018
Mar 15;10(3):82-90.
23. Yokoyama A, Kage H, Ohama Y, Sato T,
Miyashita N, Noguchi S, Okugawa S, Yamauchi
Y, Moriya K, Nagase T. Mycobacterium
heckeshornense lung infection diagnosed bymatrix-assisted laser desorption ionization-timeof flight mass spectrometry (MALDI-TOF MS). JInfect Chemother. 2018 Mar 1. pii: S1341321X(18)30047-3.

Pathology, Immunology andMicrobiology
3. Immunology

56

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

Associate Professor
Takeshi Nitta, Ph.D.

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

Homepage

http://www.osteoimmunology.com/

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

Teaching activities
All members of our department take very seriously
their responsibilities to teach and train the next
generation of scientists. Undergraduate students of thefaculty take part in departmental class work throughlectures on immunobiology, immunochemistry andmolecular immunology as well as practical training by
way of laboratory courses on basic immunology
experimental techniques. The education of graduate
students is based on weekly seminars where students
present the progress of their own research projects,
discuss the future directions of their research and theresearch of others, and are exposed to the latest
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 2017, special
lectures for undergraduate students were given byinternationally recognized scientists, Dr. Shimon
Sakaguchi (Osaka Univ.), Dr. Hajime Karasuyama(Tokyo Medical and Dental Univ.), Dr. Hiroshi
Kawamoto (Kyoto Univ.), and Dr. Tadatsugu
Taniguchi (The Univ. of Tokyo).

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

57

study is to develop epoch-making strategies for thetreatment of immune disorders such as autoimmune
diseases and severe infectious diseases.
1) Osteoimmuology
The bone marrow is a primary lymphoid organ thatplays a critical role in immune cell development. The
crucial stromal cell types that support hematopoietic
cell development in the bone marrow have not beenclarified. We reported the crucial role of osteoblasts insupporting lymphoid lineage development within thebone marrow microenvironment (Terashima et al.,Immunity. 2016). The mice genetically ablated forosteoblasts exhibited a marked reduction of thenumber of common lymphoid progenitor cells in thebone marrow and mature lymphocytes in the periphery.
Our results showed that osteoblasts play a pivotal rolein maintenance of common lymphoid progenitors
through the production of IL-7. Furthermore, using amouse model of sepsis, we showed that sepsis rapidly
ablated osteoblasts, which reduced the common
lymphoid progenitor number and thereby resulted inperipheral lymphopenia. This study demonstrates areciprocal interaction between the immune and bonesystems, in which acute inflammation induces a defectin bone cells resulting in lymphopenia-associatedimmunodeficiency, suggesting that osteoblasts are apotential therapeutic target of the treatment ofinflammatory diseases.
Osteoclasts are polynuclear cells derived from themonocyte/macrophage lineage, which are responsible
for bone resorption. Aberrant osteoclast function anddevelopment is involved in the pathogenesis of several
diseases such as the inflammatory bone destruction
observed in rheumatoid arthritis as well as postmenopausal osteoporosis and osteopetrosis. Osteoclast
development is dependent on TNF family cytokine
receptor activator of nuclear factor kappa-B ligand(RANKL). We studied the receptor signal transduction
pathway for RANKL and identified nuclear factor of
activated T cells c1 (NFATc1) as a master regulator for
osteoclast differentiation (Takayanagi et al., Dev Cell.
2002; Asagiri et al., J. Exp. Med., 2005). We also
identified an ITAM-harboring co-receptor for RANK
(Koga et al., Nature 2004) and the importance ofbridging signal cascade between RANK and ITAM
via Btk for RANK dependent osteoclastogenesis(Shinohara et al., Cell. 2008; Shinohara et al., Bone.
2014). Our recent proteomic analysis identified
multiple target proteins phosphorylated upon
differentiation of osteoclasts (Sumiya et al., Biochem
Biophys Res Commun. 2015).
Furthermore, we have revealed the roles of
Semaphorin4D on osteoblast differentiation (NegishiKoga et al., Nature Med. 2011) and Semaphorin3A on
inhibition of bone resorption as well as promotion ofbone formation (Hayashi et al., Nature 2012). We also
found that immune complexes in serum activate
osteoclastogenesis and cause bone loss throughbinding to Fc receptors (Negishi-Koga et al., Nat
Commun. 2015). Regarding osteoclast-inducing
factors, we examined the physiological significance oflysil oxidase (LOX), the enzyme that was previously
reported to be an osteoclast inducer (Tsukasaki et al., J
Bone Miner Res. 2017). Our results demonstrated that
LOX failed to substitute for RANKL in inducing
osteoclastogenesis in vivo, while LOX facilitated theosteoclast differentiation by inducing RANKL
expression in bone marrow stromal cells.
Furthermore, we also reported that, using a bonefracture model in mouse, the cytokine IL-17 promotesbone fracture healing via osteoblastic bone formationand that T cells are the major source of IL-17
produced in the bone injury site (Ono et al., Nat
Commun. 2016). Although it has been known that
IL-17 enhances osteoclastic bone resorption in certain
pathological situations, our current results clearlyshow the promoting effect of IL-17 on boneformation,
Most recently, we found that oral bacteria promote
the conversion of Foxp3+T cells into Th17 cells(exFoxp3Th17 cells) in periodontitis which is one of
the most common infectious diseases. exFoxp3Th17
cells were found to be the most potent bone-damaging
T cells.
Interestingly, these bone-damaging
exFoxp3Th17 cells protect against oral bacteria in two
different ways. First, they elicit mucosal immune
responses mainly by the production of anti-bacterial
products. Second, they inhibit bacterial dissemination by removing the tooth. Thus, exFoxp3Th17
cells play a beneficial role in the host defense against
oral bacteria. This investigation highlighted the notionthat T-cell-mediated bone damage, which wasconsidered to be an adverse consequence of inflam-

58

mation, may have developed to contribute to hostdefense against oral bacteria
These findings provided a new paradigm forphysiological interaction between bone and immune
system.
2) Lymphocyte development and lymphoid tissue
microenvironment
Thymus is the primary lymphoid organ that
supports development of useful T cells (positive
selection) and eliminates self-reactive T cells(negative selection). The microenvironment of thethymus is mainly composed of thymic epithelial cells(TECs) that regulate selections of developing T cells(Nitta and Suzuki, Cell Mol Life Sci. 2016).
Recently we studied the human genetic variationsof the PSMB11 gene, which encodes 5t, a cortical
TEC (cTEC)-specific proteasome subunit that
regulates positive selection of CD8 T cells (Nitta et al.,Sci Immunol. 2017). PSMB11 is highly enriched fornucleotide changes (‘damaging’ variations) thatinterfere with protein function. The introduction of
PSMB11 ‘damaging’ variations into the mouse
genome by CRISPR/Cas9 genome editing revealed
that these variations affected the MHC class I-boundpeptide repertoire in cTECs and impaired the positive
selection of CD8 T cells in the thymus. One of the
PSMB11 polymorphisms, G49S, detected in theJapanese population at a high frequency, altered the
CD8 T cell repertoire in mice and was associated witha higher risk of Sjögren’s syndrome in humans. These
results suggested that, in addition to the MHC
haplotype, genetic variations of proteasome influence
T cell repertoire selection and susceptibility to
autoimmunity.
We also tried to decipher the T cell receptor (TCR)
signaling pathways that control T cell development(Muro et al., J Clin Invest. 2018). Our data showedthat the tyrosine kinase Syk is essential for TCR
signal transduction and development of IL-17producing T cells (T17) in the thymus. The SykdependentTCR signal induced the transcriptional
program toward the T17 lineage, through theactivation of the PI3K pathway. Moreover, T17dependent skin inflammation was attenuated in mice
deficient in Syk. These findings suggest that the
Syk-PI3K pathway might be a therapeutic target of

inflammatory diseases.
Much attention has been paid to the development
and function of the gut-associated lymphoid tissues(GALTs) and the symbiotic relationship between thegut microbiota and host immune system.
We
identified a previously unrecognized subset ofmesenchymal cells in the subepithelial dome of
GALTs (Nagashima et al., Nat Immunol. 2017).
These cells expressed high levels of RANKL anddirectly interacted with the gut epithelium to induce
microfold (M) cell differentiation and CCL20
expression. The deletion of RANKL in mesenchymal
cells impaired M cell-dependent antigen sampling,which resulted in a reduction in IgA production and adecrease in microbial diversity, indicating thatsubepithelial RANKL-expressing mesenchymal cells(M cell inducer (MCi) cells) are key players in themaintenance of host-microbe symbiosis. Furthermore,
we reported that Col6a1-Cre driver mice are useful tostudy the function of MCi cells (Nagashima et al.,Biochem Biophys Res Commun. 2017). Manipulationof MCi cells may provide a molecular basis for novel
treatments of intestinal diseases such as inflammatory
bowel disorders and infectious diseases.
3) 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 IBas an indispensable transcription
factor for Th17 cell differentiation (Okamoto et al.,Nature. 2010). However, in both RA and EAE models,effector mechanisms of Th17 cells have been unclear.
Recently, we identified a subset of Th17 cells thatrobustly produces IL-17 and RANKL and exacerbates
both inflammation and bone destruction in CIA mice.
Interestingly these Th17 cells are the progeny of CD4
T cells expressing Foxp3, a master regulator for
immunosuppressive Treg cells (Komatsu et al., Nat
Med. 2014). We also reported that RANKL producedby synovial fibroblasts is primarily responsible for theformation of bone-destructive osteoclasts in inflammatory arthritis. These results show that the targetingthese cells and/or molecules could be effective inpreventing bone destruction in RA (Danks et al., Ann
Rheum Dis. 2016).

59

To elucidate a role of RANKL on T cells, we
generated T cell-specific RANKL-deficient mice.
These mice were protected from EAE, a mouse modelof multiple sclerosis, due to an impairment of
infiltration of pathogenic T cells into the central
nervous system (CNS). RANKL on T cells stimulates
the chemokine production by astrocytes, leading to thechronic inflammation in the CNS. Pharmacologicalinhibition of RANKL prevented the development of
EAE, indicating that RANKL is a potential therapeutictarget for treatment of multiple sclerosis (Guerrini etal., Immunity. 2015).
We have also been studying the mechanism of T
cell tolerance induction, because a breakdown of T
cell tolerance induces autoimmune diseases. Selftolerance of T cells is primarily established during
their development in the thymic medulla, where
medullary thymic epithelial cells (mTECs) ectopically
express a variety of tissue-restricted antigens (TRAs)
and thereby TRA-reactive immature T cells aredeleted. It has been known that expression of a set of
TRAs is regulated by the transcriptional regulator Aire,although how the remaining TRAs are regulated has
been unclear. Recently, we identified a novel key
transcription factor Fezf2, which is highly expressedin mTECs and controls the expression of a large
fraction of Aire-independent TRAs (Takaba et al.,Cell. 2015). Mice lacking Fezf2 in mTECs exhibitedsevere autoimmune disorders in peripheral organs, andthe spectrum of autoimmunity in Fezf2-deficient micediffered from that in Aire-deficient mice. These
results indicate that two independent factors, Fezf2
and Aire, play non-redundant and mutually complementary roles in the TRA expression to ensure T cell
tolerance induction. This study represented an important advance in our understanding of the mechanisms
underlying the immune tolerance and autoimmune
diseases.

References
1. Nagashima K, Sawa S, Nitta T, Tsutsumi M,
Okamura T, Penninger JM, Nakashima T,
Takayanagi H. Identification of subepithelial
mesenchymal cells that induce IgA and diversify
gut microbiota. Nat Immunol.18(6):675-682(2017)

2. Nitta T, Kochi Y, Muro R, Tomofuji Y, Okamura T,
Murata S, Suzuki H, Sumida T, Yamamoto K,
TakayanagiH.
Humanthymoproteasomevariations influence CD8 T cell selection. Sci
Immunol. 2(12):eaan5165 (2017)
3. Nagashima K, Sawa S, Nitta T, Prados A,
Koliaraki V, Kollias G, Nakashima T, Takayanagi
H. Targeted deletion of RANKL in M cell inducer
cells by the Col6a1-Cre driver. Biochem Biophys
Res Commun. 493(1):437-443 (2017)
4. Muro R, Nitta T, Nakano K, Okamura T,
Takayanagi H, Suzuki H. γδTCR recruits the Syk/
PI3K axis to drive proinflammatory differentiation program. J Clin Invest.128(1):415-426(2018)
5. Tsukasaki M, Komatsu N, Nagashima K, Nitta T,
Pluemsakunthai W, Shukunami C, Iwakura Y,
Nakashima T, Okamoto K, Takayanagi H. Hostdefense against oral microbiota by bone-damaging
T cells. Nat Commun.9:701 (2018)
6. Okamoto K, Nakashima T, Shinohara M,
Negishi-Koga T, Komatsu N, Terashima A, Sawa
S, Nitta T, Takayanagi H. Osteoimmunology: theconceptual framework for unifying the immune
and skeletal systems. Physiol Rev. 97:1295-1349(2017)
7. Terashima A, Takayanagi H. Overview ofOsteoimmunology.
503-511(2018)

CalcifTissueInt.

102:

Radiology and Biomedical
Engineering
1. Radiology

61

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

Professor
Osamu Abe, M.D., Ph.D.

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

Lecturer
Hideomi Yamashita M.D., Ph.D., Jiro Sato, M.D., Takeyuki Watadani, M.D., Ph.D.,
Toshihiro Furuta, M.D., Ph.D., Masaki Katsura, M.D., Ph.D.

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

Assistant Professor
Shiori Amemiya, M.D., Ph.D., Takuya Arai, M.D., Mami Ogita, M.D., Naoki Okura, M.D.,
Kouhei Kamiya, M.D., Ph.D., Wataru Gonoi, M.D., Ph.D., Wataru Takahashi, M.D., Ph.D.,
Taku Tajima, M.D., Naotoshi Ishida, M.D., Ryousuke Takenaka, M.D., Ph.D.

Homepage

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

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

Clinical activities
Clinical services on Diagnostic Radiology, Nuclear
Medicine, and Radiation Oncology are provided in thecentralized Clinical Radiology Service Department incooperation with radiology technologists and nurses.

In the section of Diagnostic Radiology, all CT and
MRI examinations are monitored and reported bydiagnostic radiologists. Diagnostic radiologists, gastroenterologists and cardiologists mainly perform
interventional procedures.
In the section of Nuclear Medicine, two cyclotronsand several remote or processor-controlled automateddevices are installed, which facilitate standardized
procedures in the PET tracer production and theimplementation of GMP in PET related work. There
are two SPECT rooms and four PET rooms. These
nuclear imaging procedures are chiefly performed andreported by nuclear medicine physicians andcardiologists.
Each year, over 700 new patients receive radiation
therapy in the Radiation Oncology section. Highly
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62

are 12 beds in the Radiology ward, which are usuallyused for oncology patients receiving radiation therapy
and chemotherapy. Some of them are sometimes used
for patients receiving invasive diagnostic procedures
such as interventional radiology (IVR), angiography
and myelography. There are two special beds forradionuclide (RN) therapy in the same floor. In
addition, four beds are allotted to terminal care ward
located in the 14th floor.

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

Research activities
Research activities in our department include
clinical research, animal experiments and development of instruments as well as computer-based newtechnology. Diagnostic Radiology group in the department promotes research activities aiming at efficacy
improvement of diagnostic imaging and expansion of
its application. Multi-row detector helical computed
tomography (MDCT) enables us to take tomographic
images in a three-dimensional (3D) fashion. Using thedata acquired by MDCT, various kinds of diseases inalmost all parts of the body, from cerebral diseases tomusculoskeletal diseases, can be displayed in 3D
images. New 3D software developed in our
departments is now widely used in the field of thegastrointestinal tract, lung, and central nervous system.

In addition, we have opened a new laboratory section
named Image Computing and Analysis Laboratory
with invitation of a new staff from the Faculty ofEngineering, the University of Tokyo. This section
will contribute to development of novel software to
abstract clinically useful information from the 3D
imaging data more sophisticatedly. In the field ofmagnetic resonance (MR) imaging, MR digital subtraction angiography, perfusion imaging, and diffusion
tensor imaging are the foci of research. These
techniques are aggressively applied to the investigation of vascular and neoplastic diseases of the brain.
Radiation oncology group promotes research
projects in two major fields, one is physicalengineering such as the optimization of dose
distribution in the radiation therapy (RT) and the otheris reduction of injuries due to radiation exposure in
vitro and in vivo. This group pushes forward studies
mainly on a brain tumor, head and neck cancer,
esophageal cancer, uterine cervical cancer, prostatecancer in conformity with recent EBM in the clinicalstudy, and was active in studies of the physicalengineering traditionally and took a main role in thehighly precise radiation therapy of our country until
now. With the purpose of achieving precise external
irradiation, a new linear accelerator with multileaf
collimator systems was developed and installed,which is utilized mainly for non-coplanar radiation
therapy in many patients especially with brain tumor
or head and neck tumor. Dynamic conical conformal
radiotherapy for metastatic brain tumors using theaccelerator is under evaluation. In addition to gamma
knife radiosurgery, this new accelerator basedstereotactic radiotherapy for brain diseases has been
undergone, and stereotactic radiotherapy (SRT) for
body tumors, such as head and neck cancer, prostatecancer, rectal cancer and lung cancer, has been
investigated (intensity modulation radiation therapy;
IMRT) for the reduction of the adverse radiation
damage. A new technology to track mobile tumors,
represented by lung tumors is under investigation incollaboration with accelerator makers.
Nuclear Medicine group promotes clinical researchon functional imaging and the development ofradio-immunotherapy (RIT) by the application ofradioisotope-labeled tracer technology, combinedwith molecular biology. In particular, emission

63

tomography (PET and SPECT) is applied for theevaluation of cerebral blood flow and metabolism inpatients with dementia, epilepsy, and cerebrovasculardiseases. Cerebral blood flow, glucose metabolism andneural synaptic functions are measured for theunderstanding of normal and pathophysiological statesof CNS disorders, using a variety of positron-emitterradiotracer, such as [O-15] H2O, CO2, O2, CO, [F-18]
FDG, [C-11] methionine, [F-18] Dopa, [C-11] NMSP,NMPB, [C-11] raclopride and [C-11] PiB. The studyof dementia using SPECT and the standard brain atlas
has made it possible to categorize the type of dementia.
Evaluation of dopaminergic function by PET is very
important in the differential diagnosis of Parkinsonism.
Cardiac PET and SPECT are also active fields.
Myocardial viability, vascular reserve and sympathetic
nerve denervation in the ischemic heart disease are
evaluated with [F-18] FDG, [N-13] NH3, Tl-201 and[I-123] MIBG. Higher brain functions such as reading,speech and thinking have been studied with PET bycomparing blood flow and receptor binding potential(BP) under various tasks and at rest. For the precise
localization of activated brain function, computer
processing and reconstruction of composite images offunction and anatomy is an essential subject forinvestigation. At present, whole body FDG-PET is oneof the most effective tool for exploring metastatic
lesions of cancer patients. Combination display of
SPECT/PET with XCT/MRI would be a routine job
and anatomo-functional images would play animportant role in the clinical management of thepatients.

3.

4.

5.

6.

7.

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68

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Single-energy metal artifact reduction for helicalcomputed tomography of the pelvis in patientswith metal hip prostheses.
Jpn J Radiol 34(9): 625-32, 2016
76. Yoshida Y, Nitadori JI, Shinozaki-Ushiku A, SatoJ, Miyaji T, Yamaguchi T, Fukayama M, Nakajima
J.
Micropapillary histological subtype in lungadenocarcinoma of 2 cm or less: impact onrecurrence and clinical predictors.
Gen Thorac Cardiovasc Surg: Epub ahead of print,
2017
77. Yoshikawa N, Shimizu N, Uehara M, Oda A,
Matsumiya R, Matsubara E, Kobayashi H,
Hosono O, Kuribara-Souta A, Baba H, Nagamura
F, Kiryu S, Tanaka H.
The effects of bolus supplementation of branchedchain amino acids on skeletal muscle mass,strength, and function in patients with rheumatic
disorders during glucocorticoid treatment.
Mod Rheumatol: Epub ahead of print, 2016

Radiology and Biomedical
Engineering
2. Biomedical Engineering

70

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

Homepage

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

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

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

Research activities
This laboratory has been pursuing the study ofbiomechanics dealing with mechanical phenomena in
the human body, especially focusing on cellularsensing and response mechanisms to mechanicalstimuli. The main theme of our work is the relation-

ships between shear stress or cyclic strain, which arehemodynamic forces generated by blood flow, andtheir target cells, vascular endothelial cells (ECs). This
would be of benefit not only to understanding blood
flow-mediated regulation of vascular functions but
also to the elucidation of clinically important
problems such as angiogenesis, vascular remodeling,atherogenesis, and development of cerebral aneurysm
which occur in a blood flow-dependent manner.
Original biomedical engineering methods have been
applied, in which cultured ECs are exposed tocontrolled levels of shear stress or cyclic strain in a
fluid–dynamic flow apparatus and whose responses
are analyzed at the cellular and molecular levels.
Microcirculatory hemodynamics and oxygen transportof genetically modified mice are studied by employing
opto-electronics technology. The results of theseexperiments are listed below.
1. Cell responses to hemodynamic forces
2. Hemodynamic force-mediated gene regulation
3. Hemodynamic force-induced cell differentiation
4. Mechanosensing and mechanotransduction
1. Cell responses to hemodynamic forces
Our studies have demonstrated that ECs havefunctional responses to hemodynamic forces, shear
stress and cyclic strain. When a cultured EC
monolayer was partially denuded, surrounding cells
migrated and proliferated in the denuded area, andcovered the denuded area. Shear stress enhanced theregenerative functions of ECs. Shear stress increased
the production of nitric oxide, a potent vasodilator, in
ECs in a dose-dependent manner. Shear stress also
increased the expression of thrombomodulin, an
antithrombotic molecule, in ECs. In contrast, it71

decreased the expression of vascular cell adhesion,
which leads to the inhibition of leukocyte adhesion tovascular cell adhesion molecule-1 (VCAM-1). It was
shown that shear stress increases the levels of
adrenomedulin and C-type natriuretic peptide mRNA
which have vasodilating effects in addition to nitricoxide, and that it also augmented the expression oflectin like low density lipoprotein receptor (LOX-1) at
the protein and mRNA level.
2. Hemodynamic force-mediated gene regulation
We have demonstrated that shear stress regulates
endothelial gene expression transcriptionally and/or
posttranscriptionally. Shear stress downregulates
VCAM-1 gene transcription via the double AP-1
binding element (TGACTCA) in the promoter whichfunctions as a shear stress-responsive element. Shearstress has also been shown to increase the expression
level of granulocyte/macrophase-colony stimulating
factor (GM-CSF) via mRNA stabilization. Differential
display and DNA microarray analysis showed thataround 600 known and unknown transcripts were upor down-regulated in human umbilical vein ECs
exposed to a shear stress. From these shear stressresponsive genes, a cDNA encoding an unknown
G-protein coupled receptor was cloned. We showedthat the transcription factor SP1 is involved in theshear stress-induced down-regulation of P2X4 (anATP-gated cation channel) gene expression in ECs.
We also revealed that endothelial genes aredifferentially regulated by laminar and turbulent shear
stress. Laminar shear stress decreases the gene
expression of urokinase plasminogen activator (uPA),which plays a role in fibrinolysis and vascular remodeling, via both GATA6-mediated down-regulationof gene transcription and an acceleration of mRNAdegradation, while turbulent shear stress increases theuPA gene expression through mRNA stabilization. We
demonstrated that shear stress up-regulates the gene
expression of plasminogen activator inhibitor-1(PAI-1) through activation of transcription factors
Sp-1 and Ets-1 in human hepatocytes. We developed acompliant tube-type flow-loading device that allows
simultaneous application of physiological levels ofshear stress and cyclic strain to cultured cells andobserved that the response of endothelial genes toshear stress or cyclic strain depends on whether thetwo forces are applied separately or together.
3. Hemodynamic force-induced cell differentiation
We have revealed that endothelial progenitor cells(EPCs) circulating in human peripheral blood
proliferate and differentiate into mature ECs in
response to shear stress, thereby forming tube-likestructures in collagen gel. Moreover, we revealed thatshear stress increased the gene expression of thearterial EC marker ephrinB2 in EPCs, while itdecreased the gene expression of the venous EC
marker EphB4, suggesting that shear stress affects
arterial-venous differentiation of EPCs.
Embryonic stem (ES) cells have the potential todifferentiate into every cell type in the body, andattracting interest as a promising source of cells foruse in regenerative medicine. Embryonic cells are
exposed to fluid-mechanical forces, including shear
stress and the cyclic strain generated by beating heart
during the process of embryonic development. We
found that shear stress induces the differentiation ofmurine ES cells into vascular EC lineage in vitro;
cyclic strain induces the differentiation into vascularsmooth muscle cell (SMC) lineage. Differentiation
into the EC lineage and differentiation into SMC
lineage are mediated by ligand-independent
phosphorylation of vascular endothelial growth factor
receptor 2 (VEGFR2) and platelet derived growth
factor receptor (PDGFR), respectively. Moreover, ourstudy has shown that shear stress increases expressionof ephrinB2 in murine ES cells via the VEGF-Notch
signaling pathways, suggesting that shear stress canalso affect the arterial-venous differentiation of ES
cells. Based on these findings, in a collaborative study,
a new hybrid type of artificial blood vessel, in which
ES cells were cultured on the surface of polymer tubes
and exposed to pulsatile shear stress and cyclic strain,
was developed.
4. Mechanosensing and mechanotransduction
We were the first to show that Ca2+ signaling plays
an important role in the mechanism by which ECs
recognize the shear stress signal and transmit it into
the cell interior. Strong shearing forces induced by
dragging ECs with a balloon causes an increase in

72

cytoplasmic Ca2+ concentrations. A relatively weak
shearing force like shear stress generated by fluid flowneeds the presence of extracellular ATP to induce Ca2+
response, and at several hundred nanomolar of ATP,intracellular Ca2+ concentrations increase in a shear
stress-dependent manner. Generally, flow-induced
Ca2+ responses are initiated at a locus at the cell edge
and propagate throughout the entire cell in the form ofa Ca2+ wave. The initiation locus corresponded
precisely to caveolae rich cell edges. We found that a
subtype of ATP-gated cation channel, the P2X4
receptor, is expressed in human vascular ECs and that
P2X4 receptors play a crucial role in the shear stressdependent Ca2+ response. Endogeneously released
ATP by shear stress is involved in the P2X4-mediated
Ca2+ responses. We produced P2X4-deficient mice andobserved that the P2X4-deficent mice have impaired
flow-dependent control of vascular tone and remodeling, indicating that shear stress signal transduction via
P2X4 plays a critical role in the regulation of circulatory functions. Our study revealed that cell surface
ATP synthase localized in caveolae/lipid rafts are
involved in the shear-stress-induced ATP release by
ECs.
Moreover, we recently report that the plasma
membrane itself differentiates between shear stressand stretch by undergoing transitions in its lipid
phases. Shear stress decreased the lipid order ofhuman pulmonary artery EC plasma membranes,
thereby causing a transition from the liquid-orderedphase to the liquid-disordered phase in some areas,
along with an increase in membrane fluidity. In
contrast, uniaxial stretching and hypotonic swellingincreased the membrane lipid order and decreased
membrane fluidity. A similar increase in lipid orderoccurred when the artificial lipid bilayer membranesof giant unilamellar vesicles were stimulated by shear
stress by using a flow-loading apparatus or stretchedby hypotonic swelling, indicating that mechanicalforce-mediated responses of lipid membranes are
physical phenomena. The cholesterol content of EC
plasma membranes significantly decreased in response
to shear stress but clearly increased in response to
stretch. Blocking these changes in the membrane lipid
order by depleting membrane cholesterol with methyl-cyclodextrin or by adding cholesterol resulted in amarked inhibition of the EC response specific to shear

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

References
1. Nakajima H, Yamamoto K, Agarwala S, Terai K,
Fukui H, Fukuhara S, Ando K, Miyazaki T,
Yokota Y, Schmelzer E, Belting HG, Affolter M,
Lecaudey V, Mochizuki N. Flow-dependent
endothelial YAP regulation contributes to vessel
maintenance. Dev. Cell 40:523-536, 2017.
2. Yamamoto K and Ando J. “Shear stress sensing”
in Sokabe M (ed.). From Mechanobiology To
Mechanomedicine, Ishiyaku publishers, Tokyo,
pp 44-50, 2017.
3. Ando J and Yamamoto K. "Cell mechanotransduction and gene response" in Sato M (ed.).
Multiscale Mechanobiology in Cells. Morikita
Publishing, Tokyo, pp. 95-118, 2017.

73

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

Lecturer
Mako Kamiya, Ph.D.

Assistant Professor
Ryosuke Kojima, Ph.D.

Webpage

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

Introduction and Organization
The Laboratory of Chemical Biology and Molecular
Imaging is one of the laboratories in the department ofRadiology and Biomedical Engineering. Ourlaboratory is located in the annex of the medicalbuilding 3. Our lab members consist of 1 postdoctoral
researcher, 11 PhD students, 4 master course students
and one technical staff, as of FY2017.

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

Research activities
Our lab aims at developing novel fluorescenceprobes and applying these molecules to biology andmedicine. So far, we have succeeded in establishingrational design strategies of fluorescence probes basedon several mechanism including intramolecularspirocyclization. In FY2017, we have succeeded todevelop fluorescence probes for cancer detection,functional photosensitizers for selective cell ablation,and fluorescence probes suitable for super-resolution

microscopy.
As for cancer-imaging probes, we have developed ahepsine/matriptase-activated fluorescence probe,
aiming for detecting prostate cancers. By means offluorescence imaging of cancer cell lines and in vivo
cancer imaging using tumor-bearing mice models, wehave succeeded to develop a fluorescence probe thatcan effectively visualize prostate cancers (Reference1). Also, we have succeeded to develop a siliconrhodamine based near-infrared fluorescence probe for-glutamyltransferase (GGT) (Reference 2). Thisprobe has significantly longer absorption/emission
wavelengths than the GGT-activated green/yellow
fluorescence probes (gGlu-HMRG etc) that we
previously developed and proved their usefulness forvisualizing several kinds of cancers (e.g. breast
cancer) (Sci. Transl. Med. 3, 110ra119 (2011), etc).
This near-infrared fluorescence probe should enablehighly sensitive signal detection in vivo, as well as
multi-color imaging with fluorescence probes emitting
lights in different wavelengths.
As for functional photosensitizers, we havedeveloped a GGT-activated photosensitizer bychanging oxygen atom at 10 potition of the xanthenemoiety of gGlu-HMRG into selenium. By usingcancer cell lines, cancer-cell spheroids, andtumor-bearing chick chorioallantoic membrane(CAM) models, we have successfully showed that

74

selective ablation of GGT positive cancer cells can beachieved without damaging normal tissues (Reference3).
As for fluorescence probes for super-resolution
microscopy, we previously developed a spontaneously
blinking red fluorophore, HMSiR, by optimization of
the intramolecular nucleophile and rhodamine-based
fluorophore (electrophile) to provide a suitable life
time for the fluorescent open form and equilibrium
between the open form and the non-fluorescent closed
form (Nat. Chem. 6, 681-689 (2014)). This probe wasproven to be useful for single-molecule localization
microscopy imaging. In this fiscal year, we aimed to
expand the variety of the color of the fluorophore
while keeping the appropriate photochemical propertyof spontaneous blinking. Concretely, by optimizing
the atom to use for 10 position in the xanthene moiety,as well as substituents of amino groups in 3 and 6
positions, we developed a spontaneously blinking
fluorophore that can be excited with a 488 nm laserand emits green light. With this fluorophore, we havesuccessfully obtained 3D super-resolution images in amild condition without using thiols or oxygen
scavengers that are often required for super-resolution
imaging when using conventional fluorophores(Reference 4).

References
1. T. Yogo, K. Umezawa, M. Kamiya, R. Hino, Y.
Urano, Development of an activatable fluorescentprobe for prostate cancer imaging, Bioconjugate
Chem. 28 (2017) 2069-2076.
2. R.J. Iwatate, M. Kamiya, K. Umezawa, H.
Kashima, M. Nakadate, R. Kojima, Y. Urano,
Silicon rhodamine-based near-infrared fluorescentprobe for -Glutamyltransferase, Bioconjugate
Chem. 29 (2018) 241-244.
3. M. Chiba, Y. Ichikawa, M. Kamiya, T. Komatsu, T.
Ueno, K. Hanaoka, T. Nagano, N. Lange, Y.
Urano, An activatable photosensitizer targeted to-Glutamyltranspeptidase, Angew. Chem. Int. Ed.
56 (2017) 10418-10422.
4. S.N. Uno, M. Kamiya, A. Morozumi, Y. Urano, A
green-light-emitting, spontaneously blinking
fluorophore based on intramolecular spirocyclization for dual-colour super-resolution imaging,Chem. Commun. 54 (2017) 102-105.
5. M. Kawatani, M. Kamiya, H. Takahashi, Y. Urano,
Factors affecting the uncaging efficiency of 500
nm light-activatable BODIPY caging group,
Bioorg. Med. Chem. Lett. (2017) 28, 1-5.
6. Y. Kuriki, M. Kamiya, H. Kubo, T. Komatsu, T.
Ueno, R. Tachibana, K. Hayashi, K. Hanaoka, S.
Yamashita, T. Ishizawa, N. Kokudo, Y. Urano,
Establishment of molecular design strategy toobtain activatable fluorescent probes for carboxypeptidases, J. Am. Chem. Soc. 140 (2018) 17671773.
7. Y. Miyata, T. Ishizawa, M. Kamiya, S. Yamashita,
K. Hasegawa, A. Ushiku, J. Shibahara, M.
Fukayama, Y. Urano, N. Kokudo, Intraoperative
imagingofhepatic
cancersusing-glutamyltranspeptidase-specificfluorophoreenabling real-time identification and estimation ofrecurrence, Sci. Rep. 7 (2017) 3542.
8. T. Mizushima, S. Ohnishi, Y. Shimizu, Y.
Hatanaka, K.C. Hatanaka, Y. Kuriki, M. Kamiya,
A. Homma, K. Yamamoto, S. Ono, Y. Urano, N.
Sakamoto, Rapid detection of superficial head andneck squamous cell carcinoma by topicallyspraying fluorescent probe targeting dipeptidyl
peptidase-IV, Head Neck, 40 (2018) 1466-1475.
9. K. Okubo, M. Kurosawa, M. Kamiya, Y. Urano, A.
Suzuki, K. Yamamoto, K. Hase, K. Homma, J.
Sasaki, H. Miyauchi, T. Hoshino, M. Hayashi, T.N.
Mayadas, J. Hirahashi, Macrophage extracellular
trap formation promoted by platelet activation is a
key mediator of rhabdomyolysis-induced acutekidney injury, Nat. Med. 24 (2018) 232-238.
10. J. Onagi, T. Komatsu, Y. Ichihashi, Y. Kuriki, M.
Kamiya, T. Terai, T. Ueno, K. Hanaoka, H.
Matsuzaki, K. Hata, T. Watanabe, T. Nagano, Y.
Urano, Discovery of cell-type-specific anddisease-related enzymatic activity changes via
global evaluation of peptide metabolism, J. Am.
Chem. Soc. 139 (2017) 3465-3472.
11. T. Shiratori, Y. Kyumoto-Nakamura, A. Kukita, N.
Uehara, J. Zhang, K. Koda, M. Kamiya, T.
Badawy, E. Tomoda, X. Xu, T. Yamaza, Y. Urano,
K. Koyano, T. Kukita, IL-1 induces pathologically activated osteoclasts bearing extremely highlevels of resorbing activity: a possible pathological subpopulation of osteoclasts, accompanied

75

by suppressed expression of kindlin-3 and talin-1,
J. Immunol. 200 (2018) 218-228.
12. H. Takakura, Y. Zhang, R.S. Erdmann, A.D.
Thompson, Y. Lin, B. McNellis, F. Rivera-Molina,
S.N. Uno, M. Kamiya, Y. Urano, J.E. Rothman, J.
Bewersdorf, A. Schepartz, D. Toomre, Long timelapse nanoscopy with spontaneously blinking
membrane probes, Nat. Biotechnol. 35 (2017)773-780.

76

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

Lecturer
Takashi Isoyama, Ph.D.

Homepage

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

Introduction and Organization
As the first research institute for medical engineeringin Japan, Institute of Medical Electronics wasestablished in 1963. Department of Clinical Medicine
in the Institute of Medical Electronics was started in1964 for research and development of advanced
diagnostic and therapeutic medical engineering technologies. To date, medical engineering has grown up
not only to a very important academic discipline but
also to a very important means for clinical medicine.
With the structural reformation of Faculty of Medicine,
Institute of Medical Electronics has been shifted to
Graduate School of Medicine, and Department ofClinical Medicine in the Institute of Medical
Electronics has been reformed to the present department since April 1, 1997.
The current members include an associate professor, alecturer, two project researchers, 3 graduate students,
17 visiting researchers, a senior technical specialist,
and a project academic support stuff.
Since our research covers wide area of interdisciplinary and comprehensive research fields basedon the advanced medical and engineering technologies,
we are cooperating with various laboratories.

Teaching activities
We take a part in systematic lectures for the 3rd year
medical students. We also provide practice in the “freequarter” course for the 2nd year medical students. In
systematic lectures, we teach an introduction of theadvanced diagnostic and therapeutic medical
engineering technologies. The lectures for artificialorgan technologies are included.
For post-graduate education, we provide lectures forthe master course students, and we take a part in seriesof lectures for the doctor course students. For the
master course students, we offer lectures on artificialorgan technologies. For the doctor course students, weoffer lectures on advanced medical engineering
technologies.
The educational practice of the post-graduate students
is performed mainly by on-the-job training method in
the daily research works. Through the development
and animal experiments of the artificial hearts,
research strategy, methods of in-vitro, ex-vivo andin-vivo studies, design and fabrication techniques,machining technique, pre-operative management,
anesthesia, surgery, post-operative management,
measurement, data processing, ethical factor, andother important knowledge, techniques and experiences are acquired. In the practice, we give the mastercourse students several assignments from the field of
the artificial organs as a subject of their research. The
doctor course students have to find the subject of theirresearch by themselves. The research subject of thedoctor course students is not limited to the field of theartificial organs but is found from the wide area ofadvanced medical and engineering technologies.
Students must attend to the weekly meeting. They canlearn how to perform the research work and how toreport it through the meeting.

77

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

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

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

78

Concerning the materials, we have been developing a
new method to develop hybrid materials. In general, it
is not easy to develop mechanical parts for complex
artificial organs such as artificial hearts from thecomponents of living tissue because these components
have insufficient strength and durability, even though
they have excellent tissue compatibility. To overcome
these problems, an insert molding method, which iscommonly used for resin molding in the industrial
field, was introduced. In this method, the mold, inwhich an artificial material was inserted, was
implanted in the animal, and the tissue grew into themold to make a hybrid material. The method was first
applied to the Jellyfish valve that was originally apolymer valve for the artificial hearts. The hybrid
Jellyfish valve demonstrated a good result. Then, we
started to develop the hybrid conduit of the inflow
cannula for the left ventricular assist device (LVAD).
The conduit is inserted into the apex of the left
ventricle where the thrombus often formed. In thismethod, the mold in which the core of the conduit wasinserted was implanted under the skin of a goat. Afterseveral months, the hybrid conduit was extirpated, andthen freeze-dried, sterilized and used. The experimentof the LVAD using the hybrid conduit is going on witha goat. This hybrid technique will be an important
technology for developing the next generation
artificial organs.
A project of the novel gas-exchange system forbridging to lung transplantation has started. The
device consists of a blood pump, an oxygenator, adrive and control unit, and a battery unit. To realize
several-months support, the left side blood pump ofhelical flow TAH has been employed. This system is
expected to offer more opportunities and safer surgicalinterventions to those who are waiting for lungtransplants. In case of high afterload, the sequential
flow pump (SFP) would be applied. The SFP in which
fluid is given centrifugal force sequentially twice in apump was invented in our laboratory in 2013. Thissequential pressurization mechanism enables highpressure output without high impeller speed, which
can reduce the sheer stress of the blood. To realize
integration of the pump with the artificial lung, inlet
and outlet ports are located at lateral side and center ofthe pump, respectively, which is the reverse
configuration of conventional centrifugal pumps.

References
1. Shintaro Hara, Erina Maeno, XinYang Li,Terumi
Yurimoto, Takashi Isoyama, Itsuro Saito, Toshiya
Ono, Yusuke Abe, Principle and basic property ofthe sequential flow pump. Journal of Artificial
Organs, 2017; 20: 217-220, DOI: 10.1007/
s10047-017-0959-4.
2. Mizuta S, Saito I, Isoyama T, Hara S, Yurimoto T,
Li X, Murakami H, Toshiya O, Mabuchi K, Abe Y,
Appropriate control time constant in relation tocharacteristics of the baroreflex vascular system
in 1/R control of the total artificial heart. Journalof Artificial Organs, 2017; 20: 200-205, DOI: 10.
1007/s10047-017-0965-6.
3. Inoue Y, Yokota T, Sekitani T, Kaneko A, Woo T,
Kobayashi S, Shibuya T, Tanaka M, Kosukegawa
H, Saito I, Isoyama T, Abe Y, Yambe T, Someya T,
SekinoM.,

Antithrombotic

Protein

FilterComposed of Hybrid Tissue-Fabric Material has aLong Lifetime. Ann Biomed Eng. 2017; 45-5:
1352-1364, DOI: 10.1007/s10439-016-1781-5.
4. Yuta Kawasaki, Koichi Hosomi, Keita Yamamoto,
Shintaro Hara, Yusuke Abe, Youichi Saitoh,
Masaki Sekino, Quantitative Assessment of the
Focality of a Double-D Coil in the Human Brain.
32nd URSI GASS, Montreal, 2017; DOI: 10.
23919/URSIGASS.2017.8104975.

Neuroscience
1. Basic Neuroscience80

Department of Neuropathology
Professor
Takeshi Iwatsubo, M.D.

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

Homepage

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

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

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

81mechanistic roles of protein cofactors in the formationand function of γ-secretase (see reviews; Iwatsubo
Mol Psychiatr, 2004; Curr Opin Neurobiol, 2004). His
group has also shown by establishing in vitro
γ-secretase assays that sulindac sulfide, a major
non-steroidal anti-inflammatory drugs, directly acts on
γ-secretase and selectively reduce Aβ42-generating
activities (Takahashi et al., J Biol Chem, 2003),
providing important implications to the therapeuticstrategies of AD by γ-secretase modulation. Recently,
he has established a novel method for an efficient invitro reconstituion of γ-secretase complex, paving theway towards the structural analysis of active
γ-secretase (Hayashi et al. J Biol Chem, 2004), andusing thus highly purified γ-secretase particles, they
have partially unveiled the submolecular structure ofthis complex by single-particle EM analysis (Ogura etal. BBRC, 2006). Very recently, his group has
established an elegant strategy to analyze thestructure-function relationship within the catalytic
structure of γ-secretase complex by cystein chemistry,and demonstrated that γ-secretase harbors a waterpermeable catalytic pore (Sato et al. J Neurosci, 2006),
and that substrate proteins enter the catalytic porethrough the lateral gate located at the C terminal sideof PS (Sato et al. J Neurosci, 2008). Thus, Dr.
Iwatsubo’s group started from an elegant immunohistochemical analysis of Aβ deposits in AD brains
and extended it to a contemporary molecular/cellularbiology of PS, that proved to play a key role in“intramembrane proteolysis”.
2. Identification and characterization of α-synuclein
as a major component of Lewy bodies.
Using cortical Lewy bodies purified frompostmortem brains of patients with dementia with
Lewy bodies (DLB) by his original method (Iwatsubo
et al. Am J Pathol 1996) as immunogens, Dr.
Iwatsubo’s group, in collaboration with Drs. Virginia
Lee and John Trojanowski at Univ. Penn, performed
an extensive immunochemical search for componentsof Lewy bodies. They have demonstrated by raising a
specific monoclonal antibody that α-synuclein, thatproved to be a product of pathogenic gene for familial
form of Parkinson’s disease, is one of the major
constituent of Lewy bodies in sporadic Parkinson’s
disease and DLB (Baba et al. Am J Pathol 1998). His

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

82

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

References
1) Fujishima M, Kawaguchi A, Maikusa N, Kuwano
R, Iwatsubo T, Matsuda H, for the Alzheimer’s
Disease Neuroimaging Initiative (ADNI) and theJapanese Alzheimer’s Disease Neuroimaging
Initiative (J-ADNI): Sample size estimation for
Alzheimer’s disease trials from Japanese ADNI
serial MRI. J Alz Dis 56:75-88, 20172) Yamamoto T, Furihata K, Hisaka A, Moritoyo T,
Furihata S, Ogoe K, Kusayama S, Motohashi K,
Mori A, Iwatsubo T, Suzuki H: Notable drug-druginteraction between etizolam and itraconazole inpoor metabolizers of cytochrome P450 2C19. J
Clin Pharmacol 57:1491-1499, 20173) Mano T, Tsuchida T, Ohtomo R, Nagata K,
Takahashi-Fujigasaki J, Murayama S, Saido TC,
Yamashita S, Ushijima T, Hashimoto T, Tamaoka
A, Ikeuchi T, Iwatsubo T, Tsuji S, Iwata A:
Epigenetic regulation and tau-related dysfunctionof BRCA1 in Alzheimer’s disease. Proc Natl
Acad Sci USA 114:E9645-E9654, 20174) Suzuki K, Iwata A, Iwatsubo T: The past, present
and future of disease-modifying therapies for

Alzheimer’s disease. Proc Jap Acad Sci 93:757771, 2017

83

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

Assistant Professor
Hajime Fujii, Ph.D., Masayuki Sakamoto, Ph.D.

Homepage

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

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

are the molecular rules that govern these local andglobal changes, both electrical and chemical? How arethese events, in turn, converted into more profoundmodifications of the synaptic wiring mechanisms?
And finally do these alterations genuinely underlie
certain kinds of information processing and storage?
To address these issues, this Department currently focuses its resources into two basic aims:
1) Molecular investigation (including identification,
characterization and real-time visualization) of
signaling molecules involved in calcium-dependent
synaptic modification, especially during signalingfrom synapse-to-nucleus, and back from nucleusto-synapses.
2) Understanding molecular mechanisms controlling
cytoskeletal dynamics and remodeling on both sidesof the synapses, in the dendritic spines and in axon
terminals.
Following the retirement of Professor Tatsuya
Haga (who became the President of Life Sciences
Institute at the Faculty of Science at Gakushuin
Univisersity) in March 2001, and the departure of
Associate Professor David Saffen to initially University of Minnesota and then to Ohio State University inAugust 2001, Associate Professor Haruhiko Bito was
appointed as Head of Department since January 2003.
The Department is located on the 6th floor, in the Westwing of the third building of the Medical School. The
Department currently enrolls one professor, four
assistant professors, one postdoctoral scholar, one
technical staff member, four Ph.D. graduate students,
three rotating medical students, three technicalassistants and two administrative assistants.

84

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

Research activities
The Department of Neurochemistry currently
focuses its resources into two core projects:
1) Molecular investigation (including identification,
characterization and real-time visualization) of
signaling molecules involved in calcium-dependent
synaptic modification, especially during signalingfrom synapse-to-nucleus, and back from nucleus-tosynapses.
Changes in efficacy of synaptic transmission
have been shown to strongly correlate with functional
plasticity of many brain circuits including the
hippocampus, the amygdala, the striatum, theneocortex, the cerebellum or the spinal cord. An earlyphase of long-term synaptic plasticity is induced byvirtue of specific post- and/or presynaptic modifications of the biochemical machinery dedicated tosynaptic release and neurotransmitter recognition. It
then is expressed by bistable mechanisms that arestrongly governed and dictated by the pattern ofsynaptic calcium influxes experienced during theinitial conditioning period. While the molecular
identity of the involved synaptic proteins is now(almost) being solved (or is becoming much lesscontroversial than before), several essential questions
remain unanswered.
The “Old” question was: What are the moleculardeterminants that enable these plastic changes to be
induced and maintained locally? Yet, related issues ofcritical importance that still remain wide open
questions are:1) What are the full-range of calcium-triggered
molecular signaling cascades which are activated atand near the potentiated/depressed synapses? And
how do they influence plasticity per se?
2) What is the contribution of activity-dependent gene
expression in prolongation and consolidation ofsuch synapse-restricted changes?
In order to begin to address these issues, we havebeen investigating in particular the role of several
calcium-calmodulin dependent protein kinases.
We previously showed the critical importanceof a CaMKK/CaMKIV cascade in triggering
synaptically-stimulated nuclear CREB phosphorylation in hippocampal neurons. The extreme
biochemical efficacy and the relative poor frequencydependence of this signaling cascade, in combination
with the robust correlation between prolonged pCREB
response and downstream gene expression led us topropose that CaMKK/CaMKIV/pCREB cascade was
likely to act as a critical temporal integrator for
activity-dependent gene expression in excitatoryneurons (Bito et al., Cell, 1996; Bito et al., Curr. Opin.
Neurobiol., 1997; Bito, Cell Calcium, 1998). Thishypothesis has now been critically tested in various
brain systems and indeed pCREB immunofluorescence is now considered as a universal marker
for integrated synaptic activity that is more sensitive
than that of c-Fos (Nonaka, J. Neurosci. 2009). The
critical function of CaMKK/CaMKIV/pCREB cascadein the expression of long-term synaptic plasticity was
also validated in long-term potentiation in the
hippocampus (Redondo et al., J Neurosci. 2010).
Furthermore,
CaMKIV-KO,
CaMKK-KO
and
CaMKIV-dominant negative transgenic studies bymany laboratories have confirmed the critical role for
CaMKIV as synaptic activity-triggered CREB kinase.
We subsequently also showed that CaMKIV inthe cerebellar granule cells played a critical role intuning the pCREB response necessary for
depolarization-mediated neuronal survival, and that in

85

fact CaMKIV stability was actively maintained bydepolarization. Loss of depolarizing signal led to a
caspase-mediated proteolytic degradation of CaMKIV.
This in turn severely impaired CREB phosphorylation,
facilitating apoptosis, and conversely rescuing pCREB
by overexpressing an active form of CaMKIV was
sufficient to prevent apoptosis (See et al., FASEB J.,
2001). Consistent with our observation that subtle
CREB regulation may underlie the neuronal cell
survival, CREB-dependent gene expression mechanisms, especially CBP regulation, have actually been
proposed to be affected in one way or another in manyneurodegenerative disorders such as hereditary
polyglutamine diseases. We thus speculated that if
CREB-opathies (or various defects in CREB-mediatedgene activation mechanisms) were critical determinants in exacerbating neurodegeneration, certain
disease forms may actually accompany deficit in
CaMKIV / pCREB signaling (Bito and TakemotoKimura, Cell Calcium 2003). We also identified
kinase/phosphatase signaling responsible for activitydependent nuclear trafficking of CRTC1, a key
cofactor of CREB, and demonstrated its roles in
CREB-dependent transcription and contextual fear
memory in amygdala (Nonaka et al., Neuron 2014).
To elucidate the significance of the genes
regulated downstream of CREB during learning andmemory, we set out to uncover the most elementary
regulatory element required and sufficient to trigger
robust activity-dependent gene induction of theimmediate early gene Arc, whose expression in many
brain areas have been invariably associated with key
cognitive activities mediated by these areas. We
discovered a fundamentally novel synaptic activityresponsive element (SARE) which was present as a
distal regulatory promoter element and was conserved
across most mammalian species (Kawashima et al.,PNAS 2009; Kim et al., Nature 2010; Inoue et al.,Commun. Integr. Biol. 2010). Surprisingly, SARE
contained juxtaposed binding elements for all three
activity-regulated transcription factors, CREB, MEF2
and SRF. The identification of SARE enables us tobuild reporter virus and mouse lines that are expected
to be useful to map the extent of neuronal circuit
activation during various kinds of cognitive activities(Kawashima et al., Nat. Methods 2013). In addition
to the transcriptional regulation, we are currently

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

86that CaMKIIα and calcineurin are fine-tuned to uniquebandwidths and compute input variables in an
asymmetric manner (Fujii et al., Cell Reports 2013).
In line with the visualization of neuronal activity
and Ca2+ signaling, we have developed R-CaMP2, a
red genetically-encoded Ca2+ indicator that has singleaction-potential sensitivity based on rational designthat takes advantage of our long-standing effort andknowledge about CaMKK-CaMKIV signaling. By
combining R-CaMP2 with green Ca2+ indicator
G-CaMP, distinct activity patterns between excitatory
and inhibitory neurons in somatosensory cortex was
revealed (Inoue et al., Nat. Methods 2015).
One further important topic that we have been
focusing for a number of years is the role of gene
expression in prolongation / consolidation of synapsespecific local changes. Neurons undergoing various
stimulus patterns have been followed up in time andthe amount of newly synthesized proteins and the
local distribution of induced gene products have beenmonitored. Using state-of-the-art multi-wavelength
fluorescence imaging techniques, we are now quantitatively assessing how local distribution of these
newly synthesized gene products affect synaptic
protein complexes (Okuno and Bito, AfCS/Nature
Mol. Pages 2006).
2) Understanding molecular mechanisms controlling
cytoskeletal dynamics and remodeling on both sidesof the synapses, in the dendritic spines and in axon
terminals.
Both synaptic maturation and synaptic plasticity
have been shown to include a morphological component that is directed by the dynamics of actin
cytoskeleton, a major cytoskeletal component both in
the dendritic spines and at the very proximity ofboutons in the axon terminals. Few studies in the past,
however, had directly addressed what moleculardeterminants regulate actin dynamics in living central
neurons undergoing synaptic activity. This was in part
because actin filament assembly and disassembly wereclassically studied mostly at the moving edges oflamellipodia of large growth cones in large-size
neurons from either mollusc or peripheral nerve cells.
Such visualization turned out to be much moredifficult in seemingly far less mobile spine structures
tightly apposed to presynaptic active zones.

We (and others) used GFP-actin imaging to try tounderstand how neuronal actin cytoskeleton in
hippocampal neurons was organized and reorganizedby exposure to synaptic activity. In our dissociatedculture system, virtually all spines contained a highamount of GFP-actin and most of them with few
exceptions were apposed to FM4-64-positive active
presynaptic termini. In these cultures, increases insynaptic glutamatergic transmission by repeated burstsof high-frequency synaptic activity clearly induced
several distinct kinds of activity-dependent actin
mobilization, including a slow but sustained synaptic
delivery of GFP-actin in a non-negligible number ofactivated spines and a massive but transientenhancement in cortical actin at the somatic periphery.
The former was entirely dependent on NMDAdependent Ca2+-influx while the latter was likely to be
mediated at least in part by L-type voltage-gated Ca2+
channel activity. Thus, distinct patterns and sources of
Ca2+ influx were likely to trigger a complex spatiallysegregated patterns of actin cytoskeletal reorganization, with variable impact on either neuronalmorphology and/or synaptic protein assembly(Furuyashiki et al., PNAS, 2002).
Similar studies are now ongoing in cerebellar
Purkinje neurons, where spinogenesis is also subject
to complex regulation during development, and where
calcium dynamics is key to pre- and postsynaptic
plasticity.
What are the key signaling pathways controlling
actin dynamics in central neurons? We were especiallykeen to resolve the contribution of the small GTPase
Rho and its downstream effectors, initially in thecontext of developmentally regulated neuronalmorphogenesis. We first established in a model cellline N1E-115 that neurite retraction was directly
linked to Rho/ROCK activity (Hirose et al., J. Cell
Biol., 1998). We subsequently revealed that in central
neurons, in addition to its essential role in regulating
growth cone motility, Rho/ROCK activity in fact acted
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/ branch

87

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

PSD complex and the morphogenetic activity of eachspine (Nonaka et al. J. Neurosci., 2006).
In parallel with this work, we and others determinedthat protein-protein interaction was key to determining
the physical distance between the synaptic vesicles in
the active zone and the voltage-gated calcium
channels in its vicinity, the opening of which triggers
their release (Kiyonaka et al., Nat. Neurosci. 2007).

Publications by lab members(January 2017- December 2017)
1. Rapanelli M, Frick L, Pogorelov V, Ohtsu H, Bito H,
Pittenger C. (2017) Histamine H3R receptor
activation in the dorsal striatum triggers stereotypies
in a mouse model of tic disorders. Transl. Psychiatry
7: e1013. (DOI: 10.1038/tp.2016.290.)
2. Takemoto-Kimura S, Suzuki K, Horigane S, Kamijo
S, Inoue M, Sakamoto M, Fujii H, Bito H. (2017)
Calmodulin kinases: essential regulators in healthand disease. J Neurochem. 141: 808-818. (DOI:
10.1152/jn.00834.2015.)
3. Inokuchi K, Imamura F, Takeuchi H, Kim R, Okuno
H, Nishizumi H, Bito H, Kikusui T, Sakano H.
(2017) Nrp2 is sufficient to instruct circuit formationof mitral-cells to mediate odour-induced attractive
social responses. Nat Commun. 8:15977. (DOI: 10.
1038/ncomms15977.)
4. Nikolaienko O, Eriksen MS, Patil S, Bito H,
Bramham CR. (2017) Stimulus-evoked ERKdependent phosphorylation of activity-regulated
cytoskeleton-associated protein (Arc) regulates its
neuronal subcellular localization. Neuroscience.
360:68-80. (DOI: 10.1016/j.neuroscience.2017.07.
026.)
5. Jenks KR, Kim T, Pastuzyn ED, Okuno H, Taibi AV,
Bito H, Bear MF, Shepherd JD. (2017) Arc restores
juvenile plasticity in adult mouse visual cortex. Proc
Natl Acad Sci U S A. 114: 9182-9187. (DOI: 10.
1073/pnas.1700866114.)
6. Honjoh S, de Vivo L, Okuno H, Bito H, Tononi G,
Cirelli C. (2017) Higher Arc Nucleus-to-Cytoplasm
Ratio during Sleep in the Superficial Layers of the
Mouse Cortex. Front Neural Circuits.11: 60. (DOI:
10.3389/fncir.2017.00060.)

88

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

Assistant Professor
Shigeyuki Namiki, Ph.D.,

Homepage

Daisuke Asanuma, Ph.D.

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

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

Teaching activities
We accept Free-Quarter students. Students are expected to experience various experimental techniques
including basic fluorescence imaging techniques inliving cells as well as cutting-edge technologies
developed in our lab, based on their interests. 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 seminar by 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 new development of novel technologies. The main subjects of ourresearch are as follows
1) Development of novel strategy for visualizing
neurotransmitters
Imaging techniques which visualize neurotransmittersin living neuronal cells are powerful method tounderstand the mechanism underling synaptictransmission in neuronal circuits. To facilitate thisprocess, we developed a high-throughput screening
system based on 96-well plate format protocol. Afterscreening, we obtained high performance glutamate
indicators showing large fluorescence changes uponglutamate binding. This result indicates that our
screening system should be applicable to develop thefluorescent indicator for other signaling molecules aswell as for glutamate in short periods.
2) Study of the mechanism underlying the exocytosisof neurotransmitterFor understanding of regulation mechanism
underlying neuronal circuit in mammalian central
nervous system, elucidation of the exocytosis process
is indispensable. Aiming at imaging neurotransmitter
glutamate, we developed a novel optical glutamate
probe by our high-throughput screening system. By
using this probe, we successfully visualized presynaptically released glutamate following presynaptic
firing with a single synapse resolution. These results
indicate that our glutamate probe is useful to study
presynaptic modulation and plasticity. To clarify the
dynamics of exocytosis in an excitatory synapse, we
tried to quantitatively analyze released glutamate atindividual synapses. Our results suggest that single
hippocampal synapses contain several release units.

893) Analysiins of supra-molecular assemblies ofsynaptic molecules in central synapse
Recently, nanoscale molecular distribution in synapse
is suggested to be a key determinant of synaptic
function. To reveal the relationship between the nanoscale molecular assemblies and synaptic functions, weare trying to perform a supereresolution microscopic
analysis and imaging of synaptically released
glutamate. These advanced imaging techniquerevealed that dynamics of neurotransmitter release isprecisely controlled by the highly coordinatednanoscale molecular assemblies of presynaptic
molecules. We are also trying to identify thefunctional changes in nanoscale molecular assemblies
in psychiatric disease model.

References

Neuroscience
2. Integrative Medical Neuroscience91

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

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

Homepage

http://childpsy.umin.jp/

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

Education
In the year of 2017, we had 5 graduate students.
In addition to research training, educational program
including full-year lectures of child psychiatry, caseconference and journal club was implemented withfurther improvement.

Research
Main subjects of our research are Autism Spectrum
Disorder (ASD), Attention-Deficit/Hyperactivity
Disorder (ADHD), Tourette syndrome which is asevere and chronic tic disorder, and child & adolescentobsessive-compulsive disorder (OCD). We are trying
to combine scientific analysis of objective mental andbehavioral indicators with neuropsychological, brainimaging, and genetic studies into comprehensive andmultidimensional approach to problems in development of brain and mind. We are applying this comprehensive approach to intervention studies including
pharmacotherapy.
Major research projects with full or preliminary
performance in 2017 are as follows:・Epidemiological, behavior phenotype, neuropsychological, genetic and treatment study of Tourette
syndrome and child & adolescent OCD
・Brain-imaging study of ASD, ADHD and Tourette
syndrome by structural-MRI, functional-MRI andnear-infrared spectroscopy (NIRS)
・Genomic and epigenomic analysis of ASD
・Development of predictor of pharmacotherapy andparent training for ADHD
・Effectiveness study of early intervention for autisticpreschoolers and group cognitive behavior therapy
for adults with high-functioning ASD

92・Investigation on clinical evaluation and psychological education for adults with developmental
disordersPublications
1.

2.

3.

4.

Eriguchi Y, Kuwabara H, Inai A, Kawakubo Y,
Nishimura F, Kakiuchi C, Tochigi M, Ohashi J,
Aoki N, Kato K, Ishiura H, Mitsui J, Tsuji S, Doi
K, Yoshimura J, Morishita S, Shimada T,
Furukawa M, Umekage T, Sasaki T, Kasai K,
Kano Y. Identification of candidate genes
involved in the etiology of sporadic Tourette
syndrome by exome sequencing. Am J Med
Genet B Neuropsychiatr Genet. 2017; 174(7):712-723.
Owada K, Kojima M, Yassin W, Kuroda M,
Kawakubo Y, Kuwabara H, Kano Y, Yamasue H.
Computer-analyzed facial expression as asurrogate marker for autism spectrum social core
symptoms. PLoS One. 2018; 13(1): e0190442.
Yoshikawa A, Nishimura F, Inai A, Eriguchi Y,
Nishioka M, Takaya A, Tochigi M, Kawamura Y,
Umekage T, Kato K, Sasaki T, Kasai K, Kakiuchi
C. Novel rare variations in genes that regulate
developmental change in N-methyl-d-aspartate
receptor in patients with schizophrenia. Hum
Genome Var. 2018; 5: 17056.
Yoshikawa A, Nishimura F, Inai A, Eriguchi Y,
Nishioka M, Takaya A, Tochigi M, Kawamura Y,
Umekage T, Kato K, Sasaki T, Ohashi Y,
Iwamoto K, Kasai K, Kakiuchi C. Mutations of
the glycine cleavage system genes possibly affectthe negative symptoms of schizophrenia throughmetabolomic profile changes. Psychiatry Clin
Neurosci. 2018 ; 72(3):168-179.

Neuroscience
3. Clinical Neuroscience94

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

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

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

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

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

Research Associate
Shinsuke Kondo, M.D.

Kayo Ichihashi, M.D.

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

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

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

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

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

Tomoko Ando, M.D.

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

Oji Tomoatsu, MD.

Fumichika Nishimura, M.D., Ph.D.

Homepage

http://npsy.umin.jp/

Introduction and Organization
The Department of Neuropsychiatry is the oldest
department of psychiatry in Japan which wasestablished in 1886. "Anti-Psychiatry" movement in
the last 3 decades had brought highly negative impacts
on the progress of all aspects of our activities.
However, in 1994, our department has been normalized and restarted to play a leading role in psychiatryin Japan. Since 2005, we have launched the new
department of child neuropsychiatry to focus on basic
and clinical neuroscience in the developmental
disorders including autism spectrum disorder (ASD).
Dr. Kiyoto Kasai has been serving as a professor since2008. Now the Department of Neuropsychiatry is
dedicated to high quality clinical services, excellent
training, education for students and innovative
research.

Clinical activities
For our clinical services, we have more than 20

staff psychiatrists, 4 clinical psychologists and 2 psychiatric social workers. In 2017, approximately 700
new patients visited our outpatient clinic, and the total
visits per day were about 140.
In our inpatient wards, the secluded ward has 27
beds including 3 seclusion rooms, as well as 21 beds
for the open general ward. Approximately 430 patientswith various psychiatric disorders were admitted in2017. Recently, the number of inpatients who werereferred from the emergency unit is increasing. Mean
hospitalization is 30 day long, and the age of patientsis from teenager to senior. The majority of the patientsare schizophrenia, mood disorder and the psychosis
based on the somatic diseases. Modified electroconvulsive therapy was performed for over 400
patients per year.
We established the day care unit for outpatientswith schizophrenia in 1974, and the patients areengaged in rehabilitation and re-work programs. We
also have Japan's first child psychiatry day care unit innational university hospitals since 1967, and mainly

95

patients with pervasive developmental disorders areengaged in clinical and educational activities.

disorder).

Publications
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 (for 2nd year
students), and clinical clerkship (for 3rd year students).
For postgraduate, currently 13 neuropsychiatry Ph.D.
students are studying.

Research
Our mission in research is to clarify the pathophysiology of the mental illness to develop better
treatment approach.
1) Neuroimaging
Our research plays a leading role in psychiatricneuroimaging in Japan and aims at multi-modality
neuroimaging (structural and functional MRI, MR
spectroscopy, EEG, MEG, near-infrared spectroscopy(NIRS)) in schizophrenia, mood disorders and autism
spectrum disorders.
2) Molecular/cellular neuroscience
The goal of the molecular/cellular neuroscience groupis to build causal bridges among the molecular,
cellular, neural systems, and behavior on the rodent
model of neuropsychiatric disorders. We employ
integrated multidisciplinary techniques including
genetics, cell biology, biochemistry, histology,
electrophysiology, imaging and behavioral analysis
for elucidating molecular pathophysiology of rodent
models of neuropsychiatric disorder. We have focusedon schizophrenia and hippocampal neuronal circuits.
3) Genetic and Epidemiology research
The Genetic Research Group of the department isinvestigating genetic as well as environmental
mechanism of psychiatric disorders. A major focus of
the studies is exploration of susceptibility genes of thedisorders including schizophrenia, autism, theirspectrum disorders and anxiety disorder (mainly panic(1) Tamune H, Taniguchi G, Morita S, Kumakura Y,
Kondo S, Kasai K: Emotional stimuli-provokedseizures potentially misdiagnosed as psychogenic
non-epileptic attacks: A case of temporal lobe epilepsy with amygdala enlargement Epilepsy &Behavior Case Reports 9: 37-41, 2018.
(2) Koshiyama D, Fukunaga M, Okada N, Yamashita
F, Yamamori H, Yasuda Y, Fujimoto M, Ohi K,
Fujino H, Watanabe Y, Kasai K, Hashimoto R:
Role of subcortical structures on cognitive andsocial function in schizophrenia. Sci Rep 8: 1183,
2018. Jan 2018. 10.1038/s41598-017-18950-2.
(3) Yoshikawa A, Nishimura F, Inai A, Eriguchi Y,
Nishioka M, Takaya A, Tochigi M, Kawamura Y,
Umekage T, Kato K, Sasaki T, Ohashi Y, Iwamoto
K, Kasai K, Kakiuchi C: Mutations of the glycinecleavage system genes possibly affect the negative symptoms of schizophrenia through metabolomic profile changes. Psychiatry Clin Neurosci
72: 168-179, 2018. 2018 Mar; doi: 10.1111/pcn.
12628.
(4) Hashimoto N, Ito YM, Okada N, Yamamori H,
Yasuda Y, Fujimoto M, Kudo N, Takemura A, Son
S, Narita H, Yamamoto M, Tha KK, Katsuki A,
Ohi K, Yamashita F, Koike S, Takahashi T, Nemoto K, Fukunaga M, Onitsuka T, Watanabe Y,
Yamasue H, Suzuki M, Kasai K, Kusumi I,
Hashimoto R: The effect of duration of illness
and antipsychotics on subcortical volumes inschizophrenia: Analysis of 778 subjects. Neuroimage: Clin 17: 563-569, 2017. (Nov. 2017)
doi: 10.1016/j.nicl.2017.11.004.
(5) Otowa T, Shimada M, Miyagawa T, Umekage T,
Kawamura Y, Bundo M, Iwamoto K, Ikegame T,
Tochigi M, Kasai K, Kaiya H, Tanii H, Okazaki Y,
Tokunaga K, Sasaki T: An epigenome-wide
methylation study of healthy individuals with orwithout depressive symptoms. J Hum Genet 63:
319-326, 2018. Mar; doi: 10.1038/s10038-0170382-y.
(6) Yoshikawa A, Nishimura F, Inai A, Eriguchi Y,
Nishioka M, Takaya A, Tochigi M, Kawamura Y,
Umekage T, Kato K, Sasaki T, Kasai K, Kakiuchi

96

C: Novel rare variations in genes which regulate
the developmental change in N-Methyl-DAspartate receptor in patients with schizophrenia
Hum Genome Var 5, 17056, 2018. 2018 Feb; doi:
10.1038/hgv.2017.56.
(7) Koshiyama D, Fukunaga M, Okada N, Yamashita
F, Yamamori H, Yasuda Y, Fujimoto M, Ohi K,
Fujino H, Watanabe Y, Kasai K, Hashimoto R:
Subcortical association with memory performance in schizophrenia: a structural magnetic
resonance imaging study. Transl Psychiatry 8: 20,
2018. Jan. 2018 doi: 10.1038/s41398-017-0069-3.
(8) Koike S, Satomura Y, Kawasaki S, Nishimura Y,
Kinoshita A, Sakurada H, Yamagishi M, Ichikawa
E, Matsuoka J, Okada N, Takizawa R, Kasai K:
Application of functional near infrared spectroscopy as supplementary examination for diagnosisof clinical stages of psychosis spectrum. Psychiatry Clin Neurosci 71: 794-806, 2017. 2017 Dec;
doi: 10.1111/pcn.12551.
(9) Koshiyama D, Kirihara K, Tada M, Nagai T,
Koike S, Suga M, Araki T, Kasai K: Duration andfrequency mismatch negativity shows no progressive reduction in early stages of psychosis.
Schizophr Res 190: 32-38, 2017. 2017 Dec; doi:
10.1016/j.schres.2017.03.015.
(10) Murata Y, Bundo M, Ueda J, Kubota-Sakashita M,
Kasai K, Kato T, Iwamoto K: DNA methylationand hydroxymethylation analyses of the active
LINE-1 subfamilies in mice. Sci Rep 7: 13624,
2017. 2017 Oct 19; doi: 10.1038/s41598-01714165-7.
(11) Sasabayashi D, Takayanagi Y, Takahashi T, Koike
S, Yamasue H, Katagiri N, Sakuma A, Obara C,
Nakamura M, Furuichi A, Kido M, Nishikawa Y,
Noguchi K, Matsumoto K, Mizuno M, Kasai K,
Suzuki M: Increased Occipital gyrification anddevelopment of psychotic disorders in individuals
with an at-risk mental state: a multicenter study.
Biol Psychiatry 82: 737-745, 2017. 2017 Nov 15;
doi: 10.1016/j.biopsych.2017.05.018.
(12) Eriguchi Y, Kuwabara H, Inai A, Kawakubo Y,
Nishimura F, Kakiuchi C, Tochigi M, Ohashi J,
Aoki N, Kato K, Ishiura H, Mitsui J, Tsuji S, Doi
K, Yoshimura J, Morishita S, Shimada T, Furukawa M, Umekage T, Sasaki T, Kasai K, Kano
Y: Identification of candidate genes involved in

the etiology of sporadic Tourette syndrome byexome sequencing. Am J Med Genet B Neuropsychiatr Genet 174: 712-723, 2017. 10.1002/
ajmg.b.32559(Oct. 2017)(13) Kanehara A, Kotake R, Miyamoto Y, Kumakura Y,
Morita K, Ishiura T, Shimizu K, Fujieda Y, Ando
S, Kondo S, Kasai K: The Japanese version of thequestionnaire about the process of recovery: development and validity and reliability testing.
BMC Psychiatry 17: 360, 2017.
(14) Kondo S, Kumakura Y, Kanehara A, Nagato D,
Ueda T, Matsuoka T, Tao Y, Kasai K: Premature
deaths among individuals with severe mental illness after discharge from long-term hospitalization in Japan: a naturalistic observation during a
24-year period. BJPsych Open 3: 193-195, 2017.
(15) Higuchi Y, Sumiyoshi T, Seo T, Suga M,
Takahashi T, Nishiyama S, Komori Y, Kasai K,
Suzuki M: Associations between daily living
skills, cognition, and real-world functioning
across stages of schizophrenia; A study with the
Schizophrenia Cognition Rating Scale Japaneseversion. Schizophr Res Cogn 7: 13-18, 2017.
2017 Feb 22; doi: 10.1016/j.scog.2017.01.001.
(16) Nagai T, Kirihara K, Tada M, Koshiyama D,
Koike S, Suga M, Araki T, Hashimoto K, Kasai
K: Reduced mismatch negativity is associatedwith increased plasma level of glutamate infirst-episode psychosis. Sci Rep 7(1):2258. [May23, 2017; PMID: 28536477; doi: 10.1038/s41598017-02267-1](17) Ueda J, Murata Y, Bundo M, Oh-Nishi A, Kassai
H, Ikegame T, Zhao Z, Jinde S, Aiba A, Suhara T,
Kasai K, Kato T, Iwamoto K: Use of human
methylation arrays for epigenome research in thecommon marmoset (Callithrix jacchus). Neurosci
Res 120: 60-65, 2017. 2017 Jul; doi: 10.1016/j.
neures.2017.02.005.
(18) Watanabe T, Otowa T, Abe O, Kuwabara H, Aoki
Y, Natsubori T, Takao H, Kakiuchi C, Kondo K,
Ikeda M, Iwata N, Kasai K, Sasaki T, Yamasue H:
Oxytocin receptor gene variations predict neuraland behavioral response to oxytocin in autism.
Soc Cogn Affect Neurosci 12: 496-506, 2017.
2017 Mar 1; doi: 10.1093/scan/nsw150.
(19) Sawada K, Kanehara A, Sakakibara E, Eguchi S,
Tada M, Satomura Y, Suga M, Koike S, Kasai K:

97

Identifying neurocognitive markers for outcome
prediction of global functioning in ultra-high-riskfor psychosis and first episode psychosis. Psychiatry Clin Neurosci 71: 318-327, 2017. 2017 May;
doi: 10.1111/pcn.12522.
(20) Fujino H, Sumiyoshi C, Yasuda Y, Yamamori H,
Fujimoto M, Fukunaga M, Miura K, Takebayashi
Y, Okada N, Isomura S, Kawano N, Toyomaki A,
Kuga H, Isobe M, Oya K, Okahisa Y, Takaki M,
Hashimoto N, Kato M, Onitsuka T, Ueno T,
Ohnuma T, Kasai K, Ozaki N, Sumiyoshi T,
Imura O, Hashimoto R; for COCORO. Estimatedcognitive decline in patients with schizophrenia:
A multicenter study. Psychiatry Clin Neurosci 71:
294-300, 2017. 2017 May; doi: 10.1111/pcn.
12474.
(21) Inoue T, Morita M, Wada A, Kasai K, Kondo S: Acase of persistent delirium resolved promptly withsuvorexant. Prim Care Companion CNS Disord
19: 16102026, 2017.
(22) Shimada-Sugimoto M, Otowa T, Miyagawa T,
Umekage T, Kawamura Y, Bundo M, Iwamoto K,
Tochigi M, Kasai K, Kaiya H, Tanii H, Okazaki Y,
Tokunaga K, Sasaki T: Epigenome-wide association study of DNA methylation in panic disorder.
Clin Epigenetics 9: 6, 2017. 2017 Jan 21; doi:
10.1186/s13148-016-0307-1.
(23) Morita K, Miura K, Fujimoto M, Yamamori H,
Yasuda Y, Iwase M, Kasai K, Hashimoto R: Eyemovement as a biomarker of schizophrenia: using
an integrated eye movement score. Psychiatry
Clin Neurosci 71: 104-114, 2017. 2017 Feb; doi:
10.1111/pcn.12460.
(24) Takano Y, Aoki Y, Yahata N, Kawakubo Y, Inoue
H, Iwashiro N, Natsubori T, Koike S, Gonoi W,
Sasaki H, Takao H, Kasai K, Yamasue H: Neuralbasis for inferring false beliefs and social emotions in others among individuals with schizophrenia and those at ultra-high risk for psychosis.
Psychiatry Res: Neuroimaging 259: 34-41, 2017.
2017 Jan 30; doi: 10.1016/j.pscychresns.2016.11.
003.

98

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

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

LecturerAtsushi Iwata, M.D., Ph.D.
Toshihiro Hayashi, M.D., Ph.D. (～2017/11)
Kaori Sakuishi, M.D., Ph.D. (2017/12～)

Associate
Kaori Sakuishi, M.D., Ph.D. (～2017/11), Masashi Hamada, M.D., Ph.D.,
Hiroyuki Ishiura, M.D., PhD., Akatsuki Kubota, M.D., Ph.D.,
Yuichiro Shirota, M.D., PhD., Toji Miyagawa, M.D., Ph.D.,
Tatsuo Mano, M.D., PhD. (2017/12～)

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, Ichiro Kanazawa, and Shoji
Tsuji. The organization of the Brain Research Institutewas reorganized as the Division of Neuroscience of
the Graduate School of Medicine in 1997.

Clinical activities
We offer clinical services in the field of
Neurology. We are putting our effort to provide thepatients with highly advanced clinical practice as wellas on clinical activities connected to postgraduate
education of Neurology.
We have outpatient clinics covering the broad
fields of Neurology. Furthermore, we also provide
clinics specialized to movement disorders anddementia (Memory Clinic).

In the in-patient ward, we offer programs forpostgraduate education including the program for the
first stage postgraduate education. We also offer the
excellent training program with the goal to get theboard of Neurologist. In 2005, we initiated deep brain
stimulation for the treatment of movement disorders incooperation with Department of Neurosurgery.

Teaching activities
As for under-graduate education, our Department
takes a part in lectures of Neurology for the 4th and5th grade medical students, and clinical clerkship forthe 5th grade medical students.
In the clinical clerkship we include small group
lectures including neurophysiology, and stroke care.
We are also putting our effort for Free Quarters where
we offer various opportunities for medical students to
be involved in research activities, and 2-3 medical
students are conducting their research activities in thelaboratories.

99

In postgraduate education we offer the integrated
program including Neurology as the part of the
program of Internal Medicine.
Regarding training for board-certified neurologists, we offer the excellent program including
patients’ care, training in Neurophysiology and Neuropathology, consultation for Neurology, rotation at ER
and supervising of junior trainees. This program is
integrated with clinical practice at the affiliatedhospitals where rich experience is obtained fornumerous cases in Clinical Neurology.
In Graduate School, we offer highly advanced
research activities based on the interest of graduate
students.

Research activities
Our research field covers broad fields related toneurological diseases, with the goals to elucidate themechanisms of neurological diseases, and to eventually develop new therapeutic strategies. Our research
activities include molecular genetics, developmental
biology, cell biology, pharmacology, pathology, andphysiology. We aim to integrate these broad research
fields to better contribute to clinical neurology.
In the development of molecular therapeutics thatameliorate α-dystroglycan (α-DG)-associated diseases,
we identified the glycan unit ribitol 5-phosphate(Rbo5P) in α-DG and showed that enzyme activitiesof α-DG-associated diseases are involved in thesynthesis of tandem Rbo5P. We also found that FKTN
and FKRP can transfer GroP to O-mannosyl glycans
by using CDP-glycerol (CDP-Gro) as a donor
substrate. The analysis of mouse models of α-DGassociated diseases indicated that spatiotemporalpersistence of functionally glycosylated α-DG may be
crucial for brain development. These findings provide
insight into pathogenesis and therapeutic strategies in
α-DG-associated diseases. (Toda, T., Kanagawa, M.,
Kobayashi, K., Sudo, A.)
We perform case-control association studies in
Parkinson disease (PD) employing whole-exome
sequence analysis to discover rare PD susceptibility
variants. Employing a novel bioinformatics approach
using GWAS loci in PD along with in vitro functional
studies and MPTP mouse model analysis, we
identified a novel drug candidate for the prevention ofneurodegeneration in PD. We also identified genetic
factors responsible for the individual difference of theeffects of zonisamide by using GWAS. (Toda, T.,
Satake, W., Uenaka, T., Cha, P.C., Fujino, G.)
In the field of molecular genetics, we havedeveloped the Genomic Medicine Research Support
Center, and introduced next-generation sequencers to
conduct comprehensive genome analyses to elucidate
molecular bases of various neurological diseases.
Regarding monogenic neurologic diseases, we
conduct pedigree analyses in various neurologicaldiseases including epilepsy, multiple system atrophy,
amyotrophic lateral sclerosis, hereditary spastic
paraplegia, and spinocerebellar atrophy. As forsporadic neurologic diseases, we perform case-control
association studies in multiple system atrophy andamyotrophic lateral sclerosis to identify genetic
factors underlying these diseases. On the basis of thefindings that mutations in COQ2 are associated withfamilial as well as sporadic multiple system atrophy,
we are conducting an investigator-initiated clinical
trial using coenzyme Q10 for patients with multiple
system atrophy. Collaborative researches haveachieved multiple accomplishments including
case-series studies of amyotrophic lateral sclerosis(TBK1), Charcot-Marie-Tooth disease (MFN), andspinocerebellar atrophy 42 (CACNA1G). Applicationof next generation sequencers for molecular diagnosis
for various diseases has been conducted, with casereports of muscular dystrophy (LAMA2), amyotrophic
lateralsclerosis(HNRNPA1),
minifascicular
neuropathy (DHH), early-onset spinocerebellar
atrophy (PEX10), and polyglucosan disease (GBE1).
(Toda, T., Tsuji, S., Date, H., Mitsui, J., Ishiura, H.,
Matsukawa, T., Tanaka, M., Sato, N., Naruse, H.,
Matsukawa, M., Kanda, J., Shibata, S., Chikada, A.,
Nagasako, Y., Hao, A., Shinmi, J, Mitsue, A.)
The human neurophysiology section specializes
in studying the physiology of the human motor andsensory systems in awake healthy volunteers and thepathophysiology of neurological disorders using
several non-invasive physiological methods, such as
TMS, EEG, MEG, fMRI, NIRS and EOG. Our final
goal is to devise new therapeutic techniques for
intractable neurological disorders. To this end, thework extends from the study of spinal systems to basal
ganglia and cerebral cortex. We are especially100interested in plasticity induction by non-invasive brain
stimulation (NIBS) techniques, offering potential forclinical application. Our lab has a long experience inthe use of transcranial magnetic stimulation (TMS)
which is able to stimulate neurons in intact humanbrain and has devised a highly effective repetitive
TMS method to induce long-term effects (quadripulse
stimulation, QPS). We have recently started a clinical
trial of repetitive TMS to treat patients with
Parkinson’s disease. (Hamada, M., Shirota, Y.,
Kodama, S., Sugiyama., Y., Sato, K., and Otsuka, J.)
In the field of neuromuscular diseases, we
provide pathological diagnosis of biopsied materials
from patients with myopathy or neuropathy. We also
provide autoantibody testing for anti-gangliosideantibodies, muscle specific antibodies and paraneoplastic neurological antibodies. In research field,
using biopsied muscles and collected serum samples,
we have been studying the mechanisms of inflammatory myopathies from the view points of pathological changes, myositis specific autoantibodies,
serum cytokines, and expression profiling of muscle
samples. Our aim is to increase understanding of the
etiology and pathogenesis of neuromuscular diseases.
(Shimizu, J., Kubota A., Maeda M., Kadoya M.,
Ikenaga C., Uchio N., Taira K., Unuma, A).
Biochemistry lab is currently working on neuroepigenetics using post-mortem brains of Alzheimer’s
disease (AD), Lewy body disease (LBD), multiple
system atrophy and amyotrophic lateral sclerosis,
which revealed a novel pathomechanism in AD. Basedon the methylome analysis, we found dysfunction of
BRCA1 and and demonstrated the accumulation of
DNA damage is potentially responsible thepathomechanism of AD. We are further analyzing thehistonemodification
throughneuron-specific
ChIP-seq assay, which is one of the major transcriptional regulators. We also analyzed neuron-specificmethylome in LBD to demonstrate the relationshipbetween FGFR3 accumulation and α-synuclein. We
also work on molecular pathology of chronic ischemia
using mouse models. Other activities include
development of new imaging techniques using Raman
microspectroscopy. Recently we visualized spatial
distribution of chemical shifts within Aβ aggregates
formedinvitro.
We
also
observed
globotriaosylceramide distribution within peripheral

nerve of Fabry’s disease patient in non-labeledmanner. We also developed a new optical sensor
device detecting biomarkers for Alzheimer’s diseaseusing
nanoimprint
lithography(NIL)-based
two-dimensional photonic crystal (2D-PhC). In a pilot
study quantifying Aβ in CSF and serum samples, oursensor achieved higher sensitivity than conventional
ELISA. Clinical study includes preclinical sporadic
Alzheimer’s disease cohort (AMED Preclinical study)
and familial Alzheimer’s disease (DIAN-J) andclinical trial of florbetapir. (Iwata, A., Nagashima, Y.,
Miyagawa, T., Ohtomo, R., Mano, T., Bannai, T.,
Tsuchida, T., Hamada, K., Mano, K, Ohtomo, G.)
Higher brain function section aims to elucidate
pathophysiology and neural basis of the higher brain
dysfunction in neurological disorders by means of two
approaches: neuropsychological analysis of individual
cases and multimodal big-data analysis. (Hayashi, T.)
Neuroimmunology section is focused onunderstanding inflammatory disease of the CNS:
namely Mutiple Sclerosis and Neuromyelitis Optica.
Through application of both conventional and more
contemporary immunological methods (FACS, ELISA,
cell culture and NGS analysis), we aim to reveal
disease-specificpatho-mechanisms
forbetterdiagnosis and treatment of immune-mediated CNS
inflammation. (Sakuishi, K, Koguchi, A)

Publication
1. Kanagawa M, Toda T. Muscular Dystrophy with
Ribitol-Phosphate Deficiency: A Novel PostTranslational Mechanism in Dystroglycanopathy.
J Neuromuscul Dis. 2017;4(4):259-267.
2. Nishihara R, Kobayashi K, Imae R, Tsumoto H,
Manya H, Mizuno M, Kanagawa M, Endo T,
Toda T. Cell endogenous activities of fukutin and
FKRP coexist with TMEM5. Biochem Biophys
Res Commun. 2018 Mar 18;497(4):1025-1030.
3. Kobayashi K, Kato R, Kondo-Iida E,
Taniguchi-Ikeda M, Osawa M, Saito K, Toda T.
Deep-intronic variant of fukutin is the mostprevalent point mutation of Fukuyama congenital
muscular dystrophy in Japan. J Hum Genet 2017
Nov;62(11):945-948.
4. Morita K, Nakamura F, Sakuishi K, Yamamoto T,
Shimizu J, Tsuji S, Kurokawa M. Successful

101management of chronic myeloid leukemia with acomplication of anti-SRP antibody-associatedmyopathy. Leuk Lymphoma. 2017 May; 58(5):1242-1245.
5. Ikeda T, Nakahara A, Nagano R, Utoyama M,
Obara M, Moritake H, Uechi T, Mitsui J, Ishiura
H, Yoshimura J, Doi K, Kenmochi N, Morishita S,
Nishino I, Tsuji S, Nunoi H. TBCD may be acausal gene in progressive neurodegenerative
encephalopathy with atypical infantile spinal
muscular atrophy. J Hum Genet. 2017 Apr;
62(4):473-480.
6. Udagawa T, Jo T, Yanagihara T, Shimizu A,
Mitsui J, Tsuji S, Morishita S, Onai R, Miura K,
Kanda S, Kajiho Y, Tsurumi H, Oka A, Hattori M,
Harita Y. Altered expression of Crb2 in podocytes
expands a variation of CRB2 mutations in steroidresistant nephrotic syndrome. Pediatr Nephrol.
2017 May;32(5):801-809.
7. Matsukawa T, Koshi KM, Mitsui J, Bannai T,
Kawabe M, Ishiura H, Terao Y, Shimizu J,
Murayama K, Yoshimura J, Doi K, Morishita S,
Tsuji S, Goto J. Slowly progressive d-bifunctional
protein deficiency with survival to adulthood
diagnosed by whole-exome sequencing. J Neurol
Sci. 2017 Jan 15;372:6-10.
8. Mitsui J, Koguchi K, Momose T, Takahashi M,
Matsukawa T, Yasuda T, Tokushige SI, Ishiura H,
Goto J, Nakazaki S, Kondo T, Ito H, Yamamoto Y,
Tsuji S. Three-Year Follow-Up of High-Dose
Ubiquinol Supplementation in a Case of Familial
Multiple System Atrophy with Compound
Heterozygous COQ2 Mutations. Cerebellum.
2017 Jun;16(3):664-672.
9. Amiya E, Morita H, Ishiura H, Tsuji S, Komuro I.
Authors' response to "Compound heterozygous
Fukutin mutation-related non-compaction" byFinsterer and Zarrouk-Mahjoub. Int J Cardiol.
2017 Apr 15;233:102.
10. Yamashita T, Mitsui J, Shimozawa N, Takashima
S, Umemura H, Sato K, Takemoto M, Hishikawa
N, Ohta Y, Matsukawa T, Ishiura H, Yoshimura J,
Doi K, Morishita S, Tsuji S, Abe K. Ataxic formof autosomal recessive PEX10-related peroxisomebiogenesis disorders with a novel compound
heterozygous gene mutation and characteristic
clinical phenotype. J Neurol Sci. 2017 Apr 15;

375:424-429..
11. Kodama S, Mano T, Masuzawa A, Hirata Y,
Nagasako Y, Koshi Mano K, Hamada M, Terao Y,
Hayashi T, Ono M, Tsuji S. Tacrolimus-Induced
Reversible Cerebral Vasoconstriction Syndrome
with Delayed Multi-Segmental Vasoconstriction. J
Stroke Cerebrovasc Dis. 2017 May;26(5):e75e77.
12. Kimura M, Yabe I, Hama Y, Eguchi K, Ura S,
Tsuzaka K, Tsuji S, Sasaki H. SCA42 mutation
analysis in a case series of Japanese patients withspinocerebellar ataxia. J Hum Genet. 2017 Sep;
62(9):857-859.
13. Eriguchi Y, Kuwabara H, Inai A, Kawakubo Y,
Nishimura F, Kakiuchi C, Tochigi M, Ohashi J,
Aoki N, Kato K, Ishiura H, Mitsui J, Tsuji S, Doi
K, Yoshimura J, Morishita S, Shimada T,
Furukawa M, Umekage T, Sasaki T, Kasai K,
Kano Y. Identification of candidate genes
involved in the etiology of sporadic Tourette
syndrome by exome sequencing. Am J Med GenetB Neuropsychiatr Genet. 2017 Oct;174(7):712723.
14. Ando M, Hashiguchi A, Okamoto Y, Yoshimura A,
Hiramatsu Y, Yuan J, Higuchi Y, Mitsui J, Ishiura
H, Umemura A, Maruyama K, Matsushige T,
Morishita S, Nakagawa M, Tsuji S, Takashima H.
Clinical and genetic diversities of Charcot-MarieTooth disease with MFN2 mutations in a largecase study. J Peripher Nerv Syst. 2017 Sep;
22(3):191-199.
15. Hosoe J, Kadowaki H, Miya F, Aizu K,
Kawamura T, Miyata I, Satomura K, Ito T, Hara K,
Tanaka M, Ishiura H, Tsuji S, Suzuki K, Takakura
M, Boroevich KA, Tsunoda T, Yamauchi T,
Shojima N, Kadowaki T. Structural Basis andGenotype-Phenotype Correlations of INSR
Mutations Causing Severe Insulin Resistance.
Diabetes. 2017 Oct;66(10):2713-2723.
16. Ikenaga C, Kubota A, Kadoya M, Taira K, Uchio
N, Hida A, Maeda MH, Nagashima Y, Ishiura H,
Kaida K, Goto J, Tsuji S, Shimizu J.
Clinicopathologic features of myositis patients
with
CD8-MHC-1
complexpathology.
Neurology. 2017 Sep 5;89(10):1060-1068.
17. Naito T, Nagashima Y, Taira K, Uchio N, Tsuji S,
Shimizu J. Identification and segmentation of

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myelinated nerve fibers in a cross-sectional
optical microscopic image using a deep learningmodel. J Neurosci Methods. 2017 Nov 1;291:
141-149.
18. Mano T, Nagata K, Nonaka T, Tarutani A,
Imamura T, Hashimoto T, Bannai T, Koshi-Mano
K, Tsuchida T, Ohtomo R, Takahashi-Fujigasaki J,
Yamashita S, Ohyagi Y, Yamasaki R, Tsuji S,
Tamaoka A, Ikeuchi T, Saido TC, Iwatsubo T,
Ushijima T, Murayama S, Hasegawa M, Iwata A.
Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):E9645-E9654.
19. Terao Y, Fukuda H, Tokushige SI, Inomata-Terada
S, Yugeta A, Hamada M, Ugawa Y. Distinguishingspinocerebellar ataxia with pure cerebellar
manifestation from multiple system atrophy(MSA-C) through saccade profiles. Clin
Neurophysiol. 2017 Jan;128(1):31-43.
20. Hordacre B, Goldsworthy MR, Vallence AM,
Darvishi S, Moezzi B, Hamada M, Rothwell JC,
Ridding MC. Variability in neural excitability andplasticity induction in the human cortex: A brain
stimulation study. Brain Stimul. 2017 May - Jun;
10(3):588-595.
21. Terao Y, Fukuda H, Tokushige SI, Inomata-Terada
S, Hamada M, Ugawa Y. Saccades abnormalities
in posterior cortical atrophy - A case report. Clin
Neurophysiol. 2017 Feb;128(2):349-350.
22. Hanajima R, Tanaka N, Tsutsumi R, Enomoto H,
Abe M, Nakamura K, Kobayashi S, Hamada M,
Shimizu T, Terao Y, Ugawa Y. The effect of age
on the homotopic motor cortical long-term
potentiation-like effect induced by quadripulse
stimulation. Exp Brain Res. 2017 Jul;235(7):2103-2108.
23. Huang YZ, Lu MK, Antal A, Classen J, Nitsche M,
Ziemann U, Ridding M, Hamada M, Ugawa Y,
Jaberzadeh S, Suppa A, Paulus W, Rothwell J.
Plasticity induced by non-invasive transcranialbrain stimulation: A position paper. Clin
Neurophysiol. 2017 Nov;128(11):2318-2329.
24. Kim K, Shimizu J, Isu T, Inoue K, Chiba Y,
Iwamoto N, Morimoto D, Isobe M, Morita A.
Low back pain due to superior cluneal nerve
entrapment: A clinicopathologic study. Muscle
Nerve. 2017 Nov 3. doi: 10.1002/mus.26007.
[Epub ahead of print]

25. Sato NS, Maekawa R, Ishiura H, Mitsui J, Naruse
H, Tokushige SI, Sugie K, Tate G, Shimizu J,
Goto J, Tsuji S, Shiio Y. Partial duplication of
DHH causes minifascicular neuropathy: A novel
mutation detection of DHH. Ann Clin Transl
Neurol. 2017 May 22;4(6):415-421.

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

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

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

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

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

Shota Tanaka, M.D.

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

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

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

Masashi Nomura, M.D., Ph.D.

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

Hirotaka Hasegawa, M.D.

Mariko Kawashima, M.D.

Tsuguto Takizawa, M.D.

Homepage

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

Introduction and Organization

Clinical activities

The Department of Neurosurgery at the Universityof Tokyo Hospital consists of 13 staff neurosurgeons,
who participate in the three major academic activities:
patient care, research, and education. The staffs include
a professor/chairman, an associate professor, four
lecturers and eight associates.
Clinical ward for neurosurgery in our university
hospital was founded in 1951 as the first neurosurgicalclinic in Japan. Dr. Keiji Sano, as the founding
professor, established the Department of Neurosurgery
in 1962. Dr. Kintomo Takakura and Dr. Takaaki Kirino
served as the second and the third professor,
respectively. The incumbent professor, Dr. Nobuhito
Saito, has been serving as the fourth professor since
2006.
Our department provides expertise for patients withbrain tumor, cerebrovascular disease, spinal disease,functional disorder, head trauma, etc.

General outpatient clinic including new patient clinic
is open every weekday and subspecialty clinic is open
three days a week (Monday, Wednesday and Friday).
The latter is open for patients with brain tumor,
pituitary disease, spinal disease, cerebrovasculardisease, endovascular intervention, epilepsy, andgamma knife treatment. From April 2017 to March
2018, 18,443 patients were treated at the outpatient
clinics.
The neurosurgery ward has approximately 40 beds
on the seventh floor of the new hospital building
opened in September 2001. In 2017, 939 patients wereadmitted to the neurosurgery ward. 519 surgicalprocedures and 151 gamma knife procedures were
performed in 2017. Our practice covers a wide varietyof neurosurgical diseases including malignant andbenign brain tumors, hemorrhagic and thromboembolic
cerebrovascular diseases, spinal disorders, epilepsy,

104pain and movement disorders.
Intraoperative functional monitoring in brain tumor
surgery and pre- and intra-operative functional mapping in epilepsy surgery are frequently used to preserve
brain function as much as possible. State-of-the-art
techniques including intraoperative computer-aided
navigation and intravascular procedures help ourcontinuous effort to increase the safety of surgicaltreatment.
Our department is affiliated with 34 neurosurgicalinstitutions in and around the city of Tokyo including 5
university medical centers, where our residents andstudents are exposed to various clinical experiences.
Surgical case volume in all hospitals exceeds 11,000
cases.

Teaching activities
Medical students take lectures of clinicalneurosurgery in their second year. Clinical case studies
and bedside teaching are scheduled in the third andfourth years. The lecturers introduce general
neurosurgery as well as the state-of-art neurosurgicalpractice to the students. At the bedside teaching andclinical clerkship, they are offered opportunities tolearn clinical management of neurosurgical patients in
the hands-on style, and also are exposed to practice invarious subspecialties in neurosurgery through special
seminars given by experts in the fields.
We accepted 14 residents in 2015, 4 in 2016, 16 in2017, and 5 in 2018 in our neurosurgical residency
program. These residents are trained in the university
hospital and affiliated hospitals to experience every
aspect of neurosurgical practice for five years on
average. Our residency training is finalized after thesixth year, when the finishing residents serve as seniorresidents at the university hospital for 6 months.
Academic training is provided through numerous
intramural clinical and research conferences, journal
clubs, seminars as well as quarterly regional meetingsof the Japan Neurosurgical Society. After or duringresidency training, our residents can choose to be
admitted into the Ph.D. course at the Graduate Schoolof Medicine, the University of Tokyo, to be involved inadvanced basic research activities for 4 years. Uponcompletion of training, our graduates stay in thedepartment to be associates in our university hospitalor become clinical staffs in our affiliated hospitals.

Research activities
Clinical research in the last few years have mainly
focused on treatments of acoustic neurinoma, techniques of skull base surgery, treatments of malignant
brain tumors, epilepsy surgery, and stereotactic
radiosurgery. The results were presented at domestic aswell as international meetings including Annual
Meetings of the Japan Neurosurgical Society andAnnual Meetings of American Association of
Neurological Surgeons.
Our department has maintained prominent basic
research activities as well. The fields of our current
research are as follows:
1) Pathogenesis of cerebral ischemia and neuronal
regeneration after ischemic brain damage
One of the major topics in recent basic science is toregenerate the brain with endogenous neuralprogenitors. Our laboratory has started basic research
to regenerate neurons in vivo following ischemic insult.
We have demonstrated that the 40% of the lost neurons
could be regenerated by administration of growth
factors. We also succeeded in regeneration of striatal
neurons. Molecular mechanisms of adult neurogenesis
are currently investigated using various models toenhance post-ischemic regeneration. By extending the
research into primate model, we are pursuing clinicalapplication in the future.
2) Development of new therapeutic modalities formalignant brain tumors
Genotyping is now widely accepted as an essential
component of pathological diagnosis in glioma. We
have been routinely analysisng surgically resected
tumor specimens in a semi-prospective fashion. The
genetic analyses includes sequencing of IDH1/2, TP53,
and histone gene mutations, as well as loss ofheterozygosity analysis of 1p, 19q, and 10q, andmethylation analysis of MGMT promotor. We optimize
therapy based upon the results of the above genetic
analyses. In addition, we have been searching for novel
biomarkers and therapeutic targets using comprehesive
genetic and epigenetic approches with whole exome

105

sequencing, RNA sequencing, expression profiling,
and methylation analysis. Our particular interest lies intumor heterogeneity and malignant progression.
To develop a novel strategy for the treatment ofmalignant glioma, we have isolated brain tumor
initiating cells, which are supposed to be responsible
for resistance to conventional therapies, from surgical
specimens, and we are studying specific targetingtherapy against these cells.
We have been collaborating with a basic research lab
in our university and developing new fluorescenceprobes specifically detecting glioma with a hope thatfluorescence-guided surgery may result in greater
extent of resection.
3) Development and evaluation of function-preserving
and less invasive treatment of intractable epilepsy
We have been promoting the research on
development, evaluation and standardization of thenovel treatment for intractable epilepsy. Since ourfacility was the first in Japan to provide vagus nerve
stimulation therapy, we evaluated its efficacy andsafety in epilepsy treatment. We established a new
intraoperative monitoring method of vagus-nerve
evoked potential. Efficacy evaluation and developmentof surgical instruments were promoted for novel
function-preserving techniques, multiple subpial
transection and multiple hippocampal transection.
Basic and clinical research on gamma knife treatmentof epilepsy has been performed as well. For the purposeof more precise localization of epileptic foci andelucidation of epileptogenesis, we are now developing
novel types of intracranial eletrodes.
4) Research on brain function using non-invasive andinvasive techniques
We have been studying human brain function using
not only non-invasive techniques such as fMRI, MEG,NIRS but also electrocorticography (ECoG) obtainedby intracranial electrodes implanted in epilepsy
patients. The latter is our markedly advantageous
feature that enables us to extract brain information withmuch higher spatial resolution and SN ratio. We aim tounderstand brain mechanisms as complicated network
systems and to improve the reliability of non-invasive
techniques. Since ECoG is a strong candidate for a
decoding source of brain-computer interface (BCI), weare planning to expand the research on this field toclinical implementation of BCI for communication andmotor control in cooperation with other brain researchlaboratories and engineering laboratories.
5) Clinical applications of the functional brain
imaging and operative simulation using threedimensional computer graphics for neurosurgery
Our department intensively utilizes various kinds offunctional and metabolic imaging modalities including
magnetoencephalography, functional MRI, and diffusion tensor imaging-based tractography for presurgicalbrain mapping. Combining the results of the multimodalities enables to visualize all cortical andsubcortical networks of the motor, language and othercognitive functions in each patient. Furthermore, we
succeeded to import the combined information into a
neuronavigation system (functional neuronavigation),
which quickly and accurately indicates the eloquent
brain areas. We could develop virtual reality operative
simulation using multi-modal fusion threedimensional computer graphics. Then, it was possible
to precisely examine surgical strategy.
6) Gamma knife radiosurgery
Gamma knife is a kind of devices for stereotactic
radiosurgery in which high doses of radiation aredelivered at one session and has been widely accepted
as one of treatment options for various intracranial
disorders such as brain tumors, vascular disorders andfunctional disorders. The first gamma knife in Japanwas introduced at our department and diverse clinicalresults have been published. Recently, less invasive
treatment has taking on an added significance in thefield of neurosurgery as well. Therefore, appropriate
combination of radical surgery and radiosurgery isnecessary to manage difficult-to-treat lesions such as
skull base tumors and deeply seated cerebral
arteriovenous malformations, and thus gamma knife
radiosurgery would play a more important role inneurosurgery. Further, technological progress has
refined treatment as an example of integration ofdiffusion tensor tractography which was firstly
attempted at our department. Such technologicalprogresses might contribute to better outcomes ofgamma knife radiosurgery in the future.

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References (2017)
1. Aihara K., Mukasa A., Nagae G., Nomura M.,
Yamamoto S., Ueda H., Tatsuno K., Shibahara J.,
Takahashi M., Momose T., Tanaka S., Takayanagi
S., Yanagisawa S., Nejo T., Takahashi S., Omata M.,
Otani R., Saito K., Narita Y., Nagane M.,
Nishikawa R., Ueki K., Aburatani H., Saito N.
Genetic and epigenetic stability of oligodendrogliomas at recurrence. Acta neuropathologica
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2. Fujitani S., Ishikawa O., Miura K., Takeda Y., Goto
H., Maeda K. Factors predicting contralateral
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M., Suzuki T., Mishima K., Yanagisawa T., MukasaA., Saito N., Kanamori M., Kumabe T., Tominaga
T., Nagane M., Iuchi T., Yoshimoto K., Mizoguchi
M., Tamura K., Sakai K., Sugiyama K., Nakada M.,
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4. Hana T., Tanaka S., Nakatomi H., Shojima M.,
Fukumoto S., Ikemura M., Saito N. Definitive
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64(10):1033-1039, 2017
5. Hasegawa H., Hanakita S., Shin M., Shojima M.,
Koga T., Takahashi W., Sakuramachi M., Nomoto
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Smaller outer diameter of atherosclerotic middle
cerebral artery associated with RNF213 c.
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Int 8:104, 2017
7. Ibayashi K., Kunii N., Kawai K., Saito N. A Secure
Approach to the Inferior Horn Using the Deep
Medullary Vein as an Anatomic Guide. World
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from the motor cortices to the subthalamic nucleus
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10. Kimura T., Koizumi S., Ohshima A., Inoue T.
Indocyanine green visualization "during" craniotomy for moyamoya disease. Acta Neurochir(Wien) 159(8):1493-1494, 2017
11. Kin T., Nakatomi H., Shono N., Nomura S., Saito
T., Oyama H., Saito N. Neurosurgical Virtual
Reality Simulation for Brain Tumor Using Highdefinition Computer Graphics: A Review of the
Literature. Neurol Med Chir (Tokyo) 57(10):513520, 2017
12. Ko S., Nakazawa A., Kurose Y., Harada K.,
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scaling. Neurosurg Focus 42(5):E5, 2017
13. Koizumi S., Takai K., Shojima M., Kunimatsu A.,
Ishii K., Imai H., Nakatomi H., Saito N. Spinal
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Takai K., Shibahara J., Ikegami M., Nakao Y.,
Takeshita K., Matsutani M., Saito N. Successfultreatment of mixed yolk sac tumor and mature
teratoma in the spinal cord: case report. J
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Tanaka M., Saito N., Lohse C. M., Driscoll C. L.
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21. Ono H., Inoue T., Suematsu S., Tanishima T.,
Tamura A., Saito I., Saito N. Middle cerebral artery
dissection causing subarachnoid hemorrhage andcerebral infarction: Trapping with high-flow
bypass preserving the lenticulostriate artery. Surg
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23. Raja E., Komuro A., Tanabe R., Sakai S., Ino Y.,
Saito N., Todo T., Morikawa M., Aburatani H.,
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ALK-2 and DLX2 regulates apoptosis in gliomainitiating cells. Oncogene 36(35): 4963-4974,
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24. Shimada S., Kunii N., Kawai K., Matsuo T.,
Ishishita Y., Ibayashi K., Saito N. Impact ofvolume-conducted potential in interpretation ofcortico-cortical evoked potential: Detailed analysis
of high-resolution electrocorticography using twomathematical approaches. Clin Neurophysiol
128(4):549-557, 201725. Shin M., Kondo K., Hanakita S., Hasegawa H.,
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31(3):250-259, 2017
29. Takanashi S., Sakka M., Sato I., Watanabe S.,
Tanaka S., Ooshio A., Saito N., Kamibeppu K.
Factors influencing mother-child communication
about fathers with neurobehavioural sequelae after
brain injury. Brain injury 31(3):312-318, 201730. Takayanagi S., Mukasa A., Tanaka S., Nomura M.,
Omata M., Yanagisawa S., Yamamoto S., Ichimura
K., Nakatomi H., Ueki K., Aburatani H., Saito N.
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between von Hippel-Lindau disease-related andsporadic hemangioblastomas of the central nervous
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M., Shinohara N., Shuin T., Saito N. Developmentof Database and Genomic Medicine for vonHippel-Lindau Disease in Japan. Neurol Med

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Chir (Tokyo) 57(2):59-65, 201732. Torazawa S., Hasegawa H., Kin T., Sato H., Sora S.
Long-Term Patency of Posterior Auricular ArteryMiddle Cerebral Artery Bypass for Adult-Onset
Moyamoya Disease: Case Report and Review of
Literature. World Neurosurg 108:994.e991994.e995, 2017

Social Medicine
1. Occupational, Environmental
and Preventive Medicine

110

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

Lecturer
Satoshi Ueha, Ph. D.

Assistant professor
Takeshi Shimaoka, Ph.D.,

Yuya Terashima, Ph.D.

Project Assistant professor
Etsuko Toda, Ph.D.

Homepage

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

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

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

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

111

References
1: Ueha S, Yokochi S, Ishiwata Y, Kosugi-Kanaya M,
Shono Y, Shibayama S, Ito S, Matsushima K.
Combination of anti-CD4 antibody treatment anddonor lymphocyte infusion ameliorates graftversus-host disease while preserving graft-versustumor effects in murine allogeneic hematopoietic
stem cell transplantation. Cancer Sci. 2017 Oct;108(10):1967-1973.
2: Kosugi-Kanaya M, Ueha S, Abe J, Shichino S,
Shand FHW, Morikawa T, Kurachi M, Shono Y,
Sudo N, Yamashita A, Suenaga F, Yokoyama A,
Yong W, Imamura M, Teshima T, Matsushima K.
Long-Lasting Graft-Derived Donor T Cells
Contribute to the Pathogenesis of Chronic Graftversus-Host Disease in Mice. Front Immunol.
2017 Dec 18;8:1842.
3: Shichino S, Abe J, Ueha S, Otsuji M, Tsukui T,
Kosugi-Kanaya M, Shand FH, Hashimoto S,
Suzuki HI, Morikawa T, Inagaki Y, Matsushima K.
Reduced supply of monocyte-derived macrophages leads to a transition from nodular todiffuse lesions and tissue cell activation in silicainduced pulmonary fibrosis in mice. Am J Pathol.
2015 Nov;185(11):2923-38.
4: Tsukui T, Ueha S, Shichino S, Inagaki Y,
Matsushima K. Intratracheal cell transfer demonstrates the profibrotic potential of resident fibroblasts in pulmonary fibrosis. Am J Pathol. 2015
Nov;185(11):2939-48.
5: 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.
6: 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.

7: Tomura M, Hata A, Matsuoka S, Shand FH,
Nakanishi Y, Ikebuchi R, Ueha S, Tsutsui H, Inaba
K, Matsushima K, Miyawaki A, Kabashima K,
Watanabe T, Kanagawa O. Tracking and quantification of dendritic cell migration and antigen
trafficking between the skin and lymph nodes. Sci
Rep. 2014 Aug 12;4:6030.
8: Yoshie O, Matsushima K. CCR4 and its ligands:
from bench to bedside. Int Immunol. 2015 Jan;27(1):11-20.
9: 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.
10: 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.
11: 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.
12: 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.

112

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

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

Project Associate Professor
Jung Su Lee, Ph.D.

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

Associate
Masayoshi Zaitsu, M.D., Ph.D. (seconded to Harvard University)
Taeko Oguma, M.D., Ph.D.

Homepage

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

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

Health (Department of Health Policy) and remained
being a part of Division of Social Medicine(Department of Public Health).
The objectives of the Department are botheducation and research of public health. The
Department trains graduate and undergraduate
students through lectures, seminars, field practice, andlaboratory work in public health and occupational
medicine, for the degrees of Medical Doctor (MD),Master of Public Health (MPH), and Doctor of
Medical Sciences (equivalent to PhD). The
Department has conducted research on a wide variety
for public health issues, including health policy andeconomics, occupational medicine, clinical epidemiology, health services research, and so on. In addition,
the staff members of the Department have offeredpublic and occupational health services to the governments, industries, and local communities.
In the academic year of 2017, the Department
consists of six faculty members above listed, one
project lecturer (part-time), three project researchers

113(1 full-time, 2 part-time), 2 supporting staff, 12
graduate students (11in PhD program and 1 temporary
supervised), 19 part-time lecturers, and 29 visiting
fellows.

Teaching activities
1) Undergraduate Program (Medical School)
In the winter term of the fourth grade in School of
Medicine (M2), students are provided with thefollowing lectures; current issues of public health,preventive services, epidemiology, evidence based
medicine (EBM), health economics, quality of care,
community medicine, infection and tuberculosis
control, mental health, human ecology, global health,current health policy and administration in Japan, andso on. Similarly, in the sixth grade (M4), an intensive
course of public health (e.g., health care systems,
current health policy, occupational and environmental
health, nutritional epidemiology, and health services
research) is provided. All the above lectures are given
by faculty members and part-time lectures including
governmental officials and health practitioners.
Field practice and laboratory work in public healthis due in the summer term of the fifth grade (M3),which is jointly provided by 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 (more than 40 courses) are given by
those departments affiliated with School of Public
Health. Among them, our Department offers threecourses; “Health Policy”, “Public Health Preparedness”, and “Public Health Practice”.

3) PhD Program
The Department offers special lectures, seminars,
field practice, and laboratory work on public healthand occupational medicine to graduate students. In
these training, special emphasis has been placed on
the following points: (1) how to conduct epidemiological studies, (2) how to use epidemiological andstatistical methods, (3) how to use economic concepts
and methods in the health fields, (4) how to establish
the collaboration with health professionals in thevarious fields, and (5) how to read and write original
papers.

Research activities
1) Health policy and economics
Our research activities focus on the topics of healthcare system and economics in general. We have
performed and published those studies related tosupply and demand sides of health services in Japan;such as supply and distribution of physicians, accessto health care, cost studies of outpatient and inpatient
services, and the efficiency and equity issues of theJapan's health insurance system as well as universal
health coverage system. We also conduct research on
quality of care (cancer, diabetes, and osteoporosis).
These studies have been published in health policy
and health services research journals. We havecontinued a collaborative study on a system of
HIV/AIDS care with the introduction of highly active
anti-retroviral therapy (HAART) in developing
countries, since such a system involves medical,
behavioral, social, and economic factors, and would
inevitably become an important health policy issue.
2) Occupational health
We have carried on a longitudinal study on life-style,socio-economic status, occupational stress, and healthstatus of workers in various occupational settings forthe purpose of preventing occupational and life-stylediseases.
3) Others
Other research activities include, (1) evaluation ofdisaster preparedness in local communities and healthcare facilities, (2) study on risk communication in
public health emergencies, and (3) epidemiological114

study on incidence and survival rate of children withcerebral palsy.

8.

References
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Zaitsu M, Kurita Y, Iwahana M, Akiyama H,
Watanabe F, Higashikawa A, Kaneko R, Konishi
R, Itoh M, Kobayashi Y. Hypnotics use and falls
in hospital inpatients stratified by age. Global
Journal of Health Science 9(4): 148-155, 2017.
doi: org/10.5539/gjhs.v9n4p148.
Miyawaki A, Tomio J, Kobayashi Y, Takahashi H,
Noguchi H, Tamiya N. Impact of long-hours
family caregiving on non-fatal coronary heartdisease risk in middle-aged people: Results froma longitudinal nationwide survey in Japan.
Geriatrics Gerontology International 17(11):2109-2115, 2017. doi: 10.1111/ggi.13061.
Morioka N, Tomio J, Seto T, Kobayashi Y. The
association between higher nurse staffing
standards in the fee schedules and the geographic
distribution of hospital nurses: A cross-sectional
study using nationwide administrative data. BMC
Nursing doi: 10.1186/s12912-017-0219-1, 2017.
Tanaka H, Toyokawa S, Tamiya N, Takahashi H,
Noguchi H, Kobayashi Y. Changes in mortality
inequalities across occupations in Japan: anational register based study of absolute andrelative measures, 1980-2010. BMJ Open doi:
10.1136/bmjopen-2016-015764, 2017.
Miyawaki A, Noguchi H, Kobayashi Y. Impact of
medical subsidy disqualification on children’s
healthcare utilization: A difference-in-differences
analysis from Japan. Social Science & Medicine
191: 89–98, 2017 doi: 10.1016/j.socscimed.2017.
09.001.
Sugiyama T, Goryoda S, Inoue K, SugiyamaIhana N, Nishi N. Construction of a simulation
model and evaluation of the effect of potential
interventions on the incidence of diabetes andinitiation of dialysis due to diabetic nephropathy
in Japan. BMC Health Services Research 17(1):833, 2017. doi: 10.1186/s12913-017-2784-0.
Kinoshita Y, Ishikawa A, Hara K, Sugihara T,
Ishibashi Y, Homma Y. Plasma cell neoplasm as arisk factor for early thrombosis of arteriovenous
fistula. Hemodialysis International doi: 10.1111/

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hdi.12581 Epub 2017 Aug 1.
Pei L, Toyokawa S, Kobayashi Y. Labor factor
barriers to seeking medical services among
metropolitan workers: A cross-sectional analysis
by sex using the J-SHINE study. Journal of
Occupational Health 59(5): 418-427, 2017. doi:
10.1539/joh.16-0242-OA.
Itoh M, Tomio J, Toyokawa S, Tamura M,
Isojima T, Kitanaka S, Kobayashi Y. Vitamin
D-Deficient Rickets in Japan. Global PediatricHealth 4: 1-5, 2017. doi: 10.1177/2333794X
17711342
Tomio J, Yamana H, Matsui H, Yamashita H,
Yoshiyama T, Yasunaga H. Tuberculosis
screening prior to anti-tumor necrosis factor
therapy among patients with immune-mediatedinflammatory diseases in Japan: a longitudinal
study using a large-scale health insurance claims
database. International Journal of Rheumatic
Diseases 20(11): 1674-1683, 2017. doi: 10.1111/
1756-185X.13190.
Tomio J, Nakahara S, Takahashi H, Ichikawa M,
Nishida M, Morimura N, Sakamoto T. Effectiveness of Prehospital Epinephrine Administration in Improving Long-term Outcomes ofWitnessed Out-of-hospital Cardiac Arrest
Patients with Initial Non-shockable Rhythms.
Prehospital Emergency Care 21(4): 432-441,
2017. doi:10.1080/10903127.2016.1274347.
Inada H, Tomio J, Nakahara S, Xu X, Taniguchi
A, Ichikawa M. National 10-year trend in roadinjuries involving school children on the way toand from school in Japan, 2003-2012. Injury
Prevention 23(5): 297-302, 2017. doi:10.1136/
injuryprev-2016-042042.
Mishra GD, Lee JS, Hayashi K, Watanabe E,
Mori K, Kawakubo K. How do health behaviors
relate to dietary practice patterns among Japanese
adults? Asia Pacific Journal of Clinical Nutrition(APJCN) 26(2): 351-357, 2017. doi: 10.6133/
apjcn.022016.01.
Hino K, Lee JS, Asami Y. Associations between
seasonal meteorological conditions and the daily
step count of adults in Yokohama, Japan: Resultsof year-round pedometer measurements in a large
population. Preventive Medicine Reports 8:
15-17, 2017. doi: 10.1016/j.pmedr.2017.07.0097.

115

15. Ideno Y, Hayashi K, Abe Y, Ueda K, Iso H,
Kiyohara Y, Noda M, Lee JS, Suzuki S. Blood
Pressure-lowering Efficacy of Shinrin-yoku(Forest Bathing): A Systematic review and metaanalysis. BMC Complementary and Alternative
Medicine (BCAM) 17: 409, 2017. DOI 10.1186/
s12906-017-1912-z.
16. Mishra GD, Pandeya N, Dobson AJ, Chung HF,
Anderson D, Kuh D, Sandin S, Giles GG,
Bruinsma F, Hayashi K, Lee JS, Mizunuma H,
Cade JE, Burley V, Greenwood DC, Goodman A,
Simonsen MK, Adami HO, Demakakos P,
Weiderpass E. Early Menarche Nulliparity, andthe Risk for Premature and Early Natural
Menopause: Results from Pooled Analysis of
Data from 51,126 Women. Human Reproduction
32(3): 679-686, 2017. doi:10.1093/humrep/dew
350.
17. Katanoda K, Noda M, Goto A, Mizunuma H, Lee
JS, Hayashi K. Impact of birth weight on
adult-onset diabetes mellitus in relation to current
body mass index: The Japan Nurses' Health Study.
J Epidemiol. 27(9):428-434, 2017. doi:10.1016/j.
je.2016.08.016.
18. Hasegawa H, Hanakita S, Shin M, Sugiyama T,
Kawashima M, Takahashi W, Nomoto AK,
Shojima M, Nakatomi H, Saito N. Does
Advanced Age Affect the Outcomes of Stereotactic Radiosurgery for Cerebral Arteriovenous
Malformation? World Neurosurgery doi: 10.
1016/j.wneu.2017.10.071. Epub 2017 Oct 21.
19. Tsujimoto T, Kajio H, Sugiyama T. Statin
Therapy in Patients with Low Serum Levels of
Low-Density Lipoprotein Cholesterol. American
Journal of Cardiology 120(11): 1947-1954, 2017.
doi: 10.1016/j.amjcard.2017.08.011.
20. Tsujimoto T, Kajio H, Sugiyama T. Association
Between Caffeine Intake and All-Cause andCause-Specific Mortality: A Population-Based
Prospective Cohort Study. Mayo Clinic Proceedings 92(8): 1190-1202, 2017. doi: 10.1016/j.
mayocp.2017.03.010.
21. Tsujimoto T, Sugiyama T, Shapiro MF, Noda M,
Kajio H. Risk of Cardiovascular Events inPatients With Diabetes Mellitus on β-Blockers.
Hypertension 70(1):103-110, 2017. doi: 10.1161/
HYPERTENSIONAHA.117.09259.

22. Tsujimoto T, Kajio H, Sugiyama T. Association
between hyperinsulinemia and increased risk ofcancer death in nonobese and obese people: A
population-based observational study. International Journal of Cancer 141(1):102-111, 2017.
doi: 10.1002/ijc.30729.
23. Ihana-Sugiyama N, Yamamoto-Honda R,
Sugiyama T, Tsujimoto T, Kakei M, Noda M.
Cross-Over Study Comparing Postprandial
Glycemic Increase After Addition of a FixedDose Mitiglinide/Voglibose Combination or a
Dipeptidyl Peptidase-4 Inhibitor to Basal Insulin
Therapy in Patients with Type 2 Diabetes
Mellitus. Medical Science Monitor Basic Research 23: 36–44, 2017. doi: 10.12659/MSMBR.
902218.
24. Tsujimoto T, Sugiyama T, Kajio H. Effects of
β-blockers on all-cause mortality in patients with
type 2 diabetes and coronary heart disease.
Diabetes, Obesity & Metabolism 19(6):800-80,
2017. doi: 10.1111/dom.12878.
25. Zaitsu M, Kawachi I, Takeuchi T, Kobayashi.
Alcohol consumption and risk of upper-tract
urothelial cancer. Cancer Epidemiology 48(2017): 36-40, 2017. doi: org/10.1016/j.canep.
2017.03.002.
26. Maeda E, Ishihara O, Tomio J, Sato A, Terada Y,
Kobayashi Y, Murata K. Cesarean section rates
and local resources for perinatal care in Japan: A
nationwide ecological study using the national
database of health insurance claims. Obstetrics
and Gynaecology Research doi: 10.1111/jog.
13518. Epub 2017 Nov 2.
27. Okamoto M, Kobayashi Y, Nakamura F.
Association Between Nonrestorative Sleep and
Risk of Diabetes: A Cross-Sectional Study.
Behavioral Sleep Medicine 15:483-490, 2017.
doi: 10.1080/15402002.2016.1163701.
28. Toyokawa S, Maeda E, Kobayashi Y. Estimationof the number of children with cerebral palsy
using nationwide health insurance claims data inJapan. Developmental Medicine & Child Neurology 59(3):317-321, 2017. doi: 10.1111/dmcn.
13278.
29. Sugiyama T, Miyo T, Tsujimoto T, Kominami R,
Ohtsu H, Ohsugi M, Waki K, Noguchi T, Ohe K,
Kadowaki T, Kasuga M, Ueki K, Kajio H. Design

116

of and rationale for the Japan Diabetes
comprehensive database project based on an
Advanced electronic Medical record System(J-DREAMS). Diabetology International 8: 375382, 2017.

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

118

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

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

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

Homepage

http://ut-forensic.jp/

Introduction and Organization
Associate Professor Kuniyoshi Katayama lectured“judicial medicine” in the University of Tokyo since1881 before our department was founded as the firstdepartment of forensic medicine in Japan in 1889. He
renamed “judicial medicine” to “forensic medicine” in1891 since the department should cover legislation as
well as general forensic practices. Dr. Katayama
became the first professor of forensic medicine inJapan.
The 2nd Professor Sadanori Mita also founded theserological department (Department of Immunology atpresent). He studied the antigen-antibody reaction anddiscovered complement fixation reaction.
The 3rd Professor Tanemoto Furuhata was very
famous for ABO blood group genetics, and also
contributed to the development of criminology. He
autopsied several cases of historical crimes.
The 4th Professor Shokichi Ueno discovered acomplex complement. He helped foundation ofnational police academy for death investigators.
The 5th Professor Toshiyuki Miki could not perform
autopsy for four years due to the University of Tokyo
strike. However, he left many achievements in thefield of blood typing and paternity examination.
The 6th Professor Ikuo Ishiyama encouraged
forensic pathology. He also introduced DNA fingerprinting and PCR technique in the forensic practices.
The 7th Professor Takehiko Takatori studied thebiochemical changes of the lipid in cadavers. He

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

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

119

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

Research
In cooperation with other universities including
Chiba University and Tokyo Medical and Dental
University, researches in 6 sections (forensic
pathology, clinical forensic medicine, forensic
toxicology, forensic radiology, forensic odontology
and forensic genetics) have proceeded.
1. Forensic Pathology
In autopsy, it is difficult to examine a vertebral
artery. We therefore conduct study on a method of
the artery using angioscopy. We also conduct
research about the usefulness of coronary
angiography using 3D-CT. As to pathologicalresearch, we investigate about the lipid peroxidationin the cases of stimulant intoxication and crash
syndrome.
2. Clinical Forensic Medicine
We have started to liaise with child consultation
centers to examine children suspected of suffering
abuse. We will also collaborate with otherinstitutions to establish a framework for child abuse
examinations in Chiba Prefecture. Through these
activities, we will continue to work to establish thepractice of clinical forensic medicine while
educating students and conducting research on theprevention of child abuse, with the objective of
laying the foundations for the discipline of clinicalforensic medicine in Japan.
3. Forensic Toxicology
Using LC/MS/MS and LC/QTOF-MS themethods to detect illegal drugs are investigated. We
also conduct study on the post-mortem
redistribution of some drugs by experiments using
animals. We try to figure out the standardized
method of drug testing in the field of Japanese
forensic medicine.
4. Forensic Odontology
A new method of personal identification (ageestimation and DNA testing) and drug analysis
using a single tooth at once is developed.
5. Forensic Genetics
We try to find gene alterations that cause asudden death of an individual. We also try to figureout new methods to predict the birth place of the
cadaver by analyzing the DNA types of parasites.
6. Forensic Radiology
Using 3D-CT, we develop new methods toperform stature and sex estimation using themeasurements of various bones. We investigate themerit and demerit of post-mortem imaging todetermine the cause of death.

Publications
1. Rutsuko Yamaguchi, Yohsuke Makino, FumikoChiba, Suguru Torimitsu, Daisuke Yajima, Go
Inokuchi, Ayumi Motomura, Mari Hashimoto,
Yumi Hoshioka, Tomohiro Shinozaki, Hirotaro
Iwase. Frequency and influencing factors ofcardiopulmonary resuscitation-related injuries
during implementation of the American Heart
Association 2010 Guidelines: a retrospective
study based on autopsy and postmortem
computed tomography. Int J Legal Med. 2017;
131: 1655-1663

120

2. Torimitsu S, Makino Y, Saitoh H, Sakuma A, Ishii
N, Yajima D, Inokuchi G, Motomura A, Chiba F,
Yamaguchi R, Hashimoto M, Hoshioka Y, Iwase
H. Stature estimation in a contemporary Japanese
population based on clavicular measurements
using multidetector computed tomography.
Forensic Sci Int. 2017; 275: 316.e1-316.e6.
3. Torimitsu S, Makino Y, Saitoh H, Sakuma A, Ishii
N, Yajima D, Inokuchi G, Motomura A, Chiba F,
Yamaguchi R, Hoshioka Y, Iwase H. Sex
assessment based on clavicular measurements in amodern Japanese population using multidetector
computed tomography. Forensic Sci Int. [Epubahead of print]
4. Torimitsu S, Makino Y, Saitoh H, Ishii N, Yajima
D, Inokuchi G, Motomura A, Chiba F, Yamaguchi
R, Hoshioka Y, Iwase H. Determination of sex on
the basis of hyoid bone measurements in a
Japanese
populationusing
multidetector
computed tomography. Int J Legal Med. [Epubahead of print]
5. Makino Y, Yokota H, Nakatani E, Yajima D,
Inokuchi G, Motomura A, Chiba F, Torimitsu S,
Uno T, Iwase H. Differences between postmortem
CT and autopsy in death investigation of cervicalspine injuries. Forensic Sci Int, 281:44–51, 2017.
6. Chiba F, Inokuchi G, Makino Y, Torimitsu S,
Motomura A, Yamaguchi R, Hashimoto M,
Hoshioka Y, Nasgasawa S, Sakuma A, Yajima D,
Saito H, Iwase H. Postmortem angiography
revealing traumatic rupture of the intracranialinternal carotid artery. Int J Legal Med [Epubahead of print] http://doi/ 10.1007/s00414-0171752-x
7. Abe H, Yajima D, Hoshioka Y, Nara A, Nagasawa
S, Iwase H. Myoglobinemia markers withpotential applications in forensic sample analysis:
lipid markers in myoglobinemia for postmortem
blood. Int J Legal Med. 2017;131(6):1739-1746.
8. Kinoshita H, Tanaka N, Takakura A, Abe H,
Kumihashi M, Shibayama T, Jamal M, Ito A,
Tsutsui K, Kimura S, Iwase H, Ameno K. An
autopsy case of death by combined use of
benzodiazepines and diphenidine. Soud Lek. 2017
Winter; 62(4):40-43.

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

Assistant Professor
Katsuya Tanaka, Ph.D., Hidenao Atarashi, M.P.H, Ph.D., Yoshimasa Kawazoe, M.D., Ph.D.

Homepage

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

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

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

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

Medical Informatics in the Medical Science
Graduate Program: Graduate School of Medicine,the University of Tokyo, offers the master course in
Medical Sciences. The course was established forstudents who graduate from faculties other than a
6-year program at Faculty of Medicine andeventually wish to advance to the Medical Sciences
doctoral course of the University of Tokyo.
The students in FY2017 are five in doctor’s course for
Biomedical Informatics.
The researches cover various topics; developmentof medical decision support system, analysis of
medical human resources in Japan, research for
medical and e-Phenotyping in large healthcare
database, etc.

Research activities
The research domains are 1) application studies ondevelopments of clinical information systems, hospital
information system and electronic health records
system, 2) medical knowledge discovery fromdatabases of hospital information system, 3) structured
representations and standardization of medical terms
and concepts, 4) privacy protection and security inhealthcare information systems, 5) analysis of
localization and restructuring of medical humanresources.
In these domains, major research topics are as listed
below.
1) A study on development of large scale ontology
databases of medical terms and concepts anddevelopment of application systems using theontology: This research is to develop a methods tobuild a large scale medical ontology, which is adatabase for hundreds of thousand of clinicalterms and concepts and their relationships. The
medical ontology covers over 6000 diseases andwhole of human anatomical structures using
HOZO ontology describing tool, and the ontology
was converted from the HOZO-proprietary XML
data format into the LOD format. Using the LOD
format, a web application for browsing the disease
ontology was developed and published on the website; http://lodc.med-ontology.jp/
2) Development of Multi-purpose Clinical Data

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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. Yokota S, Endo M, Ohe K. Establishing aClassification System for High Fall-Risk Among
Inpatients Using Support Vector Machines. CIN:
Computers, Informatics, Nursing. 2017;35(8).
408-416.
2. Takehiro Sugiyama, Kengo Miyo, Tetsuro
Tsujimoto, Ryota Kominami, Hiroshi Ohtsu,
Mitsuru Ohsugi, Kayo Waki, Takashi Noguchi,
Kazuhiko Ohe, Takashi Kadowaki, Masato
Kasuga, Kohjiro Ueki, Hiroshi Kajio : Design ofand rationale for the Japan Diabetes
compREhensive database project based on an
Advanced electronic Medical record System(J-DREAMS), Diabetology International, 27.06.
2017
3. Watanabe H, Kimura M, Ohe K. Survey on Usageof Medical Referral Information in JapanesePhysicians. Healthc Inform Res. 2017 Apr;23(2):126-134.
4. Yokota S, Endo M, Ohe K. Establishing aclassification system for high fall risk among
inpatients using support vector machines. Comput
Inform Nurs. 2017 Aug;35(8):408-416.
5. Hayashi A, Yamaguchi S, Waki K, Fujiu K,
Hanafusa N, Nishi T, Tomita H, Kobayashi H,
Fujita H, Kadowaki T, Nangaku M, Ohe K.:
Testing the Feasibility and Usability of a Novel
Smartphone-Based Self-Management Support
System for Dialysis Patients: A Pilot Study. JMIRRes Protoc. 2017 Apr 20;6(4):e63. doi: 10.2196/
resprot.7105.
6. Shibuta T, Waki K, Tomizawa N, Igarashi A,
Yamamoto-Mitani N, Yamaguchi S, Fujita H.
Kimura S, Fujiu K, Waki H, Izumida Y, Sasako T,
Kobayashi M, Suzuki R, Yamauchi T, Kadowaki T,
Ohe K.: Willingness of patients with diabetes touse an ICT-based self-management tool: a crosssectional study. BMJ Open Diabetes Res Care.
2017 Feb 7;5(1):e000322. doi: 10.1136/bmjdrc2016-000322. eCollection 2017.

Internal Medicine
1. Medicine Ⅰ125

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

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

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

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

Jiro Andoh, M.D.

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

Homepage

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

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

Introduction and Organization
The Department of Cardiovascular Medicine wasestablished in 1998 by regrouping cardiologists of fiveprevious internal medical departments. After Yoshio
Yazaki, the first professor, and Ryozo Nagai, thesecond professor, the present professor Issei Komuro
was elected in August, 2012. Our department
comprises one professor, 4 lecturers, 2 hospital
lecturers, 15 research assistants, 10 staff members, and
45 graduate school students.

Clinical activities
The Department of Cardiovascular Medicine isactively involved in clinical medicine, basic researchand teaching. Not only do we have the most advanced
equipment and facilities (e.g., 24-hour cardiac careunit), but our personnel are also highly trained to beknowledgeable and experts in modern methods ofdiagnosis and treatment. Especially, we make a special
effort to treat patients with severe heart failures. As ateaching and research hospital, we also emphasize thedevelopment and integration of new treatment
methods if they may be beneficial to patients.
In 2017, a total of 1,923 patients were newly
admitted to our hospital ward of 63 beds. The average
duration of hospitalization was 12.1 days.

Because we are an authorized facility for hearttransplantation, the use of left ventricular assist device
in cases of severe heart failure has been increasing. In
2006, the first patient with heart failure from ourdepartment underwent a heart transplant procedure atthe Department of Cardiovascular Surgery. In 2017,17 patients underwent heart transplant (total 95 cases).
In March 2014, our facility was also authorized toperformlungtransplantation.
Cardiovascularangiography was performed in 1,343 patients, ofwhich 476 patients underwent interventional
procedures.
CTcoronary
angiography
andcardiovascular MRI were performed in 454 and 85
patients, respectively. With regard to arrhythmias,
there were 274 cases of catheter ablation, 114 cases of
implantation or replacement of pacemakers and otherspecialized pacemaker devices, including 34 cases of
implantation or replacement of implantablecardioverter-defibrillator and 32 cases of implantation
or replacement of a cardiac resynchronization device.
Out-patient clinics are available as a specialized
department and as part of the Department of Medicine.
Out-patient clinics are open in the mornings and afternoons from Monday to Friday, and approximately
202.0 patients visit each day. The disease profile includes ischemic heart disease, heart failure, arrhythmia. hypertension and peripheral artery disease, There126

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

and adult congenital heart disease
11. New treatments for pulmonary hypertension
12. New treatments for congenital heart disease
13. Aerobic threshold and cardiac rehabilitation
14. Imaging techniques (echocardiography, MRI, CT,
and SPECT) in cardiovascular diseases

Education

Publications (2017)

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

1. Abe H, Semba H, Takeda N. The roles of hypoxia
signaling in the pathogenesis of cardiovasculardiseases. J Atheroscler Thromb. 2017;1;24(9):884-94.
2. Adachi Y, Kinoshita O, Hatano M, Shintani Y,
Naito N, Kimura M, Nawata K, Nitta D, Maki H,
Ueda K, Amiya E, Takimoto E, Komuro I, Ono M.
Successful bridge to recovery in fulminant
myocarditis using a biventricular assist device: acase report. J Med Case Rep. 2017;24;11(1):295.
3. Amiya E, Morita H, Ishiura H, Tsuji S, Komuro I.
Authors' response to "Compound heterozygous
Fukutin mutation-related non-compaction" byFinsterer and Zarrouk-Mahjoub. Int J Cardiol.
2017;15;233:102.
4. Amiya E. ICD for patients with severe renal
dysfunction. Int Heart J. 2017;31;58(3):303-4.
5. Aoyama N, Suzuki JI, Kobayashi N, Hanatani T,
Ashigaki N, Yoshida A, Shiheido Y, Sato H,
Kumagai H, Ikeda Y, Akazawa H, Komuro I,
Izumi Y, Isobe M. Periodontitis deteriorates
peripheral arterial disease in Japanese population
via enhanced systemic inflammation. Heart
Vessels. 2017;32(11):1314-9.
6. Aoyama N, Suzuki JI, Kobayashi N, Hanatani T,
Ashigaki N, Yoshida A, Shiheido Y, Sato H,
Kumagai H, Ikeda Y, Akazawa H, Komuro I,
Minabe M, Izumi Y, Isobe M. A peptide vaccine
targeting angiotensin II attenuates the cardiac
dysfunction induced by myocardial infarction. Sci
Rep. 2017;7:43920.
7. Aoyama N, Suzuki JI, Kobayashi N, Hanatani T,
Ashigaki N, Yoshida A, Shiheido Y, Sato H,
Kumagai H, Ikeda Y, Akazawa H, Komuro I,
Minabe M, Izumi Y, Isobe M. Detrimental effectsof specific periodontopathic bacterial infection ontachyarrhythmia compared to bradyarrhythmia.
BMC Cardiovasc Disord. 2017;17(1):267.

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

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8. Caine C, Shohat M, Kim JK, Nakanishi K,
Homma S, Mosharov EV, Monani UR. A
pathogenic S250F missense mutation results in amouse model of mild aromatic l-amino aciddecarboxylase (AADC) deficiency. Hum Mol
Genet. 2017;26(22):4406-15.
9. Costet A, Melki L, Sayseng V, Hamid N,
Nakanishi K, Wan E, Hahn R, Homma S,
Konofagou E. Electromechanical wave imaging
and electromechanical wave velocity estimation ina large animal model of myocardial infarction.
Phys Med Biol. 2017;62(24):9341-56.
10. Dos Santos MR, Saitoh M, Ebner N, Valentova M,
Konishi M, Ishida J, Emami A, Springer J, Sandek
A, Doehner W, Anker SD, von Haehling S.
Sarcopenia and endothelial function in patientswith chronic heart failure: results from the studies
investigating comorbidities aggravating heart
failure (SICA-HF). J Am Med Dir Assoc. 2017;18(3):240-5.
11. Goodwin J, Neugent ML, Lee SY, Choe JH, Choi
H, Jenkins DMR, Ruthenborg RJ, Robinson MW,
Jeong JY, Wake M, Abe H, Takeda N, Endo H,
Inoue M, Xuan Z, Yoo H, Chen M, Ahn JM,
Minna JD, Helke KL, Singh PK, Shackelford DB,
Kim JW. The distinct metabolic phenotype of lungsquamous cell carcinoma defines selective
vulnerability to glycolytic inhibition. Nat
Commun. 2017;8:15503.
12. Hara H, Takeda N, Morita H, Hatano M, Amiya E,
Maki H, Minatsuki S, Taki M, Shiraishi Y,
Fujiwara T, Maemura S, Komuro I. Three novel
B(MPR2 mutations associated with advanced
pulmonary arterial hypertension. Hum Genome
Var. 2017;4:17010.
13. Higo T, Naito AT, Sumida T, Shibamoto M, Okada
K, Nomura S, Nakagawa A, Yamaguchi T, Sakai T,
Hashimoto A, Kuramoto Y, Ito M, Hikoso S,
Akazawa H, Lee JK, Shiojima I, McKinnon PJ,
Sakata Y, Komuro I. DNA single-strand breakinduced dna damage response causes heart failure.
Nat Commun. 2017;8:15104.
14. Hirose K, Daimon M, Miyazaki S, Chiang SJ,
Morimoto-Ichikawa R, Maruyama M, Kawata T,
Ohmura H, Daida H. Estrogen variation during
the menstrual cycle does not influence left
ventricular diastolic function and untwisting ratein premenopausal women. J Cardiol. 2017;69(1):389-93.
15. Hori YS, Kodera S, Nagai Y, Suzuki Y. FulminantBacillus cereus septicaemia with multiple organ
ischaemic/haemorrhagic complications in apatient undergoing chemotherapy for acute
myelogenous leukaemia. BMJ Case Rep. 2017;10.
16. Ishida J, Konishi M, Saitoh M, Anker M, Anker
SD, Springer J. Myostatin signaling is upregulated in female patients with advanced heart
failure. Int J Cardiol. 2017;238:37-42.
17. Ishida J, Saitoh M, Doehner W, von Haehling S,
Anker M, Anker SD, Springer J. Animal models
of cachexia and sarcopenia in chronic illness:
Cardiac function, body composition changes andtherapeutic results. Int J Cardiol. 2017;238:12-8.
18. Ishimoto Y, Inagi R, Yoshihara D, Kugita M,
Nagao S, Shimizu A, Takeda N, Wake M,
Honda K, Zhou J, Nangaku M. Mitochondrial
abnormality facilitates cyst formation in
autosomal dominant polycystic kidney disease.
Mol Cell Biol. 2017 Oct 9. pii: MCB.00337-17.
19. Iuchi H, Sakamoto M, Matsutani D, Suzuki H,
Kayama Y, Takeda N, Utsunomiya K. Association
between day-by-day and ambulatory bloodpressure variability in type 2 diabetes patients.
Blood Press Monit. 2017;22(6):351-4.
20. Iuchi H, Sakamoto M, Matsutani D, Suzuki H,
Kayama Y, Takeda N, Minamisawa S,
Utsunomiya K. Time-dependent effects ofipragliflozin on behaviour and energy homeostasis
in normal and type 2 diabetic rats: continuous
glucose telemetry analysis. Sci Rep. 2017;7(1):11906.
21. Kamo T, Akazawa H, Suda W, Saga-Kamo A,
Shimizu Y, Yagi H, Liu Q, Nomura S, Naito AT,
Takeda N, Harada M, Toko H, Kumagai H, Ikeda
Y, Takimoto E, Suzuki JI, Honda K, Morita H,
Hattori M, Komuro I. Dysbiosis andcompositional alterations with aging in the gut
microbiota of patients with heart failure. PLoS
One. 2017;12(3):e0174099.
22. Kamo T, Akazawa H, Suzuki JI, Komuro I. Novel
concept of a heart-gut axis in the pathophysiologyof heart failure. Korean Circ J. 2017;47(5):663-9.
23. Katoh M, Takeda N, Arimoto T, Abe H, Oda K,
Osuga Y, Fujii T, Komuro I. Bevacizumab-related

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microvascular angina and its management withnicorandil. Int Heart J. 2017;58(5):803-5.
24. Kawata T, Daimon M, Lee SL, Kimura K, Sawada
N, Chiang SJ, Mahara K, Okubo T, Nakao T,
Hirokawa M, Xu B, Kato TS, Watanabe M,
Yatomi Y, Komuro I. Reconsideration of inferior
vena cava parameters for estimating right atrial
pressure in an east asian population - comparative
simultaneous ultrasound-catheterization study.
Circ J. 2017;81(3):346-52.
25. Kawata T, Daimon M, Kimura K, Nakao T, Lee
SL, Hirokawa M, Kato TS, Watanabe M, Yatomi
Y, Komuro I. Echocardiographic assessment ofright ventricular function in routine practice:which parameters are useful to predict one-year
outcome in advanced heart failure patients withdilated cardiomyopathy? J Cardiol. 2017;70(4):316-22.
26. Kiriyama H, Amiya E, Hatano M, Hosoya Y, Maki
H, Nitta D, Saito A, Shiraishi Y, Minatsuki S, SatoT, Murakami H, Uehara M, Manaka K, Makita N,
Watanabe M, Komuro I. Rapid improvement of
thyroid storm-related hemodynamic collapse by
aggressive anti-thyroid therapy including steroid
pulse: a case report. Medicine (Baltimore). 2017;
96(22):e7053.
27. Kodera S, Kiyosue A, Ando J, Akazawa H, Morita
H, Watanabe M, Komuro I. Cost-effectivenessanalysis of cardiovascular disease treatment injapan. Int Heart J. 2017;58(6):847-52.
28. Krzywinska E, Kantari-Mimoun C, Kerdiles Y,
Sobecki M, Isagawa T, Gotthardt D, Castells M,
Haubold J, Millien C, Viel T, Tavitian B, Takeda
N, Fandrey J, Vivier E, Sexl V, Stockmann C.
Loss of HIF-1α in natural killer cells inhibits
tumour growth by stimulating non-productive
angiogenesis. Nat Commun. 2017;8(1):1597.
29. Lin HC, Daimon M, Wang CH, Ho Y, Uang YS,
Chiang
SJ,
Wang
LH.
Allopurinol,
benzbromarone and risk of coronary heart disease
in gout patients: A population-based study. Int J
Cardiol. 2017;233:85-90.
30. Liu Q, Akazawa H. MicroRNA-99a. Int Heart J.
2017;58(3):310-2.
31. Lu Q, Schnitzler GR, Vallaster CS, Ueda K,
Erdkamp S, Briggs CE, Iyer LK, Jaffe IZ, Karas
RH. Unliganded estrogen receptor alpha regulates

vascular cell function and gene expression. Mol
Cell Endocrinol. 2017;442:12-23.
32. Matsuda J, Fujiu K, Roh S, Tajima M, Maki H,
Kojima T, Ushiku T, Nawata K, Takeda N,
Watanabe M, Akazawa H, Komuro I. Cardiac
sarcoidosis diagnosed by incidental lymph nodebiopsy. Int Heart J. 2017;58(1):140-3.
33. Momomura SI, Saito Y, Yasumura Y, Yamamoto K,
Sakata Y, Daimon M, Kinugawa K, Okamoto H,
Dohi N, Komuro I. Efficacy and safety ofswitching from oral bisoprolol to transdermal
patch in japanese patients with chronic heart
failure. Circ J. 2017;82(1):141-7.
34. Nagata N, Iwanari H, Kumagai H, Kusano-Arai O,
Ikeda Y, Aritake K, Hamakubo T, Urade Y.
Generation and characterization of an antagonistic
monoclonal antibody against an extracellulardomain of mouse DP2 (CRTH2/GPR44) receptors
for prostaglandin D2. PLoS One. 2017;12(4):e0175452.
35. Nagura F, Kodera S, Hayakawa N, Kushida S,
Kanda J. A case of congestive heart failure causedby secondary hypocortisolism. Clin Case Rep.
2017;5(5):630-5.
36. Nakanishi K, Di Tullio MR, Qian M, Thompson
JLP, Labovitz AJ, Mann DL, Sacco RL, Pullicino
PM, Freudenberger RS, Teerlink JR, Graham S,
Lip GYH, Levin B, Mohr JP, Buchsbaum R, Estol
CJ, Lok DJ, Ponikowski P, Anker SD, Homma S;
WARCEF Investigators. Resting heart rate andischemic stroke in patients with heart failure.
Cerebrovasc Dis. 2017;44(1-2):43-50.
37. Nakanishi K, Fukuda S, Tanaka A, Otsuka K,
Taguchi H, Shimada K. Relationships between
periventricular
epicardial
adiposetissueaccumulation, coronary microcirculation, and left
ventricular diastolic dysfunction. Can J Cardiol.
2017;33(11):1489-97.
38. Nakanishi K, Fukuda S, Yamashita H, Hasegawa
T, Kosaka M, Shirai N, Shimada K, Yoshikawa J,
Tanaka A. High-sensitive cardiac troponin T as anovel predictor for recurrence of atrial fibrillation
after radiofrequency catheter ablation. Europace.
2017;19(12):1951-7.
39. Nakanishi K, Jin Z, Homma S, Elkind MS,
Rundek T, Tugcu A, Yoshita M, DeCarli C,
Wright CB, Sacco RL, Di Tullio MR. Left ventri-

129

cular mass-geometry and silent cerebrovasculardisease: The cardiovascular abnormalities andbrain lesions (CABL) study. Am Heart J. 2017;
185:85-92.
40. Nakanishi K, Jin Z, Homma S, Elkind MSV,
Rundek T, Tugcu A, Sacco RL, Di Tullio MR.
Association of blood pressure control level withleft ventricular morphology and function and with
subclinical cerebrovascular disease. J Am Heart
Assoc. 2017;6(8).
41. Nakanishi K, Jin Z, Russo C, Homma S, Elkind
MS, Rundek T, Tugcu A, Sacco RL, Di Tullio MR.
Association of chronic kidney disease with
impaired left atrial reservoir function: A
community-based cohort study. Eur J Prev Cardiol.
2017;24(4):392-8.
42. Nakanishi K, Yoshiyama M, Homma S. Patent
foramen ovale and cryptogenic stroke. Trends
Cardiovasc Med. 2017;27(8):575-81.
43. Nakao T, Morita H. Omega-3 polyunsaturated
fatty acid and coronary atherosclerotic plaques.
Int Heart J. 2017;58(6):837-9.
44. Nitta D, Kinugawa K, Imamura T, Iino J, Endo M,
Amiya E, Hatano M, Kinoshita O, Nawata K, Ono
M, Komuro I. Association of the number of hla-drmismatches with early post-transplant acute
cellular rejection among heart transplantation
recipients: a cohort study in japanese population.
Transplant Proc. 2017;49(1):125-9.
45. Numata G, Amiya E, Kojima T, Fujiu K, Hatano
M, Watanabe M, Komuro I. Cardiac resynchronization therapy in patients with ebstein's
anomaly. Int Heart J. 2017;58(5):816-9.
46. Numata G, Kodera S, Kiriyama H, Nakayama A,
Amiya E, Kiyosue A, Hatano M, Takimoto E,
Watanabe M, Komuro I. Usefulness of central
venous saturation as a predictor of thiamine
deficiency in critically ill patients: a case report. J
Intensive Care. 2017;5:61.
47. Numata N, Makinae H, Yoshida W, Daimon M,
Murakami H. Disaster victim identification using
orthopedic implants in the 2011 east-japan earthquake and tsunami. Tohoku J Exp Med. 2017;
241(3):219-23.
48. Ohmae S, Noma N, Toyomoto M, Shinohara M,
Takeiri M, Fuji H, Takemoto K, Iwaisako K,
Fujita T, Takeda N, Kawatani M, Aoyama M,

Hagiwara M, Ishihama Y, Asagiri M. Actinbinding protein coronin 1A controls osteoclastic
bone resorption by regulating lysosomal secretionof cathepsin K. Sci Rep. 2017;7:41710.
49. Oshima T, Hara H, Takeda N, Hasumi E, Kuroda
Y, Taniguchi G, Inuzuka R, Nawata K, Morita H,
Komuro I. A novel mutation of NFIX causes
Sotos-like syndrome (Malan syndrome) complicated with thoracic aortic aneurysm and dissection.
Hum Genome Var. 2017;4:17022.
50. Saito A, Amiya E, Hatano M, Hosoya Y, Maki H,
Nitta D, Minatsuki S, Watanabe M, Komuro I.
Newly developed atrial fibrillation progresses to amore severe INTERMACS score in a patient withadvanced heart failure due to dilated cardiomyopathy. Clin Case Rep. 2017;5(12):2028-33.
51. Saitoh M, Ishida J, Doehner W, von Haehling S,
Anker MS, Coats AJS, Anker SD, Springer J.
Sarcopenia, cachexia, and muscle performance inheart failure: Review update 2016. Int J Cardiol.
2017;238:5-11.
52. Sakamoto A, Tanaka T, Hirano K, Koike K,
Komuro I. Immunoglobulin G4-related coronary
periarteritis and luminal stenosis in a patient witha history of autoimmune pancreatitis. Intern Med.
2017;56(18):2445-50.
53. Salim HM, Fukuda D, Higashikuni Y, Tanaka K,
Hirata Y, Yagi S, Soeki T, Shimabukuro M, Sata
M. Teneligliptin, a dipeptidyl peptidase-4
inhibitor, attenuated pro-inflammatory phenotype
of perivascular adipose tissue and inhibited
atherogenesis in normoglycemic apolipoproteinE-deficient mice. Vascul Pharmacol. 2017;96-98:
19-25.
54. Sato H, Suzuki JI, Aoyama N, Watanabe R,
Kaneko M, Shiheido Y, Yoshida A, Wakayama K,
Kumagai H, Ikeda Y, Akazawa H, Komuro I,
Isobe M, Izumi Y. A periodontal pathogen porphyromonas gingivalis deteriorates isoproterenolinduced myocardial remodeling in mice.
Hypertens Res. 2017;40(1):35-40.
55. Sawada N, Nakayama A, Takahashi M, Tanaka M,
Morita H, Akazawa H, Komuro I. Correct
diagnosis of wild-type transthyretin-related
amyloidosis followed by the introduction of anovel therapy in a patient with cardiac wall
thickening of unknown cause. Int Heart J. 2017;

130

58(1):147-50.
56. Suzuki JI, Sato H, Kaneko M, Yoshida A, Aoyama
N, Akimoto S, Wakayama K, Kumagai H, Ikeda Y,
Akazawa H, Izumi Y, Isobe M, Komuro I.
Periodontitis and myocardial hypertrophy.
Hypertens Res. 2017;40(4):324-8.
57. Suzuki J, Ohnuma T, Sanayama H, Ito K,
Fujiwara T, Yamada H, Kawarai Lefor, A, Sanui
M. The optimal timing of continuous renal
replacement therapy according to the modified
RIFLE classification in critically ill patients withacute kidney injury: a retrospective observational
study. Renal Replacement Therapy 2017;3:30.
58. Takanashi M, Taira Y, Okazaki S, Takase S,
Kimura T, Li CC, Xu PF, Noda A, Sakata I,
Kumagai H, Ikeda Y, Iizuka Y, Yahagi N,
Shimano H, Osuga JI, Ishibashi S, Kadowaki T,
Okazaki H. Role of hormone-sensitive lipase inleptin-promoted fat loss and glucose lowering. J
Atheroscler Thromb. 2017;24(11):1105-16.
59. Takata M, Amiya E, Watanabe M, Hosoya Y,
Nakayama A, Fujiwara T, Taya M, Oguri G,
Hyodo K, Takayama N, Takano N, Mashiko T,
Uemura Y, Komuro I. An exploratory study on
the efficacy and safety of a BCAA preparation
used in combination with cardiac rehabilitation
for patients with chronic heart failure. BMC
Cardiovasc Disord. 2017;17(1):205.
60. Tobita T, Nomura S, Morita H, Ko T, Fujita T,
Toko H, Uto K, Hagiwara N, Aburatani H,
Komuro I. Identification of MYLK3 mutations infamilial dilated cardiomyopathy. Sci Rep. 2017;
7(1):17495.
61. Umei M, Kishi M, Sato T, Shindo A, Toyoda M,
Yokoyama M, Matsushita M, Ohnishi S,
Yamasaki M. Indications for suboptimal low-dose
direct oral anticoagulants for non-valvular atrial
fibrillation patients. J Arrhythm. 2017;33(5):47582.
62. Wakayama K, Shimamura M, Suzuki JI, Watanabe
R, Koriyama H, Akazawa H, Nakagami H,
Mochizuki H, Isobe M, Morishita R. Angiotensin
II peptide vaccine protects ischemic brain throughreducing oxidative stress. Stroke. 2017;48(5):1362-8.
63. Wang Q, Oka T, Yamagami K, Lee JK, Akazawa
H, Naito AT, Yasui T, Ishizu T, Nakaoka Y, Sakata

Y, Komuro I. An EP4 receptor agonist inhibits
cardiac fibrosis through activation of pka
signaling in hypertrophied heart. Int Heart J.
2017;58(1):107-14.
64. Watanabe R, Suzuki JI, Wakayama K, Maejima Y,
Shimamura M, Koriyama H, Nakagami H,
Kumagai H, Ikeda Y, Akazawa H, Morishita R,
Komuro I, Isobe M. A peptide vaccine targetingangiotensin II attenuates the cardiac dysfunction
induced by myocardial infarction. Sci Rep. 2017;
7:43920.

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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.,

Kousuke Watanabe, M.D.,Ph.D.,

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

Hirokazu Urushiyama, M.D.,Ph.D.,

Yosuke Amano, M.D.,Ph.D.,

Satoshi Noguchi, M.D.,Ph.D.,

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

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

Homepage

http://kokyuki.umin.jp/

Introduction and Organization

Clinical activities

The staff of the Department of Respiratory Medicine,
Graduate School of Medicine, University of Tokyo,
consists of 1 professor, 2 lecturers, and 8 associates. In
the University of Tokyo, affiliated hospitals andforeign institutions, approximately 70 members
belong to the Department. In the University of Tokyo
Hospital, about 24 respiratory physicians are doingclinical works.
Based on the fact that the number of patients withrespiratory diseases such as primary lung cancer and
COPD is tremendously increasing, advancement andfruitful results of researches on respiratory medicine
are more and more expected. In this era, we areconducting basic and clinical researches for wide
variety of respiratory disorders including primary lungcancer, COPD, asthma and interstitial lung diseases.
Especially, we have been intensively studying themolecular mechanisms underlying the pathogenesis oflung disorders. Our research goal is to develop novel
diagnostic and therapeutic modalities for better
management of these pulmonary diseases.

The Department of Respiratory Medicine is responsible for the out-patient care as well as care of
in-patients (35 cases on average), which is taken at the13th floor of the hospital ward A of the University ofTokyo Hospital. Our practice is performed by thethree-member system of a junior resident, a seniorresident and an experienced associate.
Main diseases of in-patients are primary lung cancer,
respiratory infections, interstitial pneumonia, and
COPD. Many patients with primary lung cancer also
have interstitial pneumonia or COPD as their background pulmonary diseases. There are many
emergency visits and admissions with pneumonia,
respiratory failure due to exacerbation of COPD orinterstitial pneumonia, progression of lung cancer, andso on. In cases of severe respiratory failure such as
severe pneumonia and ARDS, we conduct ventilatory
support of such patients in collaboration with ICU
staff in an effort to rescue them. A specialized clinicalconference for respiratory disease has been held oncea week since late 1990s, where staff of our department,
department of thoracic surgery and department of132radiology join and discuss together to make best
diagnostic and therapeutic approach to individual
patients. This conference has been highly appreciatedas prototype of Cancer Board of the University ofTokyo Hospital, and, is now held as Respiratory
Cancer Board. This conference is still one of themost frequently held Cancer Board in our hospital.
Our department contributes to the pre- and postsurgical evaluation of respiratory functions, and also
receives consultation about respiratory complications
from almost every department in our hospital
At present, there increase highlighted interests in
respiratory medicine. Primary lung cancer is now
leading cause of cancer death, and is one of the major
medical and social problem to be overcome. Recently,
the new developments and their remarkable effectiveness of molecular-targeted therapies in primary lungcancer attract much attention in the fields of bothbasic science and clinical practice. Respiratory
infections are now the 3rd leading cause of all deathand COPD also will be major leading cause of alldeath in the near future. Among respiratory diseases,
there are several disorders to which no effective
therapeutic modalities are currently available. For
example, ARDS is an acute lung injury and themortality rate for ARDS is extremely high despite ofintensive care using currently available tools.
Idiopathic pulmonary fibrosis is a progressive andfatal inflammatory and fibrotic disorder of the lungparenchyma, while only a few medications are
currently available to treat the disease. We would liketo make every effort to develop a novel and potential
therapeutic approach to these diseases.
Total numbers of in-patients in 2017
1. Primary lung cancer
394
2. Interstitial pneumonia
63
3. Respiratory infections
42
4. Malignancy other than
primary lung cancer
18
5. Non-tuberculous
mycobacterial infections
15
6. COPD
11
7. Asthma
9
8. Pleural effusion
5
A weekly chart round and professor’s round arescheduled for Tuesday afternoon.
A specialized clinical conference for patients withrespiratory diseases is held as Respiratory Cancer
Board on every Thursday evening, together withthoracic surgeons and radiologists. In this conference,
radiological diagnosis, indication of CT-guided biopsy
and thoracoscopic biopsy, and treatment strategies not
only about thoracic malignancies but also about broad
spectrum of respiratory diseases are discussed, making
it possible to give best care to individual patients.

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

133affiliated hospitals for a relatively long period (eachfor two weeks). Several lectures on the specialized
theme on respiratory diseases are also provided.
As for post-graduate education, respiratory physicians(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.

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

Research activities
Our department is conducting basic and clinicalresearches for various respiratory disorders including
primary lung cancer, COPD, asthma, interstitial
pneumonia, respiratory infections and others.
Epidemiological, clinical, cellular and molecularbiological techniques are utilized for the elucidation ofpathogenic mechanisms and for the development ofnovel diagnostic and therapeutic modalities in
respiratory medicine. Postgraduate students as well as
the Faculty members make considerable effort tostudy about genetic alterations in primary lung cancer,
cell biological analysis using airway epithelial cells,
fibroblast and smooth muscle cells, both incollaboration with the Faculty of the Department ofThoracic Surgery, analysis of genetically-engineered
mice as disease-models and so on. These results havebeen presented and/or published in the Scientific
Meeting and/or peer-review Journals. Our main
research projects are as follows.
Search for diseases-susceptibility genes and elucidation of their pathophysiological roles in respiratory
diseases.
Analysis of disease-models using genetically engineered mice.
Analysis of DNA methylation, histone modificationand miRNA in primary lung cancer and their clinicalapplications.
Search for previously unidentified oncogenic driver
mutations in lung cancer and elucidation of resistantmechanisms against molecular-targeted dugs.

References
1. Sakamoto Y, Yamauchi Y, Yasunaga H, Takeshima
H, Hasegawa W, Jo T, Matsui H, Fushimi K,
Nagase T.

Guidelines-

concordant

empiric

antimicrobial therapy and mortality in patientswithseverecommunity-acquired

pneumonia

requiring mechanical ventilation. Respir Investig.
2017 Jan;55(1):39-44.
2. Noguchi S, Saito A, Mikami Y, Urushiyama H,
Horie M, Matsuzaki H, Takeshima H, Makita K,
Miyashita N, Mitani A, Jo T, Yamauchi Y,
Terasaki Y, Nagase T. TAZ contributes topulmonary fibrosis by activating profibrotic
functions of lung fibroblasts. Sci Rep. 2017 Feb
14;7:42595.
3. Ikeda T, Uchida K, Yamauchi Y, Nagase T, Oba K,
Yamada Y. Relationship between pre-anesthetic
and intra-anesthetic airway resistance in patients
undergoing general anesthesia: A prospective
observational study. PLoS One. 2017 Feb 17;
12(2):e0172421.
4. Suzuki HI, Katsura A, Mihira H, Horie M, Saito A,
Miyazono K. Regulation of TGF-β-mediatedendothelial-mesenchymal
microRNA-27.

J

transition

Biochem.

2017

by
May

1;161(5):417-420.
5. Sakamoto Y, Yamauchi Y, Yasunaga H, Takeshima
H, Hasegawa W, Jo T, Sasabuchi Y, Matsui H,
Fushimi K, Nagase T. Development of a

134

nomogram for predicting in-hospital mortality of

12. Ando T, Kawashima M, Masuda K, Takeda K,

patients with exacerbation of chronic obstructive

Okuda K, Suzuki J, Ohshima N, Matsui H,

pulmonary disease. Int J Chron Obstruct Pulmon

Tamura A, Nagai H, Akagawa S, Ohta K. ClinicalDis. 2017 May 29;12:1605-1611.

and Angiographic Characteristics of 35 Patients

6. Sakatani T, Maemura K, Hiyama N, Amano Y,
Watanabe K, Kage H, Fukayama M, Nakajima J,

With Cryptogenic Hemoptysis. Chest. 2017
Nov;152(5):1008-1014.

Yatomi Y, Nagase T, Takai D. High expression of

13. Mitani A, Azam A, Vuppusetty C, Ito K, Mercado

IRE1 in lung adenocarcinoma is associated with a

N, Barnes PJ. Quercetin restores corticosteroid

lower rate of recurrence. Jpn J Clin Oncol. 2017sensitivity in cells from patients with chronic

Jun 1;47(6):543-550.

obstructive pulmonary disease. Exp Lung Res.

7. Matsuki R, Okuda K, Mitani A, Yamauchi Y,

2017 Nov - Dec;43(9-10):417-425.

Tanaka G, Kume H, Homma Y, Hinata M, Hayashi

14. Mitani A, Hakamata Y, Hosoi M, Horie M,

A, Shibahara J, Fukayama M, Nagase T. A case of

Murano Y, Saito A, Yanagimoto S, Tsuji S,

delayed exacerbation of interstitial lung disease

Yamamoto K, Nagase T. The incidence and risk

after discontinuation of temsirolimus. Respir Med

factors of asymptomatic primary spontaneous

Case Rep. 2017 Aug 11;22:158-163.

pneumothorax detected during health check-ups.

8. Hasegawa

W,

YamauchiY,

Yasunaga

H,

Takeshima H, Sakamoto Y, Jo T, Sasabuchi Y,
Matsui H, Fushimi K, Nagase T. Prognostic
nomogram for inpatients with asthma exacerbation. BMC Pulm Med. 2017 Aug 4;17(1):108.
9. Urushiyama H, Jo T, Yasunaga H, Yamauchi Y,
Matsui H, Hasegawa W, Takeshima H, Hiraishi Y,
Mitani A, Fushimi K, Nagase T. Adjuvant chemotherapy versus chemoradiotherapy for small celllung cancer with lymph node metastasis: aretrospective observational study with use of anational database in Japan. BMC Cancer. 2017
Sep 2;17(1):613.
10. Jo T, Yasunaga H, Sasabuchi Y, Michihata N,
Morita K, Yamauchi Y, Hasegawa W, Takeshima
H, Sakamoto Y, Matsui H, Fushimi K, Nagase T.
Association between dementia and discharge
status in patients hospitalized with pneumonia.
BMC Pulm Med. 2017 Oct 6;17(1):128.
11. Horie M, Kaczkowski B, Ohshima M, Matsuzaki
H, Noguchi S, Mikami Y, Lizio M, Itoh M,
Kawaji H, Lassmann T, Carninci P, Hayashizaki Y,
Forrest ARR, Takai D, Yamaguchi Y, Micke P,
Saito A, Nagase T. Integrative CAGE and DNA
Methylation Profiling Identify Epigenetically
Regulated Genes in NSCLC. Mol Cancer Res.
2017 Oct;15(10):1354-1365.

BMC Pulm Med. 2017 Dec 7;17(1):177.

135

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Homepage

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

Introduction and Organization
The Department of Gastroenterology wasestablished through a reorganization of the Graduate
School of Medicine and that of the Division ofInternal Medicine of The University of Tokyo
Hospital in 1998. The department is responsible forclinical services, education and research activities in
the field of liver, pancreato-biliary and digestive canal.
It is comprised of a professor, 3 lecturers, 22
associates, 7 fellows, 67 graduates and other visiting
researchers including students from abroad. A numberof others are under a temporary transfer in- andoutside the country. The North and South wings on the
11th floor of Ward A have provided core hospitalrooms for the department. At present, 9th floors of
Ward B also take important part for providing rooms
for inpatients. Laboratories of the department are
scattered in each floor, mainly of Clinical ResearchCenter and First Research Building as in the otherdepartments.

Clinical Activities
The Department of Gastroenterology is in chargeof about 87 inpatients on average, which are about
2,900 in total per year. We receive about 110 new
patients in and out of the hospital each week, with anaverage hospital stay of 10.7 days. Resident, juniorand senior staff members bear the responsibility for a

136

medical management of each inpatient, in collaboration with subspecialty groups concerned. The staff
members examine about 5,300 outpatients withvarious digestive diseases in a month. Professor’s
ward round is performed on Monday and Wednesday
mornings. Specialty and subspecialty clinical conferences are held on Monday evening.
Hepatocellular carcinoma is the most common
disease in patients who are admitted to the department(～600 cases in 2017). Number of treatments forhepatocellular carcinoma treatments, represented by
percutaneous radiofrequency ablation, exceeded 300
cases per year, showing one of the greatest achievements in the field. Number of cases undergoingradiofrequency ablation for metastatic liver tumors is
also increasing recent years. In addition, we aremaking efforts to develop an innovation for dailyclinical activities. For example, fibrosis progression inchronic liver disease is conventionally assessed byliver biopsy. Recently we can evaluate the stage ofliver fibrosis by FibroScan®, newly developed
equipment that measures liver stiffness by ultrasound,which is useful for the evaluation of increasing
non-alcoholic steatohepatitis patients. In addition,nearly 100% cure for the HCV hepatitis can beachieved now by the use of oral anti-viral agents
instead of IFN therapy. This will be especiallybeneficial for the elderly patients and advanced
fibrotic patients.
In the pancreato-biliary field, about 1000 ERCPs
are performed annually. The cumulative number ofendoscopic treatment of bile duct stones using endoscopic papillary balloon dilation (EPBD) andendoscopic sphincterotomy (EST) exceeds 1,000 cases.
Endoscopic placement of a metal stent is the standardof care for malignant obstructive jaundice and ourgroup has led the development of covered metal stents.
Pancreatic interventions such as pancreatic stenting,cystic drainage and stone extraction are also
performed, which are often technically challenging. In
addition to these conventional ERCPs, we have
performed a number of advanced endoscopic
procedures such as 1,000 balloon-assisted ERCPs for
surgically altered anatomy cases, 1,000 EUS-FNAs
and 250 EUS-guided interventions. In combination
with these interventions, we have conducted clinical
trials of chemotherapy for advanced pancreatobiliary

cancer.
In the gastrointestinal field, ESD (endoscopic
submucosal dissection) is performed as a curativeendoscopic treatment for neoplasms in esophagus,
stomach or colon (approximately 400 patients a year).
Collaborative endoscopic surgery with other departments is actively performed: 1) ESD for superficial
pharyngeal cancer is often performed in cooperation
with the department of otorhinolaryngology; 2) as for
Non-exposed endoscopic wall-inversion surgery(NEWS), which was developed with the Department
of Gastrointestinal Surgery, its clinical indication has
been now expanded from the resection of GIST to thetreatment of gastric cancer. Double-balloon endoscopy
and capsule endoscopy enabled the examination ofwhole small intestines (approximately 320 cases in2017). All those interventions are performed by themembers of our department, who are specially trainedfor each technique. In addition, for the management of
inoperative malignancies, we effectively combine theinterventional treatments with various chemotherapy
regimens including new molecular-targeting drugs.
On outpatient basis, the number of performed
ultrasonography, gastroduodenal endoscopy, andcolonoscopy is 12,500 patients, 12,000 patients, and
6,000 patients per year respectively. In the endoscopy
examinations, we diagnose approximately 370 casesof esophageal cancer, 760 cases of gastric cancer and1300 cases of colorectal tumor annually, and half ofthem are treated endoscopically. Using these resected
tissues, we perform various basic studies in order tofeed the new finding back to actual clinical activities.

Educational Activities
The undergraduate medical students regularly
take the clinical lectures of the staffs in our
department. Several courses of practical teaching arealso provided for the students. Particularly, in theClinical Clerkship program during the fourth grade,each student joins in the medical treatment of inward
patients as a member of the clinical team in our
hospital. At the end of period, the students make thesummary presentation of the patients and also outline
the articles from world’s leading medical journals.
The residents of internal medicine participate in the
training of our department for 1-4 months in the firstyear. They learn the knowledge of therapeutics and137

diagnostics in gastroenterology as well as generalinternal medicine. Our department deals with thetraining curriculum as a medical specialist of internal
medicine. The residents in the course are supported toexperience some diseases in the gastrointestinal field.
The residents who major in gastroenterology as
subspecialty take the expert training of gastroenterology in the affiliated hospitals for several years.
The students of Department of Gastroenterology
in the Graduate School of Medicine perform highstandard of medical research in the basic or clinicalfield for 4 years. Currently, 67 students are in our
department.

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

References
1. Takahara N, Nakai Y, Isayama H, Sasaki T, Saito
K, Noguchi K, Suzuki T, Nakamura T, Sato T,
Ishigaki K, Hakuta R, Takeda T, Uchino R,
Mizuno S, Kogure H, Tada M, Koike K.CA19-9
kinetics during systemic chemotherapy in patientswith advanced or recurrent biliary tract cancer.
Cancer Chemother Pharmacol. 2017;80:11051112.
2. Mizutani H, Ono S, Ohki D, Takeuchi C, Yakabi S,
Kataoka Y, Saito I, Sakaguchi Y, Minatsuki C,
Tsuji Y, Niimi K, Kodashima S, Yamamichi N,
Fujishiro M, Koike K. Recent Development ofTechniques and Devices in Colorectal Endoscopic
Submucosal Dissection. Clin Endosc. 2017;50:
562-568.
3. Sato M, Tateishi R, Yasunaga H, Matsui H,
Horiguchi H, Fushimi K, Koike K. Mortality andhemorrhagic complications associated withradiofrequency ablation for treatment of hepatocellular carcinoma in patients on hemodialysis forend-stage renal disease: A nationwide survey. J
Gastroenterol Hepatol. 2017;32:1873-1878.
4. Nakatsuka T, Tateishi K, Kudo Y, Yamamoto K,
Nakagawa H, Fujiwara H, Takahashi R,
Miyabayashi K, Asaoka Y, Tanaka Y, Ijichi H,
Hirata Y, Otsuka M, Kato M, SakaiJ, Tachibana M,
Aburatani H, Shinkai Y, Koike K. Impact ofhistone demethylase KDM3A-dependent AP-1
transactivity on hepatotumorigenesis induced by
PI3Kactivation.Oncogene. 2017;36:6262-6271.
5. Hakuta R, Hamada T, Nakai Y, Isayama H,
Kogure H, Mizuno S, Naminatsu T, Yagioka H,
Togawa O, Matsubara S, Ito Y, Yamamoto N,
Tsujino T, Koike K. Multicenter retrospective andcomparative study of 5-minute versus 15-second

138

endoscopic papillary balloon dilation for removalof bile duct stones. Endosc Int Open. 2017;5:
E1027-E1034.
6. Chantarojanasiri T, Isayama H, Nakai Y,
Matsubara S, Mizuno S, Kogure H, Koike K.
Simultaneous duodenal stenting and endoscopic
ultrasound-guided hepaticogastrostomy using aforward-oblique view echoendoscope.Endoscopy.
2017;49:1109-1110.
7. Chantarojanasiri T, Matsubara S, Isayama H,
Nakai Y, Takahara N, Mizuno S, Kogure H,
Hakuta R, Ito Y, Tada M, Koike K.Feasibility of
conversion of percutaneous cholecystostomy tointernal transmural endoscopic ultrasound-guided
gallbladder drainage.Saudi J Gastroenterol. 2017;23:318-322.
8. Nakai Y, Isayama H, Matsubara S, Kogure H,
Mizuno S, Hamada T, Takahara N, Nakamura T,
Sato T, Takeda T, Hakuta R, Ishigaki K, Saito K,
Tada M, Koike K. A novel "hitch-and-ride" deep
biliary cannulation method during rendezvous
endoscopic ultrasound-guided ERCP technique.
Endoscopy. 2017;49:983-988.
9. Nakai Y, Isayama H, Yamamoto N, Matsubara S,
Ito Y, Sasahira N, Umefune G, Takahara N,
Hamada T, Mohri D, Kogure H, Tada M, Koike
K.Conversion to endoscopic ultrasound-guided
biliary drainage by temporary nasobiliary
drainage placement in patients with prior biliary
stenting. Endosc Ultrasound. 2017;6:323-328.
10. Nakai Y, Isayama H, Watanabe T, Mizuno S,
Kogure H, Matsubara S, Tada M, Koike K.
Transesophageal Endoscopic Ultrasound-guided
Fine Needle Aspiration for the Diagnosis of aLung Nodule that Was Non-abutting on CT. Intern
Med. 2017;56:2745-2746.
11. Ishigaki K, Nakai Y, Isayama H, Saito K, Hamada
T, Takahara N, Mizuno S, Mohri D, Kogure H,
Matsubara S, Yamamoto N, Tada M, Koike K.
Thromboembolisms in Advanced Pancreatic
Cancer: A Retrospective Analysis of 475 Patients.
Pancreas. 2017;46:1069-1075.
12. Shichijo S, Hirata Y, Niikura R, Hayakawa Y,
Yamada A, Koike K. Association between gastriccancer and the Kyoto classification of gastritis. J
Gastroenterol Hepatol. 2017;32:1581-1586.
13. Ota Y, Yamada A, Kobayashi Y, Niikura R,

Shimpoh T, Narita A, Yoshida S, Suzuki N,
Watabe H, Hirata Y, Ishihara S, Sunami E,
Watanabe T, Koike K. Diagnostic capability ofcolon capsule endoscopy for advanced colorectal
cancer: A pilot study. Dig Endosc. 2017;29:695-701.
14. Ono S, Koike K. Endoscopists should keep up
with the current trends of antithrombotic therapy
in other fields. Dig Endosc. 2017;29:676-677.
15. Niikura R, Hirata Y, Suzuki N, Yamada A,
Hayakawa Y, Suzuki H, Yamamoto S, Nakata R,
Komatsu J, Okamoto M, Kodaira M, Shinozaki T,
Fujishiro M, Watanabe T, Koike K. Colonoscopy
reduces colorectal cancer mortality: A multicenter,long-term, colonoscopy-based cohort study. PLoS
One. 2017;12:e0185294.
16. Ono S, Myojo M, Harada H, Tsuji K, Murakami D,
Suehiro S, Doyama H, Ando J, Saito I, Fujishiro
M, Komuro I, Koike K. Is it possible to perform
gastric endoscopic submucosal dissection without
discontinuation of a single antiplatelet ofthienopyridine derivatives? Endosc Int Open.
2017;5:E943-E949.
17. Yamaguchi D, Kodashima S, Fujishiro M, Ono S,
Niimi K, Mochizuki S, Tsuji Y, Asada-Hirayama I,
Sakaguchi Y, Shichijo S, Minatsuki C, Yamamichi
N, Koike K. Evaluation of image-enhanced
endoscopic technology using advanced diagnostic
endoscopy for the detection of early gastriccancer: a pilot study. Endosc Int Open. 2017;5:
E825-E833.
18. Hirao C, Mikoshiba N, Shibuta T, Yamahana R,
Kawakami A, Tateishi R, Yamaguchi H, Koike K,
Yamamoto-Mitani N. Adherence to oral
chemotherapy medications among gastroenterological cancer patients visiting an outpatient clinic.
Jpn J Clin Oncol. 2017;47:786-794.
19. Tsujino T, Isayama H, Kogure H, Sato T, Nakai Y,
Koike K. Endoscopic management of biliary
strictures after living donor liver transplantation.
Clin J Gastroenterol. 2017;10:297-311.
20. Yamada A, Niikura R, Maki K, Nakamura M,
Watabe H, Fujishiro M, Oka S, Fujimori S,
Nakajima A, Ohmiya N, Matsumoto T, Tanaka S,
Koike K, Sakamoto C. Proton pump inhibitor
therapy did not increase the prevalence of smallbowel injury: A propensity-matched analysis.

139

PLoS One. 2017;12:e0182586.
21. Mizuno S, Isayama H, Nakai Y, Yoshikawa T,
Ishigaki K, Matsubara S, Yamamoto N, Ijichi H,
Tateishi K, Tada M, Hayashi N, Koike K.
Prevalence of Pancreatic Cystic Lesions Is
Associated With Diabetes Mellitus and Obesity:
An Analysis of 5296 Individuals Who Underwent
a Preventive Medical Examination. Pancreas.
2017;46:801-805.
22. Takahara N, Isayama H, Nakai Y, Yoshida S, Saito
T, Mizuno S, Yagioka H, Kogure H, Togawa O,
Matsubara S, Ito Y, Yamamoto N, Tada M, Koike
K. A Novel Partially Covered Self-Expandable
Metallic Stent with Proximal Flare in Patientswith Malignant Gastric Outlet Obstruction. Gut
Liver. 20175;11:481-488.
23. Sakaguchi Y, Tsuji Y, Fujishiro M, Kataoka Y,
Saito I, Shichijo S, Minatsuki C, Asada-Hirayama
I, Yamaguchi D, Niimi K, Ono S, Kodashima S,
Yamamichi N, Koike K. Evaluation of endoscopic
submucosal dissection using a new endosurgicalknife DN-D2718B: a first clinical feasibility study.
Endosc Int Open. 2017;5:E670-E674.
24. Umefune G, Kogure H, Hamada T, Isayama H,
Ishigaki K, Takagi K, Akiyama D, Watanabe T,
Takahara N, Mizuno S, Matsubara S, Yamamoto
N, Nakai Y, Tada M, Koike K. Procalcitonin is a
useful biomarker to predict severe acutecholangitis: a single-center prospective study. J
Gastroenterol. 2017;52:734-745.
25. Nakada A, Niikura R, Yamada A, Yoshida S,
Hirata Y, Koike K. The incidence of postcolonoscopy colorectal cancer: a retrospective
long-term cohort study using a colonoscopy
database. Int J Colorectal Dis. 2017;32:839-845.
26. Shimpoh T, Hirata Y, Ihara S, Suzuki N, Kinoshita
H, Hayakawa Y, Ota Y, Narita A, Yoshida S,
Yamada A, Koike K. Prevalence of pks-positive
Escherichia coli in Japanese patients with orwithout colorectal cancer. Gut Pathog. 2017;9:35.
27. Otsuka M, Ishibashi R, Tanaka E, Seimiya T,
Suzuki T, Sekiba K, Yamagami M, Ohno M,
Kishikawa T, Koike K. A tiny but crucial player
bridging microbes and colonic carcinogenesis.
Transl Cancer Res. 2017;6: S1467-70.
28. Hamada T, Nakai Y, Isayama H, Koike K.
Toward routine use of non-steroidal anti-

inflammatory drugs for patients undergoingendoscopic retrograde cholangiopancreatography.
Dig Endosc. 2017;29:291-293.
29. Hamada T, Hakuta R, Nakai Y, Isayama H, Koike
K. Lack in Standardized Reporting of Biliary
Stents: A Meta-Analysis Complicated by theInconsistency. Am J Gastroenterol. 2017;112:809810.
30. Hamada T, Hakuta R, Takahara N, Sasaki T,
Nakai Y, Isayama H, Koike K. Covered versus
uncovered metal stents for malignant gastricoutlet obstruction: Systematic review and metaanalysis. Dig Endosc. 2017;29:259-271.
31. Nakai Y, Isayama H, Matsubara S, Koike K.
Conversion of transpapillary drainage toendoscopic ultrasound-guided hepaticogastrostomy and gallbladder drainage in a case of
malignant biliary obstruction with recurrent
cholangitis and cholecystitis (with videos).
Endosc Ultrasound. 2017;6:205-207.
32. Nakagawa H, Suzuki N, Hirata Y, Hikiba Y,
Hayakawa Y, Kinoshita H, Ihara S, Uchino K,
Nishikawa Y, Ijichi H, Otsuka M, Arita J,
Sakamoto Y, Hasegawa K, Kokudo N, Tateishi K,
Koike K. Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands. Proc Natl
Acad Sci U S A. 2017;114:E3806-E3815.
33. Takata A, Otsuka M, Kishikawa T, Yamagami M,
Ishibashi R, Sekiba K, Suzuki T, Ohno M,
Yamashita Y, Abe T, Masuzaki R, Ikenoue T,
Koike K. RASAL1 is a potent regulator of hepatic
stellate cell activity and liver fibrosis. Oncotarget.
2017;8:64840-64852.
34. Sekiba K, Yamagami M, Otsuka M, Suzuki T,
Kishikawa T, Ishibashi R, Ohno M, Sato M,
Koike K. Transcriptional activation of the MICA
gene with an engineered CRISPR-Cas9 system.
Biochem Biophys Res Commun. 2017;486:521525.
35. Niimi K, Ishibashi R, Mitsui T, Aikou S,
Kodashima S, Yamashita H, Yamamichi N, Hirata
Y, Fujishiro M, Seto Y, Koike K Laparoscopic andendoscopic cooperative surgery for gastrointestinal tumor. Ann Transl Med. 2017;5:187.

Internal Medicine
2. Medicine Ⅱ141

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

Lecturer
Akihiro Tojo, M.D., Ph.D. (-May),

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

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

Hideki Kato, M.D., Ph.D.(Sep-),

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

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

Hideki Kato, M.D., Ph.D.(-Aug),

Takahisa Kawakami, M.D., Ph.D.,

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

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

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

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

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

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

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

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

Official website

http://www.todai-jinnai.com

Introduction and Organization

Clinical activities

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

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

142

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

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

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

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

Department of Hemodialysis &Apheresis
Introduction and Organization
Hemodialysis and related blood purification therapy
had been individually performed in their respective
departments. However, all the departments’ apparatus
and human resources were centralized to form the
Department of Hemodialysis and Center for Hemodialysis in 2000 at the University Hospital. The Centerfor Hemodialysis was further renovated and started
operations in Fall of 2006.
This new Center for Hemodialysis is equipped with
one pressure control unit in addition to 12 hemodialysis machines under a state-of-the-art hemodialysis control system. Our concept of a hemodialysis
controlling system is a hub to transfer all digital andanalog data from patients and to monitor machines,
including blood purification machines, to the hostcomputer in our hospital, centralizing all data andadministering medical coding and billing robustly.
Blood purification machines in the ICU can bemonitored seamlessly under the cloud system of our
hospital. Blood purification machines are selected
uniformly to secure patients’ safety while avoiding
human error and increasing the overall educational
quality of staff members.
Clinical activities
1. Start of maintenance hemodialysis therapy forend-stage renal disease (ESRD).
2. Regular hemodialysis therapy for hospitalized
ESRD patients. Please note that our center does
not accept holiday dialysis.
3. Emergency hemodialysis and hemodiafiltration

143

4.

5.
6.
7.
8.
9.

for ICU patients.
Plasma exchange for neurodegenerative diseases,
SLE, TTP, TMA, and pre/post-liver transplantpatients.
DFPP for collagenous diseases, MG, HCV, anddermatological disorders.
LDL apheresis for nephrotic syndrome and ASO
patients.
White blood cell elimination therapy forulcerative colitis and rheumatological arthritis.
Cell-free and concentrated ascites reinfusion
therapy (CART) for refractory ascites.
Induction and maintenance of peritoneal dialysis
for ESRD.

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

5.
6.
7.
8.

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

Publications(1) Clinical characteristics and genetic backgroundsof Japanese patients with atypical hemolytic
uremic syndrome. Fujisawa M, Kato H, Yoshida
Y, Usui T, Takata M, Fujimoto M, Wada H,
Uchida Y, Kokame K, Matsumoto M, Fujimura Y,
Miyata T, Nangaku M. Clin Exp Nephrol. 2018
Mar 6 [Epub ahead of print](2) Genome-wide analysis revealed that DZNep
reduces tubulointerstitial fibrosis via downregulation of pro-fibrotic genes. Mimura I,
Hirakawa Y, Kanki Y, Nakaki R, Suzuki Y,
Tanaka T, Aburatani H, Nangaku M. Sci Rep.
2018 Feb 28;8(1):3779.
(3) Association of dialysis with in-hospital disability
progression and mortality in community-onset
stroke. Usui T, Hanafusa N, Yasunaga H,
Nangaku M. Nephrology (Carlton). 2018 Feb 22.
[Epub ahead of print](4) Response to different furosemide doses predicts
AKI progression in ICU patients with elevatedplasma NGAL levels. Matsuura R, Komaru Y,
Miyamoto Y, Yoshida T, Yoshimoto K, Isshiki R,
Mayumi K, Yamashita T, Hamasaki Y, Nangaku
M, Noiri E, Morimura N, Doi K. Ann Intensive
Care. 2018 Jan 17;8(1):8.
(5) H(+)-ATPase blockade reduced renal gluconeogenesis and plasma glucose in a diabetic rat
model. Tojo A, Hatakeyama S, Nangaku M,
Ishimitsu T. Med Mol Morphol. 2018 Jun;51(2):89-95.
(6) Controversies of the classification of TMA andthe terminology of aHUS. Kato H, Nangaku M,
Okada H, Kagami S. Clin Exp Nephrol. 2018
Aug;22(4):979-980.

144(7) The Longitudinal Study of Liver Cysts in Patients
With Autosomal Dominant Polycystic Kidney
Disease and Polycystic Liver Disease. Matsuura
R, Honda K, Hamasaki Y, Doi K, Noiri E,
Nangaku M. Kidney Int Rep. 2016 Oct 6;2(1):60-65.
(8) Mitochondrial Abnormality Facilitates Cyst
Formation in Autosomal Dominant Polycystic
Kidney Disease. Ishimoto Y, Inagi R, Yoshihara
D, Kugita M, Nagao S, Shimizu A, Takeda N,
Wake M, Honda K, Zhou J, Nangaku M. Mol
Cell Biol. 2017 [Epub ahead of print].
(9) D-serine, a novel uremic toxin, induces
senescence in human renal tubular cells via
GCN2 activation. Okada A, Nangaku M, Jao TM,
Maekawa H, Ishimono Y, Kawakami T, Inagi R.
Sci Rep. 2017 Sep 11;7(1):11168.
(10) Importance of glomerular filtration rate change assurrogate endpoint for the future incidence ofend-stage renal disease in general Japanese
population: community-based cohort study.
Kanda E, Usui T, Kashihara N, Iseki C, Iseki K,
Nangaku M. Clin Exp Nephrol. 2018 Apr;22(2):318-327.
(11) Use of the anion gap and intermittent
hemodialysis following continuous hemodiafiltration in extremely high dose acute-on-chronic
lithium poisoning: A case report. Komaru Y,
Inokuchi R, Ueda Y, Nangaku M, Doi K.
Hemodial Int. 2018 Jan;22(1):E15-E18.
(12) Echinomycin inhibits adipogenesis in 3T3-L1
cells in a HIF-independent manner. Yamaguchi J,
Tanaka T, Saito H, Nomura S, Aburatani H, Waki
H, Kadowaki T, Nangaku M. Sci Rep. 2017 Jul
26;7(1):6516.
(13) Pulmonary nonsegmental micronodules in apatient undergoing hemodialysis. Tomura M,
Hirakawa Y, Nangaku M. Clin Exp Nephrol.
2018 Feb;22(1):201-202.
(14) Rationale and design of oBservational clinicalResearch In chronic kidney disease patients withrenal anemia: renal proGnosis in patients with
Hyporesponsive anemia To Erythropoiesisstimulating agents, darbepoetin N alfa
(BRIGHTEN Trial). Kato H, Nangaku M,
Hirakata H, Wada T, Hayashi T, Sato H,
Yamazaki Y, Masaki T, Kagimura T, Yamamoto

H, Hase H, Kamouchi M, Imai E, Mizuno K,
Iwasaki M, Akizawa T, Tsubakihara Y,
Maruyama S, Narita I. Clin Exp Nephrol. 2018
Feb;22(1):78-84.
(15) Prolyl hydroxylase domain inhibitors as a novel
therapeutic approach against anemia in chronic
kidney disease. Sugahara M, Tanaka T, Nangaku
M. Kidney Int. 2017 Aug;92(2):306-312.
(16) Observation period for changes in proteinuria andrisk prediction of end-stage renal disease ingeneral population. Usui T, Kanda E, Iseki C,
Iseki K, Kashihara N, Nangaku M. Nephrology(Carlton). 2017 Jun 20. [Epub ahead of print](17) Epigenetic Changes in the Acute Kidney
Injury-to-Chronic Kidney Disease Transition.
Nangaku M, Hirakawa Y, Mimura I, Inagi R,
Tanaka T. Nephron. 2017;137(4):256-259.
(18) Applications of the CRISPR-Cas9 system inkidney research. Higashijima Y, Hirano S,
Nangaku M, Nureki O. Kidney Int. 2017 Aug;92(2):324-335.
(19) The role of renal proximal tubule transport in theregulation of blood pressure. Horita S, Nakamura
M, Suzuki M, Satoh N, Suzuki A, Homma Y,
Nangaku M. Kidney Res Clin Pract. 2017 Mar;36(1):12-21.
(20) Novel lnc RNA regulated by HIF-1 inhibits
apoptotic cell death in the renal tubular epithelial
cells under hypoxia. Mimura I, Hirakawa Y,
Kanki Y, Kushida N, Nakaki R, Suzuki Y,
Tanaka T, Aburatani H, Nangaku M. Physiol Rep.
2017 Apr;5(8). pii: e13203.
(21) Changes in bone metabolic parameters following
oral calcium supplementation in an adult patientwith vitamin D-dependent rickets type 2A.
Kinoshita Y, Ito N, Makita N, Nangaku M,
Fukumoto S. Endocr J. 2017 Jun 29;64(6):589596.
(22) Vascular adhesion protein-1 enhances neutrophil
infiltration by generation of hydrogen peroxide inrenal ischemia/reperfusion injury. Tanaka S,
Tanaka T, Kawakami T, Takano H, Sugahara M,
Saito H, Higashijima Y, Yamaguchi J, Inagi R,
Nangaku M. Kidney Int. 2017 Jul;92(1):154-164.
(23) Three cases of posterior reversible encephalopathy syndrome with chronic kidney disease
triggered by infection. Nasu K, Fujisawa M, Kato145

H, Nangaku M. Nephrology (Carlton). 2017 Apr;
22(4):322-325.
(24) Mechanisms of metabolic memory and renal
hypoxia as a therapeutic target in diabetic kidneydisease. Hirakawa Y, Tanaka T, Nangaku M. J
Diabetes Investig. 2017 May;8(3):261-271.
(25) Selective plasma exchange can reduce autoantibodies in patients with bullous pemphigoid
without affecting factor XIII and fibrinogen. Nasu
K, Hanafusa N, Nangaku M. J Clin Apher. 2017
Dec;32(6):589-591.
(26) Impact of end-stage renal disease on hospitaloutcomes among patients admitted to intensive
care units: A retrospective matched-pair cohort
study. Iwagami M, Yasunaga H, Matsui H,
Horiguchi H, Fushimi K, Noiri E, Nangaku M,
Doi K. Nephrology (Carlton). 2017 Aug;22(8):617-623.

146

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

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

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

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

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

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

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

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

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

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

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

Yoshitaka Sakurai, M.D., Ph.D. (since June 2017)

URL http://dm.umin.jp/
Introduction and Organization
In 1998 the Department of Internal Medicine at the
University of Tokyo was reorganized to the morefunctional units based on clinical specialties. The
physicians specialized in diabetes and metabolic
diseases from 3 former departments of Internal
Medicine were unified to the Department of Metabolic
Diseases. The Department of Diabetes and Metabolic
Diseases is one of the major divisions in the
Department of Internal Medicine at the University ofTokyo, and covers diabetes mellitus and metabolic
diseases including obesity disease and dyslipidemia.
Under the supervision and direction of the previous
professors Dr. Satoshi Kimura (1998-2003) and Dr.
Toshiro Fujita (2003) and current professor Dr.
Takashi Kadowaki (2003-present), we have been
providing a wide-ranged clinical, teaching andresearch activities. Currently, we hold 28 beds mainlyon the 12th floor of the North Wing Ward A and the
4th floor of the Ward B of the University of Tokyo
Hospital, and take care of 482 new inpatients per year.
Besides the staffs listed above, our division holds
faculties in branches, for example, Department ofClinical Nutrition Therapy (Associate Professor: Dr.
Naoto Kubota), Department of Molecular Sciences on
Diabetes (Project Associate Professor: Dr. Hironori
Waki and Project Assistant Professor: Dr. Masatoshi
Kobayashi), Department of Integrated Molecular
Science on Metabolic Diseases (Project Associate
Professor: Dr. Masato Iwabu), Laboratory for
Advanced Research on Pathophysiology of Metabolic
Diseases (Project Associate Professor: Dr. Miki
Okada-Iwabu [since Sep 2017]), Genomic Research
Support Center (Project Associate Professor: Dr.
Nobuhiro Shojima), Ubiquitous Health Informatics(Project Associate Professor: Dr. Kayo Waki),Division of Biophysics, Center for Disease Biology

147

and Integrative Medicine (Lecturer: Dr. Noriko
Takahashi [until Aug 2017]), Department of ClinicalLaboratory (Lecturer: Dr. Makoto Kurano), Division
for Health Service Promotion, The University ofTokyo (Assistant Professor: Drs. Sachiko Okazaki andTomohide Yamada), Clinical Research Support Center(Project Assistant Professor: Dr. Akiko Kishi) andCenter for Epidemiology and Preventive Medicine(Project Assistant Professor: Dr. Yukari Masuda). With
all these staffs, we actively instruct and teach theresidents and medical school students; annual
evaluation of the teaching skill by the students always
rates our department within the three places of the top.
In addition, there are 18 students of Graduate Schoolin our division. With all these 60 members, we
enthusiastically work on the research activities, whichlead to the outstanding contributions in the field of
metabolism.

Clinical activities
Based on the update clinical evidences and with theexperienced skills, we provide patient-centered
medical services in the highest quality. We haveoutpatient clinics from Monday through Friday, andhave been following approximately 174 patients perday (total 42,482 patients per year). On the inpatientward, we not only take care of around 28 patients inour division as mentioned above, but also provide a
sophisticated management to all patients sufferingfrom metabolic diseases, especially diabetes mellitus.
Diabetes mellitus, metabolic syndrome, dyslipidemia
and obesity disease are becoming more prevalent inJapan, and lead to complications including nephropathy, retinopathy, neuropathy and cardiovasculardiseases. Thus, in collaboration with other departments, we optimize the treatment of each patient.
We provide the educational classes to the patients
every weekday in the inpatient ward, and also givelectures twice a week in the outpatient unit. In
addition, in collaboration with ancillary staffs of our
hospital, we provide patients well-reasoned
instructions regarding nutritional management, excise
therapy and medical therapy.
The weekly official activities of our department
consist of the pre-round case conference and the Ward
Round by the Professor on Monday. We also hold aweekly case conference by the consultation group
staffs.

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

Research activities
There are several laboratories in our departments;
collaborating with each other or with other departments, we focus on the molecular mechanisms of themetabolic diseases and the establishment of the novel
therapeutics.

1481) Molecular mechanisms of type 2 diabetes
We have been attempting to elucidate the mechanisms
underlying the development of type 2 diabetes at themolecular and genetic levels. To this end, in
collaboration with RIKEN and several cohorts, we
explored the comprehensive catalog of genomic
variations to identify variations conferring susceptibility to type 2 diabetes in the Japanese population.
We are also exploring the signal transduction
pathways and physiological roles of insulin andadipokines in various tissues and the mechanisms ofinsulin secretion under the normal or pathologicalconditions, such as diabetes and obesity disease, using
a number of transgenic and knockout animal models,in parallel with information obtained by wholegenome analysis of human patients. In particular, we
are interested in the physiological and pathophysiological functions of adipokines secreted by adipocytes,
including adiponectin, and the signal transduction
pathway of adiponectin through the receptors,
AdipoR1 and AdipoR2, that we discovered andcharacterized. We have also identified “AdipoRon” asan adiponectin receptor agonist, which will contributeto the development and optimization of AdipoRtargeted therapeutics. In addition, we have beensuccessfully unraveling the molecular mechanisms of
β cell proliferation and inter-tissue communication of
glucose metabolism in obesity disease and type 2
diabetes. Recently, we are investigating brown andwhite adipocyte-specific transcriptional and epigenetic
regulations in obesity. We believe that these findings
and research activities will lead to novel therapeuticstrategies for diabetes and the metabolic syndrome.
2) Pathophysiological roles of lipid storage andatherosclerosis
Our aim is to clarify the significance of metabolic risk
factors in the onset and development of atherosclerosis. We are currently investigating thepathophysiological roles of lipid storage in obesity
disease, fatty liver, diabetes, hyperlipidemia andatherosclerosis using strategies of molecular biology
and genetic engineering techniques. Utilizing theanimal models of lipid disorders and molecularbiological technique, we are analyzing the roles oflipid transporters, nuclear receptors and the antioxidative proteins on the lipid disorders and athero-sclerosis. We are currently interested in the cholesterol
and lipid absorption from the intestine and lipid
handling in the cells.
3) Clinical trials and epidemiological studies
We are conducting clinical trials and epidemiologicalstudies including “Japan Diabetes Optimal Integrated
Treatment study for 3 major risk factors ofcardiovascular diseases (J-DOIT3)” follow-up study,"Japan Diabetes compREhensive database projectbased on an Advanced electronic Medical record
System (J-DREAMS)", systematic reviews and metaanalyses with a focus on important issues such as
metabolic syndrome, and investigator initiated clinical
trials targeting for a new class of anti-diabetic agents.

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Noda M, Kadowaki T, and the J-DOIT3 Study
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Oki K, Yoneda M, White AP, Tseng YH, Cypess
AM, Larsen TJ, Jespersen NZ, Scheele C, Tsutsumi
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Kubota T, Kubota N, Kadowaki T: Imbalanced
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Yaqoob Z, Saghir T, Rizvi SNH, Memon A,
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Qureshi IH, Tanveer-Us-Salam, Iqbal W, Malik U,
Mehra N, Kuo JZ, Sheu WH, Guo X, Hsiung CA,
Juang JJ, Taylor KD, Hung YJ, Lee WJ,
Quertermous T, Lee IT, Hsu CC, Bottinger EP,
Ralhan S, Teo YY, Wang TD, Alam DS, Di
Angelantonio E, Epstein S, Nielsen SF,
Nordestgaard BG, Tybjaerg-Hansen A, Young R;
CHD Exome+ Consortium, Benn M, FrikkeSchmidt R, Kamstrup PR; EPIC-CVD Consortium;
EPIC-Interact Consortium; Michigan Biobank,Jukema JW, Sattar N, Smit R, Chung RH, Liang
KW, Anand S, Sanghera DK, Ripatti S, Loos RJF,
Kooner JS, Tai ES, Rotter JI, Chen YDI, Frossard P,
Maeda S, Kadowaki T, Reilly M, Pare G, Melander
O, Salomaa V, Rader DJ, Danesh J, Voight BF &Saleheen D: Identification of new susceptibility locifor type 2 diabetes and shared etiological pathways
with coronary heart disease. Nat Genet. 2017 Oct;49(10):1450-1457
Hosoe J, Kadowaki H, Miya F, Aizu K, Kawamura
T, Miyata I, Satomura K, Ito T, Hara K, Tanaka M,
Ishiura H, Tsuji S, Suzuki K, Takakura M,
Boroevich KA, Tsunoda T, Yamauchi T, Shojima N,
Kadowaki T: Structural Basis and GenotypePhenotype Correlations of INSR Mutations Causing
Severe Insulin Resistance. Diabetes 66:2713-2723,
2017
Sasaki M, Sasako T, Kubota N, Sakurai Y,
Takamoto I, Kubota T, Inagi R,Seki G, Goto M,
Ueki K, Nangaku M, Jomori T, Kadowaki T: Dualregulation of gluconeogenesis by insulin andglucose in the proximal tubules of the kidney.
Diabetes. 2017 Sep;66(9):2339-2350.
Sakurai Y, Kubota N, Takamoto I, Obata A,
Iwamoto M, Hayashi T, Aihara M, Kubota T,
Nishihara H, Kadowaki T: Role of insulin receptor
substrates in the progression of hepatocellular
carcinoma. Sci Rep. 2017 Jul 14;7(1):5387.
Take K, Waki H, Sun W, Wada T, Yu J, Nakamura
M, Aoyama T, Yamauchi T, Kadowaki T: CDK5
Regulatory Subunit-Associated Protein 1-like 1
Negatively Regulates Adipocyte Differentiation
through Activation of Wnt Signaling Pathway. Sci
Rep. 2017 Aug 4;7(1):7326.

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restriction. Cell Cycle. 16:1-2. 2017
Araki E, Haneda M, Kasuga M, Nishikawa T,
Kondo T, Ueki K, Kadowaki T. New glycemic
targets for patients with diabetes from the Japan
Diabetes Society. J Diabetes Investig. 2017 Jan;8(1):123-125
Japan Diabetes Society (JDS)/Japan Geriatrics
Society (JGS) Joint Committee on Improving Carefor Elderly Patients with Diabetes: Committee
report: Glycemic targets for elderly patients withdiabetes. J Diabetes Invest. 8:126-128, 2017
Sugiyama T, Miyo K,Tsujimoto T, Kominami
R,Ohtsu H, Osugi M,Waki K,Noguchi T,Ohe K,
Kadowaki T, Kasuga M, Ueki K, Kajio H: Designof and rationale for the Japan Diabetes
compREhensive database project based on an
Advanced electronic Medical record System(J-DREAMS). Diabetol. Int. 8(4):375-382, Nov,
2017.
Nakamura J, Kamiya H, Haneda M, Inagaki N,
Tanizawa Y, Araki E, Ueki K, Nakayama T：Causesof death in Japanese patients with diabetes based on
the results of a survey of 45,708 cases during
2001-2010：Report of the Committee on Causes of
Death in Diabetes Mellitus. J Diabetes Investig.
Mar 27, 2017
Kadowaki T, Jinnnouchi H, Kaku K, Hersløv ML,
Hyllested-Winge J, Nakamura S: Insulin degludec
in a simple or stepwise titration algorithm in a
Japanese population of patients with type 2
diabetes: a randomized, 26-week, treat-to-target
trial. Diabetol. Int.8:87-94, 2017
Kadowaki T, Inagaki N, Kondo K, Nishimura K,
Kaneko G, Maruyama N, Nakanishi N, Iijima H,
Watanabe Y, Gouda M: Efficacy and safety of
canagliflozin as add-on therapy to teneligliptin in
Japanese patients with type 2 diabetes mellitus:
results of a 24-week, randomised, double-blind,placebo-controlled trial. Diabetes Obes.Metab. 19:
874-882, 2017
Kadowaki T, Inagaki N, Kondo K, Nishimura K,
Kaneko G, Maruyama N, Nakanishi N, Watanabe Y,
Gouda M, Iijima H: Long-term safety and efficacy
of canagliflozin as add-on therapy to teneligliptin in

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Obes Metab. 2018 Jan;20(1):77-84.
Kadowaki T, Kondo K, Sasaki N, Miyayama K,
Yokota S, Terata R, Gouda M:Efficacy and safety ofteneligliptin add-on to insulin monotherapy inJapanese patients with type 2 diabetes mellitus:a
16-week, randomized, double-blind, placebocontrolled trial with an open-label long-term period.
ExpertOpinion on Pharmacotherapy18:1291-1300,
2017
Kadowaki T, Muto S, Ouchi Y, Shimazaki R, Seino
Y:Efficacy and safety of saxagliptin in combination
with insulin in Japanese patients with type 2
diabetes mellitus: a 16-week double-blind randomized controlled trial with a 36-week open-label
extension. Expert Opin Pharmacother. 2017 Dec;
18(18):1903-1919.
Yamada T, Shojima N, Hara K, Noma H, Yamauchi
T, Kadowaki T. Glycemic control, mortality,
secondary infection, and hypoglycemia in criticallyill pediatric patients: a systematic review andnetwork meta-analysis of randomized controlled
trials. Intensive Care Med. 2017 Sep;43(9):14271429
Yamada T, Shojima N, Noma H, Yamauchi T,
Kadowaki T: Glycemic control, mortality, andhypoglycemia in critically ill patients: a systematic
review and network meta-analysis of randomized
controlled trials. Intensive Care Med. 43:1-15, 2017
Yamada T, Yanagimoto S. Dose-Response Relationship between the Risk of Vasovagal Syncope andBody Mass Index or Systolic Blood Pressure in
Young
AdultsUndergoing
Blood
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Neuroepidemiology. 2017;49(1-2):31-33.
Yamada T, Yanagimoto S, Kadowaki T: Doseresponse relationship between severe hypercholesterolemia and body mass index in healthy
young adults. Mayo Clin. Proc. 2017 Jul;92(7):1167-1168.

23. Asano T, N Kubota, Koizumi N, Itani K, Miyake T,
Yuhashi K, Liao H, Mitsuishi M, Takeishi S,
Takahashi T, Ohnishi S, Sasaki S, Sakuma I,
Kadowaki T: Novel and simple ultrasonographic
methods for estimating the abdominal viseceral fat
area. Int. J. Endocrinol. vol. 2017, Article ID
8796069, 12 pages, 2017

24. Fujishiro M, Kushiyama A, Yamazaki H, Kaneko A,
Koketsu Y, Yamamotoya T, Kikuchi T, Sakoda H,
Suzuki R, Kadowaki T: Gastrointestinal symptom
prevalence depends on disease duration andgastrointestinal region in type 2 diabetes mellitus.
World J Gastroenterol. 2017 Sep 28;23(36):66946704
25. Abe-Doi M, Oe M, Murayama R, Takahashi M,
Zushi Y, Tanabe H, Takamoto I, Suzuki R,
Yamauchi T, Kadowaki T, Komiyama C, Sanada H:
Development of an Automatic Puncturing andSampling System for a Self-Monitoring Blood
Glucose Device. Diabetes Technol Ther. 2017 Nov;
19(11):651-659.
26. Nawaz A, Aminuddin A, Kado T, Takikawa A,
Yamamoto S, Tsuneyama K, Igarashi Y, Ikutani M,
Nishida Y, Nagai Y, Takatsu K, Imura J, Sasahara M,
Okazaki Y, Ueki K, Okamura T, Tokuyama K, Ando
A, Matsumoto M, Mori H, Nakagawa T, Kobayashi
N, Saeki K, Usui I, Fujisaka S, Tobe K.:CD206+
M2-like macrophages regulate systemic glucose
metabolism by inhibiting proliferation of adipocyte
progenitors. Nat Commun. Aug 18;8(1):286. doi:
10.1038/s41467-017-00231-1,2017
27. Hayashi A, Yamaguchi S, Waki K, Fujiu K,
Hanafusa N, Nishi T, Tomita H, Kobayashi H,
Fujita H, Kadowaki T, Nangaku M, Ohe K: Testing
the fasibility and usability of a novel smartphonebased self-management support system for dialysis
patients: A pilot study. JMIR Res.Protoc. 6:e63,
2017
28. Kato A, Fujimaki Y, Fujimori S, Isogawa A, Onishi
Y, Suzuki R, Yamauchi T, Ueki K, Kadowaki T,
Hashimoto H: Psychological and behavioural
patterns of stigma among patients with type 2
diabetes: a cross-sectional study. BMJ Open. 7:
e013425, 201729. Marangoni RG, Masui Y, Fang F, Korman B, Lord G,
Lee J, Lakota K, Wei J, Scherer PE, Otvos L,
Yamauchi T, Kubota N, Kadowaki T, Asano Y, SatoS, Tourtellotte WG, Varga J: Adiponectin is an
endogenous anti-fibrotic mediator and therapeutictarget. Sci. Rep. 7:4397, 201730. Masamoto Y, Arai S, Sato T, Kubota N, Takamoto I,
Kadowaki T, Kurokawa M: Adiponectin enhances
quiescence exit of murine hematopoietic stem cells

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Ueki K, Kadowaki T, Sanada H: Thermographic
findings in a case of type 2 diabetes with foot ulcer
due to callus deterioration. Diabetol. Int. 8:328-33,
2017
Shibuta T, Waki K, Tomizawa N, Igarashi A,
Yamamoto-Mitani N, Yamaguchi S, Fujita H,
Kimura S, Fujiu K, Waki H, Izumida Y, Sasako T,
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Ishibashi S, Kadowaki T, Okazaki H: Role ofhormone-sensitive lipase in leptin-promoted fat loss
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152

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

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

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

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

Mizuki Ogura, M.D., Ph.D.,

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

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

Kensuke Takaoka, M.D., Ph.D.,

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

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

Homepage

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

Introduction and Organization
The Department of Hematology and Oncology is
responsible for clinical activities in outpatient as wellas inpatient clinics of hematological disorders,
research activities for hematology/oncology, and education of undergraduate as well as graduate students.
We are also engaged in continuous education of
post-graduate doctors who develop into sophisticatedhematologists of eminent distinction. These activities
are performed by the united efforts of all members
who belong to the department. Dr. Mineo Kurokawa
was assigned as Professor of the Department of
Hematology and Oncology in 2005. Other staff of ourdepartment consists of one lecturer and 7 assistantprofessors.

Clinical activities
On the average, 55-65 patients with hematologicaldiseases are treated in the ward. Clinical facilities
include patient rooms with high-efficiency particulate
air filtration and filtrated water supply. Patients whoare eligible for the treatment with high-grade infection
prophylaxis are admitted to the facilities. Patient careis provided by team management. That is, three
doctors (a junior resident, a senior resident, and an
assistant professor) are assigned to a single patient.
Since clinical issues are highly related to hematopoietic stem cell transplantation especially for patientswith hematological diseases, a substantial portion of
our clinical conferences are shared with staff membersof the Department of Cell Therapy and Transplantation Medicine and the Department of Pediatrics(Hematology/Oncology). Many problems arising indaily clinical practice are discussed in the morning
clinical conference held thrice a week. Diagnostic andtherapeutic issues as well as pathological aspects ofindicative and/or educational cases are discussed inclinical conferences held twice a month.
Outpatient clinical services are provided from
Monday to Friday in the morning and afternoon using
three booths. Approximately 60-65 patients visit our
outpatient clinic every weekday. One of our ultimate
goals in the clinical activities is to cure patients withhematological malignancies.
We perform various kinds of genetic or molecular
tests to detect, characterize, and monitor neoplastic
cells and their results are used in the diagnosis and153

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

Teaching activities
A lecture course on etiology, pathogenesis, clinicaland laboratory features, differential diagnosis, therapy
and prognosis for all hematological diseases isprovided for the second grade medical students. The
course contents include:
1. Mechanisms of hematopoiesis, transplantation
medicine and cell therapy
2. Acute leukemia and myeloproliferative disorders
3. Bone marrow failure syndrome (aplastic anemia
and myelodysplastic syndrome)
4. Lymphoma and myeloma
5. Hemostasis and thrombosis
6. Hemolytic anemia and anemia of various causes
Clinical clerkships on diagnostic and therapeutic
issues and arts are given for the third grade medical
students on a man-to-man basis with a senior faculty

member who is erudite both in general internal
medicine and in hematology and oncology. During thecourse, students are required to learn the basic techniques of medical interview and physical examination,interpretation of laboratory tests, and practical
medical procedures.
Undergraduate students are educated to become
independent researchers both in basic and clinicalresearch.
Education of clinical fellows to train hematologists
is also provided. They are trained to achieve knowledge and techniques necessary for hematologists in
our hospital and encouraged to present clinical studies
at academic meetings.

Research activities
The major research projects are as follow: (1)molecular mechanisms of hematopoietic neoplasms,(2) hematopoietic transcription factors, (3) signaltransduction in hematopoietic cells, (4) chromosomal
and genomic approaches to leukemogenesis, (5)generation of murine models for leukemias, (6)reprogramming of leukemic cells into iPS cells, (7)regulation of hematopoiesis. Translational research todevelop novel methods for diagnosis and treatment
based on basic research is also performed. Everyeffort has been made to achieve the highest quality inboth clinical and basic medical research. The ultimate
aims of our research are the application of
epoch-making discoveries in research fields to theclinical hematology and oncology. Representative
publications from our departments published in thepast year are listed in the reference.

References
1. Miyauchi M, Koya J, Arai S, Yamazaki S, Honda
A, Kataoka K, Yoshimi A, Taoka K, Kumano K,
Kurokawa M. Stem Cell Reports. ADAM8 Is an
Antigen of Tyrosine Kinase Inhibitor-Resistant
Chronic Myeloid Leukemia Cells Identified by
Patient-Derived Induced Pluripotent Stem Cells.
2018, 10:1115-1130.
2. Suzuki Y, Koya J, Ebisawa K, Abe H,
Shinozaki-Ushiku A, Nakamura F, Kurokawa M.
Sequential development of monoclonal B cell
lymphocytosis-derived small lymphocytic lym-

154

3.

4.

5.

6.

7.

8.

phoma and plasma cell leukemia. Ann Hematol.
2018; 97:917-919.
Wang Y, Tian H, Cai W, Lian Z, Bhavanasi D,
Wu C, Sato T, Kurokawa M, Wu D, Fu L, Wang
H, Shen H, Liang D, Huang J. Tracking
hematopoietic precursor division ex vivo in realtime. Stem Cell Res Ther. 2018; 9:16.
Matsuda K, Toyama K, Toya T, Ikemura M,
Nakamura F, Kurokawa M. Reactivation of
Hemophagocytic Lymphohistiocytosis Triggeredby Antithymocyte Globulin. Intern Med. 2018;57:583-586.
Matsuda K, Taoka K, Jona M, Masuda A, Arai S,
Nakamura F, Yatomi Y, Kurokawa M. Clinicalfeatures of hematological disorders with increased
large
granularlymphocytes(LGLs):aretrospective study. Ann Hematol. 2017; 96:2113-2115.
Kobayashi T, Nannya Y, Ichikawa M, Oritani K,
Kanakura Y, Tomita A, Kiyoi H, Kobune M, Kato
J, Kawabata H, Shindo M, Torimoto Y,
Yonemura Y, Hanaoka N, Nakakuma H,
Hasegawa D, Manabe A, Fujishima N, Fujii N,
Tanimoto M, Morita Y, Matsuda A, Fujieda A,
Katayama N, Ohashi H, Nagai H, Terada Y, Hino
M, Sato K, Obara N, Chiba S, Usuki K, Ohta M,
Imataki O, Uemura M, Takaku T, Komatsu N,
Kitanaka A, Shimoda K, Watanabe K, Tohyama
K, Takaori-Kondo A, Harigae H, Arai S,
Miyazaki Y, Ozawa K, Kurokawa M; for National
Research Group on Idiopathic Bone Marrow
Failure Syndromes. A nationwide survey ofhypoplastic myelodysplastic syndrome (a multicenter retrospective study). Am J Hematol. 2017;
92:1324-1332.
Matsuda K, Koya J, Toyama K, Ikeda M, Arai S,
Nakamura F, Okugawa S, Moriya K, Kurokawa
M. A therapeutic benefit of daptomycin against
glycopeptide-resistantgram-positive
cocci
bloodstream infections under neutropenia. J InfectChemother. 2017; 23:788-790.
Kaburaki T, Taoka K, Matsuda J, Yamashita H,
Matsuda I, Tsuji H, Tanaka R, Nakazaki K,
Nakamura F, Kamiya K, Kurokawa M, Ohtomo K,
Aihara M. Combined intravitreal methotrexate
and immunochemotherapy followed by reduceddose whole-brain radiotherapy for newly

diagnosed B-cell primary intraocular lymphoma.
Br J Haematol. 2017; 179:246-255.
9. Chiba A, Nakamura F, Nakazaki K, Kurokawa M.
Cytomegalovirus antigenemia and end-organdisease in Japanese patients treated withbendamustine. Leuk Lymphoma. 2018; 59:749751.
10. Kondo T, Nagamura-Inoue T, Tojo A, Nagamura
F, Uchida N, Nakamae H, Fukuda T, Mori T,
Yano S, Kurokawa M, Ueno H, Kanamori H,
Hashimoto H, Onizuka M, Takanashi M, Ichinohe
T, Atsuta Y, Ohashi K. Clinical impact ofpretransplant use of multiple tyrosine kinase
inhibitors on the outcome of allogeneic
hematopoietic stem cell transplantation forchronic myelogenous leukemia. Am J Hematol.
2017; 92:902-908.
11. Kawabata H, Tohyama K, Matsuda A, Araseki K,
Hata T, Suzuki T, Kayano H, Shimbo K, Zaike Y,
Usuki K, Chiba S, Ishikawa T, Arima N, Nogawa
M, Ohta A, Miyazaki Y, Mitani K, Ozawa K, Arai
S, Kurokawa M, Takaori-Kondo A; Japanese
National Research Group on Idiopathic Bone
Marrow Failure Syndromes. Validation of therevised International Prognostic Scoring System
in patients with myelodysplastic syndrome inJapan: results from a prospective multicenter
registry. Int J Hematol. 2017; 106:375-384.
12. Masamoto Y, Arai S, Sato T, Kubota N,
Takamoto I, Kadowaki T, Kurokawa M.
Adiponectin Enhances Quiescence Exit of Murine
Hematopoietic Stem Cells and Hematopoietic
Recovery Through mTORC1 Potentiation. StemCells. 2017; 35:1835-1848.
13. Koya J, Ibaraki T, Yamazaki I, Nakamura F,
Kurokawa M. Acute basophilic leukemia withadd(3)(q12) accompanied by histamine excess
symptoms. Ann Hematol. 2017; 96:1197-1199.
14. Shintani-Domoto Y, Shinozaki-Ushiku A, Okuma
H, Kurokawa M, Fukayama M. Laminar crystal
deposition in large vessels in a patient withcrystalglobulinemia. Pathol Int. 2017; 67:269272.
15. Harashima S, Yoneda R, Horie T, Kayano M,
Fujioka Y, Nakamura F, Kurokawa M, Yoshiuchi
K. Development of the Japanese Version of thePsychosocial Assessment of Candidates for155Transplantation in Allogeneic Hematopoietic
Stem Cell Transplantation. Psychosomatics. 2017;58:292-298.
16. Mizuno H, Koya J, Fujioka Y, Ibaraki T,
Nakamura F, Hayashi A, Shinozaki-Ushiku A,
Akamatsu N, Hasegawa K, Kokudo N, Fukuyama
M, Kurokawa M. Extranodal NK/T cell
lymphoma in a living donor liver transplant
recipient. Ann Hematol. 2017; 96:1051-1052.
17. Miyamoto T, Fukuda T, Nakashima M, Henzan T,
Kusakabe S, Kobayashi N, Sugita J, Mori T,
Kurokawa M, Mori SI. Donor Lymphocyte
Infusion for Relapsed Hematological Malignancies after Unrelated Allogeneic Bone Marrow
Transplantation Facilitated by the Japan Marrow
Donor Program. Biol Blood Marrow Transplant.
2017; 23:938-944.
18. Morita K, Nakamura F, Sakuishi K, Yamamoto T,
Shimizu J, Tsuji S, Kurokawa M. Leuk
Lymphoma. Successful management of chronic
myeloid leukemia with a complication ofanti-SRP antibody-associated myopathy. 2017;58:1242-1245.

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

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

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

Research Associate
Yukiko Iwasaki, M.D., Ph.D. (Rheumatology)
Hiroaki Harada, M.D., Ph.D. (Allergology)
Oh Sasaki, M.D., Ph.D. (Allergology)
Yasuo Nagafuchi，M.D., Ph.D. (Rheumatology)
Yumi Tsuchida，M.D., Ph.D. (Rheumatology)

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

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

The Department of Allergy and Rheumatology
presently consists of 12 staffs mentioned above, who
preside over 5 medical staff, 17 graduate students for"Doctor of Medical Science". The outpatient facilities
are situated on the 2nd floor of the Outpatient Clinic.
The inpatient facility is mainly located on the 13th
floor of the Hospital Ward A. The physician's office issituated in the East Hospital Ward and the researchrooms are located in the East Hospital Ward, theCentral Ward and the Clinical Research Center A.

Education
In regard to undergraduate education, the Depart-

ment is in charge of internal medicine diagnosis andsystemic lectures for M2 students and clinical lecturesand bedside education for M3 and M4 students incooperation with other departments of internal
medicine. The systemic lectures and clinical lectures
cover clinical immunology, connective tissue diseases
and allergy. Bedside education provides students witha good opportunity to learn about patients as well aspractical knowledge through numerous seminars.
For postgraduate education, internal medicine
trainees are accepted on rotation basis and trained asinternist. Our department accepts students for "Doctorof Medical Science". Our 4-year education covers

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clinical immunology, molecular immunology, rheumatology and allergology.

Medical Care
General and special outpatient clinics are opened from
Monday to Friday. Special outpatients clinics include
clinics for rheumatoid arthritis, connective tissue
diseases, bronchial asthma, allergy, and kidney
disorders. For inpatients, there are presently 25 to 30
beds. Every week on Monday afternoon the charts arerounded and on Tuesday afternoon the professor
makes his rounds. To achieve the highest quality of
medical care, clinical conferences are held. Majorityof patients in the ward are suffered from connective
tissue diseases and usually exhibit multiple organ
involvements. Therefore, a careful, well-rounded
approach to each patient as a whole is required rather
than a limited special approach to a single organsystem.

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

References

2017

1. Overview of LAG-3-Expressing, IL-10-Producing
Regulatory T Cells.Fujio K, Yamamoto K,
Okamura T. Curr Top Microbiol Immunol. 2017;
410:29-45
2. Increased serum concentrations of IL-1 beta,
IL-21 and Th17 cells in overweight patients withrheumatoid arthritis. Shoda H, Nagafuchi Y,
Tsuchida Y, Sakurai K, Sumitomo S, Fujio K,
Yamamoto K. Arthritis Res Ther. 2017 May 31;
19(1):111.
3. Polygenic burdens on cell-specific pathways
underlie the risk of rheumatoid arthritis. Ishigaki
K, Kochi Y, Suzuki A, Tsuchida Y, Tsuchiya H,
Sumitomo S, Yamaguchi K, Nagafuchi Y,
Nakachi S, Kato R, Sakurai K, Shoda H, Ikari K,
Taniguchi A, Yamanaka H, Miya F, Tsunoda T,
Okada Y, Momozawa Y, Kamatani Y, Yamada R,
Kubo M, Fujio K, Yamamoto K. Nat Genet. 2017
Jul;49(7):1120-1125.
4. Investigation of the pathogenesis of autoimmune
diseases by iPS cells. Natsumoto B, Shoda H,
Fujio K, Otsu M, Yamamoto K. Nihon Rinsho
Meneki Gakkai Kaishi. 2017;40(1):48-53.
5. The metabolic regulation in immune cells andpathogenesis of systemic lupus erythematosus ∼toward new therapeutic applications. Takeshima
Y, Iwasaki Y, Okamura T, Fujio K, Yamamoto K.
Nihon Rinsho Meneki Gakkai Kaishi. 2017;40(1):12-20
6. Interleukin-10-producing LAG3+ regulatory T
cells are associated with disease activity andabatacept treatment in rheumatoid arthritis.
Nakachi S, Sumitomo S, Tsuchida Y, Tsuchiya H,
Kono M, Kato R, Sakurai K, Hanata N, Nagafuchi
Y, Tateishi S, Kanda H, Okamura T, Yamamoto
K, Fujio K. Arthritis Res Ther. 2017 May 16;
19(1):97.
7. Efficacy of combination therapy with tacrolimus
and mizoribine for cyclophosphamide-resistantANCA-associated glomerulonephritis. Sakurai K,
Kubo K, Kanda H, Fujio K, Yamamoto K. Int J
Rheum Dis. 2017 Dec;20(12):2214-2216
8. Enhanced gut homing receptor expression of
unswitched memory B cells in rheumatoid
arthritis. Nagafuchi Y, Shoda H, Sumitomo S,

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Nakachi S, Kato R, Tsuchida Y, Tsuchiya H,
Sakurai K, Hanata N, Tateishi S, Kanda H, Fujio
K, Yamamoto K. Clin Exp Rheumatol. 2017
Mar-Apr;35(2):354-355
9. TGF-β3 Inhibits Antibody Production by Human
B Cells. Tsuchida Y, Sumitomo S, Ishigaki K,
Suzuki A, Kochi Y, Tsuchiya H, Ota M, Komai T,
Inoue M, Morita K, Okamura T, Yamamoto K,
Fujio K. PLoS One. 2017 Jan 4;12(1):e0169646
10. Macrophage activation syndrome associated withtocilizumab treatment in adult-onset Still's disease.
Tsuchida Y, Sumitomo S, Shoda H, Kubo K,
Fujio K, Yamamoto K. Mod Rheumatol. 2017
May;27(3):556-557.
11. Identification of tonsillar CD4+CD25-LAG3+ T
cells as naturally occurring IL-10-producing
regulatory T cells in human lymphoid tissue.
Sumitomo S, Nakachi S, Okamura T, Tsuchida Y,
Kato R, Shoda H, Furukawa A, Kitahara N,
Kondo K, Yamasoba T, Yamamoto K, Fujio K. J
Autoimmun. 2017 Jan;76:75-84.
12. Systemic lupus erythematosus with ADAMTS13
inhibitor-negative thrombotic microangiopathy
treated with combination of mycophenolate
mofetil, plasma exchange and steroid. Okubo M,
Shoda H, Bannai E, Kubo K, Kanda H, Fujio K,
Yamamoto K. Lupus. 2017 Mar;26(3):334-336.
13. Characteristics of antisynthetase syndrome
patients with hyperferritinaemia. Kobayashi S,
Shoda H, Seri Y, Nagafuchi Y, Sasaki O, Kubo K,
Fujio K, Yamamoto K. Scand J Rheumatol. 2017
Mar;46(2):161-163
14. Efficacy of intensive immunosuppression in
exacerbatedrheumatoid
arthritis-associatedinterstitial lung disease. Ota M, Iwasaki Y,
Harada H, Sasaki O, Nagafuchi Y, Nakachi S,
Sumitomo S, Shoda H, Tohma S, Fujio K,
Yamamoto K. Mod Rheumatol. 2017 Jan;27(1):22-28
15. Thoracic intradural extramedullary lesions
causing progressive myelopathy as an initial
manifestation of granulomatosis with polyangiitis:
a case report and review of literature. Taniguchi Y,
Chikuda H, Oshima Y, Ohya J, Matsubayashi Y,
Morikawa T, Shirai H, Sasaki O, Shibuya M,
Fujio K, Yamamoto K, Tanaka S. J Spinal Cord
Med. 2017 Jan;40(1):122-125.

159

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

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

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

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

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

Clinical activities
We have hospital beds on the 11th floor of the Ward
A of University of Tokyo Hospital. Diseases include
HIV infection, viral hepatitis, pneumonia, drug-

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

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

160

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

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

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

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

References
1. Kanno Y, Wakabayashi Y, Ikeda M, Tatsuno K,
Misawa Y, Sato T, Yanagimoto S, Okugawa S,
Moriya K, Yotsuyanagi H: Catheter-related bloodstream infection caused by Kodamaea ohmeri: A
case report and literature review. J InfectChemother 2017.
2. Tabuchi F, Matsumoto Y, Ishii M, Tatsuno K,
Okazaki M, Sato T, Moriya K, Sekimizu K:
Synergistic effects of vancomycin and betalactams against vancomycin highly resistant
Staphylococcus aureus. J Antibiot (Tokyo) 2017.
3. Ikeda M, Kobayashi T, Suzuki T, Wakabayashi Y,
Ohama Y, Maekawa S, Takahashi S, Homma Y,
Tatsuno K, Sato T et al: Propionimicrobium
lymphophilum and Actinotignum schaalii bacte
raemia: a case report. New Microbes New Infect2017, 18:18-21.
4. Matsuda K, Koya J, Toyama K, Ikeda M, Arai S,
Nakamura F, Okugawa S, Moriya K, Kurokawa
M: A therapeutic benefit of daptomycin against
glycopeptide-resistant gram-positive cocci bloodstream infections under neutropenia. J InfectChemother 2017.
5. Hirano J, Okamoto T, Sugiyama Y, Suzuki T,
Kusakabe S, Tokunaga M, Fukuhara T, Sasai M,
Tougan T, Matsunaga Y et al: Characterization of
SPP inhibitors suppressing propagation of HCV
and protozoa. Proc Natl Acad Sci U S A 2017,
114(50):E10782-E10791.
6. Kawaguchi Y, Sakamoto Y, Ito D, Ito K, Arita J,
Akamatsu N, Kaneko J, Hasegawa K, Moriya K,

161

Kokudo N: Statin use is associated with a reduced
risk of hepatocellular carcinoma recurrence after
initial liver resection. Biosci Trends 2017, 11(5):574-580.
7. Hatakeyama S, Ohama Y, Okazaki M, Nukui Y,
Moriya K: Antimicrobial susceptibility testing of
rapidly growing mycobacteria isolated in Japan.
BMC Infect Dis 2017, 17(1):197.
8. Kamei J, Yagihara Y, Kume H, Horiuchi T, Sato T,
Nakagawa T, Fujimura T, Fukuhara H, Moriya K,
Homma Y: Prevalence and characteristics of fecal
antimicrobial-resistant Escherichia coli in a cohortof Japanese men undergoing prostate biopsy. Int J
Urol 2017, 24(4):295-300.

162

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

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

Homepage

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

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

Clinical activities
Our department is responsible for both outpatient
clinic and inpatient ward. The ward is managed as apart of the Division of General Internal Medicine, andsenior residents, an associate, and the associate
professor attend it every day and provide close sideby-side instruction to junior residents. The weekly
professor’s round is scheduled on Thursday morning.
During 2017 April to 2018 March, overall 1,547
patients (51 individuals) were admitted to the ward,
many of whom were eating disorder patients.
Outpatient clinic is attended on every morning andafternoon in three consultation rooms by approximately fifteen physicians. During 2017 April to 2018
March, the numbers of the new outpatients and of theoverall outpatients in our department were 227 and
4,541, respectively.

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

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

163

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. Hiraide M, Harashima S, Yoneda R, Otani M,
Kayano M, Yoshuchi K.Longitudinal course ofeating disorders after transsexual treatment: a reportof two cases. BioPsychoSoc Med 11:32, 2017
2. Moriya J, Kayano M, Yoshiuchi K. Impact of a new
medical network system on the efficiency of treatment for eating disorders in Japan: a retrospective
observational study. BioPsychoSoc Med 11:27, 2017
3. Matsuoka H, Yoshiuchi K, Koyama A, Makimura C,

Fujita Y, Tsurutani J, Sakai K, Sakamoto R, Nishio
K, Nakagawa K. Expectation of a decrease in pain
affects the prognosis of pain in cancer patients: A
prospective cohort study of response to morphine.
Int J Behav Med 24:535-541, 2017
4. Harashima S, Yoneda R, Horie T,Kayano M, Fujioka
Y, Nakamura F, Kurokawa M, Yoshiuchi K*.
Development of the Japanese version of thePsychosocial Assessment of Candidates for Transplantation in allogeneic hematopoietic stem celltransplantation. Psychosomatics 58:292-298, 2017
5. Fukui S, Morita T, Yoshiuchi K. Development of aclinical tool to predict home death of a discharged
cancer patient in Japan: a case-control study. Int J
Behav Med 24:584-592, 2017

Internal Medicine
3. Clinical Laboratory Medicine
and Pathology

165

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

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

Homepage

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

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

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

1661) Pre-operative autologous blood collection andpreservation;2) Collection and preservation of peripheral blood
stem cells for transplantation;

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

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

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

167

References
1. Yazer MH, van de Watering L, Lozano M,
Sirdesai S, Rushford K, Wood EM, Yokoyama AP,
Kutner JM, Lin Y, Callum J, Cserti-Gazdewich C,
Lieberman L, Pendergrast J, Pendry K, Murphy
MF, Selleng K, Greinacher A, Marwaha N,
Sharma R, Jain A, Orlin Y, Yahalom V, Perseghin
P, Incontri A, Masera N, Okazaki H, Ikeda T,
Nagura Y, Zwaginga JJ, Pogłod R, Rosiek A,
Letowska M, Yuen J, Cid J, Harm SK, Adhikari
P:Development of RBC transfusion indications
and the collection of patient-specific pretransfusion information. Vox Sang.112:487-494,
2017
2. Maeda T, Nakagawa K, Murata K, Kanaumi Y,
Seguchi S, Kawamura S, Kodama M, Kawai T,
Kakutani I, Ohnishi Y, Kokame K, Okazaki H,
Miyata S: Identifying patients at high risk ofheparin-induced
thrombocytopenia-associatedthrombosis with a platelet activation assay using
flow cytometry. Thromb Haemost. 117:127-138,2017
3. Morishita Y, Nomura Y, Fukui C, Kawakami T,
Ikeda T, Mukai T, Yuba T, Inamura KI, Yamaoka
H, Miyazaki KI, Okazaki H, Haishima Y: Pilot
study on novel blood containers with alternative
plasticizers for red cell concentrate storage. PLoS
One 28;12:e0185737. 2017
4. Yoshikawa N, Masuda A, Sato T, Jona M, Maki H,
Masamoto Y, Sone S, Okazaki H, Kurokawa M,
Yatomi Y: Evaluation of the clinical utility ofhematopoietic progenitor cell (HPC) measurement
obtained by a multi-item hematology analyzer.
Rinsho Byori 66:144-51, 2018
5. Masuda R, Iijima T, Kondo R, Itoda Y,
Matsuhashi M, Hashimoto S, Kohira T,
Kobayashi N, Okazaki H: Preceding haemorrhagic shock as a detrimental risk factor for
respiratory distress after excessive allogeneic
blood transfusion. Vox Sang 113:51-59, 2018

Reproductive, Developmental andAging Sciences
1. Obstetrics and Gynecology

169

Department of
Reproductive Endocrinology
Professors
Tomoyuki Fujii

Associate Professors
Takeshi Nagamatsu

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

Activities
In clinical section, we have an out-patient clinic for
infertility, gynecological endocrine diseases, genetic
counseling and assisted reproductive technologies(ART).
We have a highly organized infertility clinic, where
every patient is systemically examined and after diagnosis of underlying infertility factor (s) appropriate
treatment is performed following our protocol. Once itturns out that higher level of treatment is necessary,
ART is applied to such cases. We have been engaged
in in vitro fertilization and embryo transfer (IVF-ET)
as a main axis of ART for twenty years. Conventional
IVF-ET is mainly indicated to cases with tubal factor,
mild male factor, immunological factor or of
unexplained infertility factor. In case of severe male
factor or other fertilization disorder intracytoplasmic
sperm injection (ICSI) is performed. Now we haveabout 200 OPU cycles of IVF-ET every year, whichconventional IVF-ET and ICSI share almost equally.
The clinical pregnancy rate of conventional IVF-ET isaround 30% per embryo transfer cycle, which iscomparable with that of ICSI. Other ART techniquessuch as embryo cryopreservation and assisted hatching
are also performed.
In basic research section, a couple of projects asfollows are under way, some of which have alreadyyielded interesting findings; 1) the mechanism offolliculogenesis and follicular apoptosis in the ovary,2) the functions of gynecologic hormones such as
gonadotropins and ovarian steroids, 3) the analysis /etiology of endometriosis, adenomyosis and fibroma
4) effect of ovarian steroid hormones on bonemetabolism, and 5) effects of endocrine disrupters on
the reproductive system.

References published in 2017
1. Egashira M, Hirota Y, Shimizu-Hirota R,
Saito-Fujita T, Haraguchi H, Matsumoto L, et al.
F4/80+ Macrophages Contribute to Clearance ofSenescent Cells in the Mouse Postpartum Uterus.
Endocrinology. 2017;158(7):2344-53.
2. Izumi G, Koga K, Takamura M, Bo W, Nagai M,
Miyashita M, et al. Oil-Soluble Contrast Medium(OSCM) for Hysterosalpingography Modulates
Dendritic Cell and Regulatory T Cell Profiles in
the Peritoneal Cavity: A Possible Mechanism by
Which OSCM Enhances Fertility. Journal of
immunology. 2017;198(11):4277-84.
3. Saito A, Hirata T, Koga K, Takamura M, Fukuda

170S, Neriishi K, et al. Preoperative assessment offactors associated with difficulty in performing
total laparoscopic hysterectomy. The journal ofobstetrics and gynaecology research. 2017;43(2):320-9.
4. Takahashi N, Harada M, Hirota Y, Nose E, Azhary
JM, Koike H, et al. Activation of Endoplasmic
Reticulum Stress in Granulosa Cells from Patientswith Polycystic Ovary Syndrome Contributes toOvarian Fibrosis. Scientific reports. 2017;7(1):10824.
5. Takahashi N, Harada M, Hirota Y, Zhao L,
Azhary JM, Yoshino O, et al. A Potential Role forEndoplasmic Reticulum Stress in Progesterone
Deficiency in Obese Women. Endocrinology.
2017;158(1):84-97.

171

Department of
Gynecologic Oncology
Professor
Yutaka Osuga

Associate Professor
Katsutoshi Oda

Homepage http://square.umin.ac.jp/tkyobgyn/
http://www.h.u-tokyo.ac.jp/patient/depts/a_joseika01/index.html
Organization
The Department of Gynecologic Oncology isorganized by one professor and one associate
professors, being directed practically by Professor
Yutaka Osuga, the Department of Obstetrics andGynecology. The staff members are taking part in bothclinical and research activities, as well as teachingactivities, with 19 associates of the University of Tokyo
Hospital. For the clinical aspect, they are engaged within-patient and out-patient care.

Activities(1) Oncology research
In our division, the pathogenesis of cervical cancer,
endometrial cancer, and ovarian cancer have been
investigated these two decades.
Cervical cancer is associated with a subset of highrisk HPVs. The most prevalent of these, types 16 and18, together account for more than 70% of cases. HPV
infections are very common among young sexuallyactive women, and the majority of infections aretransient and cleared by their immune system within ashort period, with 70% of infections deleted in 1 year
and 90% in 2 years.
Studies of virus neutralization by antibody are
prerequisite for development of a prophylactic vaccine
strategy against HPVs. To determine whether neutralizing anti-bodies (NAs) against HPV16 is responsible
for a higher regression rate of low-grade cervicalintraepithelial neoplasia (CIN1), we investigated an
association between the presence of the NAs and thefate of the HPV16-related CIN1. The incidence of thepresence of the NAs in the women with a nonpathological cervix (85.7%) was significantly higher
than in the CIN1 cases (21.5%), the CIN2/3 cases(15.7%), and the cervical cancer cases (0%) (p<0.0001).
The regression of the CIN1 lesion was closely
associated with the presence of the NAs (p=0.0002).
The presence of the NAs was associated with low-level
copy number of the viral DNA relative to the NAnegative group (p=0.05). The presence of the NAs
against HPV16 was associated with a higher regression
rate of HPV-related CIN1 lesions. The NAs seem tohave a role in deterring HPV-related cervical lesions
from progressing to CIN2/3 by inhibiting the infection
with de novo replicated HPV. Then we designed aplacebo-controlled trial in healthy adults to evaluate thesafety and immunogenicity of a synthetic peptide
consisting of the aa 108-120 of HPV16 L2 (L2108/120) region, because this region contains a crossneutralization epitope against genital HPV.. A total of
13 volunteers were given nasal inoculations with 0.1(n=5) or 0.5mg (n=5) doses of the peptides or placebo(n=3) without adjuvant at weeks 0, 4, and 12. Sera werecollected before inoculation and at 6, 16 and 36 weeks.
The inoculation caused no serious local and systemic
complications. The inoculation generated anti-L2
antibodies binding to both HPV16 and 52 L1/L2capsids in four of the five recipients in the 0.5mg group.

172

Sera of the four recipients showed neutralizing
activities against HPV16 and 52. Serological responses
to the peptides were not found in the 0.1mg group andthe placebo group recipients. This study suggests theL2-108/120 peptide is tolerable in humans and has thepotential as a broad-spectrum prophylactic vaccine
against genital HPV.
In endometrial cancer, we identified novel mutations
in PIK3CA and AKT1, and reported that inhibiting the
Phosphatidylinositol 3-kinase (PI3K) / Akt pathway
showed anti-tumor effect in endometrial cancer cells.
We have identified other candidate molecular targets inendometrial cancer. For example, high expression ofsurvivin, an anti-apoptotic protein, is associated withpoor prognosis. We found that survivin inhibitor,
YM155, dose-dependently and significantly increased
the apoptotic cell population in all endometrial cancer
cell lines examined. In addition, we elucidated that thehistone methyltransferase EZH2, a key epigenetic
modifier, is significantly overexpressed in endometrial
cancers, and that EZH2 inhibitor suppressed
endometrial cancer cell growth. We also investigatedmolecular biomarkers to predict the prognosis and/or
drug sensitivity in endometrial cancer, using genomewide analyses in clinical samples. Of note, extensive
chromosomal instability was an independent poor
prognostic factor in endometrial cancer.
In ovarian cancer, we also investigated genomewide analyses, including whole-exome sequencing andgene expression array, in high-grade serous and clear
cell carcinomas. As well, we examined various types ofmolecular-targeted drugs in ovarian cancer cell lines.
For example, we identified a subgroup in ovarian clear
cell carcinomas, which is associated with prognosis andchemosensitivity. We reported several moleculartargets in ovarian clear cell carcinomas. Targeting thePI3K pathway showed anti-tumor effect throughinduction of wild-type TP53. We further identified that
MDM2, a negative regulator of TP53, is frequently
overexpressed and that MDM2 inhibitor induced TP53mediated apoptosis in ovarian clear cell carcinomas.
We also reported a role of the dysregulation of
epigenetic modifier in carcinogenesis and ovariancancer progression. For example, histone methyltransferase WHSC1 was overexpressed in ovarian clear
cell carcinoma. Overexpression of WHSC1 wasinvolved in the proliferation of cancer cells.

(2) Clinical oncology
In our department, more than 150 patients withgynecological cancer are treated every year. And also,
we play an important role in clinical trials of JCOG
(Japan Clinical Oncology Group) and JGOG (Japanese
Gynecologic Oncology Group). For example, we
conducted a non-randomized confirmatory phase III
trial (JCOG1101) in Japan to evaluate the efficacy ofmodified radical hysterectomy in patients with tumor
diameter 2 cm or less FIGO Stage IB1 uterine cervicalcancer, for which the current standard is radical
hysterectomy. This study began in January 2013 and a
total of 240 patients will be accrued from 44
institutions within 5 years. The primary endpoint is 5year survival. The secondary endpoints are overall
survival, relapse-free survival, local relapse-freesurvival, percent completion of modified radical
hysterectomy, percent local relapse, percent
pathological parametrial involvement, days until selfurination and residual urine disappearance, blood loss,
operation time, percent post-operative radiation
therapy, adverse events and severe adverse events.
In addition, we have performed a lot of singleinstitution analyses in clinical setting. For example, toevaluate the efficacy and toxicity of systematic
lymphadenectomy and postoperative radiotherapy(PORT) in the treatment of endometrial cancer (EC), a
total of 256 patients with EC between 2000 and 2008
were retrospectively analyzed. Surgery included
systematic pelvic and aortic lymphadenectomy,
whereas pelvic lymphadenectomy alone was performed
to preoperative stage I patients with superficial
myometrial invasion and G1 endometrioid adenocarcinoma. PORT was administered to 67 patients withpositive lymph nodes, deep myometrial invasion, or
adnexal/peritoneal metastases. Prior to PORT, 37
patients with adnexal/peritoneal involvement or aortic
node metastases were treated with chemotherapy.
Surgery was undergone in 247 patients, including with
215 pelvic lymphadenectomy and 126 aortic
lymphadenectomy. Five-year survival was 97.0% forstage I, 83.3% for stage II, 84.1% for stage III, and45.2% for stage IV. In PORT group, 13 (19%) wererecurred including one (1.5%) intrapelvic recurrence,and five-year survival was 96.7% for intermediate-risk
group and 85.3% for high-risk group. Among thepatients who had received lymphadenectomy, 19173(8.8%) experienced severe (more than grade 3) ileus
and 18 (8.4%) developed severe lymphocystitis. The
frequency of severe ileus in PORT group was
significantly higher than that in non-PORT group(14/65 vs. 5/150, P<0.0001). The rates of adverse
effects were irrespective of aortic lymphadenectomy.
This study suggested that surgery with systematic
lymphadenectomy followed by PORT was associatedwith good prognosis but increased rates of ileus inpatients with EC. PORT subsequent to lymphadenectomy should limit to relatively high-risk patients.

References published in 2017
(1) Fukui Y, et al. Polycystic Ovarian Morphology
may be a Positive Prognostic Factor in Patientswith Endometrial Cancer who Achieved Complete
Remission after Fertility-Sparing Therapy with
Progestin. Asian Pac J Cancer Prev. 2017 Nov
26;18(11):3111-3116.
(2) Oda K, et al. Recent advances in targeting DNA
repair pathways for the treatment of ovarian cancer
and their clinical relevance. Int J Clin Oncol. 2017
Aug;22(4):611-618.
(3) Sato M, et al. Intracellular signaling entropy canbe a biomarker for predicting the development ofcervical intraepithelial neoplasia. PLoS One. 2017
Apr 28;12(4) Oki S, et al. Oncogenic histone methyltransferase
EZH2: A novel prognostic marker with therapeuticpotential in endometrial cancer. Oncotarget. 2017
Jun 20;8(25):40402-40411.
(5) Sato M, et al. Targeting glutamine metabolism andthe focal adhesion kinase additively inhibits the
mammalian target of the rapamycin pathway inspheroid cancer stem-like properties of ovarian
clear cell carcinoma in vitro. Int J Oncol. 2017
Apr;50(4):1431-1438.
(6) Sato M, et al. Low uptake of fluorodeoxyglucose
in positron emission tomography/computed
tomography in ovarian clear cell carcinoma may
reflect glutaminolysis of its cancer stem cell-like
properties. Oncol Rep. 2017 Mar;37(3):1883-1888.

174

Department of Perinatal Medicine
Professor
Tomoyuki Fujii

Associate Professor
Kaori Koga

Homepage http://square.umin.ac.jp/tkyobgyn/
http://www.iiosan.umin.jp/index.htm
Organization
The Department of Perinatal Medicine is organized
by one professor and one associate professor, being
directed practically by Professor Tomoyuki Fujii, thechairman of the Department of Obstetrics andGynecology. All the staff members are taking part inboth the clinical and research activities, as well as theteaching activities, with 19 associates of the
University of Tokyo Hospital. For the clinical aspect,they are engaged with in-patient and out-patient careincluding the activities in the delivery units.

Activities
The clinical service for perinatology in the
University of Tokyo Hospital consists of out-patient
clinic and the Delivery Unit. [See Delivery Unit of the
University of Tokyo Hospital]
By the advance of the techniques for prenatal
diagnosis of fetal growth and congenital malformations, the area of fetal medicine is enlarging. Strictmeasurement of fetal growth during pregnancy has
made possible the accurate diagnosis of fetal growth
restriction. New techniques like fetal blood sampling
and three-dimensional ultrasonography have been
introduced into clinical service. The perinatologists
and medical engineering team in our department are
working on clinical research to clarify the pathoetiology of preterm birth and preeclampsia. Perineal
ultrasound is a new approach for assessing labor
progress. Using this technique, we are challenging toestablish objective evaluation of labor progress which

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

175

The inpatient’s wards for obstetrics and NICU unit
are now under reconstruction. The new perinatal
medical center will be one of the biggest in Tokyo. We
will provide advanced medical care for more patients.
The construction will be completed in 2019.

References published in 20152017
1: Sayama S, Takeda N, Iriyama T, Inuzuka R,
Maemura S, Fujita D, et al. Peripartum type B
aortic dissection in patients with Marfan
syndrome who underwent aortic root replacement:a case series study. BJOG. 2017. Mar 11. doi:
10.1111/1471-0528.14635.
2: Samejima T, Nagamatsu T, Schust DJ, Iriyama T,
Sayama S, Sonoda M, et al. Labor prediction
based on the expression patterns of multiple genes
related to cervical maturation in human term
pregnancy. Am J Reprod Immunol. 2017 Nov;
78(5) doi: 10.1111/aji.12711.
3: Fujii T, Nagamatsu T, Morita K, Schust DJ,
Iriyama T, Komatsu A, et al. Enhanced HIF2α
expression during human trophoblast differentiation into syncytiotrophoblast suppresses transcription of placental growth factor. Sci Rep. 2017 Sep
29;7(1):12455.
4: Hashimoto A, Iriyama T, Sayama S, Nakayama T,
Komatsu A, Miyauchi A, et al. Adenomyosis andadverse perinatal outcomes: increased risk of
second trimester miscarriage, preeclampsia, andplacental malposition. The journal of maternalfetal & neonatal medicine. 2017:1-6.
5: Motomura K, Okada N, Morita H, Hara M,
Tamari M, Orimo K, et al. A Rho-associatedcoiled-coil containing kinases (ROCK) inhibitor,
Y-27632, enhances adhesion, viability and differentiation of human term placenta-derived trophoblasts in vitro. PloS one. 2017;12(5): e0177994.
6: Machino H, Iriyama T, Nakayama T, Komatsu A,
Nagamatsu T, Osuga Y, et al. A case of a surviving
co-twin diagnosed with porencephaly and renal
hypoplasia after a single intrauterine fetal death at
21 weeks of gestation in a monochorionic monoamniotic twin pregnancy. Oxford medical casereports. 2017; 2017 (1):omw096.
7: Aikawa S, Kano K, Inoue A, Wang J, Saigusa D,

Nagamatsu T, et al. Autotaxin-lysophosphatidic
acid-LPA3 signaling at the embryo-epithelial
boundary controls decidualization pathways. The
EMBO journal. 2017;36(14):2146-60.
8: Nitta D, Kinugawa K, Imamura T, Endo M,
Amiya E, Hatano M, et al. Successful Pregnancy
and Delivery in a Heart Transplantation Recipient.
International heart journal. 2016;57(3):383-5.
9: Tanaka S, Kanagawa T, Momma K, Hori S, Satoh
H, Nagamatsu T, et al. Prediction of sustained
fetal toxicity induced by ketoprofen based on
PK/PD analysis using human placental perfusion
and rat toxicity data. British journal of clinicalpharmacology. 2017.
10: Samejima T, Nagamatsu T, Schust DJ, Itaoka N,
Iriyama T, Nakayama T, Komatsu, A, Kawana K,
Osuga Y, Fujii T. Elevated concentration of
secretory leukocyte protease inhibitor in thecervical mucus before delivery. Am J Obstet
Gynecol. 214(6):741.e1-7, 2016
11: Taguchi A, Yamashita A, Kawana K, Nagamatsu T,
Furuya H, Inoue E, Osuga Y, Fujii T. Recent
Progress in Therapeutics for InflammationAssociated Preterm Birth: A Review. Reprod Sci.
2015 Dec 1.
12: Oki S, Nagamatsu T, Iriyama T, Komatsu A,
Osuga Y, Fujii T. A case of pregnancy complicatedwith dilated cardiomyopathy 1X. Oxf Med Case
Reports. 2015(11):351-353, 2015
13: Ichikawa M, Nagamatsu T, Schust DJ,
Kawai-Iwasawa Y, Kawana K, Yamashita T,
Osuga Y, Aoki J, Yatomi Y, Fujii T. Placental
autotaxin expression is diminished in women withpre-eclampsia. J Obstet Gynaecol Res. 41(9):1406-1411, 2015.
14: Furuya H, Taguchi A, Kawana K, Yamashita A,
Inoue E, Yoshida M, Nakamura H, Fujimoto A,
Inoue T, Sato M, Nishida H, Nagasaka K, Adachi
K, Hoya M, Nagamatsu T, Wada-Hiraike O,
Yamashita T, Osuga Y, Fujii T. Resveratrol
Protects Against Pathological Preterm Birth by
Suppression of Macrophage-Mediated Inflammation. Reprod Sci. 22(12):1561-1568, 2015
15: Itaoka N, Nagamatsu T, Schust DJ, Ichikawa M,
Sayama S, Iwasawa-Kawai Y, Kawana K,
Yamashita T, Osuga Y, Fujii T. Cervical
Expression of Elafin and SLPI in Pregnancy and176

Their Association With Preterm Labor. Am J
Reprod Immunol. 73(6):536-544, 2015

177

Department of Molecular andCellular Reproductive Medicine
Professor
Yutaka Osuga

Associate Professor
Osamu Hiraike

Homepage http://www.h.u-tokyo.ac.jp/patient/depts/a_joseika02/index.html#reproduction
Organization
The Department of Molecular and Cellular
Reproductive Medicine is organized by one professor
and one associate professor.

Activities
Our department mainly aims to investigate thereproductive functions, and molecular biologicalmethods are utilized to accomplish this purpose. Basic
researches are currently performed and we arerevealing many interesting findings annualy. We
specifically focus on the role of inflammation andtranscription machinery in these issues.
1) The mechanism of folliculogenesis, follicularatresia and intrafollicular microenvironment in theovary.
2) The physiological functions of sex steroid
hormones and gonadotoropins.
3) The molecular mechanisms of endometriosis.
4) The molecular mechanisms of uterine fibroid andadenomyosis.
5) The effects of aging on the reproductive system.
In clinical section, we have an out-patient clinic for
infertility, gynecological endocrine disorders andgenetic counseling. We also perform minimallyinvasive surgery for benign gynecological diseases
including endometriosis, uterine fibroid, adenomyosis,
infertility, and pelvic organ prolapse. More than 90%of surgery cases for benign gynecological disorders
are operated using endoscope, and we deal with 400
cases annually.
In accordance with the notion of life stage specificapproches, we also manage patients complaining
primary/secondary amenorrhea, infertility, dysmenorrhea, heavy menstrual bleeding, and climactirium.
Osteoporosis in relatively younger generation might
be a heavy burden for patinets and we have alreadyestablished the primary care system for these women.

References published in 2017
1. Isono W, Wada-Hiraike O, Kawamura Y, Fujii T,
Osuga Y, Kurihara H. Administration of Oral
Contraceptives Could Alleviate Age-Related
Fertility Decline Possibly by Preventing Ovarian
Damage in a Mouse Model. Reproductive
sciences. 2017:1933719117746758.
2. Izumi G, Koga K, Takamura M, Makabe T, Nagai
M, Urata Y, et al. Mannose receptor is highly
expressed by peritoneal dendritic cells in endometriosis. Fertility and sterility. 2017;107(1):167-73
e2.
3. Makabe T, Koga K, Miyashita M, Takeuchi A,
Sue F, Taguchi A, et al. Drospirenone reduces
inflammatory cytokines, vascular endothelial
growth factor (VEGF) and nerve growth factor(NGF) expression in human endometriotic stromalcells. Journal of reproductive immunology. 2017;

178

119:44-8.
4. Nose-Ogura S, Yoshino O, Yamada-Nomoto K,
Nakamura M, Harada M, Dohi M, et al. Oralcontraceptive therapy reduces serum relaxin-2 inelite female athletes. The journal of obstetrics andgynaecology research. 2017;43(3):530-5.
.

Reproductive, Developmental andAging Sciences
2. Pediatric Sciences

180

Department ofPediatrics, Department ofDevelopmental Pediatrics
Professor
Akira Oka, M.D.,Ph.D.
Naoto Takahashi, M.D., Ph.D. (Department of pediatric and neonatal intensive care)

Associate Professor
Sachiko Kitanaka, M.D., Ph.D.
Junko Takita, M.D., Ph.D.

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

Associate
Hiroko Asakai, M.D., Kouji Hirohata, M.D., Moe Hidaka, M.D., Chiharu Irisa, M.D., Yuu
Kakimoto, M.D., Sho-ichirou Kanda, M.D., Ph.D., ., Yuichi Mitani, M.D., Takayuki Mori,
M.D., Hiroshi Mutoh, M.D., Riki Nishimura, M.D.,Ph.D., Shigeru Nomura M.D.,Ph.D., ,Atsushi Satou, M.D. Ph.D., Masafumi Seki, M.D. Ph.D., Konomi Shimoda, M.D.,
Takahiro Shindo,M.D., Ph.D. , Kazuhiro Shiraga M.D., Satoshi Takenaka, M.D., Hiroki
Takehara, M.D, Susumu Urata, M.D., Hiroki Yasudo, M.D., Ph.D.
(As of March 31, 2018)

Homepage

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

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

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

181

Clinical activities

Teaching activities

We have specialized outpatient clinics covering allpediatric fields in addition to general pediatrics. In
July, 2008, the capacity of the pediatric and pediatricsurgery ward was increased to 100 beds, including 9
beds in the neonatal intensive care unit (NICU), 15
beds in the growing care unit (GCU) and 6 beds in thepediatric intensive care unit (PICU), and our institution is going to fulfill the designation as children’s
hospital affiliated to the university hospital. In
NICU, we are taking care of small premature babies
weighing from 400g to 4,000g often associated withcongenital disorders requiring invasive interventions.
A variety of patients with diseases, such ashematological/oncological disorders (acute leukemia,
neuroblastoma, rhabdomyosarcoma, hepatoblastoma,
brain tumors, etc.), cardiac disorders (congenital heartdiseases and Kawasaki disease), neuromuscular disorders, immunological/allergic disorders (common
variable immunodeficiency, chronic granulomatous
disease and bronchial asthma), renal and urinary tract
diseases (nephrotic syndrome, chronic glomeluronephritis, purpura nephritis and renal and/or urinary
tract anomalies), endocrinological disorders, metabolic disorders and psychosomatic diseases are admitted
in the wards. Approximately 10 patients received
hematopoietic stem cell transplantation every year.
There are patients with severe combined immunodeficiency, aplastic anemia-myelodysplastic syndrome,
relapse/refractory acute lymphoblastic leukemia, acute
myeloid leukemia and high-risk neuroblastoma.
Many patients need to stay long in the hospital. We
provide an official in-hospital school ”Kodama
Gakkyu” where patients receive education and havechances to communicate with other patients as well as
their family members. “Niko-niko Volunteer” members, an official volunteer group in the hospital, visit
the pediatric ward every weekday to play with thepatients and help their mothers, providing enormous
comfort to both the patients and their mothers. Various
activities are scheduled for the patients in the hospitalsuch as the Tanabata festival, a Christmas party andmusic concerts. All the residents, fellows and nurses
participate in these activities. We have two child carespecialists in the pediatric ward.

The staff members and the visiting lecturers givelectures of general pediatrics to the second year
students. The third year students have clinicalclerjship in the inpatient ward for 2 weeks. During
bedside learning, teaching sessions on variety ofpediatric fields are held every day. We also offer anelective clinical clerkship course for selected students
in their third year. In the outpatient learning of theforth year students, students take histories andperform physical examinations of patients under thesupervision of the teaching staff. During the period,
students visit the local pediatric clinic or hospitals inand around Tokyo. On the last day of clinical learning,
the Professor and an Associate Professor evaluate thestudents’ achievements.

Research activities
Our departments have the following researchgroups: nephrology, hematology/oncology, neurology,
cardiology, endocrinology/metabolism, immunology/
allergy, and neonatology. We also have multidisciplinary research groups and laboratories such ascell biology, genetic molecular biology and epidemiology. The main subjects of research during the lastyear are listed as follows.
① Hematology/Oncology
group:
To
exploremolecular mechanisms of pediatric malignancies,
we performed target capture sequencing, wholetranscriptome sequencing and genome-wide
methylation analysis in T cell acute lymphoblastic
leukemia (T-ALL), pancreatoblastoma (PBL) andneuroblastoma (NBL) using next-generation
sequencing and array based technologies. Subsequently, we found novel recurrent SPI1-related
fusions in approximately 4% of T-ALL.
Importantly, this SPI1 fusions were significantly
associated with poor prognosis. In PBL, we found
WNT pathway abnormalities in 100% of cases.
Uniparental disomy of chromosome 11q was alsofrequently observed in PBL. In addition, based on
the genetic signatures, 6 distinct genetic subgroups
were detected in NBL. These subgroups were wellcorrelated with clinical features and outcomes.
② Nephrology group: Our aim is to reveal themolecular mechanism of pediatric kidney diseases.

182

We identified novel causative mutations on several
proteinuric diseases including pediatric nephrotic
syndrome. By analyzing the mechanism of
endocytosis of proteins in renal tubular cells, we
identified the molecular cause of low-molecular
proteinuria in Imerslund-Grasbeck syndrome.
③ Endocrinology and Metabolism group: We are
analyzing genes and mechanisms involved in
endocrinology and bone diseases. We analyzed
the function of the novel gene identified in a rarecongenital disease using model animals and iPS
cells. We also analyzed the responsible gene forhereditary rickets and found novel mutations andetiology.
④ Cardiology group: We performed genome-wide
association studies for congenital heart disease andstudies to develop a novel treatment for Kawasaki
disease using mouse models.
⑤ Neurology Group: The pathogenetic mechanism ofacute encephalopathy as well as congenital CNS
anomalies such as tuberous sclerosis is investigated. Regarding congenital cytomegalovirus
infection, an important and common cause ofperinatal brain injury, diagnostic method andtreatment are being investigated.
⑥ Neonatology group: Epigenetic changes in cord
blood and postnatal peripheral blood of pretermand SGA infants are investigated using
epigenome-wide methylation analysis. Influenceof microbiome on neonatal immune function is
also investigated. Neonatal brain function has been
investigated using near infra-red spectro-scopy(NIRS) with researchers of Department of
Education. A clinical trial of formula suppliedwith biotin has been conducted with groups of theother Universities. Cytokine profiles have been
investigated in order to elucidate pathophysiologyof several diseases in perinatal period.
⑦ Immunology group: Research area of interest
includes refractory Kawasaki disease and epidemiology of childhood infectious disease.

2.

3.

4.

5.

6.

Referencess
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Nakazawa A, Suzuki H, Yoshida K, Seki M,
Hiwatari M, Isobe T, Shiraishi Y, Chiba K, Tanaka

7.

H, Miyano S, Koh K, Hanada R, Oka A, Hayashi
Y, Ohira M, Kamijo T, Nagase H, Takimoto T,
Tajiri T, Nakagawara A, Ogawa S, Takita J:
Identification of the genetic and clinical characteristics of neuroblastomas using genome-wide
analysis. Oncotarget. 8:107513-107529, 2017
Takagi M, Yoshida M, Nemoto Y, Tamaichi H,
Tsuchida R, Seki M, Uryu K, Nishii R, Miyamoto
S, Saito M, Hanada R, Kaneko H, Miyano S,
Kataoka K, Yoshida K, Ohira M, Hayashi Y,
Nakagawara A, Ogawa S, Mizutani S, Takita J:
Loss of DNA Damage Response in Neuroblastoma and Utility of a PARP Inhibitor. J NatlCancer Inst. 109: (11). doi: 10.1093/jnci/djx062.,
2017
Takita J: The role of anaplastic lymphoma kinase
in pediatric cancers. Cancer Sci. 108:1913-1920,
2017
Hiwatari M, Seki M, Akahoshi S, Yoshida K,
Miyano S, Shiraishi Y, Tanaka H, Chiba K,
Ogawa S, Takita J: Molecular studies reveal
MLL-MLLT10/AF10 and ARID5B-MLL genefusions displaced in a case of infantile acutelymphoblastic leukemia with complex karyotype.
Oncol Lett. 14:2295-2299, 2017
Watanabe K, Kato M, Ishimaru T, Hiwatari M,
Suzuki T, Minosaki Y, Takita J, Fujishiro J, Oka
A: Perioperative management of severe congenital
protein C deficiency. Blood Coagul Fibrinolysis.
28:646-649, 2017
Seki M, Kimura S, Isobe T, Yoshida K, Ueno H,
Nakajima-Takagi Y, Wang C, Lin L, Kon A,
Suzuki H, Shiozawa Y, Kataoka K, Fujii Y,
Shiraishi Y, Chiba K, Tanaka H, Shimamura T,
Masuda K, Kawamoto H, Ohki K, Kato M,
Arakawa Y, Koh K, Hanada R, Moritake H,
Akiyama M, Kobayashi R, Deguchi T, Hashii Y,
Imamura T, Sato A, Kiyokawa N, Oka A, Hayashi
Y, Takagi M, Manabe A, Ohara A, Horibe K,
Sanada M, Iwama A, Mano H, Miyano S, Ogawa
S, Takita J: Recurrent SPI1 (PU.1) fusions inhigh-risk pediatric T cell acute lymphoblastic
leukemia. Nat Genet. 49:1274-1281, 2017
Osumi T, Kato M, Ouchi-Uchiyama M, Tomizawa
D, Kataoka K, Fujii Y, Seki M, Takita J, Ogawa S,
Uchiyama T, Ohki K, Kiyokawa N: Blastictransformation of juvenile myelomonocytic

183

leukemia caused by the copy number gain of
oncogenic KRAS. Pediatr Blood Cancer. 64(9).
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8. Hirabayashi S, Ohki K, Nakabayashi K, Ichikawa
H, Momozawa Y, Okamura K, Yaguchi A, Terada
K, Saito Y, Yoshimi A, Ogata-Kawata H,
Sakamoto H, Kato M, Fujimura J, Hino M,
Kinoshita A, Kakuda H, Kurosawa H, Kato K,
Kajiwara R, Moriwaki K, Morimoto T, Nakamura
K, Noguchi Y, Osumi T, Sakashita K, Takita J,
Yuza Y, Matsuda K, Yoshida T, Matsumoto K,
Hata K, Kubo M, Matsubara Y, Fukushima T, Koh
K, Manabe A, Ohara A, Kiyokawa N. Tokyo
Children’s Cancer Study Group (TCCSG) ：ZNF384-related fusion genes consist of a
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in childhood B-cell precursor acute lymphoblastic
leukemia. Haematologica. 102:118-129, 2017
9. Yoshida M, Hamanoue S, Seki M, Tanaka M,
Yoshida K, Goto H, Ogawa S, Takita J, Tanaka Y.
Metachronous anaplastic sarcoma of the kidney
and thyroid follicular carcinoma as manifestationsof DICER1 abnormalities. Hum Pathol. 61:205209, 2017
10. Kato M, Ishimaru S, Seki M, Yoshida K, Shiraishi
Y, Chiba K, Kakiuchi N, Sato Y, Ueno H, Tanaka
H, Inukai T, Tomizawa D, Hasegawa D, Osumi T,
Arakawa Y, Aoki T, Okuya M, Kaizu K, Kato K,
Taneyama Y, Goto H, Taki T, Takagi M, Sanada M,
Koh K, Takita J, Miyano S, Ogawa S, Ohara A,
Tsuchida M, Manabe A. Long-term outcome ofsix-month maintenance chemotherapy for acutelymphoblastic leukemia in children. Leukemia.
31:580-584, 2017
11. Tamura M, Isojima T, Kasama T, Mafune R,
Shimoda K, Yasudo H, Tanaka H, Takahashi C,
Oka A, Kitanaka S. Novel DHCR7 mutation in acase of Smith-Lemli-Opitz syndrome, showing
46,XY disorder of sex development. Hum
Genome Var. 4:17015、2017．
12. Itoh M, Tomio J, Toyokawa S,Tamura M, Isojima
T, Kitanaka S, Kobayashi Y. Vitamin D-deficient
rickets in Jpan. Glob Pediatr Health. 4:2333794X
17711342, 2017.
13. Tamura M, Ishizawa M, Isojima T, Özen S,
Makishima M, Oka A, Kitanaka S. Functional
analyses of a novel missense and other mutationsof the vitamin D receptor in association withalopecia. Sci Rep. 7:5102, 2017.
14. Takeuchi M, Inuzuka R, Hayashi T, Shindo T,
Hirata Y, Shimizu N, Inatomi J, Yokoyama Y,
Namai Y, Oda Y, Takamizawa M, Kagawa J,
Harita Y, Oka A. Novel Risk Assessment Tool for
Immunoglobulin Resistance in Kawasaki Disease:
Application Using a Random Forest Classifier.
Pediatr Infect Dis J. 36(9):821-826, 201715. Nakagama Y, Inuzuka R, Ichimura K, Hinata M,
Takehara H, Takeda N, Kakiuchi S, Shiraga K,
Asakai H, Shindo T, Hirata Y, Saitoh M, Oka A.
Accelerated Cardiomyocyte Proliferation in theHeart of a Neonate With LEOPARD SyndromeAssociated Fatal Cardiomyopathy. Circ Heart Fail.
11(4):e004660, 2018
16. Inuzuka R, Hsu S, Tedford RJ, Senzaki H.
Single-Beat Estimation of Right Ventricular
Contractility and Its Coupling to Pulmonary
Arterial Load in Patients With Pulmonary
Hypertension. J Am Heart Assoc. 7(10), 201817. Shiozawa Y, Inuzuka R, Shindo T, Mafune R,
Hayashi T, Hirata Y, Shimizu N, Inatomi J,
Yokoyama Y, Namai Y, Oda Y, Takamizawa M,
Harita Y, Kawahara T, Oka A. Effect of i.v.
immunoglobulin in the first 4 days of illness in
Kawasaki disease. Pediatr Int. 60(4):334-341,
2018
18. Takeda N, Inuzuka R (equivalent co-first),
Maemura S, Morita H, Nawata K, Fujita D,
Taniguchi Y, Yamauchi H, Yagi H, Kato M,
Nishimura H, Hirata Y, Ikeda Y, Kumagai H,
Amiya E, Hara H, Fujiwara T, Akazawa H, Suzuki
JI, Imai Y, Nagai R, Takamoto S, Hirata Y, Ono M,
Komuro I. Impact of Pathogenic FBN1 Variant
Types on the Progression of Aortic Disease inPatients With Marfan Syndrome. Circ Genom
Precis Med.11(6), 2018
19. Watanabe H, Shitara Y, Aoki Y, Inoue T, Tsuchida
S, Takahasi N, Taga G. Hemoglobin phase ofoxygenation and deoxygenation in early brain
development measured using fNIRS. Proc Natl
Acad USA 2017; 114(9): E1737-1744. doi: 10.
1073/pnas.1616866114. Epub 2017 Feb 14.
20. Nakamura T, Hatanaka D, Kusakari M, Kashima
K, Takizawa Y, Takahashi H, Yoshika T,
Takahashi N, Kamohara T. Neonatal leukemoid

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reaction with fetal inflammatory response
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granulocyte colony stimulating factor andinterleukin-6. Tohoku JEM 2018, 244:145-149.
21. Shitara Y, Takahashi N, Aoki Y, Kato M,
Nishimura R, Tsuchida S, Oka A. Cytokine
profiles in pericardial effusion in a Down syndrome infant with transient abnormal myelopoiesis. Tohoku J Exp Med 2017; 241 (2): 149153.
22. Nakamura T, Nakamura M, Takahashi N.
Neonatal high-permeability pulmonary edema
based on serial cytokine profiles and KL-6 inserum: case report. Fukushima J Med Sci. 2017;
63: 1-6.
23. Kakiuchi S, Tsuji M, Nishimura H, Wang L,
Takayama-Ito M, Kinoshita H, Lim CK,
Taniguchi S, Oka A, Mizuguchi M, Saijo M.
Human Parainfluenza Virus Type 3 Infections inPatients with Hematopoietic Stem Cell Transplants: the Mode of Nosocomial Infections andPrognosis. Jpn J Infect Dis. 71(2);109-115, 2018.
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K, Ito Y, Yoshikawa T, Yamada H, Suzutani T,
Inoue N, Japanese Congenital Cytomegalovirus
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infants with congenital cytomegalovirus infectionin Japan. Pediatr Int. 60(1);57-62, 201825. Shimoda K, Mimaki M, Fujino S, Takeuchi M,
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Manifestations and Evaluation of DNA-based
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Fujii H, Yamada S, Harada S, Oka A, Mizuguchi
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28. Ohta S, Isojima T1, Mizuno Y, Kato M, Mimaki
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Pediatr Int. 59(1):99-102, 2017.

185

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

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

Research Associate
Miho Watanabe, M.D.,Ph.D.
Toshiko Takezoe, M.D.

Homepage

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

Naohiro Takamoto, M.D.

Kentaro Hayashi, M.D.

pedsurg.umin.jp/

History and organization
In 1951, a pediatric surgical team was established in
the Department of Second Surgery. Subsequently, in
1961, a pediatric surgical research team, which would
eventually research diaphragmatic hernia, was established, with a chief, Dr. Ishida, appointed by Professor
Kimoto.
In 1971, the department was authorized to be the firstclinical Department of Pediatric Surgery at a national
university.
A pediatric intensive care unit was founded by Prof.
Ishida in 1973, and the construction of a ward capableof accommodating mainly pediatric surgical patientswas completed.
Assistant Prof. Saito assumed office as the first
director of this clinical department.
Dr. Sumio Saito became a professor of pediatricsurgery in 1983. Professor Saito has enthusiastically
performed clinical studies on operation techniques andthe use of biliary atresia.
Dr. Nakajo took office as a professor in 1985. Prof.
Nakajo has developed original operative procedures,such as a radical operation for umbilical hernia, andan anti-reflex valve for biliary atresia. These original
operative procedures have since been inherited byother pediatric surgeons as Nakajo methods.
Our department was authorized as the Department ofPediatric Surgery of Kyusyu University by the

Ministry of Education in 1989.
Dr. Yoshiaki Tsuchida assumed the role of Professor in1990 and published many highly regarded articles,
mainly concerning neuroblastoma and Wilm’s tumor,
based on his research and clinical work.
In 1995, the department was reorganized as the
Department of Reproductive, Developmental andAging Science, Pediatric Science and PediatricSurgery, due to a university policy for the graduate
school.
In 1997, Dr. Hashizume became a professor in the
Department of Pediatric Surgery. He started
performing living-related partial liver transplantation(LRPLT) for children with Professor Makuuchi in the
Department of Second Surgery.
Dr. Tadashi Iwanaka became the sixth professor in
August 2006. He engaged in clinical and research
activity on pediatric minimally invasive surgery, andretired in 2015.
The present staff includes one associate professor andchief, one lecturer, and five research associates. Morethan 20 members of our department shoulder theclinical work as pediatric surgeons.

Clinical activities
Staff members higher than the level of research
associate take charge of the outpatient clinic from
Monday through Friday. The pediatric surgical186

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

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

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

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

References(1) Amano H, Fujishiro J, Hinoki A, Uchida H.
Intralobar pulmonary sequestration expanding
toward the contralateral thorax: two case reports.
BMC Surg. 17(1) 2017. PMID: 29179706(2) Watanabe K, Kato M, Ishimaru T, Hiwatari M,
Suzuki T, Minosaki Y, Takita J, Fujishiro J, Oka A.
Perioperative management of severe congenital

187

(3)

(4)

(5)

(6)

(7)

(8)

(9)

protein C deficiency. Blood Coagul Fibrinolysis.
28(8) 2017. PMID: 28737523
Deie K, Ishimaru T, Takazawa S, Harada K, Sugita
N, Mitsuishi M, Fujishiro J, Iwanaka T. Preliminary
Study of Video-Based Pediatric Endoscopic
Surgical Skill Assessment Using a Neonatal Esophageal Atresia/Tracheoesophageal Fistula Model. J
Laparoendosc Adv Surg Tech A. 27(1) 2017. PMID:
27858521
Atarashi K, Suda W, Luo C, Kawaguchi T, Motoo I,
Narushima S, Kiguchi Y, Yasuma K, Watanabe E,
Tanoue T, Thaiss CA, Sato M, Toyooka K, Said HS,
Yamagami H, Rice SA, Gevers D, Johnson RC,
Segre JA, Chen K, Kolls JK, Elinav E, Morita H,
Xavier RJ, Hattori M, Honda K. Ectopic
colonization of oral bacteria in the intestine drives
Th1 cell induction and inflammation. Science358(6361) 2017. PMID: 29051379
Amano H, Tanaka Y, Kawashima H, Deie K, Suzuki
K, Fujiogi M, Morita K, Iwanaka T, Uchida H.
Mesh hiatal reinforcement in laparoscopic Nissen
fundoplication for neurologically impaired children
is safe and feasible. Nagoya J Med Sci. 79(4) 2017.
PMID: 29238098
Amano H, Uchida H, Tanaka Y, Tainaka T, Mori M,
Oguma E, Kishimoto H, Kawashima H, Arakawa Y,
Hanada R, Koh K. Excellent prognosis of patientswith intermediate-risk neuroblastoma and residual
tumor postchemotherapy. J Pediatr Surg. S00223468(17) 2017. PMID: 29195808
Amano H, Tanaka Y, Kawashima H, Deie K,
Fujiogi M, Suzuki K, Morita K, Iwanaka T, Uchida
H. Comparison of single-incision laparoscopic
percutaneous extraperioneal closure (SILPEC) andopen repair for pediatric inguinal hernia: a singlecenter retrospective cohort study of 2028 cases.
Surg Endosc. 31(12) 2017. PMID: 28597284
Iwanaka T. Past, Present, and Future of National
Clinical Database. Kyobu Geka. 70(1) 2017.
Japanese. PMID: 28174394
Yoshimaru K, Kinoshita Y, Yanagi Y, Obata S,
Jimbo T, Iwanaka T, Takahashi Y, Esumi G, Miyata
JA, Matsuura T, Izaki T, Taguchi T. The evaluationof rectal mucosal punch biopsy in the diagnosis ofHirschsprung’s disease: 30-year experience of 954
patients. Pediatr Surg Int. 33(2) 2017. PMID:
27832330(10) Komura M, Kanamori Y, Tanaka Y, Kodaka T,
Sugiyama M, Terawaki K, Suzuki K, Iwanaka T.
Mosapride for gastroesophageal reflux disease inneurologically impaired patients. Pediatr Int. 59(3)2017. PMID: 27561215(11) Komura M, Komura H, Komuro H, Ikebukuro K,
Hikita A, Hoshi K, Takato T. Tracheal cartilage
growth by intratracheal injection of basic fibroblast
growth factor. J Pediatr Surg. 52(2) 2017. PMID:
27887682(12) Jimbo T, Masumoto K, Takayasu H, Shinkai T,
Urita Y, Uesugi T, Goto C, Ono K, Sasaki T.
Outcome of early discharge protocol after
appendectomy for pediatric acute appendicitis.
Pediatr Int. 59(7) 2017. PMID: 28376256(13) Takayasu H, Hagiwara K, Masumoto K. Suppressed
erythropoietin expression in a nitrofen-induced
congenital diaphragmatic hernia. Pediatr Pulmonol.
52(5) 2017. PMID: 27880037(14) Yorifuji T, Horikawa R, Hasegawa T, Adachi M,
Soneda S, Minagawa M, Ida S, Yonekura T,
Kinoshita Y, Kanamori Y, Kitagawa H, Shinkai M,
Sasaki H, Nio M; (on behalf of The JapaneseSociety for Pediatric Endocrinology and The
Japanese Society of Pediatric Surgeons). Clinicalpractice guidelines for congenital hyperinsulinism.
Clin Peditr Endoclinol. 26(3) 2017. PMID:
28804205(15) Watanabe T, Amari S, Tsukamoto K, Ito Y,
Tomizawa D, Yoshioka T, Kanamori Y. Resolutionof liver disease in transient abnormal myelopoiesis
with fish oil emulsion. Pediatr Int. 59(4) 2017.
PMID: 28401746(16) Terui K, Nagata K, Kanamori Y, Takahashi S,
Hayakawa M, Okuyama H, Inamura N, Yoshida H,
Taguchi T, Usui N. Risk stratification for congenital
diaphragmatic hernia by factors within 24h after
birth. J Perinatol. 37(7) 2017. PMID: 28230834

Reproductive, Developmental andAging Sciences
3. Aging Sciences

189

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

Associate Professor
Sumito Ogawa, MD, PhD.

Lecturer
Yasuhiro Yamaguchi, MD, PhD.

Research Associate
Taro Kojima, MD.

Masaki Ishii, MD, PhD.

Shinya Ishii, MD, PhD.

Yumi Kameyama, MD, PhD.

Mitsutaka Yakabe, MD, PhD.

Koji Shibasaki, MD, PhD.

Homepage http://www.h.u-tokyo.ac.jp/geriatrics/
Introduction and Organization
The Department of Geriatric Medicine wasestablished in 1962, as the first geriatric department
in Japan.
Since elderly patients tend to have multiple organ
disorders, these patients should be taken cared as awhole from multiple points of view. In addition,
symptoms, signs and responses to the treatment in
the elderly patients could be quite different from theyounger counterparts. Specific knowledge on thephysiological and metabolic changes with aging isnecessary when these elderly patients are treated.
Quality of life of the patients is another point of viewwhich should be emphasized. The department
belongs to the division of Internal Medicine. The
staff includes one professor, one associate professor,
two lecturers, and 6 assistant professors.
Our sub-specialty includes pneumology, cardiology, neurology, hematology, endocrinology, andbone metabolism, besides geriatrics.
The main objective of our research is to elucidate
the pathophysiology of aging process and tounderstand elderly patients from viewpoints of basic
aging science using molecular biology technique andclinical aspects using the recent advancement oftechnology and geriatric assessment.

Clinical activities
In the clinical ward, there are approximately 20
patients who are taken care of by junior, senior andchief residents of our staff. Because senior and chief
residents are very experienced, they team up with ajunior resident, give instructions as to the assessmentof the patient's problem, making of future plans, andhelp the residents with various procedures. Very
important issues are discussed and decisions are
made in weekly professor's round.
Specialized services are provided to out-patientson a daily basis in all areas of internal medicine. 233
new and a total of 13,395 patients visited the outpatient clinic in the last fiscal year.

190

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

Research
Various studies have been done over a wide rangeof field, such as clinical observational studies orbasic molecular studies.
1)

Research on the molecular mechanism ofvascular calcification
2) Regulation of vascular function by sex hormone
3) Molecular biology for the control of aging:
Association of vascular and neuronal senescence and the role of Sirt1
4) Molecular biology and treatment of sarcopenia5) Multicenter-investigation of the optimal treatment strategy for hypertension or lipid disorder in the elderly
6) Clinical study on metabolic syndrome in theelderly7) Biomarkers of dementia, caregiver’s stress andgeriatric syndromes8) Research on appropriate healthcare for theelderly including pharmacotherapy9) Expression and regulation of nuclear receptors
in osteoblast and osteoclast10) Molecular mechanism under the treatment of
osteoporosis11) Genetic analysis of osteoporosis and osteoarthritis
12) Identification and functional analysis of thetarget gene networks associated with hormone
responsiveness in prostate and breast cancers13) Role of nuclear receptors in senescence andcarcinogenesis14) Molecular mechanism of vitamin K function

and its roles in aging
15) Diagnosis and prevention of aspiration pneumonia
16) Novel roles of antimicrobial peptide, defensin17) Adrenomedullin and airway hyperresponsiveness18) Klotho protein and vitamin D in lung19) Clinical investigation of sleep-related breathing
disorderPublications
Original Article
1. Ashikari D, Takayama K, Tanaka T, Suzuki Y,
Obinata D, Fujimura T, Urano T, Takahashi S,
Inoue S. Androgen induces G3BP2 and SUMOmediated p53 nuclear export in prostate cancer.
Oncogene 36(45):6272-6281, 2017.
2. Ashikari D, Takayama K, Obinata D, Takahashi
S, Inoue S. CLDN8, an androgen-regulated gene,promotes prostate cancer cell proliferation andmigration. Cancer Sci. 108(7), 1386-1393, 2017.
3. Igarashi A, Yamamoto-Mitani N, Yoshie S,
Iijima K. Patterns of long-term care services use
in a suburban municipality of Japan: Apopulation-based study. Geriatr Gerontol Int.
doi: 10.1111/ggi.12781. 17(5): 753-759. 2017.5.
4. Ishii M, Yamaguchi Y, Isumi K, Ogawa S,
Akishita M. Transgenic Mice Overexpressing
Vitamin D Receptor (VDR) Show AntiInflammatory Effects in Lung Tissues.
Inflammation.;40:2012-2019. 2017
5. Ishii S, Kojima T, Ezawa K, Higashi K, Ikebata
Y, Takehisa Y, Akishita M.The association ofchange in medication regimen and use of
inappropriate medication based on beers criteriawith adverse outcomes in Japanese long-termcare facilities. Geriatr Gerontol Int. 2017;17:591-597.
6. Kawabata H, Azuma K, Ikeda K, Sugitani
I,Kinowaki K, Fujii T, Osaki A, Saeki T, HorieInoue KInoue S: TRIM44 is a poor prognostic
factor for breast cancer patients as a modulatorof NF-B signaling. Int. J. Mol. Sci 18(9). pii:
E1931,2017.
7. Kimura T, Yoshie S, Tsuchiya R, Kawagoe S,
Hirahara S, Iijima K, AkahoshiT, Tsuji T.

191

Catheter replacement structure in home medicalcare settings and regional characteristics inTokyo and three adjoining prefectures. Geriatr
Gerontol Int. doi: 10.1111/ggi.12769. 17(4):628-636. 2017.
8. Migita T, Takayama KI, Urano T, Obinata D,
Ikeda K, Soga T, Takahashi S, Inoue S. ACSL3
promotes intratumoral steroidogenesis in prostate cancer cells. Cancer Sci. 108(10):2011-2021,
2017.
9. Mizokami F, Mizuno T, Mori T, Nagamatsu T,
Endo H, Hirashita T, Ichino T, Akishita M,
Furuta K. Clinical medication review tool forpolypharmacy: Mapping approach for pharmacotherapeutic classifications. Geriatr Gerontol
Int. 17:2025-2033, 2017.
10. Mori T, Fujishima I, Wakabayashi H, Oshima F,
Itoda M, Kunieda K, KayashitaJ, Nishioka S,
Sonoda A, Yoshitoshi Kuroda Y, Yamada M,
Ogawa S. Development and reliability of adiagnostic algorithm for sarcopenic dysphagia. J
Cahexia Sarcopenia Muscle Clinical Reports 2:
1-10, 2017.
11. Ogawa N, Mori T, Fujishima I, Wakabayashi H,
Itoda M, Kunieda K, Shigematsu T, Nishioka S,
Tohara H, Yamada M, Ogawa S. Ultrasonography to measure swallowing muscle massand quality in older patients with sarcopenic
dysphagia. J. Am. Med. Dir. Assoc. pii: S15258610(17)30634-5,2017.
12. Okumura K, Lip GYH, Akao M, Tanizawa K,
Fukuzawa M, Abe K, Akishita M, Yamashita T.
Edoxaban for the management of elderly
Japanese patients with atrial fibrillation ineligible for standard oral anticoagulant therapies:
Rationale and design of the ELDERCARE-AF
study. Am Heart J. 2017;194:99-106, 2017
14. Ota S, Kudo K, Taguchi K, Ihori M, Yoshie S,
Yamamoto T, Sudoh O, Tsuji T, Iijima K.
Development of a gateway for interoperability incommunity integrated care: an empirical study.
Technology and Health Care. 26(1): 57-67, 2018.
15. Ouchi Y, Rakugi H, Arai H, Akishita M, Ito H,
Toba K, Kai I. Joint Committee of Japan Gerontological Society (JGLS) and Japan Geriatrics
Society (JGS) on the definition and classificationof the elderly. Redefining the elderlyas aged 75

years and older: Proposal from the Joint
Committee of Japan Gerontological Society and
the Japan Geriatrics Society. Geriatr Gerontol
Int;17:1045-1047, 2017.
16. Takayama K, Suzuki T, Tanaka T, Fujimura T,
Takahashi S, Urano T, Ikeda K, Inoue S.
TRIM25 enhances cell growth and cell survival
by modulating p53 signals via interaction with
G3BP2 in prostate cancer. Oncogene 37(16),2165-2180, 2018.
17. Takayama K, Suzuki T, Fujimura T, Yamada Y,
Takahashi S, Homma Y, Suzuki Y, Inoue S.
Dysregulation of spliceosome gene expression inadvanced prostate cancer by RNA-binding
protein PSF. Proc Natl Acad Sci U S A. 114(39),10461-10466, 2017.
18. Tanaka T, Takahashi K, Akishita M, Tsuji T,
Iijima K. "Yubi-wakka" (finger-ring) test: A
practical self-screening method for sarcopenia,
and a predictor of disability and mortality among
Japanese community-dwelling older adults.
Geriatr Gerontol Int. 2018;18:224-232.
19. Takumida H, Yakabe M, Marumoto K, Shibasaki
K, Kameyama Y, Urano T, Mano T, Mori H,
Hayashi A, Ikemura M, Ogawa S, Akishita M.
Case of a 78-year-old woman with a neuronal
intranuclear inclusion disease. Geriatr. Gerontol.
Int. 17: 2623-2625, 2017.
20. Umeda-Kameyama Y, Ishii S, Kameyama M,
Kondo K, Ochi A, Yamasoba T, OgawaS,
Akishita M. Heterogeneity of odorant identification impairment in patients with Alzheimer
disease. Sci Rep. 7:4798, 2017.
21. Yakabe M, Ogawa S, Ota H, Iijima K, Eto M,
Ouchi Y, Akishita M. Inhibition of interleukin-6
decreases atrogene expression and ameliorates
tai suspension-induced skeletal muscle atrophy.
PLoS ONE 13(1):e0191318, 2018.
Reaearch letter
1. Ishii S, Umeda-Kameyama Y, Akishita M. Brain
Health: A Japanese viewpoint. J Am Med Dir
Assoc. 2016 May;17(5):455. [PMID: 26972348]
2. Ishii S, Chang C, Tanaka T, Kuroda A, Tsuji T,
Akishita M, Iijima K. The Association between
Sarcopenic Obesity and Depressive Symptoms in

192

3.

4.

5.

6.

7.

Older Japanese Adults. PLoS One. 2016 Sep 14;
11(9):e0162898 [PMID: 27627756]
Kameyama M and Umeda-Kameyam Y. Strategy
based on kinetics of O-(2-[18F] fluoroethyl)-Ltyrosine ([18F] FET). JEuropean Journal of
Nuclear Medicine and Molecular Imaging,;
43(12), 2267-2268. 2016.
Kojima T, Shimada K, Terada A, Nishizawa K,
Matsumoto K, Yoshimatsu Y, Akishita M.
Association between polypharmacy and multiple
uses of medical facilities in nursing homeresidents. Geriatr Gerontol Int. 16:770-1, 2016
Koshino S, Hamaya H, Ishii M, Kojima T, Urano
T, Yamaguchi Y, Ogawa S, Morita S, Koya J,
Nakamura F, Kurokawa M, Akishita M.
Efficacy of Fine-Needle Aspiration Cytology in
the Diagnosis of Primary Thyroid Lymphoma for
Elderly Adults. J Am Geriatr Soc. 2016 Sep;
64(9):e52-3. doi: 10.1111/jgs.14289. Epub 2016
Shibasaki K, Yamada S, Ouchi Y, Akishita M,
Ogawa S. The effect of the rehabilitation on therecovery of the sympathetic nervous activity
measured by heart rate variability in frail elderly.
J Am Geriatr Soc 64:e15-16,2016
Ogawa S, Yakabe M, Akishita M: Age-related
sarcopenia and its pathophysiological bases.
Inflammation and Regeneration 36:17, 2016

Review article
1. Takayama K. The biological and clinicaladvances of androgen receptor function in agerelated diseases and cancer. Endocr J. 64(10),933-946, 2017.
2. Takayama K, Misawa A, Inoue S. Significanceof microRNAs in Androgen Signaling and
Prostate Cancer Progression. Cancers (Basel).
9(8), pii: E102, 2017.
3. Misawa A, Takayama K, Inoue S. Long noncoding RNAs and prostate cancer. Cancer Sci.
108(11), 2107-2114, 2017.
4. Fujimura T, Takayama K, Takahashi S, Inoue S.
Estrogen and androgen blockade for advanced
prostate cancer in the era of precision medicine.
Cancers (Basel).23;10(2). pii: E29, 2018.
5. Mitobe Y, Takayama K, Horie-Inoue K, Inoue S.
Prostate cancer-associated lncRNAs. Cancer Lett.
418:159-166, 2018.

Surgical Sciences
1. Surgery

194

Department of Thoracic Surgery
Professor
Nakajima, Jun

Assistant Professor
Sato, Masaaki
Nitadori, Jun-ichi
Nagayama, Kazuhiro
Kitano, Kentaro

Homepage: http://cts.m.u-tokyo.ac.jp/
History
Study on thoracic surgery has begun since 1916
when symposium on lung surgery was held at annual
meeting of Japan Surgical Society. Clinical and basic
researches of the thoracic surgery have been
performed since the prewar era at the Second
department of Surgery in this university. Professor
Tsuduki, Masao adopted the modified Coryllos’s
thoracoplasty for the treatment of the pulmonary
tuberculosis in 1934. In 1942, they initiatedthoracoscopy for the treatment of the tuberculosis in
our country. Before the world war II, thoracic surgery
had been performed under spontaneous breathing.
Since 1950 safer anesthesia with endotracheal
intubation has been started in this university.
After the successful application of theantituberculosis drugs, surgical treatment of thethoracic malignant neoplasms was the major concernof the thoracic surgery. Case reports on surgicaltherapy for lung cancer has been present since 1920’s
in our country. In 1950, successful rightpneumonectomy for the primary lung cancer in thisuniversity was reported. Surgical therapy for the
mediastinal tumor was also begun in 1950. In 1954,
thymectomy through median sternotomy has begun inour department.
The Department of Cardiothoracic Surgery, The
University of Tokyo, was established in December 15,
1964 as the first department of this field along withthe cardiovascular surgery in the Japanese national
universities. Since then it has played an internationallyleading role and contributed to development of the
field in our country.
Professors and Chairs in the history of thedepartment are as follows: Kimoto, Seiji (1964.12.15~ 1968.3.31), Saigusa, Masahiro (1968.4.1 ~ 1981.
3.31), Asano, Ken-ichi (1981.4.1 ~ 1986.3.31), Furuse,
Akira (1986.4.1 ~ 1997.3.31) and Takamoto, Shinichi(1997.6.1 ~ 2009.3.31). Nakajima, Jun has taken overthe mission of the department since April 2011.
The Department of Cardiothoracic Surgery has been
divided into two departments, Department of
Cardiovascular Surgery and Department of Thoracic
Surgery in 1997.
The mission of the Department of Thoracic Surgery
is to cure the patients with diseases of the thoracic
organs through clinical works, basic and clinicalresearches, and education of the medical students,
postgraduates, and the surgical residents in our
university.

Clinical activities

Five staffs (Nakajima J, Sato M, Nitadori J,
Nagayama K, and Kitano 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 the195

respiratory and the mediastinal organs and the chest
wall, except for diseases of the esophagus andmammary glands.
Lung cancer is the leading cause of cancer death inour country: In 2016, Ministry of Health, Labour andWelfare documented that number of deaths frommalignant neoplasms was approximately 380 thousandout of 1.3 million total deaths in Japan. Of them, 74
thousand people were killed by malignant tracheal /pulmonary neoplasms. Surgical therapy for non-small
cell lung cancer (NSCLC) is thus the most important
issue in our department. By the practice of treatment
based on EBM, We perform basic training of thoracic
surgery for medical school students, graduate students
and clinical residents, as well as doing theprofessional education for training physicians whowish to become board-certified thoracic surgeons.
We have performed video-assisted thoracoscopy forthe diagnosis and treatment of the thoracic disease
with less surgical invasiveness since 1992 for safer
treatment of older patients with cardiovascular and/or
respiratory complications. We currently conduct a
standard surgery for clinical stage I non-small celllung cancer (NSCLC), i.e. lobectomy and lymphadenectomy through thoracoscopy: Since 2015, morethan 90% of patients with NSCLC has undergone
thoracoscopic surgery in our department. Researches
on less-invasiveness, oncological advantage of thethoracoscopic surgery are thus actively done.
We also treat patients with advanced, unresectable
NSCLC and those with recurrent NSCLC
postoperatively by an immunotherapy. We 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 are now actively participating a
multiinstitutional study on malignant thymic epithelial
neoplasms database led by Japanese Association forresearch on the thymus (JART).
Our hospital has been certified as a lung transplant
centers since March 2014. We have started to registerpatients who are eligible for lung transplantation. We
successfully performed the first case in Tokyo ofliving donor lung transplantation in April 2015: The
patients had suffered from the interstitial pneumonia.
In July 2015, We also succeeded in performing
brain-dead donor bilateral lung transplantation on apatient who had suffered from the pulmonary
hypertension. We have performed 13 lung transplants(including 3 living related donor lung transplantations) to date.

Academic education
Medical students in the fifth grade have three-weekprogram on the clinical training of the thoracic and the
cardiovascular surgery. They are also able toparticipate the clinical clerkship of the thoracic
surgery, an elective course for 4 weeks. We also
conduct a further research training for medical
students who like to study thoracic surgery. The
Department of Thoracic Surgery also offers the 4-year
postgraduate program for qualified surgeons who arewilling to specialize in the thoracic surgery. We have a
training program for surgeons who wish to be a boardcertified thoracic surgeon after 4-year residency.

Current researches
Main subjects of current research at present include
basic and clinical studies on the malignant neoplasmsin the thorax including lung cancer and thymic tumors,and transplantation of the thoracic organs. We haveconducted clinical studies on the immunotherapy withadopted gammadelta- T-cell for the treatment of thepatients with unresectable or recurrent NSCLC.
The following are the major themes under research:196(1) Minimally invasive surgeries for thoracic
malignant neoplasms.
(2) Navigation techniques for finding out small
pulmonary lesions through thoracoscopy.
(3) Image analysis of the lung cancer focusing on its
degree of malignancy.
(4) Global analysis of oncogenes and suppressor
genes associated with lung cancer.
(5) Application of new fluorescent agents fordiagnosis of lung cancer.
(6) Immunotherapy for lung cancer.
(7) Single and multi-institutional studies on surgicaltherapeutics for pulmonary metastasis fromcolorectal cancer.
(8) Analysis on mechanisms of acute or chronic
rejection of the allogeneic lung and trachea after
allogeneic transplantation.
(9) Research on donor lung preservation.
(10) Research on extracorporeal membranous oxygenation for bridge use to lung transplantation

Selected publications (2017)
1. Shinozaki-Ushiku A, Ushiku T, Morita S, Anraku
M, et al. Diagnostic utility of BAP1 and EZH2
expression in malignant mesothelioma. Histopathology. 2017; 70(5):722-733. PMID: 27859460
2. Karasaki T, Nagayama K, Kuwano H, et al.
Prediction and prioritization of neoantigens:
integration of RNA sequencing data withwhole-exome sequencing. Cancer Sci. 2017;
108(2): 170-177. PMID: 27960040
3. Sato M, Kuwata T, Yamanashi K, et al. Safety andreproducibility of virtual-assisted lung mapping: amulticentre study in Japan. Eur J Cardiothorac
Surg. 2017;51(5):861-868 PMID: 28043993
4. Inui M, Nitadori JI, Tajima S, et al. Mediastinal
seminoma associated with multilocular thymic
cyst. Surg Case Rep. 2017; 3(1):7 PMID:
28054283
5. Sato M, Murayama T, Nakajima J. Techniques ofstapler-based navigational thoracoscopic segmentectomy using virtual assisted lung mapping(VAL-MAP). J Thorac Dis. 2016;8(Suppl 9):
S716-S730. PMID: 28066675
6. Sato M, Nagayama K, Kuwano H, et al. Role ofpost-mapping computed tomography in virtual-assisted lung mapping. Asian Cardiovasc Thorac
Ann. 2017;25(2): 123-130. PMID: 28076962
7. Karasaki T, Nagayama K, Kuwano H, et al. An
Immunogram for the Cancer-Immunity Cycle:
Towards Personalized Immunotherapy of Lung
Cancer. J Thorac Oncol. 2017;1 2(5): 791-803.
PMID: 28088513
8. Ichinose J, Murakawa T, Kawashima M,
Nagayama K, et al. Prognostic significance of red
cell distribution width in elderly patients
undergoing resection for non-small cell lungcancer. J Thorac Dis. 2016; 8(12): 3658-3666.
PMID: 28149561
9. Takahashi T, Kawashima M, Kuwano H. A deep
azygoesophageal recess may increase the risk of
secondary spontaneous pneumothorax. Surg
Today. 2017; 47(9): 1147-1152. PMID: 28205019
10. Hino H, Nishimura T, Usuki C, et al. Salvage
surgery for primary lung cancer after chemotherapy in octogenarians. Thorac Cancer. 2017;8(3): 271-274. PMID: 28239985
11. Yoshida Y, Nitadori JI, Shinozaki-Ushiku A, et al.
Micropapillary histological subtype in lungadenocarcinoma of 2 cm or less: impact onrecurrence and clinical predictors. Gen Thorac
Cardiovasc Surg. 2017; 65(5): 273-279. PMID:
28243892
12. Murakawa T, Sato H, Okumura S, et al.
Thoracoscopic surgery versus open surgery forlung metastases of colorectal cancer: a multiinstitutional retrospective analysis using propensity score adjustment†. Eur J Cardiothorac Surg.
2017; 51(6): 1157-1163 PMID: 28329272
13. Sakatani T, Maemura K, Hiyama N, et al. Highexpression of IRE1 in lung adenocarcinoma is
associated with a lower rate of recurrence. Jpn J
Clin Oncol. 2017: 1-8. PMID: 28334878
14. Yanagiya M, Sato M, Kuwano H, et al.
Management of lung nodules newly found by
virtual-assisted lung mapping: a case report. Surg
Case Rep. 2017; 3(1): 49. PMID: 28353207
15. Nakajima J, Iida T, Okumura S, et al. Metastatic
Lung Tumor Study Group of Japan. Recent
improvement of survival prognosis after
pulmonary metastasectomy and advanced
chemotherapy for patients with colorectal cancer.
Eur J Cardiothorac Surg. 2017; 51(5): 869-873

197

PMID: 28369355
16. Yanagie H, Dewi N, Higashi S, et al. Selective
boron delivery by intra-arterial injection of
BSH-WOW emulsion in hepatic cancer model forneutron capture therapy. Br J Radiol. 2017;90(1074): 20170004. PMID: 28406315
17. Nagano M, Ichinose J, Sasabuchi Y, et al. Surgery
versus percutaneous transcatheter embolization
for pulmonary arteriovenous malformation:
Analysis of a national inpatient database in Japan.
J Thorac Cardiovasc Surg. 2017; 154(3): 11371143. PMID: 28629839
18. Nakao K, Sato M, Nitadori JI, Bilateralsegmentectomies using virtual-assisted lungmapping (VAL-MAP) for metastatic lung tumors.
Surg Case Rep. 2017; 3(1):104 PMID: 28921174
19. Terada Y, Sato M, Abe H, et al. Squamous cell
carcinoma of the lung showing a ground glass
nodule on high-resolution computed tomography
associated with pneumoconiosis: a case report.
Surg Case Rep. 2017; 3(1): 107. PMID: 28963659
20. Endo S, Ikeda N, Kondo T, et al. Model of lungcancer surgery risk derived from a Japanesenationwide web-based database of 78 594
patients during 2014-2015. Eur J Cardiothorac
Surg. 2017; 52(6):1182-1189. PMID: 28977408
21. Yokoi K, Kondo K, Fujimoto K, et al. JLCS
medical practice guidelines for thymic tumors:summary of recommendations. Jpn J Clin Oncol.
2017; 47(12): 1119-1122 PMID: 29036455
22. Kitano K, Schwartz DM, Zhou H, et al.
Bioengineering of functional human induced
pluripotent stem cell-derived intestinal grafts. Nat
Commun. 2017; 8(1):765. PMID: 29018244
23. Yanagiya M, Matsumoto J, Hashimoto H, et al.
Surgery of Thymic Tumor with Persistent Left
Superior Vena Cava. Ann Thorac Cardiovasc Surg.
2017; 23(6):316-319. PMID: 28637939
24. Nagano M, Kohsaka S, Ueno T., et al. A methodof high-throughput functional evaluation of EGFR
gene variants of unknown significance in cancer.
Sci Transl Med. 2017; 9(416) PMID: 29141884

198

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

Associate Professor
Yasutaka Hirata, M.D.

Lecturer
Kan Nawata, M.D.,

Haruo Yamauchi, M.D.,

Mitsutoshi Kimura, M.D.

Associate
Tetsuhiro Takaoka, M.D.,

Akihiro Masuzawa, M.D.,

Osamu Kinoshita, M.D.,

Shogo Shimada, M.D.,

Sachito Minegishi, M.D.,

Hyoe Komae, M.D.,

Noritsugu Naito, M.D.,

Tomoyuki Iwase, M.D.,

Yasuhiro Hoshino,

M.D., Ryoichi Kondo, M.D.,

Homepage

Shigeki Yokoyama, M.D.

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

Introduction and Organization
Cardiac surgery in the Department was initiated by
Dr. Seiji Kimoto, who performed ligation of patentductus arteriosus in June, aortic arch aneurysm
resection in July and first-in-Japan Blalock-Taussig
operation for Tetralogy of Fallot in October in 1951.
He also started implantation of alcohol-preserved
aortic homograft for abdominal aortic aneurysm in
1952, and closed commissurotomy for mitral valve
stenosis in 1954. The first open heart surgery (atrial
septal defect closure) was performed in 1955, using
selective brain perfusion cooling method that wasdeveloped in the Department.
Establishment of Department of Thoracic Surgery
in the University of Tokyo Hospital was approved by
the government first in Japan December 15, 1964.
Under the leadership of Professor Kimoto excellent
research works were created especially on pacemakerand artificial heart, and many opinion leaders were
produced. Dr. Masahiro Saigusa, the second Professor,
endeavored to make open heart surgery safer byintroducing new- generation heart-lung machines tothe Department. Dr. Kenichi Asano, the third
Professor, started posterior-leaflet preserving mitralvalve replacement first in Japan. He also dramatically
improved surgical results of Tetralogy of Fallot. Dr.
Akira Furuse, the fourth Professor, modernizedmanagement of extremely busy clinical works. During
this time, the Department was divided into two
Divisions, Cardiovascular and General thoracic, due
to the University policy of Graduate-school.
Dr. Shinichi Takamoto assumed the fifth Professor
in June 1997. He rearranged clinical teams into threegroups (adult cardiac disease, thoracic aortic diseaseand congenital heart disease) to adapt the rapid
progress of cardiovascular surgery. Dr. Minoru Ono
was elected as the sixth Professor in November 2009.
Additional clinical team of treatment of advanced
heart failure was established to cope with anincreasing number of patients who require ventricularassist device treatment. Present staffs are one Chief
Professor, one Associate Professor and three Lecturer

199

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.
Case volume in recent years has been about 350,
which is one of the highest in Japan. We are leading inJapan by showing excellent surgical results. There areeight Board-certified surgeons, each of whom has his
own subspecialty among adult cardiac, thoracic aortic
or congenital heart disease. We are famous for offpump coronary artery bypass surgery, mitral valve
plasty, heart transplantation, ventricular assist device
implantation, aortic valve sparing root replacement,arch replacement, treatment of extended thoracic
aortic aneurysm and repair of complex congenital
heart diseases, such as Jatene, Fontan and Norwood
operations. Transcatheter aortic valve replacement
was initiated in 2015. Many high-risk very oldpatients with aortic valve stenosis were successfully
treated.
The University of Tokyo Tissue Bank was founded
in 1997, based on the Department of Cardiovascular
Surgery. The Bank has been actively promoting
procurement, preservation and shipping of humanvalve and blood vessel allograft in Japan. We take thelead in surgical treatment using allograft for severe
active endocarditis or infection of aortic aneurysm or
vascular prosthesis. Surgical treatment using allograft
was approved as advanced medical technology by theGovernment in 2006. As of March 2018, 101 cases ofheart transplantation and 280 cases of ventricularassist device implantation were performed in The
University Hospital with excellent long-term survival.

Teaching Activities
We have the chair of systematic review of cardiovascular surgery in the spring term at the 2nd grade of
medical course. We also take charge in 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 Regular
Clinical Clerkship, in which he/she is required to learn
preoperative patient evaluation and management,
surgical treatment and postoperative care, based onparticipatory practice. There are also fifteen small
key-lectures on cardiovascular surgery. Hands-on
practice is provided during the Advanced ClinicalClerkship one-month course in the last months of 3rd
grade.
We take charge in core surgical curriculum in the“Super-rotation” postgraduate training. We offer a
program in which each resident can learn basic
knowledge of cardiovascular disease and surgery, andhemodynamic and respiratory evaluation as well asbasic surgical techniques and patient management.
Residents who take the course of cardiovascularsurgery are required three-year general surgicaltraining for General Surgery Board certification. We
have well-developed specialty/ subspecialty training
programs to allow the residents to pass Cardiovascular
Board Examination by 9-10th postgraduate year.

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

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heart failure, 4) mechanism analysis of right heart
failure and development of effective pharmacologicaltherapy, 5) development of versatile suture device, 6)
clinical research for new drug for spinal cord ischemia,7) clinical research to test the safety and efficacy ofartificial pancreas during open heart surgery.

References
1. Inoue T, Kitamura T, Torii S, Hirata M, Mishima
T, Sughimoto K, Ohkubo H, Kobayashi K,
Motokawa M, Shibata M, Matsushiro T, TsuchidaY, Miyata Y, Ono M, Miyaji K: Daily transient
discontinuation of extracorporeal LVAD toprevent thromboembolism of mechanical aortic
valve prosthesis. J Artif Organs. 2017 Sep; 20(3):274-276.
2. Yanagie H, Dewi N, Higashi S, Ikushima I,
Seguchi K, Mizumachi R, Murata Y, Morishita Y,
Shinohara A, Mikado S, Yasuda N, Fujihara M,
Sakurai Y, Mouri K, Yanagawa M, Iizuka T,
Suzuki M, Sakurai Y, Masunaga SI, Tanaka H,
Matsukawa T, Yokoyama K, Fujino T, Ogura K,
Nonaka Y, Sugiyama H, Kajiyama T, Yui S,
Nishimura R, Ono K, Takamoto S, Nakajima J,
Ono M, Eriguchi M, Hasumi K, Takahashi H.:
Selective boron delivery by intra-arterial injectionof BSH-WOW emulsion in hepatic cancer modelfor neutron capture therapy. Br J Radiol. 2017
Jun; 90(1074): 20170004.
3. Li D, Fan Q, Hirata Y, Ono M, An Q.:
Arrhythmias After Fontan Operation with
Intra-atrial Lateral Tunnel Versus Extra-cardiac
Conduit: A Systematic Review and Meta-analysis.
Pediatr Cardiol. 2017 Apr; 38(4): 873-880.
4. Naito N, Nishimura T, Iizuka K, Fujii Y, Takewa Y,
Umeki A, Ando M, Ono M, Tatsumi E: Novel
Rotational Speed Modulation System Used With
Venoarterial Extracorporeal Membrane Oxygenation. Ann Thorac Surg. 2017 Nov; 104(5):1488-1495.
5. Kimura M, Nawata K, Kinoshita O, Yamauchi H,
Hoshino Y, Hatano M, Amiya E, Kashiwa K,
Endo M, Kagami Y, Nemoto M, Ono M:
Readmissions after continuous flow left
ventricular assist device implantation. J Artif
Organs. 2017 Dec; 20(4): 311-317.

6. Kato NP, Okada I, Kagami Y, Endo M, Hatano M,
Ono M, Jaarsma T, Kinugawa K.: Quality of lifeof family caregivers of patients with a left
ventricular assist device in Japan. J Cardiol. 2018
Jan; 71(1): 81-87.
7. Yoshioka D, Toda K, Ono M, Nakatani T, Shiose
A, Matsui Y, Yamazaki K, Saiki Y, Usui A,
Niinami H, Matsumiya G, Arai H, Sawa Y;
Japanese HeartMateII Investigators: ClinicalResults, Adverse Events, and Change in
End-Organ Function in Elderly Patients With
HeartMate II Left Ventricular Assist DeviceJapanese Multicenter Study. Circ J. 2018 Jan 25;
82(2):409-418.
8. Li D, Hirata Y, Zhou X, Masuzawa A, Ono M, An
Q: Effect of cone reconstruction on rightventricular function in patients with Ebstein's
anomaly: a meta-analysis. Interact Cardiovasc
Thorac Surg. 2018 Feb 1; 26(2):301-306.
9. Naito N, Nishimura T, Iizuka K, Takewa Y, Umeki
A, Ando M, Ono M, Tatsumi E.: Rotational speed
modulation used with continuous-flow left
ventricular assist device provides good pulsatility.
Interact Cardiovasc Thorac Surg. 2018 Jan 1;
26(1): 119-123.
10. Adachi Y, Kinoshita O, Hatano M, Shintani Y,
Naito N, Kimura M, Nawata K, Nitta D, Maki H,
Ueda K, Amiya E, Takimoto E, Komuro I, Ono
M.: Successful bridge to recovery in fulminant
myocarditis using a biventricular assist device: acase report. J Med Case Rep. 2017 Oct 24; 11(1):295.
11. Kohno H, Matsumiya G, Sawa Y, Ono M, Saiki Y,
Shiose A, Yamazaki K, Matsui Y, Niinami H,
Matsuda H, Kitamura S, Nakatani T, Kyo S: The
Jarvik 2000 left ventricular assist device as abridge to transplantation: Japanese Registry for
Mechanically Assisted Circulatory Support. J
Heart Lung Transplant. 2018 Jan; 37(1): 71-78.
12. Hoshino Y, Kinoshita O, Ono M: The Incidence,
Risk Factors, and Outcomes of Hyperlactatemia
after Heart Transplantation. Int Heart J. 2018 Jan
27; 59(1): 81-86.
13. Takahashi A, Kumamaru H, Tomotaki A,
Matsumura G, Fukuchi E, Hirata Y, Murakami A,
Hashimoto H, Ono M, Miyata H. Verification of
Data
AccuracyinJapan
Congenital

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Cardiovascular Surgery Database Including Its
Postprocedural Complication Reports. World J
Pediatr Congenit Heart Surg. 2018 Mar; 9(2):150-156.
14. Miyata H, Mori M, Kokudo N, Gotoh M, Konno
H, Wakabayashi G, Matsubara H, Watanabe T,
Ono M, Hashimoto H, Yamamoto H, Kumamaru
H, Kohsaka S, Iwanaka T. Association between
institutional procedural preference and in-hospitaloutcomes in laparoscopic surgeries; Insights froma retrospective cohort analysis of a nationwide
surgical database in Japan. PLoS One. 2018 Mar
5; 13(3):e0193186. eCollection 2018.
15. Tobita T, Nomura S, Fujita T, Morita H, Asano Y,
Onoue K, Ito M, Imai Y, Suzuki A, Ko T, Satoh M,
Fujita K, Naito AT, Furutani Y, Toko H, Harada M,
Amiya E, Hatano M, Takimoto E, Shiga T,
Nakanishi T, Sakata Y, Ono M, Saito Y,
Takashima S, Hagiwara N, Aburatani H, Komuro
I. Genetic basis of cardiomyopathy and the
genotypes involved in prognosis and left
ventricular reverse remodeling. Sci Rep. 2018 Jan
31; 8(1):1998.
16. Oshima T, Minatsuki S, Myojo M, Kodera S,
Nawata K, Ando J, Akazawa H, Watanabe M, Ono
M, Komuro I. Coronary Artery Aneurysm Caused
by a Stent Fracture. Int Heart J. 2018; 59(1):203-208.

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

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

Lecturer
Hiroharu Yamashita M.D., Ph.D.

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

Koichi Yagi M.D., Ph.D.

Takashi Mitsui M.D., Ph.D.
Yasuhiro Okumura M.D.
Tetsuro Toriumi M.D.

Kotaro Wakamatsu M.D., Ph.D.
Kazuya Takahashi M.D.

Homepage

http://todai3ge.umin.jp/

Bariatric & Metabolic Care (Social Cooperation
Program)
Project Associate Professor
Susumu Aikou M.D., Ph.D.

Project Lecturer
Masako Ogawa M.D., Ph.D.

General Affairs:
Since 1997, the former Third Department ofSurgery, which was located in a branch hospital of the
University of Tokyo, has been divided into two
departments, the Department of Gastrointestinal
Surgery and the Department of Metabolic Care andEndocrine Surgery, in line with the integration of themain and branch hospitals. Department of Metabolic
Care and Endocrine Surgery has been renamed Breastand Endocrine Surgery in April 2017. Under the supports by the Social Medical Corporation Sosaikoseikai,
the Social Medical Corporation Kawakita Medical
Foundation and RIZAP Group Inc., Bariatric &Metaboric care (social cooperation program) was
newly established in April 2017.
With the prolongation of life expectancy, there are
increasing numbers of multi-morbid patients requiring
multi-organ treatment, as well as a greater need for203

multidisciplinary approaches to the patients. Our
fundamental principles of patient treatment arecomprehensive patient care which includes pre-, peri-,and postoperative management of the diseases as wellas patient care over long-term postoperative periods
which often extend to the terminal stage. We believethat patient care encompassing the entire lifespanprovides a wealth of valuable information concerning
the appropriateness of current treatment strategy, theestablishment of new surgical designs, the development of new basic research activities which can muchcontribute to clinical fields, and indications ofdesirable modes of terminal care.
Fostering good surgeons as well as scientists whomeet both clinical and academic needs has always
been the guiding principle of our Department.

Educational Activities:
The new system of clinical clerkship for medical
students has begun from 2013. During those periods,
the students are educated strictly and gently by staffs.
Clinical exercises, e.g., blood sampling, injection, andligation, etc., are performed. They can attend theoperations as an assistant.
They learn general patient care which encompasses
not only perioperative management of diseases but
also non-surgical management of postoperative
disorders and terminal care. Our educational systemprovides medical students with a great deal ofpractical information from the medical point of view
as well as better opportunities to ponder the
implications of life and death.
For the medical students, the clinical clerkshiplectures are held two or three times a week. The
experts (from outside hospital) other than the staff
give special unique and informative lectures, which
are popular among the students.
Junior residents rotate every three months. Aftercompletion of their initial training program, they go
into a further exclusive clinical training program forseveral consecutive years and become a chief resident.

Research Activities:
Our goal is to cure the cancer patients by muchbetter surgery. The development of better surgicalmethods has the highest priority. Better surgery means

radicality of the cancer control, minimal invasiveness,and good QOL after surgery. Recently, nontransthoracic radical esophagectomy with extended
lymphadenectomy (NOVEL) has been applied, whichshows less pulmonary complications, shorter postoperative hospital stay and better QOL after surgery.
To develop this surgical procedure, we and othersurgeons sharing same will established the JapaneseSociety for Nontransthoracic Radical Esophagectomyin 2016. New methods of endoscopic full-thickness
resection (NEWS) has been developed for submucosal
gastric tumor as a collaboration of endoscopy andlaparoscopy, and now NEWS is adapted for somegastric cancer. Elimination of the pulmonary
complications after esophagectomy and the detectionof minute metastasis for the establishment of better
surgery are also our important targets.
Another main research activities of the department
of Gastrointestinal Surgery has been focused on
diagnosis and therapy for gastrointestinal diseases andclinical and basic research for gastrointestinal
carcinogenesis from the view point of “Surgery andInflammation”. The department's research activities
have focused on a wide spectrum of research topics,
ranging from basic research topics to clinical ones.
Our research activities have been well organized andultimately achieved by maintaining a close connection
between hospital and laboratory activities. Our
medical staffs make every effort to promote theresearch activities and obtain successful results.

Clinical Activities:
We have outpatient clinics from Monday throughFriday. We have specialized divisions for outpatientmanagement of esophageal, gastric diseases. The ward
is divided into two subgroups, and each of them has
one medical staff for supervision, one assistantsupervisor, one chief resident, and one or two juniorresidents in rotation. They are on duty for daily patientcare under the supervision of medical staffs. Ordinary,each subgroup takes care of 15-25 patients.
The weekly official activities of our department are
Ward Rounds by the Professor on Monday. We havepost- and preoperative case conferences on Wednesday,Thursday, and Friday morning, respectively, and ajournal club on Monday. We also have a specialized

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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 180
gastric and 70 esophageal cancer surgeries performed
a year, respectively. And, hernia surgery is usually
performed, also. All residents and medical personnel
work many extra hours with high motivation
whenever it is necessary for the good of the patients.

References
1. Zong L, Wu A, Wang W, Deng J, Aikou S,
Yamashita H, Maeda M, Abe M, Yu D, Jiang Z,
Seto Y, Ji J. Feasibility of laparoscopic gastrictomy for elderly gastric cancer patients: metaanalysis of non-randomized controlled studies.
Oncotarget. 2017. doi: 10.18632/oncotarget.
16691.
2. Mori K, Yoshimura S, Yamagata Y, Aikou S,
Seto Y. Preclinical study of transcervical upper
mediastinal dissection for esophageal malignancy
by robot-assisted surgery. Int J Med Robot. 2017;13(2). doi: 10.1002/rcs.1750.
3. Zong L, Abe M, Seto Y, Ji J. The challenge ofscreening for early gastric cancer in China. Lancet.
2016; 388(10060):2606. doi: 10.1016/S0140-6736(16)32226-7.
4. Yamashita H, Seto Y. Is the transthoracic
approach no longer a viable option for Siewert
type II esophagogastric junction carcinoma?
Transl Gastroenterol Hepatol. 2016;1:14. doi: 10.
21037/tgh.
5. Yamashita H, Yagi K, Seto Y. How should we
define the no. 3b lesser curvature lymph node?
Gastric Cancer. 2017;20(3):558-9.
6. Deng J, Yamashita H, Seto Y, Liang H.
Increasing the Number of Examined Lymph
Nodes is a Prerequisite for Improvement in the
Accurate Evaluation of Overall Survival of
Node-Negative Gastric Cancer Patients. Ann Surg
Oncol. 2017;24(3):745-53.
7. Yamashita H, Seto Y, Sano T, Makuuchi H, Ando
N, Sasako M; Japanese Gastric Cancer
Association and the Japan Esophageal Society.

Results of a nation-wide retrospective study oflymphadenectomy for esophagogastric junction
carcinoma. Gastric Cancer. 2017; 20(Suppl 1):
69-83.
8. Ri M, Fukatsu K, Miyakuni T, Yanagawa M,
Murakoshi S, Yasuhara H, Seto Y. Influences of
Vagotomy on Gut Ischemia-Reperfusion Injury inMice. Shock. 2017;47(5):646-52.
9. Hatao F, Chen KY, Wu JM, Wang MY, Aikou S,
Onoyama H, Shimizu N, Fukatsu K, Seto Y, Lin
MT. Randomized controlled clinical trial
assessing the effects of oral nutritional supplements in postoperative gastric cancer patients.
Langenbecks Arch Surg. 2017;402(2):203-11.
10. Yamashita H, Deng J, Liang H, Seto Y.
Re-evaluating the prognostic validity of thenegative to positive lymph node ratio in nodepositive gastric cancer patients. Surgery. 2017;
161(6):1588-96.
11. Terabe F, Aikou S, Aida J, Yamamichi N,
Kaminishi M, Takubo K, Seto Y, Nomura S.
Columnar Metaplasia in Three Types of Surgical
Mouse Models of Esophageal Reflux. Cell Mol
Gastroenterol Hepatol. 2017;4(1):115-23.
12. Shimizu N, Hatao F, Fukatsu K, Aikou S,
Yamagata Y, Mori K, Yamashita H, Nomura S,
Seto Y. Results of a nationwide questionnairebased survey on nutrition management following
gastric cancer resection in Japan.Surg Today.
2017. doi: 10.1007/s00595-017-1552-4.
13. Mori K, Aikou S, Yagi K, Nishida M, Mitsui T,
Yamagata Y, Yamashita H, Nomura S, Seto
Y.Technical details of video-assisted transcervical
mediastinal dissection for esophageal cancer andits perioperative outcome.Ann Gastroenterol Surg.
2017 Aug 14;1(3):232-7.
14. Seto Y, Mori K, Aikou S.Robotic surgery foresophageal cancer: Merits and demerits.Ann
Gastroenterol Surg. 2017 Aug 14;1(3):193-8.
15. Ri M, Aikou S, Seto Y.Obesity as a surgical risk
factor. Ann Gastroenterol Surg. 2017 Oct 28;2(1):13-21.
16. Seto Y, Kakeji Y, Miyata H, Iwanaka T.National
Clinical Database (NCD) in Japan for gastroenterological surgery: Brief introduction. Ann
Gastroenterol Surg. 2017 Jul 28;1(2):80-1.

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17. Urabe M, Yamashita H, Akamatsu N, Seto
Y.Gastric cancer with solitary liver metastasis
accompanied by cyst formation.ANZ J Surg. 2017
Dec 11. doi: 10.1111/ans.14315. [Epub ahead ofprint] No abstract available.
18. Urabe M, Yamashita H, Seto Y.Pretreatment
Neutrophil to Lymphocyte Ratio Independently
Predicts Disease-specific Survival in Patients
With Resectable Gastroesophageal Junction and
Gastric Cancer.Ann Surg. 2017 Dec;266(6):e76-7.

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Hepato-biliary-Pancreatic Surgery
Division and Artificial Organ
and Transplantation Division
Professor and Chairman
Kiyoshi Hasegawa, MD.

Lecturers
Junichi Kaneko, MD.

Nobuhisa Akamatsu, MD.

Junichi Arita, MD.

Takeaki Ishizawa, MD.

Homepages

http://www.h.u-tokyo.ac.jp/patient/depts/hbps_md/index.html
http://www.h.u-tokyo.ac.jp/patient/depts/1512ishokugeka/index.html

Introduction and Organization
The Hepato-Biliary-Pancreatic Surgery Division,
Artificial Organ and Liver Transplantation Division,
Department of Surgery (HPB Surg Division) is
originated from Second Department of Surgery (2ndDept of Surg), which was established in 1893. This
department has a history of 125 years and has madetremendous contribution to the Japanese surgicaladvancement, such as the foundation of Japanese
Surgical Society. As departments in the style ofgraduate school have been increasingly founded in
The Tokyo University, and organ-specific medication
has been progressively recommended, 2nd Dept ofSurg has been replaced to HPB Surg Division sinceJune 1st, 1998.

Clinical Activities
Our division deals with patients with hepato-biliarypancreatic malignancies, liver cirrhosis, and HBP
benign diseases. We specialize in hepatectomies for
HCC and colorectal mets, Whipples, and livertransplantations, mainly from living donors. The
overall number of operation is about 500/year.
Elective operations are carried out on Monday,
Wednesday and Friday. The perioperative manage-

ment is strictly controlled, with nearly zero mortality.
Adjuvant chemotherapy is performed in a style ofprospective clinical trials.

Education
Education for medical students includes systematic
lectures of surgery for M2 students, and clinicallectures and bed-side practice for M3 and M4 students,
in accordance with other surgical and non-surgicaldepartments. Since 2013, the bed-side practice wasrearranged as “Clinical Clerkship,” more practical
medical training than conventional “Bed-Side
Teaching”. Our division precedes Clinical Clerkshipin the Tokyo University Hospital, and recommends
students to aggressively attend the surgical activities.
Clinical Clerkship is designed to consist of 2 parts;
2 weeks clinical practice in Tokyo University and 1
week practice in other hospitals. Medical students are
expected to join the surgical team and the surgicaloperations. They can learn about preoperative examinations & care of the patients, informed consents,
diagnosis, presentation at the conferences, operative
procedures, and postoperative managements. They
also are expected to submit a report on a theme of
specific surgical topics.

207

Research
We have published papers mainly on Hepato-BiliaryPancreatic Surgery and liver transplantations. The
ongoing topics involve clinical application of ICG
fluorescence imaging enabling visualization of
biological structures (biliary trees, hepatic tumors,
hepatic segmental boundaries, etc.), prospective
clinical trials of adjuvant chemotherapy forhepatocellular carcinoma, metastatic colorectal cancer,
neoadjuvant chemotherapy for borderline resectablepancreatic cancer, utility of contrast-enhanced
intraoperative ultrasonography, and preoperative
navigation for hepatic surgery.

Publications (2017)
1. Yang PC, Akamatsu N, Hasegawa K, et al. Twenty
years of Milan criteria: how far do we go.
Hepatobiliary Surg Nutr. 2016;5(6):488.
2. Aoki T, Matsushita H, Hoshikawa M, et al.
Adjuvant combination therapy with gemcitabine
and autologous gammadelta T-cell transfer inpatients with curatively resected pancreatic cancer.
Cytotherapy. 2017;19(4):473.
3. Arita J, Sakamoto Y, Hasegawa K, et al.
Assessment of preoperative liver function basedon indocyanine green clearance. Proc Natl Acad
Sci U S A. 2017;66(2):675.
4. Gupta R, Togashi J, Akamatsu N, et al. Impact ofincidental/misdiagnosed intrahepatic cholangiocarcinoma and combined hepatocellular cholangiocarcinoma on the outcomes of livertransplantation: an institutional case series andliterature review. Surg Today. 2017;47(8):908.
5. Hasegawa K, Yamamoto S, Inoue Y, et al.
Hepatocellular Carcinoma With Bile Duct Tumor
Thrombus: Extrahepatic Bile Duct Preserving or
Not? Reply. Ann Surg. 2017;266(6):e63.
6. Ikegami T, Ueda Y, Akamatsu N, et al.
Asunaprevir and daclatasvir for recurrent hepatitis
C after liver transplantation: A Japanese multicenter experience. Clin Transplant. 2017;31(11).
7. Ishizawa T, Lim C, Kokudo N. Reply to "Liver
Malignancies in Segment VII: The Role ofRobot-assisted Surgery". Ann Surg. 2017;265(6):E81.
8. Ito K, Akamatsu N, Kokudo N. Reply. Liver

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

208

Liver resection for hepatocellular carcinoma
associated with hepatic vein invasion: A Japanesenationwide survey. Hepatology. 2017;66(2):510.
21. Lim C, Shinkawa H, Hasegawa K, et al. Salvage
liver transplantation or repeat hepatectomy forrecurrent hepatocellular carcinoma: An intent-totreat analysis. Liver Transpl. 2017;23(12):1553.
22. Maki H, Aoki T, Ishizawa T, et al. Intraductal
papillary neoplasm originating from ananomalous bile duct. Clin J Gastroenterol. 2017;10(2):174.
23. Masuda K, Kaneko J, Kawaguchi Y, et al.
Diagnostic accuracy of indocyanine green
fluorescence imaging and multidetector row
computed tomography for identifying hepatocellular carcinoma with liver explant correlation.
Hepatol Res. 2017;47(12):1299.
24. Mihara Y, Matsuura K, Sakamoto Y, et al.
Production of pancreatic progenitor cells fromhuman induced pluripotent stem cells using athree-dimensional suspension bioreactor system. J
Tissue Eng Regen Med. 2017;11(11):3193.
25. Mise Y, Hasegawa K, Satou S, et al. How Has
Virtual Hepatectomy Changed the Practice ofLiver Surgery?: Experience of 1194 Virtual
Hepatectomy Before Liver Resection and Living
Donor Liver Transplantation. Ann Surg. 2017.
26. Miyata Y, Ishizawa T, Kamiya M, et al.
Intraoperative imaging of hepatic cancers using
gamma-glutamyltranspeptidase-specificfluorophore enabling real-time identification andestimation of recurrence. Sci Rep. 2017;7(1):3542.
27. Mizuno H, Koya J, Fujioka Y, et al. Extranodal
NK/T cell lymphoma in a living donor livertransplant recipient. Ann Hematol. 2017;96(6):1051.
28. Nakagawa H, Suzuki N, Hirata Y, et al. Biliary
epithelial injury-induced regenerative response by
IL-33 promotes cholangiocarcinogenesis fromperibiliary glands. 2017;114(19):E3806.
29. Nishioka Y, Shindoh J, Yoshioka R, et al. ClinicalImpact of Preoperative Chemotherapy on Microscopic Cancer Spread Surrounding Colorectal
Liver Metastases. Ann Surg Oncol. 2017;24(8):2326.
30. Notake T, Kobayashi A, Shinkawa H, et al.

Nomogram predicting long-term survival after the
diagnosisofintrahepatic
recurrenceofhepatocellular carcinoma following an initial liverresection. Int J Clin Oncol. 2017;22(4):715.
31. Ohtomo K, Xia J, Inagaki Y, et al. Combination of
Cinobufacini
andDoxorubicin
Increases
Apoptosis of Hepatocellular Carcinoma Cells
through the Fas- and Mitochondria-MediatedPathways. Sci Rep. 2017;45(7):1537.
32. Sakamoto Y, Kokudo N, Kawaguchi Y, et al.
Clinical Anatomy of the Liver: Review of the 19th
Meeting of the Japanese Research Society ofClinical Anatomy. Liver Cancer. 2017;6(2):146.
33. Sakamoto Y, Kokudo N, Watadani T, et al.
Proposal of size-based surgical indication criteria
for liver hemangioma based on a nationwide
survey in Japan. J Hepatobiliary Pancreat Sci.
2017;24(7):417.
34. Shinkawa H, Hasegawa K, Arita J, et al. Impact of
Sustained Virological Response to Interferon
Therapy on Recurrence of Hepatitis C VirusRelated Hepatocellular Carcinoma. Ann Surg
Oncol. 2017;24(11):3196.
35. Shirata C, Kaneko J, Inagaki Y, et al. Nearinfrared photothermal/photodynamic therapy withindocyanine green induces apoptosis of hepatocellular carcinoma cells through oxidative stress.
Sci Rep. 2017;7(1):13958.
36. Tanaka M, Ishikawa S, Ushiku T, et al. EVI1
modulates oncogenic role of GPC1 in pancreatic
carcinogenesis. Oncotarget. 2017;8(59):99552.
37. Tani K, Ishizawa T, Sakamoto Y, et al. SurgicalApproach to "Right Hepatic Core": Deepest
Region Surrounded by Major Portal Pedicles andRight Hepatic Vein. Dig Surg. 2017.
38. Tani K, Shindoh J, Takamoto T, et al. Kinetic
Changes in Liver Parenchyma After Preoperative
Chemotherapy for Patients with Colorectal Liver
Metastases. J Gastrointest Surg. 2017;21(5):813.
39. Ueda Y, Ikegami T, Akamatsu N, et al. Treatment
with sofosbuvir and ledipasvir without ribavirinfor 12 weeks is highly effective for recurrent
hepatitis C virus genotype 1b infection after living
donor liver transplantation: a Japanese multicenter
experience. J Gastroenterol. 2017;52(8):986.
40. Yamashita S, Ishizawa T, Mori K, et al. Pancreatic
Chymotrypsin Activity Rather Than Amylase

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Level Better Predicts Postoperative Pancreatic
Fistula. Ann Surg. 2017.
41. Yamashita S, Sakamoto Y, Yamamoto S, et al.
Efficacy of Preoperative Portal Vein Embolization
Among Patients with Hepatocellular Carcinoma,
Biliary Tract Cancer, and Colorectal Liver
Metastases: A Comparative Study Based onSingle-Center Experience of 319 Cases. Ann Surg
Oncol. 2017;24(6):1557.
42. Arita J, Akamatsu N, Kaneko J, et al. Proximal
total splenic artery embolization for refractory
hepatic encephalopathy. J Surg Oncol. 2018;11(2):156.
43. Hoshikawa M, Aoki T, Matsushita H, et al. NK
cell and IFN signatures are positive prognostic
biomarkers for resectable pancreatic cancer.
Biochem Biophys Res Commun. 2018;495(2):2058.
44. Igaki H. A systematic review of publications on
charged particle therapy for hepatocellular
carcinoma. J Surg Oncol. 2018;23(3):423.
45. Ito K, Kawaguchi Y, Sakamoto Y, et al. Predictorsof Postoperative Non-Chylous Massive Discharge
after Pancreaticoduodenectomy for Pancreatic
Ductal Adenocarcinoma. Dig Surg. 2018;35(3):252.
46. Kaibori M, Yoshii K, Hasegawa K, et al. Treatment Optimization for Hepatocellular Carcinoma
in Elderly Patients in a Japanese Nationwide
Cohort. Ann Surg. 2018.
47. Kawaguchi Y, Fuks D, Kokudo N, et al. Difficultyof Laparoscopic Liver Resection: Proposal for a
New Classification. Ann Surg. 2018;267(1):13.
48. Kobayashi Y, Omichi K, Kawaguchi Y, et al.
Intraoperative real-time tissue elastographyduring laparoscopic hepatectomy. HPB (Oxford).
2018;20(1):93.
49. Kokudo T, Kokudo N, Hasegawa K. Negative
phase 3 study of (90)Y microspheres versus
sorafenib in HCC. Lancet Oncol. 2018;19(2):e68.
50. Mizumoto M, Okumura T, Hasegawa K, et al.
Partial TIPE ALPPS for Perihilar Cancer. Int J
Clin Oncol. 2018;267(2):e18.
51. Okinaga H, Yasunaga H, Hasegawa K, et al.
Short-Term Outcomes following Hepatectomy in
Elderly Patients with Hepatocellular Carcinoma:
An Analysis of 10,805 Septuagenarians and 2,381

Octo- and Nonagenarians in Japan. Liver Cancer.
2018;7(1):55.
52. Shimizu A, Hasegawa K, Masuda K, et al.
Efficacy of Hyaluronic Acid/Carboxymethyl
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191.

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Department of Urology
Professor
Haruki Kume, M.D., Ph.D.

Associate Professor
Assistant Professor
Akihiko Matsumoto, M.D., Ph.D., Daisuke Yamada, M.D., Ph.D.
Taketo Kawai, M.D., Ph.D., Yusuke Sato, M.D., Ph.D.

Associate
Masaki Nakamura, M.D., Ph.D., Akira Nomiya, M.D.,
Shigekatsu Maekawa, M.D., Ph.D., Yoshiyuki Akiyama, M.D., Ph.D.
Jun Kamei, M.D., Ph.D., Taro Teshima, M.D., Hotaka Matsui, M.D.,
Yoshitaka Kinoshita, M.D., Yuji Hakozaki, M.D., Takuya Iwaki, M.D.

Homepage

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

Introduction and Organization
Urology is a special field of clinical medicine
covering the diseases of the adrenal gland, the kidney,
the urinary tract and the male genital system by meansof a surgical procedure as well as an approach ofinternal medicine. In addition, urology encompasses
pediatric urology, neurourology, female urology, renaltransplantation, renal vascular surgery, endocrine
surgery and geriatric urology. For this reason, urology
requires the scientific background of oncology,
nephrology, endocrinology, andrology, immunology,
pediatrics, histology, microbiology, neurology andgerontology. Now we have commenced to utilize
cellular and molecular biology to develop the researchin urology. It is expected for our department to devote
to the scientific progress in the frontier of urology.
In recent years, we have been taking international
leadership in applying the new and minimally invasive
treatment modalities. They are exemplified byendoscopic management of the diseases in the upper
urinary tract, ESWL or laser lithotripsy for urolithiasis,
hyperthermic and laser therapies for BPH, andminimum incision endoscopic or laparoscopic
adrenalectomy, nephrectomy, and robot-assisted
prostatectomy substituting open procedures.

Clinical activities
There are 44 beds in the ward (8th floor of the centralward-building). The professor, associate professors,
lecturers and associates are involved in in-patient andout-patient cares and teaching of the students as well
as research activities. Clinical visiting professors aremainly engaged in the teaching. The residents takecare of all the patients on 24-hour a day basis.
Associate staff members team up with the residents on
a man-to-man basis. The total number of inpatientswas about 1,100 from January 2017 to December 2017.
Elective operations are performed on Tuesday,
Wednesday, Thursday and Friday. 1,538 operations
were performed in 2017. The numbers of main
operations are adrenalectomy 17, nephrectomy 39,
partial nephrectomy 36, nephroureterectomy 30,
radical cystectomy 21, radical prostatectomy 132,transurethral resection of the bladder tumor (TUR-Bt)

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158, transurethral resection of the prostate (TUR-P) 5,
laparoscopic surgery 66, and Robot assisted surgery
164 (radical prostatectomy 132, partial nephrectomy
31).
At the weekly professor’s round on Wednesday, dataof all in patients are presented and appropriate
treatment strategies are recommended for them. On
Wednesday evening, a clinical conference is held for
discussing cases with difficult problems in detail andthe best treatment is chosen for each case.
In out-patient clinic, services are provided from
Monday to Friday. Patients assigned to specialized
services as renal tumor, adrenal surgery, bladdercancer, prostate cancer, andrology, neurourology,
urolithiasis, kidney transplantation, second opinion,
pediatric urology and female urology receive
sophisticated care on the particular day of the week.
The total number of out-patients was 14,185 patientdays from January 2017 to December 2017.

Andrology
Virology

References
1.

2.

3.

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.

4.

5.

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

6.

7.

8.

Aizawa, N., K. Ichihara, H. Fukuhara, T.
Fujimura, K. E. Andersson, Y. Homma and Y.
Igawa. Characteristics of the mechanosensitive
bladder afferent activities in relation withmicrocontractions in male rats with bladder outlet
obstruction. Sci Rep, 7, 7646, 2017
Aizawa, N., K. Ichihara, H. Fukuhara, T.
Fujimura, K. E. Andersson, Y. Homma and Y.
Igawa. Characteristics of the mechanosensitive
bladder afferent activities in relation withmicrocontractions in male rats with bladder outlet
obstruction. Sci Rep, 7, 7646, 2017
Aizawa, N., H. Ito, R. Sugiyama, T. Fujimura, H.
Fukuhara, H. Kume, Y. Homma and Y. Igawa.
Effects of Sildenafil, a Phosphodiesterase Type 5
Inhibitor, on the Primary Single Afferent Activityof the Rat Bladder. Low Urin Tract Symptoms, 9,57-61, 2017
Aizawa, N., D. Wakamatsu, J. Kida, T. Otsuki, Y.
Saito, H. Matsuya, Y. Homma and Y. Igawa.
Inhibitory effects of retigabine, a Kv7 channel
activator, on mechanosensitive primary bladderafferent activities and nociceptive behaviors in
rats. Neurourol Urodyn, 36, 280-285, 2017
Akiyama, Y., D. Maeda, T. Morikawa, A. Niimi,
A. Nomiya, Y. Yamada, Y. Igawa, A. Goto, M.
Fukayama and Y. Homma. Digital quantitative
analysis of mast cell infiltration in interstitial
cystitis. Neurourol Urodyn. 2017 in press.
Aruga, S., N. Kuwana, Y. Shiroki, S. Takahashi,
N. Samejima, A. Watanabe, Y. Seki, Y. Igawa andY. Homma. Effect of cerebrospinal fluid shunt
surgery on lower urinary tract dysfunction in
idiopathic normal pressure hydrocephalus.
Neurourol Urodyn. 2017, in press.
Fujimura, T., H. Fukuhara, S. Taguchi, Y. Yamada,T. Sugihara, T. Nakagawa, A. Niimi, H. Kume, Y.
Igawa and Y. Homma. Robot-assisted radical
prostatectomy significantly reduced biochemicalrecurrence compared to retro pubic radical
prostatectomy. BMC Cancer, 17, 45, 2017
Gong, X., Z. Siprashvili, O. Eminaga, Z. Shen, Y.

212

9.

10.

11.

12.

13.

14.

15.

Sato, H. Kume, Y. Homma, S. Ogawa, P. A.
Khavari, J. R. Pollack and J. D. Brooks. Novel
lincRNA SLINKY is a prognostic biomarker inkidney cancer. Oncotarget, 8, 18657-18669, 2017
Homma, Y., M. Gotoh, A. Kawauchi, Y. Kojima,
N. Masumori, A. Nagai, T. Saitoh, H. Sakai, S.
Takahashi, O. Ukimura, T. Yamanishi, O.
Yokoyama, M. Yoshida and K. Maeda. Clinicalguidelines for male lower urinary tract symptoms
and benign prostatic hyperplasia. Int J Urol, 24,
716-729, 2017
Ichihara, K., N. Aizawa, Y. Akiyama, J. Kamei, N.
Masumori, K. E. Andersson, Y. Homma and Y.
Igawa. Toll-like receptor 7 is overexpressed in
the bladder of Hunner-type interstitial cystitis,
and its activation in the mouse bladder can
induce cystitis and bladder pain. Pain, 158, 15381545, 2017
Kamei, J., Y. Yagihara, H. Kume, T. Horiuchi, T.
Sato, T. Nakagawa, T. Fujimura, H. Fukuhara, K.
Moriya and Y. Homma. Prevalence andcharacteristics of fecal antimicrobial-resistantEscherichia coli in a cohort of Japanese men
undergoing prostate biopsy. Int J Urol, 24 , 295300, 2017
Koyama, Y., T. Morikawa, J. Miyakawa, Y.
Miyama, T. Nakagawa, Y. Homma and M.
Fukayama. Diagnostic utility of Ki-67 immunohistochemistry in small endoscopic biopsies of
the ureter and renal pelvis. Pathol Res Pract, 213,
737-741, 2017
Makino, K., T. Nakagawa, A. Kanatani, T. Kawai,
S. Taguchi, M. Otsuka, A. Matsumoto, H.
Miyazaki, T. Fujimura, H. Fukuhara, H. Kume
and Y. Homma, Biphasic decline in renal function
after radical cystectomy with urinary diversion.
Int J Clin Oncol, 22, 359-365, 2017
Misawa, A., K. I. Takayama, T. Fujimura, Y.
Homma,Y.
SuzukiandS.
Inoue.
Androgen-induced
lncRNAPOTEF-AS1
regulates apoptosis-related pathway to facilitate
cell survival in prostate cancer cells. Cancer Sci,
108, 373-379, 2017
Miyakawa, J., T. Morikawa, Y. Miyama, T.
Nakagawa, T. Kawai, Y. Homma and M.
Fukayama. Loss of Stromal Antigen 2 (STAG2)
Expression in Upper Urinary Tract Carcinoma:

16.

17.

18.

19.

20.

Differential Prognostic Effect According to the
Ki-67 Proliferating Index. Ann Surg Oncol, 24,4059-4066, 2017
Miyazaki, H., Y. Hirano, S. Kato, N. Ioritani, T.
Ichikawa, H. Takamoto and Y. Homma. Early
Experiences of Contact Laser Vaporization of theProstate using the 980 nm High Power Diode
Laser for Benign Prostatic Hyperplasia. Low
Urin Tract Symptoms. 2017, in press.
Naito, A., S. Taguchi, T. Nakagawa, A.
Matsumoto, Y. Nagase, M. Tabata, J. Miyakawa,
M. Suzuki, H. Nishimatsu, Y. Enomoto, S.
Takahashi, T. Okaneya, D. Yamada, T. Tachikawa,
S. Minowada, T. Fujimura, H. Fukuhara, H.
Kume and Y. Homma. Prognostic significance ofserum neuron-specific enolase in small cell
carcinoma of the urinary bladder. World J Urol,35, 97-103, 2017
Nakagawa, T., Y. Komemushi, T. Kawai, M.
Otsuka, J. Miyakawa, Y. Uemura, A. Kanatani, S.
Taguchi, A. Naito, M. Suzuki, H. Nishimatsu, Y.
Hirano, Y. Tanaka, A. Matsumoto, H. Miyazaki, T.
Fujimura, H. Fukuhara, H. Kume, Y. Igawa and Y.
Homma. Efficacy of post-nephroureterectomy
cisplatin-based adjuvant chemotherapy for
locally advanced upper tract urothelial
carcinoma: a multi-institutional retrospective
study. World J Urol, 35, 1569-1575, 2017
Nakagawa, T., S. Taguchi, A. Kanatani, T. Kawai,
M. Ikeda, S. Urakami, A. Matsumoto, Y.
Komemushi, J. Miyakawa, D. Yamada, M.
Suzuki, Y. Enomoto, H. Nishimatsu, Y. Kondo, Y.
Nagase, Y. Hirano, T. Okaneya, Y. Tanaka, H.
Miyazaki, T. Fujimura, H. Fukuhara, H. Kume, Y.
Igawa and Y. Homma. Oncologic Outcome ofMetastasectomy for Urothelial Carcinoma: Who
Is the Best Candidate? Ann Surg Oncol, 24,2794-2800, 2017
Nakagawa, T., S. Taguchi, Y. Uemura, A.
Kanatani, M. Ikeda, A. Matsumoto, K. Yoshida, T.
Kawai, M. Nagata, D. Yamada, Y. Komemushi,
M. Suzuki, Y. Enomoto, H. Nishimatsu, A.
Ishikawa, Y. Nagase, Y. Kondo, Y. Tanaka, T.
Okaneya, Y. Hirano, M. Shinohara, H. Miyazaki,
T. Fujimura, H. Fukuhara, H. Kume, Y. Igawa
and Y. Homma. Nomogram for predicting
survival of postcystectomy recurrent urothelial

213

21.

22.

23.

24.

25.

26.

27.

carcinoma of the bladder. Urol Oncol, 35,457e415-457 e421, 2017
Niimi, A., Y. Igawa, N. Aizawa, T. Honma, A.
Nomiya, Y. Akiyama, J. Kamei, T. Fujimura, H.
Fukuhara and Y. Homma. Diagnostic value of
urinary CXCL10 as a biomarker for predicting
Hunner type interstitial cystitis. Neurourol
Urodyn. 2017, in press
Sugihara, T., A. Ishikawa, T. Takamoto, Y.
Kinoshita, T. Minami, Y. Yamada, Y. Homma and
M. Makuuchi. "Three-Dimensional VolumeRendering of Entrapped Malecot Nephrostomy
Catheter by Granulation Tissue. Urol Case Rep,
12, 64-66, 2017
Sugihara, T., H. Yasunaga, H. Matsui, G. Nagao,
A. Ishikawa, T. Fujimura, H. Fukuhara, K.
Fushimi, M. Ohori and Y. Homma. Accessibility
to surgical robot technology and prostate-cancer
patient behavior for prostatectomy. Jpn J Clin
Oncol, 47, 647-651, 2017
Sugiyama, R., N. Aizawa, H. Ito, T. Fujimura, M.
Suzuki, T. Nakagawa, H. Fukuhara, H. Kume, Y.
Homma and Y. Igawa. Synergic Suppressive
Effect of Silodosin and Imidafenacin on NonVoiding Bladder Contractions in Male Rats with
Subacute Bladder Outlet Obstruction. Low Urin
Tract Symptoms, 9, 94-101, 2017
Taguchi, S., S. Buti, H. Fukuhara, M. Otsuka, M.
Bersanelli, T. Morikawa, H. Miyazaki, T.
Nakagawa, T. Fujimura, H. Kume, Y. Igawa andY. Homma. Benefit of adjuvant immunotherapy
in renal cell carcinoma: A myth or a reality?
PLoS One. 12, e0172341, 2017
Takayama, K. I., T. Suzuki, T. Fujimura, Y.
Yamada, S. Takahashi, Y. Homma, Y. Suzuki and
S. Inoue. Dysregulation of spliceosome gene
expression in advanced prostate cancer by
RNA-binding protein PSF. Proc Natl Acad Sci
U S A, 114, 10461-10466, 2017
Takizawa, A., K. Kawai, T. Kawahara, T. Kojima,
S. Maruyama, N. Shinohara, S. Akamatsu, T.
Kamba, T. Nakamura, O. Ukimura, R. Jikuya, T.
Kishida, K. Kakimoto, K. Nishimura, T.
Harabayashi, S. Nagamori, S. Yamashita, Y. Arai,
Y. Sawada, N. Sekido, H. Kinoshita, T. Matsuda,
T. Nakagawa, Y. Homma and H. Nishiyama. "Theusefulness of testosterone administration in

28.

29.

30.

31.

32.

33.

34.

identifying false-positive elevation of serum
human chorionic gonadotropin in patients with
germ cell tumor. J Cancer Res Clin Oncol. 2017,
in press.
Tsuda, Y., T. Nakagawa, Y. Shinoda, A. Kanatani,
T. Kawai, S. Taguchi, Y. Yamada, R. Sawada, H.
Kume, Y. Homma, S. Tanaka and H. Kawano.
Skeletal-related events and prognosis inurothelial cancer patients with bone metastasis.
Int J Clin Oncol , 22, 548-553, 2017
Yamada, Y., T. Fujimura, H. Fukuhara, T.
Sugihara, H. Miyazaki, T. Nakagawa, H. Kume,
Y. Igawa and Y. Homma. Overactive bladder is anegative predictor of achieving continence after
robot-assisted radical prostatectomy. Int J Urol,24, 749-756, 2017
Yamada, Y., T. Fujimura, H. Fukuhara, T.
Sugihara, T. Nakagawa, H. Kume, Y. Igawa and Y.
Homma. Predictors of Early Continence after
Robot-assisted Radical Prostatectomy. Low Urin
Tract Symptoms, 2017, in press.
Yamada, Y., T. Fujimura, H. Fukuhara, T.
Sugihara, K. Takemura, S. Kakutani, M. Suzuki,
T. Nakagawa, H. Kume, Y. Igawa and Y. Homma.
Incidence and risk factors of inguinal hernia after
robot-assisted radical prostatectomy. World J
Surg Oncol. 15, 61, 2017
Yamada, Y., K. I. Takayama, T. Fujimura, D.
Ashikari, D. Obinata, S. Takahashi, K. Ikeda, S.
Kakutani, T. Urano, H. Fukuhara, Y. Homma and
S. Inoue. A novel prognostic factor TRIM44
promotes cell proliferation and migration, andinhibits apoptosis in testicular germ cell tumor.
Cancer Sci, 108, 32-41, 2017
Yokoyama, O., O. Nishizawa, Y. Homma, M.
Takeda, M. Gotoh, H. Kakizaki, H. Akino, K.
Hayashi, K. Yonemoto and O. P. Group.
Nocturnal Polyuria and Hypertension in Patientswith Lifestyle Related Diseases and Overactive
Bladder. J Urol, 197, 423-431, 2017
Hakozaki Y, Matsushima H, Kumagai J, Murata T,
Masuda T, Hirai Y, Oda M, Kawauchi N,
Yokoyama M, Homma Y. A prospective study ofmagnetic resonance imaging and ultrasonography(MRI/US)-fusion targeted biopsy and concurrent
systematic transperineal biopsy with the averageof 18-cores to detect clinically significant

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35.

36.

37.

38.

39.

40.

41.

prostate cancer. BMC urology, 17, 117-122,
2017
Igawa Y, Aizawa N. Incontinence: How do
β3-adrenoceptor agonists work in the bladder?
Nat Rev Urol, Epub, 2017
Ito H, Pickering AE, Igawa Y, Kanai AJ, Fry CH,
Drake MJ. Muro-Neuro-Urodynamics; a reviewof the functional assessment of mouse lower
urinary tract function. Front Physiol, 8,49, 2017
Taguchi S, Fukuhara H, Homma Y, Todo T.
Current status of clinical trials assessing
oncolytic virus therapy for urological cancers. Int
J Urol, Epub, 2017
Horita, S., M. Nakamura, M. Suzuki, N. Satoh, A.
Suzuki, Y. Homma and M. Nangaku. The role ofrenal proximal tubule transport in the regulationof blood pressure. Kidney Res Clin Pract, 36,
12-21, 2017
Sugihara T, Ishikawa A, Takamoto T, Kinoshita Y,
Minami T, Yamada Y, Homma Y, Makuuchi M.
Three-Dimensional Volume Rendering of
Entrapped Malecot Nephrostomy Catheter by
Granulation Tissue. Urol Case Rep, 12,64-6,
2017
Ikeda M, Kobayashi T, Suzuki T, Wakabayashi Y,
Ohama Y, Maekawa S, Takahashi S, Homma Y,
Tatsuno K, Sato T, Okugawa S, Moriya K,
Yotsuyanagi H. Propionimicrobium lymphophilum and Actinotignum schaalii bacteremia
with urinary tract infection: a case report. New
Microbes New Infect, in press, 2017
Matsuki, R., K. Okuda, A. Mitani, Y. Yamauchi,
G. Tanaka, H. Kume, Y. Homma, M. Hinata, A.
Hayashi, J. Shibahara, M. Fukayama and T.
Nagase. A case of delayed exacerbation ofinterstitial lung disease after discontinuation oftemsirolimus. Respir Med Case Rep, 22, 158163, 2017

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Department of Surgical Oncology
Associate Professor
Hiroaki Nozawa, M.D., Ph.D.

Lecturer
Kazushige Kawai, M.D., Ph.D.
Toshiaki Tanaka, M.D., Ph.D.
Keisuke Hata, M.D., Ph.D.

Assistant Professor
Takeshi Nishikawa, M.D., Ph.D.

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

Kazuhito Sasaki, H.D., Ph.D.

Manabu Kaneko, M.D. Ph.D.

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

Shigenobu Emoto, M.D., Ph.D.

Hirofumi Sonoda, M.D., Ph.D., Pharm.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 Associate Professor (Dierctor), three
Lecturers and eight Assistant Professors. The
outpatient office is located on the third floor of the
Outpatient Building. The ward is situated on theeighth floor of the Ward Building. The administrative
office and research laboratories are located in the
Administration and Research Building. Current
activities of the Department of Surgical Oncology inclinical practice, education, and research aresummarized as follows.

Clinical activities
The Department of Surgical Oncology provides
comprehensive evaluation, diagnosis, treatment andmanagement for adult patients with both general andoncologic surgical problems, in the ambulatory as wellas inpatient setting. In particular, we are trying to

identify the best way to treat each patient with theleast surgical stress by minimally invasive surgery
such as laparoscopic surgery and robotic surgery (daVinci Surgical System), and preoperative chemoradiotherapy for rectal cancer. The department is also wellknown for its innovative therapy for inflammatory
bowel disease. Department specialists have expertisein biological cancer immunotherapy, chemotherapy
for a variety of malignancies, and radiotherapy forrectal cancer. The outpatient clinic is open from
Monday through Friday, and twenty-four-hour consultation is available for urgent or emergency problems.
The outpatient clinic is specialized in the lower GI
tract. The Department was responsible for 571
surgically treated inpatients in the year of 2017. On
Monday, Wednesday and Friday mornings, pre- andpost-surgery conferences are held, and the Director'sRound takes place after the conference every
Wednesday. Operating days are Monday, Tuesday andThursday. In addition to the clinical conferences,
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

216

diagnosis and treatment of colon and rectal cancer andlong-term surveillances for inflammatory bowel
disease are performed.

Teaching activities
The Department of Surgical Oncology also offers afellowship in surgical oncology for well-qualified
surgeons who have completed their training in generalsurgery and wish to further specialize in surgicaloncology. The Department of Surgical Oncology has a
Surgical Oncology Training Program and provides
broad reaching experience in technical aspects ofdiagnosis, treatment and management for adultpatients with both surgical and oncologic problems,development of surgical judgment, and increasing
knowledge about routine and complex conditions. In
addition, the dedicated staff allows multiple
opportunities for academic development both along
clinical and basic scientific lines.
In the undergraduate education program, ourdepartment plays a role in the systemic lecture and in
the clinical introduction lecture for the 2nd year
medical students. We offer the clinical lectures and thebedside learning program for 3rd year medical
students, in cooperation with other departments ofsurgery. In the systemic lectures on surgery, various
fields were covered such as surgical oncology andimmunology, injury, somatic reaction to surgery,
infectious diseases, shock, pre- and post-surgicalmanagement and nutrition. In the clinical lectures, we
presented many diseases such as colon cancer, colonicpolyp, colonic polyposis and inflammatory bowel
disease. In the postgraduate education program, newresidents are trained to become qualified surgeons. In
addition to pre- and post-surgery clinical conferences,
the residents are expected to attend research
conferences and seminars, which are held periodically.
They are also asked to present cases at clinicalmeetings, which are held locally such as the local
meeting of the Japanese Society of Gastroenterology.

Research activities
We apply the techniques used in molecular andcellular biology to our research. The following are themajor themes under research.
1) Preoperative radiotherapy in lower rectal cancer

2)
3)
4)
5)
6)

Cancer surveillance in ulcerative colitis
Carcinogenesis in ulcerative colitis
Laparoscopically assisted colon surgery
Local immunity in colorectal cancer
Genetic analysis of colorectal cancer andadenoma
7) Prognostic factor of early colorectal cancer8) Surveillance program following colectomy forcolorectal cancer
9) Analysis of factors associated with conversion
surgery in initially unresectable/metastatic
colorectal cancer10) Cancer Immunotherapy targeting to the tumor
vessels11) Autophagy in Oncology
12) Role of LPA S1P and productive enzymes intumor metastasis
13) Lipid metabolism in carcinogenesis and tumor
progression
14) Pathological studies in obstructive colorectal
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) Clinical trials of chemotherapeutic drugs inmetastatic colorectal cancer (single- or
multi-institutional)21) Single nucleotide polymorphisms (SNPs) ininflammatory bowel disease22) Anatomy of vessels feeding the colon and rectum23) High Frequency Ultrasonography (HIFU) for
solid cancer24) Quantitative analysis of intraperitoneal cancer
cells in peritonitis carcinomatosis25) Immunomodulation in chemoradiotherapy for
locally advanced rectal cancer
26) Robot assisted laparoscopic colorectal surgery (daVinci)
27) Postoperative defecation function, urinary
function, and sexual function after rectal cancer
surgery28) Application of 3D images and 3D printers incolorectal surgery

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

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

Toshio Takayama, M.D., Ph.D.

Assistant Professor
Kota Yamamoto, M.D., Ph.D.,

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

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

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

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

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

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

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

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

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

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

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

Yasuko Kikuchi M.D., Ph.D.

Takako Wakeda M.D., Ph.D.

Yuko Ishibashi M.D., Ph.D.

Asako Sasahara M.D., Ph.D.

Kana Sakiyama M.D.

Homepage
Organization
Our section is staffed by one professor, one lecturer,
and six associates. Official activities of our sections
are run on the same schedule of the Department of
Gastrointestinal Surgery.

Clinical Activities
Endocrine Surgery had not been so familiar withJapanese; however, it has been a long time to bestudied this area by top level surgeons in westerncountries. We have started our activities for this area
since 1987 and our department has been establishedwith reconstruction of our hospital structure in 1997.
This is a result of the growth of demand nationally andinternationally and it is caused by not only treatment
for malignant disease but also functional one or giving
more attention to quality of life.
Professional skill and wider knowledge of
endocrine system are required for this area. Diseases
we treat at our department are breast, thyroid, andparathyroid. In additional to treatment for malignant
cases of these diseases, we perform surgical procedures as well as systemic treatment. We co-work withthe department of endocrine internal medicine andhave about 250 surgical procedures annually in total.
In breast surgery, more than a half of the mammary
cancer patients undergo the breast-preserving surgery.

In addition, sentinel node navigation surgery has been
adopted, resulting in better quality of postoperative
life. Reconstruction surgery for the breast cancer islikely to provide much better QOL. In this field, we
have started collaboration with the Department of
Plastic Surgery. Chemotherapy, hormone therapy andmolecular- targeting therapy play important roles intreatment of the breast cancer. We have accumulated a
lot of experience and achievement in this field.
Our clinical themes are 1) establishment of safe
procedures for endocrine surgery without complications; 2) diagnosis and treatment of micro-breast
lesions under ultrasonographic guides; 3) preoperative
diagnosis for thyroid neoplasms and breast tumors.

Research Activities
We investigate wide areas related to breast cancer,
thyroid disease, and parathyroid disease. Most of ourstudies are performed with other good institutions.
1) Hereditary Breast and Ovarian Cancer syndrome2) Precision medicine based on Todai OncoPanel
3) Clinical significance of Ki67 in the area of earlybreast cancer.
4) Clinical evaluation for the developing drugs inbreast cancer and thyroid cancer.

2265) Studies in the area of sentinel node biopsy inbreast cancer.
6) Studies about management of the toxic effects ofchemotherapies.
7) Cover makeup studies for cancer patients.
8) Epigenetic changes critical for breast cancer
development
9) Cancer stem cells in breast cancer.
10) Quantification of HER2 expression using Digital
PCR.
11) Development of molecular target drugs in the areaof TGF beta

Publications
1.

2.

3.

4.

5.

6.

Masahiko Tanabe, Takayo Fukuda, Yoshinori Ito.
The Position of Combination Chemotherapy with
Mitomycin C and Methotrexate in the Treatment ofMetastatic Breast Cancer - Especially Triple Negative Breast Cancer. Oncomedicine 2017; 2: 126-131.
Otsuji K, Sasaki T, Tanaka A, Kunita A, Ikemura M,
Matsusaka K, Tada K, Fukayama M, Seto Y. Use ofdroplet digital PCR for quantitative and automatic
analysis of the HER2 status in breast cancer patients.
Breast Cancer Res Treat. 2017 Feb;162(1):11-18.
Sasahara A, Tominaga K, Nishimura T, Yano M,
Kiyokawa E, Noguchi M, Noguchi M, Kanauchi H,
Ogawa T, Minato H, Tada K, Seto Y, Tojo A, Gotoh
N. An autocrine/paracrine circuit of growth differentiation factor (GDF) 15 has a role for maintenanceof breast cancer stem-like cells. Oncotarget. 2017
Apr 11;8(15):24869-24881.
Tada K, Nishioka K, Kikuchi Y, Niwa T, Seto Y.
Post-mastectomy radiation therapy in breast cancer
with 1-3 involved lymph nodes: the Pros.Breast
Cancer. 2017 Jul;24(4):502-504.
Ishibashi Y, Ohtsu H, Ikemura M, Kikuchi Y, Niwa T,
Nishioka K, Uchida Y, Miura H, Aikou S, Gunji T,
Matsuhashi N, Ohmoto Y, Sasaki T, Seto Y, Ogawa T,
Tada K, Nomura S. Serum TFF1 and TFF3 but not
TFF2 are higher in women with breast cancer than inwomen without breast cancer. Sci Rep. 2017 Jul
7;7(1):4846.
Kikuchi Y1, Uchida Y2, Shirakawa K3, Kanauchi
H4, Niwa T1, Nishioka K1, Tada K1, Hashimoto M5,
Yasuda H5, Sugiura R5, Kawabata H6, Seto Y1,
Ogawa T. A multicenter, observational study of metastatic breast cancer patients who were treated witheribulin mesylate or taxane-based regimens. Asia
Pac J Clin Oncol. 2018 Mar 1.
7. Ayaka Sato, Masahiko Tanabe, Yumi Tsuboi, Masako Ikemura, Keiichiro Tada, Yasuyuki Seto,
Yoshinori Murakami. Detection of the PIK3CA Mutation in Circulating Tumor DNA as a Possible Predictive Indicator for Poor Prognosis of Early-Stage
Breast Cancer. Journal of Cancer Therapy. Vol.09
No.01(2018)
8. Shien T, Tanaka T, Tanabe M, Okumura Y, Masuda
N, Yoshida A, Arima N, Komoike Y, Tanaka S,
Iwase T, Taguchi T, Nakatsukasa K, Inaji H, Ishitobi
M; Collaborative Study Group of Scientific Research of the Japanese Breast Cancer Society. Evaluation of ALDH1 expression in ipsilateral breast
cancerrecurrence.
Oncol
Lett.
2017
Mar;13(3):1071-1077.
9. Tominaga K, Shimamura T, Kimura N, Murayama T,
Matsubara D, Kanauchi H, Niida A, Shimizu S,
Nishioka K, Tsuji EI, Yano M, Sugano S, Shimono Y,
Ishii H, Saya H, Mori M, Akashi K, Tada KI, Ogawa
T, Tojo A, Miyano S, Gotoh N. Addiction to the
IGF2-ID1-IGF2 circuit for maintenance of the breast
cancer stem-like cells. Oncogene. 2017 Mar
2;36(9):1276-1286.
10. Yamamoto M, Sakane K, Tominaga K, Gotoh N,
Niwa T, Kikuchi Y, Tada K, Goshima N, Semba K,
Inoue JI. Intratumoral bidirectional transitions between epithelial and mesenchymal cells in triple-negative breast cancer. Cancer Sci. 2017
Jun;108(6):1210-1222.
11. Kawazu M, Kojima S, Ueno T, Totoki Y,
Nakamura H, Kunita A, Qu W, Yoshimura J, Soda M,
Yasuda T, Hama N, Saito-Adachi M, Sato K,
Kohsaka S, Sai E, Ikemura M, Yamamoto S, Ogawa
T, Fukayama M, Tada K, Seto Y, Morishita S,
Hazama S, Shibata T, Yamashita Y, Mano H. Integrative analysis of genomic alterations in triple-negative breast cancer in association with homologous recombination deficiency. PLoS Genet.
2017 Jun 21;13(6):e1006853.

Surgical Sciences
2. Sensory and Motor System Medicine

228

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

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

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

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

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

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

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

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

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

Ryosuke Saigusa, M.D., Ph.D.

Kaoru Funamizu, M.D.

Takashi Yamashita, M.D., Ph.D.

Naomi Shishido, M.D., Ph.D.

Jun Ogaki, M.D.

Toru Kawai, M.D.

Home page

http://www.h.u-tokyo.ac.jp/der/Introduction and Organization

Clinical Activities

The Department of dermatology celebrated its
100th anniversary in 1990. Originally it was foundedas the Department of Dermatology and Urology,
which also encompassed venereology. In 1946, theDepartment of Dermatology was separated from thatof Urology. Regarding venereology, sexually transmitted diseases only related to skin manifestations are
now dealt with in our department.
The professor, one associate professors, threelecturers, two hospital lecturer and seven associatestake part in inpatient and outpatient cares as well as
research and teaching activities. Fifty-two doctors
who basically belong to our department are currently
out in affiliated hospitals mainly engaged in clinicalworks there. Additionally, eight staff members areabroad at present, mainly involved in advanced
research activities in cell biology and molecularbiology.

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

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

229

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

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

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

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

230

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

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

231

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

232

Department of Plastic andReconstructive Surgery
Professor
Mutsumi Okazaki, M.D., Ph.D.

Associate Professor
Takuya Iida, M.D., Ph.D.

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

Associate
Koji Kanayama, M.D., Ph.D. Yoko Tomioka, M.D. Shinya Ogishima, M.D.
Takeo Numahata, M.D. Mitsunobu Harima, M.D. Kazuya Imai, 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 project lecturer, 6 associates, 4physicians, and 5 residents. There are about 100
doctors in the department, but most are serving inrotation at affiliated hospitals.
The outpatient clinic is located on the 3rd floor of
the outpatients building, while there are wards with
about 20 available beds on the 10th floor in the New
Ward. Our faculty room is located in the Medical
Laboratory Building and laboratory rooms in the East
Laboratory Building.
The present status of the educational, research andclinical activities of the department is as follows.

Clinical Activities
The outpatient clinic is opened every morning from
Monday to Friday. There are several specialized
clinics for facial paralysis, breast,, microsurgery,breasts, head and neck reconstruction, cleft lip andpalate, congenital anomalies, vascular malformations,
lymphedema, and cosmetic surgery including cos-

metic dermatology. 924 new patients visited ourdepartment, including 808 patients in emergency. 1101
surgeries were performed. Each week, the professor
goes the round of inpatients on Friday morning.
Preoperative and postoperative conferences that all
members of the department should attend are held on
Tuesday and Wednesday evening respectively.

Teaching Activities
In regard to pregraduate education, the department
has the duty of lecturing to 2nd and 4th year medical
students, and also of instructing 4th medical students
in bed side practice. The subjects taken up in thelectures include general concepts of plastic surgery,wound healing, congenital malformations, skin grafts
and flaps, microsurgery, head and neck reconstruction,
hand surgery, craniomaxillofacial surgery, burn andtrauma, cosmetic surgery, and regenerative medicine.
In the bed side practice the students have theopportunity of seeing various diseases and disorders in
the field of plastic surgery and attending inpatientsand surgical operations and clinical lectures by faculty
members. For graduate school students, microsurgical233

training program is undertaken in the laboratory room.
In the postgraduate course, after completing the 6-yeartraining program, a trainee can sit for the board
examination of the Japan Society of Plastic andReconstructive Surgery.

Research Activities
Basic and clinical researches are performed ingroups. The major research subjects are as follows:
1) Blink examination for appropriate closing-eye
function in patients with facial paralysis.
2) Studies on monitoring tissue circulation using
flexible optical probe.
3) ICG examination for evaluating blood and lymph
flow.
4) Clinical studies on fat regeneration using suctioned fat tissue and adipose stromal progenitor
cells.
5) Studies on hair regrowth using epidermal stem
cells, dermal papilla cells and dermal sheath cells.
6) Basic studies on free tissue transfer using
microsurgery.

References (2017)
1. Mashiko T, Wu SH, Feng J, Kanayama K,
Kinoshita K, Sunaga A, Narushima M, Yoshimura
K. Mechanical Micronization of Lipoaspirates:
Squeeze and Emulsification Techniques. Plast
Reconstr Surg 139:79-90, 2017
2. Yano T, Okazaki M, Tanaka K, Tsunoda A,
Aoyagi M, Kishimoto S. ""Indication for and
Limitation of the Facial Dismasking Flap
Approach for Skull Base Surgery to Achieve theBest Esthetical and Functional Results"" Annalsof Plastic Surgery 78:49〜53, 2017
3. Maruyama Y,Inoue K, Mori K, Gorai K,
Shimamoto R, Onitsuka T, Iguchi H, Okazaki M,
Nakagawa M. Neutrophil-lymphocyte ratio andplateletlymphocyte ratio as predictors of woundhealing failure in head and neck reconstruction.
Acta Oto-Laryngologica 137:106〜110, 2017
4. Kanayama K, Mineda K, Mashiko T, Wu SH,
Feng J, Kinoshita K, Sunaga A, Yoshimura K.
Blood Congestion Can Be Rescued by Hemodilution in a Random-Pattern Skin Flap. Plast

Reconstr Surg 139:365-374, 2017
5. Song D, Pafitanis G, Pont LEP, Yang P, Koshima I,
Zhang Y, Iida T, Zhou X, Li Z. Chimericthoracoacromial artery perforator flap for onestaged reconstruction of complex pharynxgoesophageal defects: A single unit experience.
Head Neck 40:302-311, 2017
6. Usami S, Okazaki M. Fingertip reconstruction
with a posterior interosseous artery perforator
flap:a minimally invasive procedure for donor andrecipient sites. Journal of Plastic, Reconstructive& Aesthetic Surgery 70:166〜172, 2017
7. Tashiro K, Yamashita S. Superficial Circumflex
Iliac Artery Perforator Flap for Dorsalis Pedis
Reconstruction Plast Reconstr Surg Glob Open20;5:e1308, 2017
8. Gorai K, Inoue K, Saegusa N, Shimamoto R,
Takeishi M, Okazaki M, Nakagawa M. Predictionof Skin Necrosis after Mastectomy for Breast
Cancer Using Indocyanine Green Angiography
Imaging. Plast Reconstr Surg Glob Open 21;
e1321, 2017
9. Sunaga A, Kamochi H, Sarukawa S, Uda H,
Sugawara Y, Asahi R, Chi D, Nakagawa S,
Kanayama K, Yoshimura K. Reconstitution of
Human Keloids in Mouse Skin. Plast Reconstr
Surg Glob Open 25;5:e1304, 2017
10. Feng J, Mineda K, Wu SH, Mashiko T, Doi K,
Kuno S, Kinoshita K, Kanayama K, Asahi R,
Sunaga A, Yoshimura K. An injectable non-crosslinked hyaluronic-acid gel containing therapeutic
spheroids of human adipose-derived stem cells.
Sci Rep 8;7:1548, 2017
11. Mashiko T, Oka A, Osawa E, Koshima I. A
Deceptively Simple Solution for Refractory
Melasma: Glycolic Acid Peels and Hydroquinone
at Home. Plast Reconstr Surg Glob Open 19;5:e1335, 201712. Ishiura R, Yamamoto T, Saito T, Mito D, Iida T.
Comparison of Lymphovenous Shunt Methods ina Rat Model: Supermicrosurgical Lymphaticovenular Anastomosis versus Microsurgical Lymphaticovenous Implantation. Plast Reconstr Surg
139:1407-1413, 2017
13. Homma T, Okazaki M, Tanaka K, Uemura N.
Simultaneous Surgical Treatment for Smile
Dysfunction and Lagophthalmos Involving a Dual234

Latissimus Dorsi Flap. Plast Reconstr Surg GlobOpen 25;e1370, 2017
14. Mashiko T, Wu SH, Feng J, Kanayama K,
Yoshimura K. Reply: Mechanical Micronizationof Lipoaspirates: Squeeze and Emulsification
Techniques. Plast Reconstr Surg 139:1370e-1372e,
2017
15. Namiki T, Nojima K, Hanafusa T, Mori H,
Okazaki M, Miura K, Tanaka M, Yokozeki H. A
case of basal cell carcinoma with a neighbouring
melanocytic nevus: dermoscopic features. Eur J
Dermatol 27:441-442, 2017
16. Yoshimatsu H, Yamamoto T, Hayashi N, Kato M,
Iida T, Koshima I. Reconstruction of the ankle
complex wound with a fabricated superficial
circumflex iliac artery chimeric flap including thesartorius muscle: A case report. Microsurgery
37(5):421-425, 201717. Usami S, Okazaki M, Nitta T, Uemura N, Hommat, Akita K.Histological investigation of common
insensate flaps obtained from the hand andforeaem regions for use in fingertip reconstruction.
Journal of Plastic, Hand Surgery 51:182-186,
2017
18. Tomioka Y, Enomoto S, Gu J, Kaneko A, Saito I,
Inoue Y, Woo T, Koshima I, Yoshimura K,
Someya T, Sekino M. Multipoint Tissue
Circulation Monitoring with a Flexible Optical
Probe. Sci Rep 29;7:9643, 201719. Yoshimatsu H, Iida T, Hayashi A, Saito T. Free
Lateral Digital Flap for Reconstruction of theFingers.Ann Plast Sur 79:477-481, 2017
20. Kato M, Watanabe S, Kato R, Kawashima H, Iida
T, Watanabe A. Spontaneous Regression of
Lymphangiomas in a Single Center Over 34 Years.
Plast Reconstr Surg Glob Open 25;5:e1501, 2017
21. Tanaka K, Igari K, Kishino M, Usami S, Homma T,
Toyofuku T, Inoue Y, Okazaki M. The possibilityof free tissue transfer as a nutrient flap for criticalischemic foot: A case report. Microsurgery 37:
694-698, 201722. Iida T, Yoshimatsu H, Koshima I. Reconstructionof Anterolateral Thigh Defects Using PerforatorBased Propeller Flaps. Ann Plast Surg 79:385-389,
2017
23. Mashiko T, Wu SH, Feng J, Kanayama K,
Yoshimura K. Reply: Mechanical Micronizationof Lipoaspirates: Squeeze and Emulsification
Techniques. Plast Reconstr Surg 140:509e-510e,
2017
24. Kobayashi H, Iida T, Yamamoto T, Ikegami M,
Shinoda Y, Tanaka S, Kawano H. Lymphaticovenous Anastomoses for Lymphedema Complicated by Severe Lymphorrhea Following
Resection of Soft-Tissue Sarcomas of the
Adductor Compartment: A Report of Two Cases.
JBJS Case Connect 7:e80, 2017
25. Tomioka YK, Uda H, Yoshimura K, Sunaga A,
Kamochi H, Sugawara Y. Studying the bloodpressures of antegrade and retrograde internal
mammary vessels: Do theyreally work as
recipient vessels? J Plast Reconstr Aesthet Surg
70:1391-1396, 2017
26. Tashiro K, Yamashita S, Koshima I, Miyamoto S.
Visualization of Accessory Lymphatic Pathways
in Secondary Upper Extremity Lymphedema
Using Indocyanine Green Lymphography. Ann
Plast Surg 79:393-396, 2017
27. Karakawa R, Narushima M, Ogishima S, Hara H,
Karino S, Iida T, Kakigi A, Koshima I. Free
anterolateral thigh full-thickness skin flap with
vascularized lateral femoral cutaneous nerve forthe reconstruction of facial nerve and external
auditory canal after the resection of facial nerve
schwannoma. SAGE Open Med Case Rep 16;5:
2050313X17741825, 201728. Yoshimatsu H, Steinbacher J, Meng S, Hamscha
UM, Weninger WJ, Tinhofer IE, Yamamoto T,
Iida T, Tzou CJ. Feasibility of Bone Perfusion
Evaluation in Cadavers Using Indocyanine Green
Fluorescence Angiography. Plast Reconstr Surg
Glob Open. 20;5:e1570, 2017
29. Tashiro K, Yamashita S, Narushima M, Koshima I,
Miyamoto S. Hemi-Intravascular Stenting for
Supermicrosurgical Anastomosis. Plast Reconstr
Surg Glob Open 20;5:e1533, 2017
30. Kanayama K, Mashiko T, Asahi R, Sunaga A,
Yoshimura K. Reply: Blood Congestion Can Be
Rescued by Hemodilution in a Random-Pattern
Skin Flap. Plast Reconstr Surg 140:831e-832e,
2017

235

Department of Oral-Maxillofacial
Surgery
Professor
Tsuyoshi Takato, M.D., Ph.D.(untill June)

Kazuto Hoshi, M.D., Ph.D.(from January)

Associate Professor
Kazuto Hoshi, M.D., Ph.D.(untill December) Hideto Saijo, D.D.S., Ph.D.

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

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

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

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

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

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

Madoka Sugiyama, D.D.S.

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

Kosuke Kanke, D.D.S., Ph.D.

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

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

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

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 in researchworks especially in bone, cartilage and vessels.
Professor Takato had established Tissue Engineering
Division in the University of Tokyo Hospital and ourdepartment has an endowment department: Department of Cartilage and Bone Regeneration (FUJI SOFT
Inc.). The department has 1 associate professor, 1assistant professor, and several graduate students.
These staffs are focusing on translational researchworks in maxillofacial regions.

Clinical activities
In the outpatient clinic, we have 12 dental treatment
booths, one operation room and one speech therapy
room. Average number of patients treated at outpatient
clinic is approximately 100 per day.
Our department has two sections mainly; one is oral

236

and maxillofacial surgery and another is dental andorthodontic dentistry.
In outward dispensary, oral surgery section performs
dental surgeries such as extraction of impacted teeth,
amputation of infected dental root and gingivoplasty
in the operation room. Patients who had been performed surgical treatment are also followed up after
release from the hospital.
Dentistry and orthodontic dentistry performs facial
growth control and tooth movements for patients withcongenital orofacial anomalies such as cleft lip andpalate, jaw deformities and other congenital
defor¬mities. Speech therapy for the patients withcleft lip and palate is also performed by speechtherapists in our department.
Special section for patients of congenital deformities
is on Monday afternoon examined by plastic surgeon,oral and maxillofacial surgeons, orthodontists.
In the ward, we have approximately 400 new
inpatients and surgical treatment is performed on
approximately 300 cases per year. The main surgicaltreatments are chiloplasty and 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 team approachthat consists of oral and maxillofacial surgeons,orthodontists and prosthodontists. In our department,
patients with congenital dento-facial deformity aretreated by utilizing several techniques such as
distraction technique, autologous bone graft technique,and the original artificial bone graft technique in
addition to orthognatic surgery. The original bone
graft is made from patient’s three dimensional imagesof CT data and this technique is now applied forpatients.

Education
Teaching activities are divided into two parts; forundergraduate medical students and for postgraduate
dental students. For undergraduate students, we make5 systematic lectures in their second year of
special¬ized course, and one lecture and one week
bedside learning in final year. Through thesecurriculums, we demonstrate the characteristics andtreatments of the diseases in oral-maxillofacial region.
Teaching is focused on following points; congenital
anomalies such as cleft lip and palate and branchialarch syndromes, dentofacial deformities caused bydevelopmental and acquired problems, surgicalresection and functional reconstruction of benign andmalignant tumors, temporomandibular joint disorders,
inflammation and maxillofacial trauma. Minimum
dental knowledge concerning jaw movement, toothpain, periodontal disease, malocclusion and dental
restorations are instructed.
For postgraduate dental students, we have two-yearresident course. This course aims to train for a wide
range of dental treatments and to learn about medical
cares. Various specialists instruct dental treatments forthem in outpatient clinic. Dental caries treatments,
periodontal cares and applications of dentures are
instructed. Tooth extractions and orthodontic
treat¬ment are instructed by oral surgeons andorthodontists. Medical cares in the ward are taught by
medical doctors and oral surgeons.
After two-year residential course, research training at
postgraduate school is positively recommended. Ouraim for education of clinician is to raise up specialists
mastered both clinic and research skills.

Research
Our research project consists of clinic and basic
sections. Each research themes are closely related on
the aim of clinical improvement.
The main projects are as follows.
Clinical research:
1) Treatment of facial deformities in patients withcleft lip/palate and/or congenital anomaly2) Treatment of jaw deformity, oral and maxillofacial
traumas and temporomandibular disorders
3) Treatment of head and neck cancer
4) Distraction osteogenesis of maxillofacial skeleton
using distractor
5) Treatment of facial deformities in patients withcleft lip/palate
6) Clinical study for safety and efficacy oftransplantation of implant-type tissue-engineered
cartilage for cleft lip-nose patients
7) Speech disorder in patients with cleft lip/palate

2378) Growth and development in patients withcranio-maxillofacial anomaly9) Evaluation of treatment in patients with cleft
lip/palate
10) Surgery, chemotherapy and radiotherapy for headand neck cancer11) Orthognathic surgery in patients with jaw
deformity12) Computer assisted surgery using computer vision
and augmented reality
13) Evaluation of treatment in temporomandibular
disorder patients
14) Repair and occlusal reconstruction by regenerated
bone in oral and maxillofacial area
Basic and experimental research:
1) Regeneration of bone and cartilage in oral andmaxillofacial area by regenerative medicine
2) Basic research for producing implant-type
tissue-engineered cartilage using human cells
3) Cartilage regenerative research using iPS cells4) Role of cell cycle-related molecules in control
mechanism of osteochondral cell differentiation
5) Role of transcription factors in pluripotency ofmesenchymal cells6) Bone and cartilage regeneration using bonemarrow mesenchymal stem cells7) Epigenetic abnormalities of oral cancers andpremalignant lesions8) A study on the involvement of tumor associatedmacrophages in immunosuppression mechanismof oral squamous cell carcinoma

Publication(Original articles，Case reports)
1. Fujihara Y, Hikita A, Takato T, Hoshi K. Roles ofmacrophage migration inhibitory factor in
cartilage tissue engineering. J Cell Physiol. 2018
Feb;233(2):1490-1499.
2. Komura M, Komura H, Komuro H, Ikebukuro K,
Hikita A, Hoshi K, Takato T. Tracheal cartilage
growth by intratracheal injection of basic
fibroblast growth factor. J Pediatr Surg. 2017 Feb;
52(2):235-238.
3. Zong L, Wu A, Wang W, Deng J, Aikou S,
Yamashita H, Maeda M, Abe M, Yu D, Jiang Z,

Seto Y, Ji J. Feasibility of laparoscopic
gastrectomy for elderly gastric cancer patients:
meta-analysis of non-randomised controlled
studies. Oncotarget. 2017 Mar 29;8(31):5187851887.
4. Watanabe S, Ogasawara T, Tamura Y, Saito T,
Ikeda T, Suzuki N, Shimosawa T, Shibata S,
Chung UI, Nangaku M, Uchida S. Targeting gene
expression to specific cells of kidney tubules invivo, using adenoviral promoter fragments. PLoS
One. 2017 Mar 2;12(3):e0168638.
5. Yamauchi M, Moriyama M, Hayashida JN,
Maehara T, Ishiguro N, Kubota K, Furukawa S,
Ohta M, Sakamoto M, Tanaka A, Nakamura S.
Myeloid dendritic cells stimulated by thymic
stromal lymphopoietin promote Th2 immune
responses and the pathogenesis of oral lichen
planus. PLos One. 2017 Mar;12(3):e0173017.
6. Abe M, Hoshi K, Shojima M, Ushiku T, Suenaga
H, Yonenaga K, Kobayashi K, Zong L, Abe T,
Takato T. A large pyogenic granuloma withextensive maxillary bone resorption penetrating
the maxillary sinus: a rare case report. J Oral
Maxillofac Surg Med Pathol. 2017 May;29(3):254-257.
7. Zujur D, Kanke K, Lichtler AC, Hojo H, Chung
UI, Ohba S. Three-dimensional system enabling
the maintenance and directed differentiation ofpluripotent stem cells under defined conditions.
Sci Adv. 2017 May 12;3(5): e1602875.
8. Kubota K, Moriyama M, Furukawa S, Rafiul
HASM, Maruse Y, Jinno T, Tanaka A, Ohta M,
Ishiguro N, Yamauchi M, Sakamoto M, Maehara
T, Hayashida JN, Kawano S, Kiyoshima T, Seiji
Nakamura S. CD163+CD204+ tumor-associatedmacrophages contribute to T cell regulation via
interleukin-10 and PD-L1 production in oral
squamous cell carcinoma. Sci Rep. 2017 May;
7(1):1775.
9. Wang J, Suenaga H, Yang L, Kobayashi E,
Sakuma I. Video see-through augmented reality
for oral and maxillofacial surgery. Int J Med
Robotics Comput Assist Surg. 2017 Jun;13(2):e1754
10. Hikita A, Chung UI, Hoshi K, Takato T. Boneregenerative medicine in oral and maxillofacial

238

region using a three-dimensional printer. Tissue
Eng Part A. 2017 Jun;23(11-12):515-521.
11. Yonenaga K, Nishizawa S, Nakagawa T, Fujihara
Y, Asawa Y, Hikita A, Takato T, Hoshi K.
Protocol for collagenase digestion of articularcartilage based on differences in the biologicalcharacteristics of articular and auricular cartilage.
Regenerative Therapy. 2017 Jun;6:9-14.
12. Horie N, Hikita A, Nishizawa S, Uto S, Takato T,
Hoshi K. Impairment of the transition fromproliferative stage to prehypertrophic stage inchondrogenic differentiation of human induced
pluripotent stem cells harboring the causative
mutation of achondroplasia in fibroblast growth
factor receptor 3. Regenerative Therapy. 2017
Jun;6:15-20.
13. Ishibashi M, Hikita A, Fujihara Y, Takato T,
Hoshi K. Human auricular chondrocytes with highproliferation rate show high production of
cartilage matrix. Regenerative Therapy. 2017 Jun;
6:21-28.
14. Hoshi K, Fujihara Y, Saijo H, Asawa Y,
Nishizawa S, Kanazawa S, Uto S, Inaki R,
Matsuyama M, Sakamoto T, Watanabe M,
Sugiyama M, Yonenaga K, Hikita A, Takato T.
Implant-type tissue-engineered cartilage forsecondary correction of cleft lip-nose patients: an
exploratory first-in-human trial. J Clin Trials.
2017;7(3):1000315.
15. Abe M, Abe T, Mogi R, Kamimoto H, Hatano N,
Taniguchi A, Saijo H, Hoshi K, Takato T. A caseof cervical necrotizing fasciitis of odontogenic
origin in a healthy young patient without presystemic disorders. J Oral Maxillofac Surg Med
Pathol. 2017 July;29(4):341-344.
16. Inagaki Y, Abe M, Inaki R, Zong L, Suenaga H,
Abe T, Hoshi K. A case of systemic infection
caused by streptococcus pyogenes oral infection
in an edentulous patient. Diseases. 2017 Aug;5(3):E17.
17. Zhou Y, Hu W, Chen P, Abe M, Shi L, Song S,
Tan S, Li Y, Zong L. Ki67 is a biological marker
of malignant risk of gastrointestinal stromal
Ttmors: a systemic review and meta-analysis.
Medicine, 2017 Aug;96(34):e7911.
18. Inaki R, Abe M, Zong L, Abe T, ShinozakiUshiku A, Ushiku T, Hoshi K. Secretory

carcinoma - impact of translocation and genefusions on salivary gland tumor. Chin J Cancer
Res. 2017 Oct;29(5):379-384.
19. Komatsu N, Mitsui K, Kusano-Arai O, Iwanari H,
Hoshi K, Takato T, Abe T, Hamakubo T.
Enhancementofanti-robo1
immunotoxin
cytotoxicity to head and neck squamous cell
carcinoma via photochemical internalization.
Arch Can Res. 2017 Oct;5(4): 157
20. Kanazawa S, Nishizawa S, Takato T, Hoshi K.
Biological roles of glial fibrillary acidic protein asa biomarker in cartilage regenerative medicine. J
Cell Physiol. 2017 Nov;232(11):3182-3193.
21. Harata M, Watanabe M, Nagata S, Ko EC, Ohba S,
Takato T, Hikita A, Hoshi K Improving
chondrocyte harvests with poly (2-hydroxyethyl
methacrylate) coated materials in the preparation
for cartilage tissue engineering. Regenerative
Therapy. 2017 Dec;7:61-71.
22. Hoshi K, Fujihara Y, Saijo H, Kurabayashi K,
Suenaga H, Asawa Y, Nishizawa S,
Kanazawa
S, Uto S, Inaki R, Matsuyama M, Sakamoto T,
Watanabe M, Sugiyama M, Yonenaga K, Hikita A,
Takato T. Three-dimensional changes of noses
after transplantation of implant-type tissueengineered cartilage for secondary correction ofcleft lip-nose patients. Regenerative Therapy.
2017 Dec;7:72-79.
23. Kanke K, Abe T, Abe M, Mori Y, Hoshi K,
Takato T. In-hospital surgical treatment forhaemorrhage after aesthetic mandibular osteotomy
performed as an office-based day surgery: A casereport. Ann Med Surg. 2017 Dec 13;24:15-18.
24. Wang G, Guo S, Xiao H, Zong L, Aaakawa T,
Abe M, Hu W, Ji J. Remarkably different results
between two studies from North America on
genomic mutations and sensitivity to DNA
demethylating agents for myelodysplastic
syndromes. Chin J Cancer Res. 2017 Dec;29(6):587-588.
(Patents)
1. Wang J, Suenaga H, Sakuma I, Kobayashi E,
Hoshi K: Surgical navigation system, surgicalnavigation method, and program. (Patent
Publication No. WO/2017/057175, International
Application No. PCT/JP2016/077979)

239

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

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

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

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

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

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

Associates
Hiroshi Inui, M.D.

Yutaka Morizaki, M.D.

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

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

Takeyuki Tanaka, M.D.

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

Yoshitaka Matsubayashi, M.D.

Ryota Yamagami, M.D.

Kensuke Kawabata, M.D.

Yusuke Sato, M.D.

Kohei Kawaguchi, M.D.

Ryo Hidaka, M.D.

Hiroyuki Hasebe, M.D.

Ken Nishimura, M.D.

Toshihide Hirai, M.D.

Homepage

http://www.u-tokyo-ortho.jp/

Introduction and Organization
In 1906 our department was established as the firsteducational institute of orthopedic surgery in Japan,
by the first professor Yoshinori Tashiro who hadlearned orthopedic surgery in Germany and Austria.
Initially, the department treated patients with
infectious disorders and congenital malformations,such as poliomyelitis, tuberculosis of the spine,congenital clubfoot and hip dislocation. The numberof outpatients visiting our department in 1910 was
estimated to be no more than 3.3% of that of the twosurgical departments in the University of Tokyo
Hospital.
The number and characteristics of the patients,

however, have changed dramatically in these 100
years. This is because our department addressed theacute needs of society from the beginning. Prof.
Tashiro believed that trauma should be treated byorthopedists, so he provided his pupils with thistraining. Since 1950’s, the department has increasingly been involved in the treatment of traffic andindustrial accident victims. Prof. Tashiro and his
successor professor Kenji Takagi devoted themselvesto the establishment of an institute for children withdisabilities. The arthroscopy was developed by Prof.
Takagi, and is now considered to represent a breakthrough in the development of minimally invasive
surgery. We have recently been conducting manystudies related to the ossification of spinal ligaments

240(OPLL), rheumatoid arthritis, biomechanics, and thedegenerative skeletal disorders such as osteoporosis
and osteoarthritis in response to the progressive agingof our society.
Our department is now adept in the entire field of
medical science and medical practice related to thehuman locomotor system, the importance of which is
now clearly recognized not only in Japan, but also all
over the world. To meet the expanding needs ofsociety, we have been conducting the teaching,clinical, and research activities described below.
Faculty members of the department are one
professor, one associate professors, 4 lecturers, 15
associates, 9 medical staff members, 8 senior residents,
and 11 part-time teachers.

Teaching activities
As for undergraduate education, our department
provides a comprehensive series of lectures, physicalassessment classes and problem-based learning (PBL)
program to 4th year medical students, clinicalclerkship programs to 5th year students and elective
clinical clerkship programs to 6th year medical
students.
A comprehensive series of lectures provides basic
knowledge of the physiology, pathology, diagnosis
and treatment of various musculoskeletal disorders.
Twelve consecutive lectures in total cover a whole
field of orthopaedics: basic science, pediatricdisorders, rheumatic diseases, metabolic bone diseases,
musculoskeletal neoplasm, trauma and regional
disorders of the musculoskeletal system (spine,
shoulder, elbow, hand, hip, knee, ankle and foot). In
the physical assessment classes, we have provided
physical diagnostic maneuvers and the radiologicalassessment of a variety of musculoskeletal diseases.
PBL has been introduced to a small group of students
to learn medical humanity and to develop a practicalmethodology to resolve clinical problems.
During the 3-week period of clinical clerkshipprogram, students have opportunities to join one ofclinical teams and experience patient care andorthopaedic practice with residents and faculty
members. We have developed an original text for the
students to learn on-site orthopedics effectively. They
are encouraged to participate in clinical conferences

and surgeries. They are also required to submit
reports on the cases they are involved in. They learn
how to conduct a medical interview, check physicalfindings and draw up actual plans for a diagnosis andtreatment including surgery.
Elective clinical clerkship provides 4 weeks ofmore intensive exposure to the clinical practice. The
students are attached to a clinical team and are
involved in most of the clinical activities performedby the team.
For postgraduate education, junior residents join
our department for 1-8 months. In 8 doctors-intraining completed our program during this fiscal year.
Since the training period is short, they are encouraged
to experience emergency cases as often as possible tolearn primary care. For senior residents, 1-year
clinical programs were conducted in coorporation with
our affiliated hospitals. A postgraduate seminar and abasic research conference are held weekly.
Including the postgraduate training, an eight-year
course has been adopted with clinical and researchtraining taking place either in the University of Tokyo
Hospital or in our 40 affiliated hospitals.

Clinical activities
We have the outpatient clinic open from Monday
through Friday, with specialized divisions for spine,
hip, rheumatoid arthritis, tumor, scoliosis, limb
reconstruction and bone lengthening, knee, hand,elbow, shoulder, sports, peripheral nerves, bonesystemic disorders, and foot. A total of 36,018 patients
visited the outpatient clinic in fiscal 2016.
The ward has approximately 60 to 70 beds available
and is divided into the subgroups above. The members
are on duty for daily patient care under the supervisionof faculty members. The weekly official activities ofour department include ward rounds by the professoron Thursday. Post- and preoperative case conferences
are held on Monday evening, Wednesday evening andThursday morning.
1,382 operations were performed in fiscal 2016.
These include 338 spine surgeries, 118 surgeries forrheumatoid arthritis patients, 134 hip surgeries, 276
knee surgeries (including 46 computer-assisted ACL
reconstructions, 107 computer-assisted TKA, 29
UKA), 228 hand surgeries, 62 foot and ankle surgeries,

241

43 pediatric surgeries, 111 surgeries for bone and soft
tissue tumor, and 183 trauma surgeries.
The main disorders of cervical spine surgery weremyelopathy due to spondylosis or OPLL. We
successfully adopted double-door open laminoplasty
by splitting the spinal processes for most of thesecases. This procedure was invented and developed inour department and is now used nationwide. Difficult
operations such as subluxation of the cervical spine
due to rheumatoid arthritis, Down’s syndrome or
cerebral palsy were treated using a navigation systemthat has been officially approved as a high-leveladvanced medical treatment.
The spine group is now converting open surgeries
to minimum invasive surgeries using endoscopic
technique.
The scoliosis group used the navigation systemespecially for patients with complex deformity. In
addition to the conventional correction surgery,
growth-assist techniques such as dual growing rods
are utilized.
Main operations performed by the rheumatoid
arthritis clinic group were total joint arthroplasty.
They are using image-free navigation system in total
knee arthroplasty operation, which is useful for theaccurate placement of the implants.
The hip surgery group treated mainly acetabular
dysplasia and osteoarthritis of the hip joint. They
performed not only total hip replacements, but also
several osteotomies including rotational acetabularosteotomy (RAO). The RAO was originated andestablished in our department. They conducted aclinical trial for a new artificial hip joint using the
MPC polymer in collaboration with the Department ofMaterials Engineering in Tokyo University.
The knee clinic group developed a new anterior
cruciate ligament reconstruction technique using thenavigation system based on intraoperative threedimensional fluoroscopic image to realize ideal graft
placement.
The peripheral nerve clinic group has developed"costal nerve transfer to the musculocutaneous nerve"
for brachial plexus injury.
The tumor group managed multidisciplinary treatment for musculoskeletal sarcoma including chemotherapy, limb sparing surgery and radiotherapy incoorporation with other departments.

Limb reconstruction operations using external
fixators included non-union, leg lengthening anddeformity correction. One of the main interests of thisgroup is the development of a system to analyze themechanical properties of a skeletal system. During
this period of analysis, the mechanical properties ofthe fracture site in vivo are to be evaluated bymonitoring the motion of a dynamic pin clamp during
simulated walking.

Research activities
Our research activities cover the full range of themusculoskeletal system medicine, using the in-depthsciences of biology and technology. Especially in thefield of molecular biology of bone and cartilage
metabolism, we are regarded as being on the leadingedge in the world. Basic research is performed under
the supervision of the faculty staff members. Four
endowment departments take an active role inresearch activities in close collaboration with ourdepartment. They deal with regenerative medicine,clinical research, and material engineering.
As for research of bone resorption, we have been
researching and released some important reports aboutbone metabolism, especially in differentiation,
activation and apoptosis of osteoclast. Recently wehave been getting achievement in the new research
topics such as “Osteoimmunology”, a new research
field studying on signaling cross-talk between bonemetabolism and immunology, or “Epigenetics”, newresearch concept in spotlight using comprehensive
analysis technique.
As for research of cartilage, we have researchedmolecular biology of cartilage with the students of thegraduate school and the members of Bone andCartilage Regenerative Medicine, Division of Tissue
Engineering. Our research activities cover thegeneration and differentiation of chondrocytes, thejoint formation, the degeneration of joint cartilage,
and the regenerative methods.
Our clinical groups also take part in many
multicenter clinical studies conducted by Japan
Musculoskeletal Oncology Group (JMOG), National
Database of Rheumatic Diseases by iR-net in Japan(NinJa), and other multicenter groups.

242

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25. Watanabe K, Moro T, Kyomoto M, Saiga K,
Taketomi S, Kadono Y, Takatori Y, Tanaka S,
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Chikuda H, Tanaka S, Takeshita K, Matsudaira K:
Prognostic factors associated with the surgicalindication for lumbar spinal stenosis patients lessresponsive to conservative treatments: An
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33. Watanabe H, Nagase Y, Tamai K, Tanaka S:
Pulmonary embolism associated with upper
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Epub ahead of print
34. Matsudaira K, Oka H, Kikuchi N, Haga Y,
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35. Akiyama T, Uehara K, Ogura K, Shinoda Y, Iwata
S, Saita K, Tanzawa Y, Nakatani F, Yonemoto T,
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adaptation and validation of the Japanese versionof the Toronto Extremity Salvage Score (TESS)
for patients with malignant musculoskeletal
tumors in the upper extremities. J Orthop Sci 2017,22(1):127-132
36. Ogura K, Higashi T, Kawai A: Statistics of bonesarcoma in Japan: Report from the Bone and Soft
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38. Oka H, Matsudaira K, Fujii T, Kikuchi N, Haga Y,
Sawada T, Katsuhira J, Yoshimoto T, Kawamata K,
Tonosu J, Sumitani M, Kasahara S, Tanaka S:
Estimated risk for chronic pain determined using
the generic STarT Back 5-item screening tool. J
Pain Res 2017,10:461-467
39. Nakashima H, Tetreault L, Kato S, Kryshtalskyj
MT, Nagoshi N, Nouri A, Singh A, Fehlings MG:
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Ligament: A Systematic Review. JBJS Rev 2017,
5(2):e540. Tsuda Y, Ogura K, Kobayashi E, Hiruma T, Iwata
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Morioka H, Kobayashi H, Kawano H: Impact ofgeriatric factors on surgical and prognostic
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41. Yamagami R, Taketomi S, Inui H, Tahara K,
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among patients with rheumatoid arthritis. Mod
Rheumatol 2017,27(5):828-832
43. Kawabata K, Ito K, Juji T, Takatori Y, Tanaka S,
Nakamura I: Pseudotumour Occurring after ametal-on-metal total hip arthroplasty that wasdiagnosed based on venous congestion in
unilateral leg: a case report. Mod Rheumatol Case
Report 2017,1(2):68-72
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management of pediatric thoracolumbar fractures.
Neurol India 2017,65(3) :477-479
45. Inoue R, Sumitani M, Ogata T, Chikuda H,
Matsubara T, Kato S, Shimojo N, Uchida K,
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48. Teraguchi M, Yoshimura N, Hashizume H,
Yamada H, Oka H, Minamide A, Nagata K,
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245

population-based cohort: the Wakayama Spine
Study. Osteoarthritis Cartilage 2017,25(7):11221131
49. Yoshimura N, Muraki S, Oka H, Iidaka T,
Kodama R, Kawaguchi H, Nakamura K, Tanaka S,
Akune T: Is osteoporosis a predictor for futuresarcopenia or vice versa? Four-year observations
between the second and third ROAD study
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50. Kawata M, Taniguchi Y, Mori D, Yano F, Ohba S,
Chung UI, Shimogori T, Mills AA, Tanaka S,
Saito T : Different regulation of limb developmentby p63 transcript variants. PLoS One 2017,12(3):e0174122
51. Nakamura S, Koyama T, Izawa N, Nomura S,
Fujita T, Omata Y, Minami T, Matsumoto M,
Nakamura M, Fujita-Jimbo E, Momoi T,
Miyamoto T, Aburatani H, Tanaka S: Negative
feedback loop of bone resorption by NFATc1dependent induction of Cadm1. PLoS One 2017,12(4):e0175632
52. Yoshimoto T, Oka H, Katsuhira J, Fujii T, Masuda
K, Tanaka S, Matsudaira K: Prognostic psychosocial factors for disabling low back pain in
Japanese hospital workers. PLoS One 2017,12(5):e0177908
53. Asai Y, Tsutsui S, Oka H, Yoshimura N,
Hashizume H, Yamada H, Akune T, Muraki S,
Matsudaira K, Kawaguchi H, Nakamura K,
Tanaka S, Yoshida M: Sagittal spino-pelvicalignment in adults: The Wakayama Spine Study.
PLoS One 2017,12(6):e0178697
54. Watanabe S, Ogasawara T, Tamura Y, Saito T,
Ikeda T, Suzuki N, Shimosawa T, Shibata S,
Chung UI, Nangaku M, Uchida S: Targeting gene
expression to specific cells of kidney tubules invivo, using adenoviral promoter fragments.PLoS
One 2017,12(3):e0168638
55. Watanabe S, Ogasawara T, Tamura Y, Saito T,
Ikeda T, Suzuki N, Shimosawa T, Shibata S,
Chung UI, Nangaku M, Uchida S: Targeting gene
expression to specific cells of kidney tubules invivo, using adenoviral promoter fragments.PLoS
One 2017,12(3):e0168638
56. Ryu Y, Ogata T, Nagao M, Kitamura T, Morioka
K, Ichihara Y, Doi T, Sawada Y, Akai M,
Nishimura R, Fujita N: The swimming test iseffective for evaluating spasticity after contusive
spinal cord injury. PLoS One 2017,12(2):e0171937
57. Tanaka Y, Oka H, Nakayama S, Ueno T,
Matsudaira K, Miura T, Tanaka K, Tanaka S:
Improvement of walking ability during postoperative rehabilitation with the hybrid assistive
limb after total knee arthroplasty: A randomized
controlled study. SAGE Open Med 2017,5:1-6
58. Hasegawa S, Kanda S, Imada H, Yamaguchi T,
Akiyama T: Melorheostosis with recurrent
soft-tissue components: a histologically confirmed
case. Skeletal Radiol 2017,46(3):399-404
59. Ohya J, Chikuda H, Takeshi O, Kato S, Matsui H,
Horiguchi H, Tanaka S, Yasunaga H: Seasonal
Variations in the Risk of Reoperation for SurgicalSite Infection Following Elective Spinal Fusion
Surgery: A Retrospective Study Using theJapanese Diagnosis Procedure Combination Database. Spine (Phila Pa 1976) 2017,42(14):10681079
60. Kato S, Nouri A, Wu D, Nori S, Tetreault L,
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Nakashima H, Nagoshi N, Reihani-Kermani H,
Fehlings MG: MRI Analysis of the Combined
Prospectively Collected AOSpine North America
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62. Nouri A, Martin AR, Kato S, Reihani-Kermani H,
Riehm LE, Fehlings MG: The Relationship
Between MRI Signal Intensity Changes, Clinical
Presentation, and Surgical Outcome in Degenerative Cervical Myelopathy: Analysis of a Global
Cohort. Spine (Phila Pa 1976) 2017,42(24):18511858
63. Ishimoto Y, Yoshimura N, Muraki S, Yamada H,
Nagata K, Hashizume H, Takiguchi N, Minamide
A, Oka H, Tanaka S, Kawaguchi H, Nakamura K,

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Akune T, Yoshida M: Association of Lumbar
Spondylolisthesis With Low Back Pain and
Symptomatic Lumbar Spinal Stenosis in a
Population-based Cohort: The Wakayama Spine
Study. Spine (Phila Pa 1976) 2017, 42(11):E666E671
64. Lewis SJ, Keshen SG, Kato S, Gazendam AM:
Posterior Versus Three-Column Osteotomy for
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Scoliosis. Spine Deformity 2017,5(3):189-196
65. Matsubayashi Y, Chikuda H, Oshima Y, Taniguchi
Y, Fujimoto Y, Shimizu T, Tanaka S: C7 sagittal
vertical axis is the determinant of the C5-C7 angle
in cervical sagittal alignment. Spine J 2017,17:622-626
66. Oichi T, Chikuda H, Ohya J, Ohtomo R, Morita K,
Matsui H, Fushimi K, Tanaka S, Yasunaga H:
Mortality and morbidity after spinal surgery inpatients with Parkinson's disease: a retrospective
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67. Nouri A, Martin AR, Nater A, Witiw CD, Kato S,
Tetreault L, Reihani-Kermani H, Santaguida C,
Fehlings MG: The Influence of MRI Features on
Surgical-Decision Making in Degenerative
Cervical Myelopathy: Results From a Global
Survey of AOSpine International Members. World
Neurosurg 2017,105:864-874
68. Kobayashi H, Ito N, Akiyama T, Okuma T,
Kinoshita Y, Ikegami M, Shinoda Y, Fukumoto S,
Tanaka S, Kawano H: Prevalence and clinicaloutcomes of hip fractures and subchondral
insufficiency fractures of the femoral head inpatients with tumour-induced osteomalacia. Int
Orthop. 2017 Dec;41(12):2597-2603.

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

Associate Professor
Satoshi Kato, M.D., Ph.D., Toshikatsu Kaburaki, M.D., Ph.D., Tomohiko Usui, M.D., Ph.D.

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

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

Homepage

http://www.todaiganka.jp/

Introduction and Organization
The Department of Ophthalmology, University ofTokyo School of Medicine, was founded in 1989.
Since then, the department has contributed to Japanese
ophthalmology not only by educating a large numberof eminent ophthalmologists in Japan, but also byproducing significant basic research in ophthalmology.
The department has been active in collaboration with
ophthalmologists around the world, sponsoring
international ophthalmological meetings, educating
fellows from foreign countries and sending our staff
and fellows abroad.

Clinical activities
Altogether, approximately 3000 new outpatients areseen every year in our hospital, which has a total of 32
beds. Residents work in the ambulatory section andtake care of inpatients. Special services are provided
in units devoted to ophthalmic subspecialties such as
cornea, glaucoma, retina, uveitis, neuro-ophthal-mology, orthoptics, diabetic retinopathy, and genetic
and color blindness problems. The staff members
supervise the ambulatory and special services
depending on each one’s specialty.
Most of the inpatients suffer from cataract, glaucoma,
corneal diseases, retinal detachment, diabetic
retinopathy, uveitis and strabismus. Surgeries are
performed in the operating theater of the hospital
under operating microscopes. Approximately 2100
cases underwent operations in our department.
Surgeries can be monitored by TV system, which ismounted on operating microscopes. Since multiple
observers can watch the same images and sharefindings, this system has a great potential in training
and promoting discussion.

Education
As an undergraduate course, we give lectures on
corneal physiology, corneal diseases, and corneal
transplantation. In addition, we are engaged in248

practical training for medical students on ophthalmological examinations at the outpatient clinic. As apostgraduate course, we give lectures on topics
concerning corneal transplantation, corneal diseases
and new medical therapies.

ResearchResearch topics in our department cover a variety offields in ophthalmology; e.g. ocular pharmacology inglaucoma, lipid mediators in ocular diseases,
regenerative medicine in the cornea and retina,
aqueous humour dynamics, immunology andmolecular biology. Special laboratories for physiology,
pharmacology and genetic engineering have been
established. Specific fields of research in our
department are as follows.
1. Lipid mediators in ocular diseases
2. Clinical investigation of normal tension
glaucoma
3. Drug development in IOP reduction of glaucoma
4. Screening method of glaucoma
5. Pathophysiology and molecular mechanisms of
diabetic retinopathy
6. Relationship between visual function and qualityof life in patient with low vision
7. Investigation of molecular mechanisms of retinal
arteritis and phlebitis
8. Investigation of gene mutations in primary
vitreoretinal lymphoma and development of newtreatment
9. Study of mechanisms involving disease-specific
HLA in Behcet's disease
10. Analysis of structure-function relationships inmacular diseases
11. Molecular analysis of corneal neovascularization
12. Gene therapy for corneal dystrophies
13. Analysis of Meibomian gland with Mibography
14. Analysis of safety of topical eye drops using
human corneal epithelial cell sheets
15. Clinical trial of corneal crosslinking for
keratoconus and keratoectasia
16. Ophthalmic examination of patients withcongenital insensitivity to pain with anhydrosis
17. Assessment of higher visual functions by fMRI
18. Relevance between ophthalmic diseases andcortical functions

Publications
1. Adachi S, Yuki K, Awano-Tanabe S, Ono T,
Murata H, Asaoka R, et al. Factors associated withthe occurrence of a fall in subjects with primary
open-angle glaucoma. BMC Ophthalmol. 2017;17:213.
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Am J Ophthalmol Case Rep. 2017;8:14-7.
5. Aoki S, Murata H, Fujino Y, Matsuura M, Miki A,
Tanito M, et al. Investigating the usefulness of acluster-based trend analysis to detect visual field
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10. Asaoka R, Murata H, Yanagisawa M, Fujino Y,
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11. Azuma K, Ueta T, Eguchi S, Aihara M. Effects ofinternal limiting membrane peeling combinedwith removal of idiopathic epiretinal membrane: asystematic review of literature and meta-analysis.
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12. Fujino Y, Murata H, Mayama C, Matsuo H,
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13. Fukuoka S, Arita R, Shirakawa R, Morishige N.
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14. Hirasawa K, Matsuura M, Murata H, Nakakura S,
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Department ofOtorhinolaryngology and Head& Neck Surgery
Professor
Tatsuya Yamasoba, M.D., Ph.D.

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

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

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

Shotaro Karino, M.D., Ph.D．

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

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

Naoya Egami, M.D., Ph.D.

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

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

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

Sayaka Suzuki, M.D., Ph.D.

Chisato Fujimoto, M.D, Ph.D.

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

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

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

Makoto Kinoshita, M.D., Ph.D.

Ken Akashi, M.D., Ph.D.

Osamu Fukuoka, M.D.

Takao Goto, M.D.

Yuya Shimizu, M.D.

Homepage

http://www.h.u-tokyo.ac.jp/orl /Introduction and Organization
The Department of Otorhinolaryngology was
founded in 1899 by Prof. Waichiro Okada who studiedin Germany. This is the first department ofotorhinolaryngology of the national university in Japan.
Our department covers all otorhinolaryngologicaldiseases and associated systemic diseases, and has
specialized clinics in middle ear and inner ear diseases,
hearing impaired infant and children, adult and elderly
patients, facial paresis, vertigo and balance disorders,olfactory disorders and paranasal diseases, voice andspeech disorders, taste and swallowing respiratory

disorders, aphasia, central auditory disorders and head& neck cancers.
A professor, associate professors, lecturers (assistantprofessors) and associates participate in surgery, outpatient and in-patient care as well as research andeducational activities. Moreover 12 Japanese graduate
students and one Chinese foreign graduate student
participate in basic research.
Weekly preoperative and postoperative conferences
are held to discuss surgical cases in detail. Special
lectures on leading research activities are presented byinvited guests on a regular basis. A weekly journal club252

is held to introduce current research papers.

Clinical activities
In the out-patient clinic, general and special services
are provided to approximately 150 out-patients on adaily basis in all areas of otorhinolaryngology andrelated specialties, and approximately 300 new patients
visit monthly.
In the new inpatient hospital, 33 beds are preparedfor patients under the supervision of lecturers andsenior residents from each subspecialty group
including head & neck surgery, middle ear surgery andcochlear implant surgery; voice and bronchoesophagological surgery, and paranasal surgery andother minor surgery. Preoperative and postoperative
problems are checked and discussed by each group, theprofessor’s and associate professor’s rounds.
Approximately 700 operations are performed annually.
Cochlear implant surgery over 400 cases has been
actively performed for infants, children and adultpatients with profound hearing loss and is very
successful to provide new hearing. Head and necksurgery is performed to extirpate malignant tumor withneighboring tissues and reconstruct upper respiratory
and swallowing functions at one stage operationcooperating with plastic surgeons. Reconstructive
surgery of microtia and atresia to reconstruct external
ear is routinely performed with plastic surgeons.
Auditory brainstem response is routinely examinedin order to diagnose peripheral and central deafness inneonates, infants and children.
Treatment of acoustic tumor using an ɤ-knife andauditory brainstem implant are performed inconsultation with neurosurgeons.

Teaching activities
For the fourth year medical students’ serial lecturesand for the fifth and sixth year medical students special
lectures on current topics are provided by the professor
and associate professor.
Clinical training is provided for the sixth year classof medical students on a one-to-one basis with staff
doctors. They are requested to write reports on aclinical case or a clinical problem. The students
participate to see surgery, special clinics and clinicalexaminations such as otoscope, fiberscope, pure-toneaudiometry, auditory brainstem response, and caloric
test. Interview with patient is encouraged. They arequestioned on many aspects of clinical problems inseminars by professor and associate professor.

Research activities
Clinical and basic research activities are highly
encouraged. Clinical research, which is supervised bysenior doctors, is very actively pursued even by young
residents. Case reports presentation and writing skills
are regarded as important experience in order todevelop young doctors’ research activity andinvestigate important findings in patients. The clinicalresearch is related to ear surgery, neurotology, audiology, head and neck surgery, bronchoesophagology andrhinology and is related to case research, clinical statistics and clinical electrophysiology. Basic research isalso encouraged to solve essence of clinical problems
and to elucidate basic phenomena or anatomical andcellular structures. Our research topics cover:1) Morphology and neurophysiology of the inner ear
focusing on sensory neural deafness: human
temporal bone pathology, electron microscopic
study in animal models, gene therapy, proteintransduction, and nanotechnology
2) Clinical application of otoacoustic emissions andauditory brainstem responses.
3) Histochemistry of olfactory epithelium in development and aging.
4) Clinical neurophysiology of the facial nerves
focusing on degeneration and regeneration inpatients.
5) Histochemistry of head and neck cancer pathology.
6) The central auditory cortex research using MEG.
7) Auditory brainstem response and speech andhearing after the new born hearing screening.
8) Pathology and electrophysiology of the larynx.
9) Vestibular research on the oculomotor and balancesystems in the brain.
10) Vestibular myogenic evoked potentials in cochlear
implant and inner ear anomaly.
11) Hair cell physiology in the vestibular end organ.
12) Newborn hearing screening and language development in deaf children.
13) Physiology bone conduction innovation of bone

253

conduction hearing and bilateral hearing.
14) Embryology of middle, inner ear and central
auditory system.
15) Therapeutic effects of growth factors on facial
nerve regeneration after injury16) Metabolic conversion of odorant molecules bynasal mucus
Various clinical and basic researches are conductedby staffs, residents, and graduate students as well as
doctors at affiliated hospitals.

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C, Iwasaki S, Shimizu T, Yamasoba T. Manganesesuperoxide dismutase influences the extent ofnoise-induced hearing loss in mice. Neurosci Lett
642; 123-128, 201743. Ueha R, Ueha S, Kondo K, Nito T, Fujimaki Y,
Nishijima H, Tsunoda K, Shand HW F,
Matsushima K, Yamasoba T. Laryngeal mucus
hypersecretion is exacerbated after smoking
cessation and ameliorated by glucocorticoid
administration. Toxicology letters 265: 140-146,
2017
44. Umeda-Kameyama Y, Ishii S, Kameyama M,
Kondo K, Ochi A, Yamasoba T, Ogawa S, Akishita
M. Heterogeneity of odorant identification

256

impairment in patients with Alzheimer's Disease.
Sci Rep 7: 4798, 201745. Umesawa M, Kobashi G, Kitoh R, Nishio SY,
Ogawa K, Hato N, Sone M, Fukuda S, Hara A,
Ikezono T, Ishikawa K, Iwasaki S, Kaga K,
Kakehata S, Matsubara A, Matsunaga T, Murata T,
Naito Y, Nakagawa T, Nishizaki K, Noguchi Y,
Sano H, Sato H, Suzuki M, Shojaku H, Takahashi
H, Takeda H, Tono T, Yamashita H, Yamasoba T,
Usami SI. Relationships among drinking andsmoking habits, history of diseases, body massindex and idiopathic sudden sensorineural hearing
loss in Japanese patients. Acta Otolaryngol 137:
S17-S23, 201746. Umezawa K, Yoshida M, Kamiya M, Yamasoba T,
Urano Y. Rational design of reversible fluorescentprobes for live-cell imaging and quantification of
fast glutathione dynamics. Nat Chem 9: 279-286,
2017
47. Yoshida T, Sone M, Kitoh R, Nishio SY, Ogawa K,
Kanzaki S, Hato N, Fukuda S, Hara A, Ikezono T,
Ishikawa K, Iwasaki S, Kaga K, Kakehata S,
Matsubara A, Matsunaga T, Murata T, Naito Y,
Nakagawa T, Nishizaki K, Noguchi Y, Sano H,
Sato H, Suzuki M, Shojaku H, Takahashi H,
Takeda H, Tono T, Yamashita H, Yamasoba T,
Usami SI.
Idiopathic sudden sensorineural
hearing loss and acute low-tone sensorineural
hearing loss: a comparison of the results of anationwide epidemiological survey in Japan. Acta
Otolaryngol 137: S38-S43, 2017
48. Yamauchi A, Yokonishi H, Imagawa H,
Sakakibara KI, Nito T, Tayama N, Yamasoba T.
Characterization of vocal fold vibration in sulcus
vocalis using high-speed digital imaging. J Speech
Lang Hear Res 60: 24-37, 2017

257

Department of
Rehabilitation Medicine
Professor
Nobuhiko Haga, M.D.

Homepage

http://todaireh.umin.ne.jp

Introduction and Organization
The Department of Rehabilitation Medicine wasestablished by Ministry of Education, Culture, Sports,
Science and Technology in April 2001. It is one of thenewest fields in Graduate School of Medicine, theUniversity of Tokyo. It belongs to the Sensory andMotor System Science Course of the Surgical Science
Division. Current authorized staff is only one
professor.
This department derives from the establishment of
the physical therapy room in the central diagnostic
and therapeutic sections in order to develop theclinical practice of rehabilitation medicine in 1963.
The chair of professor was set up as a full-time director of the central rehabilitation service in 1984, but theformal title remained a physical therapy department.
Rehabilitation medicine is a newly establishedclinical section which was born in development of themodern principle of the medical health service bywhich it came to value the enhancement of not only
adding years of patient's life but also adding life to theyears. Regardless of the rapid expansion of needs,
acknowledgment of rehabilitation medicine wasdelayed in the frame of the old-fashioned clinicaldepartments. In our country, it was 1996 when the
rehabilitation specialty was authorized as formal
clinical practice by the former Ministry of Health andWelfare.
On the other hand, it was positioned as an
assistance instructor in the sensory and motor system
medicine department with shifting to the graduate
school course systems since 1995 to 97 in the
University of Tokyo. Finally, the rehabilitation

medicine field was installed in the sensory and motor
system medicine department by a budget step of 2001.
We have accepted the graduate school student
formally since fiscal year 2001. However, thearrangement of additional teaching staff is not stillmaterialized. Therefore, the staff of the graduate
school is only one professor. Seventeen students haveentered the graduate school by 2016, and thirteen ofthem were granted Ph.D.

Clinical activities
The professor serves as a director of Rehabilitation
Center, the University of Tokyo Hospital. The
Rehabilitation Center and the Department of
Rehabilitation Medicine are united and engage inclinical practice. We have at present no charged ward,
and treat about 4,000 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258

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 6th year students from
Wednesday to Friday every week. They experience a
few patients and learn how to take a patients’ history,
physical findings, functional evaluation, and how toplan rehabilitation programs. We have introduced a
few of elective students for elective clinical clerkshipto our collaborating hospitals with specialized
rehabilitation ward.
In addition, we have provided the training ofstudents including physical therapy, occupational
therapy, and speech therapy. Twenty students or morecome and stay at the university hospital annually as along-term clerkship from several PT/OT/ST training
schools.

Research activities
Our research activities are growing up. In 2006, theRehabilitation Center moved to the new building and a
research laboratory was provided for the first time. As
the motion analysis system was partially renewed, weare planning our researches mainly in the field ofmusculoskeletal disabilities. In addition, we areplanning collaborating researches with otherdepartments in our hospital, other faculties in our
university, and institutions outside the University ofTokyo. The ongoing projects are as follows.
1) 3D Motion analysis of patients with musculoskeletal disorders
2) Study on the relationship between sensory deficit
and motor control
3) Rehabilitation and long-term outcome in patientswith skeletal dysplasias
4) Pathology and treatment for patients withcongenital limb deficiencies
5) Analysis of rehabilitation outcome using DPC
data

References
1.

Di Rocco M, Baujat G, Bertamino M, Brown M,
De Cunto CL, Delai PLR, Eekhoff EMW, Haga N,
Hsiao E, Keen R, Morhart R, Pignolo RJ, Kaplan

2.

3.

4.

5.

6.

7.

8.

FS. International physician survey on management of FOP: a modified Delphi study. Orphanet
J Rare Dis. 12(1): 110, 2017Endoh S, Yamana H, Nakahara Y, Matsui H,
Fushimi K, Yasunaga H, Haga N: Risk factors forin-hospital mortality and reamputation following
lower limb amputation. Progress in Rehabilitation Medicine 2: 20170015, 2017
Hiraoka T, Palmer JB, Brodsky MB, Yoda M,
Inokuchi H, Tsubahara A: Food transit duration isassociated with the number of stage II transport
cycles when eating solid food. Arch Oral Biol:81; 186-191, 2017
Ishikawa Y, An Q, Nakagawa J, Oka H, Yasui T,
Tojima M, Inokuchi H, Haga N, Yamakawa H,
Tamura Y, Yamashita A, Asama H: Gait analysis
of patients with knee osteoarthritis by using
elevation angle: Confirmation of the planar law
and analysis of angular difference in the approximate plane. Advanced Robotics 31: 68-79, 2017
Kaneoka A, Pisegna JM, Saito H, Lo M, Felling
K, Haga N, LaValley MP, Langmore SE: A
systematic review and meta-analysis ofpneumonia associated with thin liquid versus
thickened liquid intake in patients who aspirate.
Clin Rehabil 31(8): 1116-1125, 2017
Kaneoka A, Pisegna JM, Inokuchi H, Ueha R,
Goto T, Stepp C, Nito T, LaValley MP, Haga N,
Langmore SE: Relationship between laryngeal
sensory deficits, aspiration and pneumonia inpatients with dysphagia. Dysphagia, Epub aheadof print, 2017
Kojima T, Ishikawa H, Tanaka S, Haga N,
Nishida K、Yukioka M, Hashimoto J, Miyahara H,
Niki Y, Kimura T, Oda H, Asai S, Funahashi K,
Kojima M, Ishiguro N: Characteristics of functional impairment in patients with long-standing
rheumatoid arthritis based on range of motion of
joints: Baseline data from a multicenterprospective observational cohort study toevaluate the effectiveness of joint surgery in thetreat-to-target era. Mod Rheumatol, Epub aheadof print, 2017
Kojima T, Ishikawa H, Tanaka S, Haga N,
Nishida K、Yukioka M, Hashimoto J, Miyahara
H, Niki Y, Kimura T, Oda H, Asai S, Funahashi K,
Kojima M, Ishiguro N: Validation and reliability

259

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15.

of the Timed Up and Go test for measuring
objective functional impairment in patients withlong-standing rheumatoid arthritis: a crosssectional study. Int J Rheum Dis, Epub ahead ofprint, 2017
Mano H, Fujiwara S, Haga N: Adaptive
behaviour and motor skills in children with upper
limb deficiency. Prosthet Orthot Int, Epub aheadof print, 2017
Nakahara Y, Kitoh H, Nakashima Y, Toguchida J,
Haga N: The longitudinal study of activities ofdaily living and quality of life in Japanesepatients with fibrodysplasia ossificans progresssiva. Disabil Rehabil, Epub ahead of print, 2017
Pisegna JM, Kaneoka A, Leonard R, Langmore
SE: Rethinking residue: Determining theperceptual continuum of residue on FEES toenable better measurement. Dysphagia, Epubahead of print, 2017
Sawada R, Shinoda Y, Niimi A, Nakagawa T,
Ikegami M, Kobayashi H, Homma Y, Haga N,
Tanaka S: Multiple acrometastases in a patientwith renal pelvic urothelial cancer. Case Rep
Urol, Epub ahead of print, 2017
Togo H, Rokicki J, Yoshinaga K, Hisatsune T,
Matsuda H, Haga N, Hanakawa T: Effects offield-map distortion correction on resting statefunctional connectivity MRI. Front Neurosci, 11:656, eCollection 2017
Tsuda Y, Nakagawa T, Shinoda Y, Kanatani A,
Kawai T, Taguchi S, Yamada Y, Sawada R, Kume
H, Homma Y, Tanaka S, Kawano H: Skeletal-related events and prognosis in urothelial cancer
patients with bone metastasis. Int J Clin Oncol
22(3): 548-553, 2017
Uehara K, Ogura K, Akiyama T, Shinoda Y,
Iwata S, Kobayashi E, Tanzawa Y, Yonemoto T,
Kawano H, Kawai A: Reliability and validity ofthe musculoskeletal tumor society scoring system
for the upper extremity in Japanese patients. Clin
Orthop Relat Res 475(9): 2253-2259, 2017

Surgical Sciences
3. Vital Care Medicine

261

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

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

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

Lecturer
Kyung-Ho Chang, M.D., Ph.D.

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

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

Gaku Kawamura, M.D.

Associate
Yoshie Suzuki, M.D.,

Masaaki Asamoto, M.D.,

Yuriko Tashiro, M.D.,

Michiko Ushio, M.D.,

Mizuho Sato, M.D.,

Yuko Araki, M.D.,

Yoshiomi Kusakabe, M.D., Ph.D.
Taro Kariya, M.D., Ph.D.,

Atsuko Kato, M.D.,

Takuma Hiraiwa, M.D.,

Miki Shinokawa, M.D.,

Yasuko Okagami, M.D.,

Emi Morinushi, M.D.,

Ai Furuta, M.D.,

Seiichiro Kawashima, M.D.,

Hayato Narita, M.D.,

Satoshi Kasahara, M.D.

Ayako Hirai, M.D.,

Takuya Ohata, 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 28 faculty staffs, 11 graduate students and 15
residents. We introduce the activities about Teaching,
Research and Clinical work of our department.

Clinical activities
Our clinical services include perioperative management for patients undergoing surgeries, treatment forpatients suffering acute / chronic pain, and palliative
care for patients with malignancies.
Number of cases undergoing surgery is increasingin our hospital and annual number of surgery cases
exceeds 12,000. Recently, the number of high risk or

geriatric patients is increasing. Especially surgery fororgan transplant, such as heart, liver and lung requires
tight and meticulous anesthetic care. Our aim is toprovide optimal perioperative care including proper
preoperative assessment of patients, efficient plan for
intraoperative management, meticulous intraoperativeand / or postoperative care. We are a part ofperioperative management team established in our
hospital recently to play pivotal role in perioperative
patient care. Especially for patients with multiple
comorbidities, we provide preoperative assessment /consult clinic and accept 1,600 patients annually. Pain
clinic services are provided for outpatients (including
patients in the ward of the other departments) on adaily basis in all areas of diseases accompanied with
pain. From April 2017 to March 2018, the number of
ambulatory patients was about ten thousands; two262

hundreds and seventy of those were newcomer
patients. Currently we have three beds in the ward. Wetake care 40 patients in our ward and approximately
100 in other wards annually, with multidisciplinary
approach in collaboration with neurologists,
psychiatrist, and orthopedists. Our palliative care teammanages varied somatic symptoms and psychologicaldistress of inpatients and outpatients with cancer.
Further, we manage the “cancer treatment-related
chronic pain management” outpatient clinic and also
the second opinion outpatient clinic for cancer pain
patients with advanced and terminal cancer stages.

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

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

263

Publications(1) Ikeda T, Uchida K, Yamauchi Y, Nagase T, Oba K,
Yamada Y. Relationship between pre-anesthetic
and intra-anesthetic airway resistance in patients
undergoing general anesthesia: A prospective
observational study. PLoS One. 2017 Feb 17;12(2):e0172421. doi: 10.1371/journal.pone.0172421.
eCollection 2017.
(2) Sayama S, Takeda N, Iriyama T, Inuzuka R,
Maemura S, Fujita D, Yamauchi H, Nawata K,
Bougaki M, Hyodo H, Shitara R, Nakayama T,
Komatsu A, Nagamatsu T, Osuga Y, Fujii T.
Peripartum type B aortic dissection in patientswith Marfan syndrome who underwent aortic root
replacement: a case series study. BJOG. Epub
2017 May 2.
(3) Inoue R, Sumitani M, Ogata T, Chikuda H,
Matsubara T, Kato S, Shimojo N, Uchida K,
Yamada Y. Direct evidence of central nervous
system axonal damage in patients with postoperative delirium: A preliminary study of pNF-H
as a promising serum biomarker. Neurosci Lett.
2017 Jul 13; 653:39-44. doi: 10.1016/j.neulet.
2017.05.023. Epub 2017 May 11.
(4) Isomura T, Sumitani M, Matsudaira K,
Kawaguchi M, Inoue R, Hozumi J, Tanaka T,
Oshima H, Mori K, Taketomi S, Inui H, Tahara K,
Yamagami 7, Hayakawa K. Development of theJapanese Version of the Leeds Assessment of the
Neuropathic Symptoms and Signs Pain Scale:Diagnostic Utility in a Clinical Setting. Pain Pract.
2017 Jul;17(6):800-807. doi: 10.1111/papr.12528.
Epub 2016 Dec 1.
(5) Osumi M, Sumitani M, Abe H, Otake Y,
Kumagaya SI, Morioka S. Kinematic evaluation
for impairment of skilled hand function inchemotherapy-induced peripheral neuropathy. J
Hand Ther. 2017 Oct 14. pii: S0894-1130(16)30238-1. doi: 10.1016/j.jht.2017.06.003. [Epubahead of print](6) Kogure T, Sumitani M, Abe H, Hozumi J, Inoue
R, Mietani K, Kawahara K, Yamada Y. Ischemic
Ulcer Pain Is Both Nociceptive and Neuropathic
Pain Based on a Discriminant Function Analysis
Using the McGill Pain Questionnaire. J Pain
Palliat Care Pharmacother. 2017 Jun;31(2):98-

104. doi: 10.1080/15360288.2017.1304495. Epub
2017 Apr 24.
(7) Kogure T, Sumitani M, Ikegami K, Abe H,
Hozumi J, Inoue R, Kawahara K, Yamada Y.
Donepezil, an Acetylcholinesterase Inhibitor, Can
Attenuate Gabapentinoid-Induced Somnolence inPatients with Neuropathic Pain: A Retrospective
Chart Review. J Pain Palliat Care Pharmacother.
2017 Mar; 31(1):4-9. doi: 10.1080/15360288.
2017.1279500. Epub 2017 Feb 22.
(8) Oka H, Matsudaira K, Fujii T, Kikuchi N, Haga Y,
Sawada T, Katsuhira J, Yoshimoto T, Kawamata
K, Tonosu J, Sumitani M, Kasahara S, Tanaka S.
Estimated risk for chronic pain determined using
the generic StarT Back 5-item screening tool. J
Pain Res. 2017 Feb 24;10:461-467. doi: 10.2147/
JPR.S129585. eCollection 2017.

264

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

Associate Professor
Susumu Nakajima, M.D.

Yoichi Kitsuta, M.D.

Lecturer
Masataka Gunshin, M.D.

Kent Doi, M.D.

Yoshihiro Ueda, M.D.

Associate
Takahiro Hiruma, M.D.

Inokuchi Ryota, M.D.

Tomoyasu Morita, M.D.

Ichiro Hirayama, M.D.

Kohei Yoshimoto, M.D.

Ryohei Horie, M.D.

Akinori Maeda, M.D

Takayuki Nakagawa, M.D.

Keisuke Nyuunoya, M.D.

Takuya Sato, M.D.

Shunsuke Tagami, M.D.

Hiromu Maehara, M.D.

Naoki Hayase, M.D.

Toshifumi Asada, M.D.

Daisuke Takai, M.D.

Hitomi Nakamura, M.D.

Staff Physician
Kurato Tokunaga, M.D.
Miyuki Yamamoto, M.D.
Jinsuke Mizuno, M.D.
Haruka Yamanaka, M.D.

Homepagehttps://www.tokyodam.com/

Introduction and Organization
Department of Emergency and Critical Care
Medicine was established in 1965, as the emergency
service within the Central Clinical Service Facilities of
the University of Tokyo Hospital and at the same timeas the intensive care service for in-hospital patients, it
became a tertiary emergency care and critical carecenter in the metropolitan Tokyo and also became theprincipal teaching facility of the University of Tokyo.
It is a designated Level I Trauma Center, and also thehome of one of the newest Life Flight aeromedical
services in the country.
The Emergency Center sees approximately 17,000
patients per year. It contains major trauma and cardiac
resuscitation rooms complete with STAT X-ray and fullmonitoring and resuscitation equipment. There are 9
treatment spaces including space for orthopedics,
gynecology, and Ophthalmology-ENT evaluations.
10 overnight-stay monitored beds, X-ray, rapid spiralCT, ultrasound, angiography and STAT Lab are locatedadjacent to the Emergency Center.
In September, 2001, the University of Tokyo
Hospital opened the In-patient Ward A and ourdepartment has necessarily extended services for
management of critical patients, in the new Critical
Care Center now containing adult ICU/CCU of 16 bedsin ICU1, 18 beds in ICU2 and 6 beds in Emergency
ICU.
The Emergency Care Center and the Critical Care
Center see an excellent mix of multiple trauma, highacuity medical, surgical, pediatric, and gynecologic

265

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

Clinical activities
Our clinical activities are divided into four
categories as follows:
1) Emergency medicine
Our department is responsible for not only tertiary
emergency but also primary and secondary
emergency care on 24-hour-a-day basis. In 2017
fiscal year, we had about 6595 ambulance patientsout of total 17607 ER outpatients.
The new ER, four times the size of the previous
ER was built in November, 2006. The facility has 5
consultation rooms, 4 specialized consultation rooms
for dentistry, ophthalmology, otorhinolaryngology
and gynecology, 3 resuscitation bays, and 4
observation beds.
2) Intensive care
Staff members specialized in internal medicine,cardiovascular medicine, orthopedic surgery, surgery,neurosurgery or anesthesiology create “the semiclosed ICU” model. We are responsible for the entire
care of the critically ill patients (i.e. patients withrespiratory insufficiency such as ARDS, with sepsis,with MOF, with shock), post-operative patients, andtertiary emergency patients, placing an emphasis on
evidence-based medical therapy. We had 2,300
ICU/CCU patients in the 2016.
3) Bed management
The objective of bed management services is toprovide a timely and appropriate bed allocation for
all the patients. In our hospital, patients are allocatedto three types of wards, that is, general ward, ICU2
and ICU/CCU in accordance with their criticalcondition. The ICU2 undertakes the leading bed
management in the hospital to ensure maximum
performance as an acute hospital.
4) Risk management
It is split into two categories – in-hospital and outof hospital disasters. In regard to in-hospital risk

management, including “code blue emergency”, weare responsible for patient safety on 24-hour/365-day
basis. And in regard to out of hospital risk
management, our hospital has been authorized by the
Tokyo Metropolitan Government as a disaster basehospital, and also the Government has requested theformation of Disaster Medical Assistant Team(DMAT). We have oxygen and medical suction
equipment on the passageways in the ER in case oftreating the large number of disaster patients.

Teaching activities
The topics of lectures for the 2nd year medical
student include the prehospital emergency care, theinitial evaluation of emergency patients, disastermedicine, serious infections disease, and trauma. BasicLife Support. exercise is also mandatory for the 2ndyear medical student.
One month of elective clinical clerkship for the 3rdyear. Immediate Cardiac Life Support (ICLS) courseand 1 day Hospital MIMMS (Major Incident Medical
Management and Support) course are held for theparticipants in the clinical clerkship program, andsuccessful completion of each course will enable
students to be certified as providers.
Clinical integrated lecture for the 4th year students
includes diagnosis and treatment of serious patientsusing case studies of shock, conscious disorder, trauma,
intoxication, infections disease, burns, hypothermia,
and convulsion. Moreover, after exercise of Advanced
Life Support, students experience a real practice of
emergency medicine as fellow passengers in theambulances and as one day trainees in the emergency
centers of the affiliated hospitals.
In conformity with the guideline by Ministry of
Health, Labor and Welfare, all residents learn andpractice emergency medicine and primary care at every
level, primary, secondary and tertiary. The residents
attend the ICLS course during resident year to obtainthe knowledge and skills in CPR.
Junior residents are also assigned to ICU services togain the knowledge of intensive care from
pathophysiological and internal medicine’s point ofview.
According to the senior resident program in 2006, wetrain the senior residents to be skilled in advanced

266

critical care medicine including primary care trauma,
MOF, shock, and equipment support.

Research activities
Basic research by using the histone injection-induced
ARDS model and the ischemia reperfusion injury
models on several different organs including intestineand kidney has been conducted to clarify themechanisms of remote organ injury in multiple organ
dysfunction syndrome. Our clinical studies revealed
that organ network disruption could be observed by
network analysis with clinical parameters and new
biomarkers of ICU patients.

References
1. Hayashida K, Tagami T, Fukuda T, Suzuki M,
Yonemoto N, Kondo Y, Ogasawara T, Sakurai A,
Tahara Y, Nagao K, Yaguchi A, Morimura N;
SOS‐KANTO 2012 Study Group. Mechanical
Cardiopulmonary Resuscitation and Hospital
Survival Among Adult Patients With Nontraumatic
Out-of-Hospital Cardiac Arrest Attending theEmergency
Department:
A
Prospective,
Multicenter, Observational Study in Japan (SOSKANTO [Survey of Survivors after Out-ofHospital Cardiac Arrest in Kanto Area] 2012
Study). J Am Heart Assoc. 2017 Oct 31;6(11). pii:
e007420.
2. SOS–KANTO 2012 Study Group. A New Rule for
Terminating Resuscitation of Out-of-Hospital
Cardiac Arrest Patients in Japan: A Prospective
Study. J EmergMed. 2017 Sep;53(3):345-352.
3. Hayakawa M, Maekawa K, Kushimoto S, Kato H,
Sasaki J, Ogura H, Matsuoka T,Uejima T,
Morimura N, Ishikura H, Hagiwara A, Takeda M,
Kaneko N, Saitoh D, Kudo D, Kanemura T,
Shibusawa T, Furugori S, Nakamura Y, Shiraishi A,
Murata K, Mayama G, Yaguchi A, Kim S, Takasu
O, Nishiyama K. Hyperfibrinolysis in severe
isolated traumatic brain injury may occur without
tissue hypoperfusion: a retrospective observational
multicentre study. Crit Care. 2017 Aug 23;
21(1):222.
4. Hiromi T, Toida C, Muguruma T, Hashiba K, Doi
T, Nakamura K, Morimura N. Two cases withintra-aortic balloon pumping use for severe septic

cardiomyopathy. Acute Med Surg. 2017 Jul 13;
4(4):446-450.
5. Nakamura K, Inokuchi R, Daidoji H, Naraba H,
Sonoo T, Hashimoto H, Tokunaga K, Hiruma T,
Doi K, Morimura N. Efficacy of levetiracetam
versus fosphenytoin for the recurrence of seizures
after status epilepticus. Medicine (Baltimore).
2017 Jun;96(25):e7206.
6. Kashiura M, Hamabe Y, Akashi A, Sakurai A,
Tahara Y, Yonemoto N, Nagao K, Yaguchi A,
Morimura N; SOS-KANTO 2012 Study Group.
Association between cardiopulmonary resuscitation duration and one-month neurologicaloutcomes for out-of-hospital cardiac arrest: aprospective cohort study. BMC Anesthesiol. 2017
Apr 21;17(1):59.
7. Hayashida K, Suzuki M, Yonemoto N, Hori S,
Tamura T, Sakurai A, Tahara Y, Nagao K, Yaguchi
A, Morimura N; SOS-KANTO 2012 Study Group.
Early Lactate Clearance Is Associated With
Improved Outcomes in Patients With Postcardiac
Arrest Syndrome: A Prospective, Multicenter
Observational Study (SOS-KANTO 2012 Study).
Crit Care Med. 2017 Jun;45(6):e559-e566.
8. Ohashi-Fukuda N, Fukuda T, Doi K, Morimura N.
Effect of prehospital advanced
airwaymanagement for pediatric out-of-hospital cardiac
arrest. Resuscitation. 2017 May;114:66-72.
9. Tomio J, Nakahara S, Takahashi H, Ichikawa M,
Nishida M, Morimura N, Sakamoto T.
EffectivenessofPrehospital
Epinephrine
Administration in Improving Long-term Outcomesof Witnessed Out-of-hospital Cardiac Arrest
Patients with Initial Non-shockable Rhythms.
Prehosp Emerg Care. 2017 Jul-Aug;21(4):432-441.
10. Awaji K, Inokuchi R, Maehara H, Yamaguchi Y,
Kira K, Doi K, Morimura N. Woman with
Hypertension and Seizure. J Emerg Med. 2017
May;52(5):e207-e208.
11. Shiraishi A, Kushimoto S, Otomo Y, Matsui H,
Hagiwara A, Murata K; Japanese Observational
Study for Coagulation and Thrombolysis in Early
Trauma (J-OCTET)investigators. Effectiveness ofearly administration of tranexamic acid in patientswith severe trauma. Br J Surg. 2017 May;104(6):710-717.

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12. Nakamura Y, Ishikura H, Kushimoto S, Kiyomi F,
Kato H, Sasaki J, Ogura H, Matsuoka T, Uejima T,
Morimura N, Hayakawa M, Hagiwara A, Takeda
M, Kaneko N, Saitoh D, Kudo D, Maekawa K,
Kanemura T, Shibusawa T, Hagihara Y, Furugori S,
Shiraishi A, Murata K, Mayama G, Yaguchi A,
Kim S, Takasu O, Nishiyama K. Fibrinogen levelon admission is a predictor for massive transfusionin patients with severe blunt trauma: Analyses of a
retrospective multicentre observational study.
Injury. 2017 Mar;48(3):674-679.
13. Inokuchi R, Maehara H, Yamaguchi Y, Kira K, Doi
K, Morimura N. A Healthy Woman with Sudden
Memory Loss. J Emerg Med. 2017 Apr;52(4):e157-e158.
14. Hagiwara S, Oshima K, Aoki M, Miyazaki D,
Sakurai A, Tahara Y, Nagao K,Yonemoto N,
Yaguchi A, Morimura N; SOS-KANTO 2012
Study Group. Does the number of emergency
medical technicians affect the neurologicaloutcome of patients with out-of-hospital cardiac
arrest? Am J Emerg Med. 2017 Mar;35(3):391-396.

Health Sciences and Nursing
1. Health Sciences

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Department of Mental HealthProfessor
Norito Kawakami, M.D., Ph.D.

Project Lecturer
Kotaro Imamura, Ph.D.

Research Associate
Toshiaki Baba, M.D., MSc, Ph.D.

Homepage

http://plaza.umin.ac.jp/heart/

Introduction and Organization
The department was firstly established as
Department of Fourth Clinical Medical Nursing in
School of Health Care and Nursing in 1957. When the
School of Health Care and Nursing was reorganized as
the School of Health Sciences in 1965, the department
was renamed Department of Mental Health. In 1992,
as School of Health Sciences became The School of
Health Science and Nursing, Department of Mental
Health became Department of Mental Health andPsychiatric Nursing. As the result of the shift to thechair system of the Graduate School of Medicine in
1996, two departments were established, Departmentof Mental Health and Department of PsychiatricNursing. Faculty, staff, and students of two
departments have been working cooperatively eversince. Since 2007, Department of Mental Healthbecame a part of School of Public Health, with aperspective of “public mental health.”
The department currently has faculty members
introduced above, an associate professor, a project
lecturer, a research associate, part-time lecturers, atechnical specialist, visiting research fellows, qq
doctoral course students, 3 master course students, andsecretaries.
The department has two major objectives: one is toteach mental health to undergraduate and graduate
students in order to produce global leaders in researchand practice in this field. The other is to conductcutting-edge research in the fields of mental health.

All of the activities of the department are conductedin collaboration with staff members in the departments,
other departments within the University of Tokyo, andinstitutions within and outside Japan.

Teaching activities
The department is responsible for giving lectures onmental health; mental disorders; clinical and healthpsychology; and psychometry and behavior evaluation
to undergraduate students. Other than lectures, thedepartment provides students opportunities toexperience mental health activities in relevant mental
health settings.
The department provides graduate courses onmental health I and II, featuring epidemiology andpractice in mental health and occupational mental
health, respectively. The department also provided a
1.5 hour seminar every Wednesday evening for 20
weeks in each semester (40 weeks per year) for
graduate students and research students, withpresentations of research plans and progress, andliterature review by graduate students, as well as
presentation of and lectures by guest speakers.

Research activities
The department conducts research on mental healthand psychosocial support and provides education/
training of professionals in related fields from global
perspectives. The World Mental Health Japan survey,

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which is part of a WHO international collaboration, isa largest epidemiologic study of common mental
disorders in the community in Japan. Assessment ofhealth effects of job stressors and effectiveness ofinterventions to reduce job stress are also coreresearch activities of the department. Current issues
around occupational mental health (e.g., intervention
program using Internet-based cognitive behavioral
therapy) are also actively investigated. Furthermore,
research in the department includes various othertopics, such as supporting rehabilitation and recoveryof people with chronic mental illness, suicide
prevention, social disparity in mental health, disastermental health, and global mental health. Most of theresearch has been conducted in a close collaboration
with researchers in other domestic and foreign
institutions/universities.

References
1. Fukasawa M, Kawakami N, Umeda M, Miyamoto
K, Akiyama T, Horikoshi N, Yasumura S, Yabe H,
and Bromet EJ. Environmental radiation level,
radiation anxiety, and psychological distress of
non-evacuee residents in Fukushima five years
after the Great East Japan Earthquake: Multilevel
analyses. SSM Popul Health. 2017 Dec 3:
740–748.
2. Chiba R, Umeda M, Goto K, Miyamoto Y,
Yamaguchi S, Kawakami N. The property of theJapanese version of the Recovery Knowledge
Inventory (RKI) among mental health service
providers: a cross sectional study. International
Journal of Mental Health Systems. 2017 Dec 28;
11: 71.
3. Sakuraya A, Watanabe K, Kawakami N, Imamura
K, Ando E, Asai Y, Eguchi H, Kobayashi Y,
Nishida N, Arima H, Shimazu A, Tsutsumi A.
Work-related psychosocial factors and onset of
metabolic syndrome among workers: a systematic
review and meta-analysis protocol. BMJ Open.
2017 Jun 22;7(6): e016716.
4. Panthee B, Panthee S, Gyawali S, Kawakami N.
Prevalence and correlates of substance use among
healthcare students in Nepal: a cross sectional
study. BMC Public Health. 2017 Dec 12; 17(1):950.

5. McGrath JJ, Saha S, Lim CCW, Aguilar-Gaxiola S,
Alonso J, Andrade LH, Bromet EJ, Bruffaerts R,
Caldas de Almeida JM, Cardoso G, de Girolamo
G, Fayyad J, Florescu S, Gureje O, Haro JM,
Kawakami N, Koenen KC, Kovess-Masfety V,
Lee S, Lepine JP, McLaughlin KA, Medina-Mora
ME, Navarro-Mateu F, Ojagbemi A, Posada-Villa
J, Sampson N, Scott KM, Tachimori H, Ten Have
M, Kendler KS, Kessler RC; WHO World Mental
Health Survey Collaborators. Trauma andpsychotic experiences: transnational data from theWorld Mental Health Survey. Br J Psychiatry.
2017 Dec; 211(6): 373-380.
6. Liu YC, Meguro K, Nakamura K, Akanuma K,
Nakatsuka M, Seki T, Nakaaki S, Mimura M,
Kawakami N. Depression and Dementia in
Old-Old Population: History of Depression May
Be Associated with Dementia Onset. The Tome
Project. Front Aging Neurosci. 2017 Oct 17; 9:335.
7. Kessler RC, Aguilar-Gaxiola S, Alonso J, Benjet
C, Bromet EJ, Cardoso G, Degenhardt L, deGirolamo G, Dinolova RV, Ferry F, Florescu S,
Gureje O, Haro JM, Huang Y, Karam EG,
Kawakami N, Lee S, Lepine JP, Levinson D,
Navarro-Mateu F, Pennell BE, Piazza M,
Posada-Villa J, Scott KM, Stein DJ, Ten Have M,
Torres Y, Viana MC, Petukhova MV, Sampson NA,
Zaslavsky AM, Koenen KC. Trauma and PTSD in
the WHO World Mental Health Surveys. Eur J
Psychotraumatol. 2017 Oct 27; 8(sup5): 1353383.
8. McLaughlin KA, Koenen KC, Bromet EJ, Karam
EG, Liu H, Petukhova M, Ruscio AM, Sampson
NA, Stein DJ, Aguilar-Gaxiola S, Alonso J,
Borges G, Demyttenaere K, Dinolova RV, Ferry F,
Florescu S, de Girolamo G, Gureje O, Kawakami
N, Lee S, Navarro-Mateu F, Piazza M, Pennell BE,
Posada-Villa J, Ten Have M, Viana MC, Kessler
RC. Childhood adversities and post-traumaticstress disorder: evidence for stress sensitisation in
the World Mental Health Surveys. Br J Psychiatry.
2017 Nov; 211(5): 280-288.
9. Koenen KC, Ratanatharathorn A, Ng L,
McLaughlin KA, Bromet EJ, Stein DJ, Karam EG,
Meron Ruscio A, Benjet C, Scott K, Atwoli L,
Petukhova M, Lim CCW, Aguilar-Gaxiola S,
Al-Hamzawi A, Alonso J, Bunting B, Ciutan M,

271

de Girolamo G, Degenhardt L, Gureje O, Haro JM,
Huang Y, Kawakami N, Lee S, Navarro-Mateu F,
Pennell BE, Piazza M, Sampson N, Ten Have M,
Torres Y, Viana MC, Williams D, Xavier M,
Kessler RC. Posttraumatic stress disorder in theWorld Mental Health Surveys. Psychol Med. 2017
Oct; 47(13): 2260-2274.
10. Tsuno K, Kawakami N, Shimazu A, Shimada K,
Inoue A, P Leiter M. Workplace incivility inJapan: Reliability and validity of the Japaneseversion of the modified Work Incivility Scale. J
Occup Health. 2017 May 25; 59(3): 237-246.
11. Umeda M, Kawakami N, Miller E. Effect ofsocioeconomic conditions on health care utilization in marital violence: a cross-sectional investigation from the Japanese Study on Stratification,
Health, Income, and Neighborhood. Int J Equity
Health. 2017 Feb 28; 16(1): 41.
12. Watanabe K, Kawakami N. Effects of amulticomponent workplace intervention programme with environmental changes on physicalactivity among Japanese white collar employees:
a protocol for a cluster randomised controlled trial.
BMJ Open. 2017 Oct 24; 7(10): e017688.
13. Watanabe K, Kawakami N, Imamura K, Inoue A,
Shimazu A, Yoshikawa A, Hiro H, Asai Y, Odagiri
Y, Yoshikawa E, Tsutsumi A. Pokemon GO andpsychological distress, physical complaints, andwork performance among adult workers: a retrospective cohort study. Sci Rep. 2017 Sep 7; 7(1):10758.
14. Ali AM, Ahmed A, Sharaf A, Kawakami N,
Abdeldayem SM, Green J. The Arabic Version of
The Depression Anxiety Stress Scale-21:
Cumulative scaling and discriminant-validation
testing. Asian J Psychiatr. 2017 Dec; 30: 56-58.
15. Nomura S, Sakamoto H, Glenn S, Tsugawa Y, Abe
SK, Rahman MM, Brown JC, Ezoe S, Fitzmaurice
C, Inokuchi T, Kassebaum NJ, Kawakami N, Kita
Y, Kondo N, Lim SS, Maruyama S, Miyata H,
Mooney MD, Naghavi M, Onoda T, Ota E, Otake
Y, Roth GA, Saito E, Tabuchi T, Takasaki Y,
Tanimura T, Uechi M, Vos T, Wang H, Inoue M,
Murray CJL, Shibuya K. Population health andregional variations of disease burden in Japan,
1990-2015: a systematic subnational analysis for
the Global Burden of Disease Study 2015. Lancet.

2017 Sep 23; 390(10101): 1521-1538.
16. Yong RKFY, Inoue A, Kawakami N. The validity
and psychometric properties of the Japanese version of the Compulsive Internet Use Scale (CIUS).
BMC Psychiatry. 2017 May 30; 17(1): 201.
17. Kunie K, Kawakami N, Shimazu A, Yonekura Y,
Miyamoto Y. The relationship between work
engagement and psychological distress of hospitalnurses and the perceived communication behaviors of their nurse managers: A cross-sectional
survey. Int J Nurs Stud. 2017 Jun; 71: 115-124.
18. Koenen KC, Ratanatharathorn A, Ng L,
McLaughlin KA, Bromet EJ, Stein DJ, Karam EG,
Meron Ruscio A, Benjet C, Scott K, Atwoli L,
Petukhova M, Lim CC, Aguilar-Gaxiola S,
Al-Hamzawi A, Alonso J, Bunting B, Ciutan M,
de Girolamo G, Degenhardt L, Gureje O, Haro JM,
Huang Y, Kawakami N, Lee S, Navarro-Mateu F,
Pennell BE, Piazza M, Sampson N, Ten Have M,
Torres Y, C Viana M, Williams D, Xavier M,
Kessler RC. Posttraumatic stress disorder in theWorld Mental Health Surveys. Psychol Med. 2017
Oct; 47(13): 2260-2274.
19. Global Burden of Disease Child and Adolescent
Health Collaboration. Child and Adolescent
Health From 1990 to 2015: Findings From the
Global Burden of Diseases, Injuries, and Risk
Factors 2015 Study. JAMA Pediatr. 2017 Jun 1;
171(6): 573-592.
20. Kasai K, Ando S, Kanehara A, Kumakura Y,
Kondo S, Fukuda M, Kawakami N, Higuchi T.
Strengthening community mental health services
in Japan. Lancet Psychiatry. 2017 Apr; 4(4):268-270.
21. Sakuraya A, Imamura K, Inoue A, Tsutsumi A,
Shimazu A, Takahashi M, Totsuzaki T, Kawakami
N. Workplace social capital and the onset of major
depressive episode among workers in Japan: a
3-year prospective cohort study. J Epidemiol
Community Health. 2017 Jun; 71(6): 606-612.
22. GBD 2015 Tobacco Collaborators. Smoking
prevalence and attributable disease burden in 195
countries and territories, 1990-2015: a systematic
analysis from the Global Burden of Disease Study
2015. Lancet. 2017 May 13; 389(10082): 18851906.
23. Iwanaga M, Iwanaga H, Kawakami N.

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Twelve-month use of herbal medicines as a
remedy for mental health problems in Japan: A
cross-national analysis of World Mental Health
Survey data. Asia Pac Psychiatry. 2017 Sep; 9(3).
24. Asai Y, Imamura K, Kawakami N. Association ofjob stressors with panic attack and panic disorderin a working population in Japan: A crosssectional study. J Occup Environ Med. 2017 Jun;59(6): 516-521.
25. Sakuraya A, Shimazu A, Eguchi H, Kamiyama K,
Hara Y, Namba K, and Kawakami N. Job crafting,work engagement, and psychological distressamong Japanese employees: a cross-sectional
study. Biopsychosoc Med. 2017 Feb 10; 11: 6.
26. Atwoli L, Stein DJ, King A, Petukhova M,
Aguilar-Gaxiola S, Alonso J, Bromet EJ, deGirolamo G, Demyttenaere K, Florescu S, Maria
Haro J, Karam EG, Kawakami N, Lee S, Lepine
JP, Navarro-Mateu F, O'Neill S, Pennell BE,
Piazza M, Posada-Villa J, Sampson NA, Ten Have
M, Zaslavsky AM, Kessler RC; WHO World
Mental Health Survey Collaborators.. Posttraumatic stress disorder associated with
unexpected death of a loved one: Cross-national
findings from the world mental health surveys.
Depress Anxiety. 2017 Apr; 34(4): 315-326.
27. Thornicroft G, Chatterji S, Evans-Lacko S,
Gruber M, Sampson N, Aguilar-Gaxiola S,
Al-Hamzawi A, Alonso J, Andrade L, Borges G,
Bruffaerts R, Bunting B, Caldas de Almeida JM,
Florescu S, de Girolamo G, Gureje O, Haro JM,
He Y, Hinkov H, Karam E, Kawakami N, Lee S,
Navarro-Mateu F, Piazza M, Posada-Villa J,
Torres de Galvis Y, Kessler RC. Undertreatmentof people with major depressive disorder in 21
countries. Br J Psychiatry. 2017 Feb; 210(2): 119124.
28. Kovess-Masfety V, Evans-Lacko S, Williams D,
Andrade LH, Benjet C, Ten Have M, Wardenaar K,
Karam EG, Bruffaerts R, Abdumalik J, Haro Abad
JM, Florescu S, Wu B, De Jonge P, Altwaijri Y,
Hinkov H, Kawakami N, Caldas-de-Almeida JM,
Bromet E, de Girolamo G, Posada-Villa J, AlHamzawi A, Huang Y, Hu C, Viana MC, Fayyad J,
Medina-Mora ME, Demyttenaere K, Lepine JP,
Murphy S, Xavier M, Takeshima T, Gureje O. The
role of religious advisors in mental health care in

the World Mental Health surveys. Soc Psychiatry
Psychiatr Epidemiol. 2017 Mar; 52(3): 353-367.
29. Bromet EJ, Atwoli L, Kawakami N, NavarroMateu F, Piotrowski P, King AJ, Aguilar-Gaxiola
S, Alonso J, Bunting B, Demyttenaere K, Florescu
S, de Girolamo G, Gluzman S, Haro JM, de JongeP, Karam EG, Lee S, Kovess-Masfety V,
Medina-Mora ME, Mneimneh Z, Pennell BE,
Posada-Villa J, Salmeron D, Takeshima T, Kessler
RC. Post-traumatic stress disorder associated withnatural and human-made disasters in the World
Mental Health Surveys. Psychol Med. 2017 Jan;47(2): 227-241.
30. Suzuki Y, Yabe H, Horikoshi N, Yasumura S,
Kawakami N, Ohtsuru A, Mashiko H, Maeda M;
Mental Health Group of the Fukushima HealthManagement Survey.. Diagnostic accuracy ofJapanese posttraumatic stress measures after acomplex disaster: The Fukushima Health Management Survey. Asia Pac Psychiatry. 2017 Mar;9(1).
31. Watanabe K, Tabuchi T, Kawakami N.
Improvement of the work environment andwork-related stress: a cross-sectional multilevelstudy of a nationally representative sample ofJapanese workers. J Occup Environ Med. 2017
Mar; 59(3): 295-303.
32. Imamura K, Kawakami N, Tsuno K, Tsuchiya M,
Shimada K, Namba K, Shimazu A. Effects ofweb-based stress and depression literacy intervention on improving work engagement among
workers with low work engagement: An analysisof secondary outcome of a randomized controlled
trial. J Occup Health. 2017 Jan 24; 59(1): 46-54.
33. Watanabe K, Kawakami N, Adachi H, Inoue S,
Umstattd MR. Internal consistency, convergent
validity, and structural validity of the Japaneseversion of the Physical Activity Self-Regulation
scale (PASR-12) among Japanese workers: avalidation study. J Occup Health. 2017 Jan 24;59(1): 24-32.
34. Kachi Y, Abe A, Ando E, Kawada T. Socioeconomic disparities in psychological distress in anationally representative sample of Japaneseadolescents: A time trend study. Aust N Z J
Psychiatry. 2017 Mar; 51(3): 278-286.

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Department of Biostatistics/
Epidemiology and Preventive
Health Sciences
Professor
Yutaka Matsuyama, Ph.D.

Associate Professor
Koji Oba, Ph.D.

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

Project Research Associate
Yoshinori Takeuchi, D.V.M., Ph.D, M.P.H

Homepage

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

Introduction and Organization
The Department of Epidemiology and Biostatistics
evolved from the Department of Epidemiology in
1992. Since then, we have been responsible forproviding educational courses on methodology of
epidemiologic research and biostatistics to undergraduate students. We belong to Graduate School of
Medicine as Departments of Biostatistics/ Epidemiology and Preventive Health Sciences, providing
education for undergraduate as well as graduateschool students and consultation to clinical researchers.
Unfortunately, education programs for biostatistics and epidemiological methodology are notsufficient in Japanese universities and graduate
schools compared to the situation in the US andEuropean countries. Nevertheless, the necessity forcollaboration among biostatisticians and clinicalresearchers/epidemiologists has been claimed inrecent years. Hence, the central missions of oureducational courses are devoted to provide students
expert knowledge and extensive experience inbiostatistics and epidemiology to take part in clinical/

epidemiological research as biostatisticians or
methodologists. We do not only focus on practicalaspects on statistical analysis in medical research but
also place emphasis on the methodological principles
of biostatistics/epidemiology.
Our main research area is the development ofmethodology for clinical/epidemiological research. Of
course, it requires keeping in touch with real clinical/
epidemiological problems. So, another indispensable
research area is a support for real-world clinical andepidemiological studies including clinical trials. To
achieve these requirements simultaneously, a nonprofit organization the Japan Clinical Research
Support Unit (current EP-CRSU, Co., Ltd.) wasestablished in 2001 by the former faculty members inour department. This organization J-CRSU hadprovided research support and coordination in design,
data management, and statistical analysis in many
projects inside/outside the university. Our experiencein J-CRSU is the basis of our supportive activities forclinical research that we work through today.

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Teaching activities
 Undergraduate Courses
1) Epidemiology and Biostatistics (2 credits each;the latter is named “Statistics” in medical doctor
course)2) Applied Mathematics (2 credits)
3) Biostatistics Practice (1 credit)
4) Practical Examples in Clinical andEpidemiologic Research (1 credit)
5) Medical Data Analysis, and its Practice (2credits each)6) Theoretical Epidemiology (2 credits) School of Public Health (Graduate School)
1) Statistical Analysis of Medical Research(2 credits)
2) Practice of Biostatistics (2 credits)3) Design of Medical Research (2 credits) Doctoral Courses (Graduate School)
1) Biostatistics (4 credits)
2) Epidemiology and Preventive Health Sciences(4 credits)
3) Introduction to Medical Statistics(2 credits; for the School of Medicine)
The faculty of the department had provided
lectures in a series of educational courses organizedby “The Clinical Bioinformatics Research Unit” in
2002-2007.

Research activities
1. Methodology for designing and analyzing clinical
trials: Interim analysis
 Adaptive designs
 Multiplicity
 Data management of large-scale multicenter
clinical trials
2. Methodology of Biostatistics and theoreticalepidemiology:
 Analysis of longitudinal (time-to-event and/or
repeated measures) data
 Analysis of missing/incomplete data Causal inference Semiparametric modeling

3. International collaboration ofmeta-analysis on gastric cancer

individual-level

4. Coordination and data analysis of collaborative
epidemiological/clinical research:
 Japan Arteriosclerosis Longitudinal Study Japan Diabetes Collaborative Study Chronic Kidney Disease Japan Cohort
5. Validity/reliability studies of QOL questionnaires
and other rating scales
6. Pharmacoeconomic assessment of medical technology
We had been supporting some of the above
collaborative clinical/epidemiologic studies throughtheaforementioned
J-CRSU(anon-profit
organization), which aims to support investigatorinitiated studies and to provide education toresearchers and support staffs. Currently, we are
officially conducting a consultation for design andanalysis of clinical trials assisted by the ClinicalResearch Support Center of the University of Tokyo
Hospital.
From FY2016, the industry, academia, andgovernment-collaborative program “Support Programfor Biostatisticians” was launched by Japan Agency
for Medical Research and Development for“cultivating talent of excellent biostatisticians,
supports the efforts of training them throughcollaboration between graduate schools that conduct
school education, and hospitals that conduct practicaltraining.” (AMED website, July 4, 2017) AMED
selected the University of Tokyo as one of the 2centers for conducting the project (principal
investigator: Professor Matsuyama). Our department
is also officially participating in the program, and will
provide more and more educational/practical supports
to future biostatisticians on the basis of our richexperience in biostatistical education and support invariety of research.

References
1. Aoyama T, Kashiwabara K, Oba K, Honda M,
Sadahiro S, Hamada C, Maeda H, Mayanagi S,
Kanda M, Sakamoto J, Saji S, Yoshikawa T.
Clinical impact of tumor location on the colon

275

2.

3.

4.

5.

6.

7.

cancer survival and recurrence: analyses of pooleddata from three large phase III randomized clinical
trials. Cancer Medicine 2017; 6(11): 2523-30.
Aoyama T, Oba K, Honda M, Sadahiro S, HamadaC, Mayanagi S, Kanda M, Maeda H, Kashiwabara
K, Sakamoto J, Saji S, Yoshikawa T. Impact of
postoperative complications on the colorectal
cancer survival and recurrence: analyses of pooledindividual patients’ data from three large phase III
randomized trials. Cancer Med. 2017; 6(7): 157380.
Arakawa K, Kawai K, Ishihara S, Hata K, Nozawa
H, Oba K, Sugihara K, Watanabe T. Prognostic
Significance of Peritoneal Metastasis in Stage IV
Colorectal Cancer Patients With R0 Resection: A
Multicenter, Retrospective Study. Dis Colon
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Hagiwara Y, Ohashi Y, Okusaka T, Ueno H, Ioka T,
Boku N, Egawa S, Hatori T, Furuse J, Mizumoto K,
Ohkawa S, Yamaguchi T, Yamao K, Funakoshi A,
Cheng AL, Kihara K, Sato A, Tanaka M. Healthrelated quality of life in a randomised phase III
study of gemcitabine plus S-1, S-1 alone andgemcitabine alone for locally advanced or metastatic pancreatic cancer: GEST study. ESMO Open.
2017; 2: e000151.
Hiraoka A, Michitaka K, Kumada T, Izumi N,
Kadoya M, Kokudo N, Kubo S, Matsuyama Y,
Nakashima O, Sakamoto M, Takayama T, Kokudo
T, Kashiwabara K, Kudo M, The Liver Cancer
Study Group of Japan. Validation and potential of
albumin-bilirubin grade and prognostication in anationwide survey of 46,681 hepatocellular
carcinoma patients in Japan: the need for a moredetailed evaluation of hepatic function. Liver
Cancer. 2017; 6(4): 325-36.
Honda M, Oba K, Akiyoshi T, Maeda H,
Kashiwabara K, Kanda M, Mayanagi S, Aoyama T,
Hamada C, Sadahiro S, Fukunaga Y, Ueno M,
Sakamoto J, Saji S, Yoshikawa T. Development
and Validation of a Prognostic Nomogram for
Colorectal Cancer after Radical Resection based on
individual patient data from three large-scale phase
III trials. OncoTarget. 2017; 8: 99150-60.
Ikeda T, Uchida K, Yamauchi Y, Nagase T, Oba K,
Yamada Y. Relationship between pre-anesthetic
and intra-anesthetic airway resistance in patients

undergoing general anesthesia: A prospective
observational study. PLoS One. 2017; 12(2):e0172421.
8. Ishiguro N, Koseki N, Kaiho M, Ariga T, Kikuta H,
Togashi T, Oba K, Morita K, Nagano N, Nakanishi
M, Hara K, Hazama K, Watanabe T, Yamanaka T,
Sasaki S, Furuyama H, Shibata M, Shida S,
Ishizaka A, Tabata Y, Aoyagi H, Naito H, Yoshioka
M, Horino A, Kenri T; Hokkaido PediatricRespiratory Infection Study Group. Therapeutic
efficacy of azithromycin, clarithromycin, minocycline and tosufloxacin against macrolideresistant and macrolide-sensitive Mycoplasma
pneumoniae pneumonia in pediatric patients. PLoS
One. 2017; 12(3): e0173635.
9. Kokudo T, Hasegawa K, Matsuyama Y, Takayama
T, Izumi N, Kadoya M, Kudo M, Kubo S,
Sakamoto M, Nakashima O, Kumada T, Kokudo
N; Liver Cancer Study Group of Japan. Liver
resection for hepatocellular carcinoma associatedwith hepatic vein invasion: a Japanese nationwide
survey. Hepatology. 2017; 66(2): 510-7.
10. Kotake M, Aoyama T, Munemoto Y, Doden K,
Kataoka M, Kobayashi K, Nishimura G, Fujita H,
Nakamura K, Takehara A, Tanaka C, Sakamoto J,
Nagata N, Oba K, Kondo K. Multicenter phase II
study of infusional 5-fluorouracil (5-FU),
leucovorin, and oxaliplatin, plus biweekly
cetuximab as first-line treatment in patients withmetastatic colorectal cancer (CELINE trial). Oncol
Lett. 2017; 13(2): 747-53.
11. Kusano M, Honda M, Okabayashi K, Akimaru K,
Kino S, Tsuji Y, Watanabe M, Suzuki S, Yoshikawa
T, Sakamoto J, Oba K, Saji S. Randomized
controlled Phase III study comparing hepatic
arterial infusion with systemic chemotherapy after
curative resection for liver metastasis of colorectal
carcinoma: JFMC 29-0003. J Cancer Res Ther.
2017; 13(1): 84-90.
12. Maeda H, Kashiwabara K, Aoyama T, Oba K,
Honda M, Mayanagi S, Kanda M, Hamada C,
Sadahiro S, Sakamoto J, Saji S, Yoshikawa T.
Hazard rate of tumor recurrence over time inpatients with colon cancer: implications for
postoperative surveillance from three JapaneseFoundation for Multidisciplinary Treatment ofCancer (JFMC) clinical trials. J Cancer 2017;

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8(19): 4057-64.
13. Maeda H, Okamoto K, Oba K, Kobayashi M.
Lymph node retrieval using fat dissolution
technique after surgical resection of colorectal
cancer: a protocol paper. Ann Can Res Ther. 2017;
25: 90-1.
14. Mukai H, Hagiwara Y, Imi K, Isaka H, Watanabe K,
Matsuyama Y for the SELECT BC Study Group.
The impact of treatment preferences in second-line
chemotherapy on the prognosis of HER2-negative
metastatic breast cancer. Oncology. 2017; 93:
315-22.
15. Nagata N, Mishima H, Kurosawa S, Oba K,
Sakamoto J. mFOLFOX6 Plus Panitumumab
Versus 5-FU/LV Plus Panitumumab After Six
Cyclesof
Frontline
mFOLFOX6
Plus
Panitumumab: A Randomized Phase II Study ofPatients With Unresectable or Advanced/Recurrent,
RAS
Wild-type
Colorectal
Carcinoma(SAPPHIRE)-Study Design and Rationale. Clin
Colorectal Cancer. 2017; 16(2): 154-157.
16. Nakamura M, Aoyama T, Ishibashi K, Tsuji A,
Takinishi Y, Shindo Y, Sakamoto J, Oba K,
Mishima H. Randomized phase II study ofcetuximab versus irinotecan and cetuximab inpatients with chemo-refractory KRAS codon G13D
metastatic colorectal cancer (G13D-study). Cancer
Chemother Pharmacol. 2017; 79: 29-36.
17. Notake T, Kobayashi A, Shinkawa H, Kawahara T,
Shimizu A, Yokoyama T, Hasegawa K, Kokudo N,
Matsuyama Y, Makuuchi M, Miyagawa SI.
Nomogram predicting long-term survival after the
diagnosis of intrahepatic recurrence of hepatocellular carcinoma following an initial liverresection. Int J Clin Oncol. 2017; 22(4): 715-25.
18. Oba K, Horie N, Sato N, Saito K, Takeuchi T,
Mimori T, Miyasaka N, Koike T, Tanaka Y.
Remission induction by Raising the dose of
Remicade in RA (RRRR) study: Rationale andstudy protocol for a randomized controlled trial
comparing for sustained clinical remission after
discontinuation of infliximab in patients withrheumatoid arthritis. Contemp Clin Trials Commun
2017; 8: 49-54.
19. Sato Y, Sano S, Nakao Y, Morii J, Kashiwabara K.
Surgical strategy and retrospective analysis ofstaged posterior osteotomy for adult spinal

deformities. Journal of Spine Research 2017; 8(7):1222-6.
20. Shiga M, Maeda H, Oba K, Okamoto K,
Namikawa T, Fujisawa K, Yokota K, Kobayashi M,
Hanazaki K. Safety of laparoscopic surgery forcolorectal cancer in patients over 80 years old: apropensity score matching study. Surg Today.
2017; 47(8): 951-8.
21. Shinozaki T, Mansournia MA, Matsuyama Y. On
hazard ratio estimators by proportional hazards
models in matched-pair cohort studies. Emerg
Themes Epidemiol. 2017; 14: 6.
22. Shiroiwa T, Fukuda T, Shimozuma K, Mouri M,
Hagiwara Y, Kawahara T, Ohsumi S, Hozumi Y,
Sagara Y, Ohashi Y, Mukai H. Cost-effectivenessanalysis of the introduction of S-1 therapy forfirst-line metastatic breast cancer treatment inJapan: results from the randomized phase III
SELECT BC trial. BMC Cancer. 2017; 17: 773.
23. Takeuchi Y, Ando T, Ishiguro C, Uyama Y. Risk ofacute asthma attacks associated with non-steroidal
anti-inflammatory drugs: A self-controlled caseseries. Ther Innov Regul Sci. 2017; 51(3): 332-41.
24. Tanaka S, Matsuyama Y, Ohashi Y. Validation ofsurrogate endpoints in cancer clinical trials via
principal stratification with an application to a
prostate cancer trial. Stat Med. 2017; 36(19):2963-77.
25. Ueno M, Li CP, Ikeda M, Ishii H, Mizuno N,
Yamaguchi T, Ioka T, Oh DY, Ichikawa W,
Okusaka T, Matsuyama Y, Arai D, Chen LT, ParkYS, Furuse J. A randomized phase II study of
gemcitabine plus Z-360, a CCK2 receptor-selective
antagonist, in patients with metastatic pancreaticcancer as compared with gemcitabine plus placebo.
Cancer Chemother Pharmacol. 2017; 80: 307-15.
26. Yamaue H, Shimizu A, Hagiwara Y, Sho M,
Yanagimoto H, Nakamori S, Ueno H, Ishii H,
Kitano M, Sugimori K, Maguchi H, Ohkawa S,
Imaoka H, Hashimoto D, Ueda K, Nebiki H,
Nagakawa T, Isayama H, Yokota I, Ohashi Y,
Shirasaka T. Multicenter, randomized, open-label
Phase II study comparing S-1 alternate-day oral
therapy with the standard daily regimen as afirst-line treatment in patients with unresectableadvanced pancreatic cancer. Cancer ChemotherPharmacol. 2017; 79: 813-23.

277

Department of Biomedical Ethics &Department of Health Promotion
Sciences
Professor
Akira Akabayashi, M.D., Ph.D.

Associate Professor
Yoshiyuki Takimoto, M.D., Ph.D.

Lecturer
Eisuke Nakazawa, Ph.D.

Research Associate
Keiichiro Yamamoto, Ph.D.

Homepage

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

Introduction and Organization
The former Department of Health Administration wasestablished in 1967 and Dr. Tsuneo Tanaka became its
first professor in 1974. He devoted himself to thedevelopment of the community health care system inJapan and published numerous papers concerning thesocial theory of health administration and data
management systems for community health care. He
also contributed to the establishment of the School of
Health Sciences. In 1985, Dr. Atsuaki Gunji became
the second professor of the department. During Dr.
Gunji’s tenure, two major research projects were
undertaken. One was “The effects of physical activity
and inactivity on health.” From 1990, a 20-day bed
rest human experimental study was conducted every
year in the context of an international cooperative
research project that was supported by government
grants. The other project concerned health caresystems, especially health care economics and thequality of hospital care.
In 1996, the Department of Health Administration developed into two departments: the Department
of Health Economics and the Department of Health

Promotion Sciences. Both were established as
departments of the Graduate School of Medicine. In
1998, Dr. Yasuki Kobayashi became the professor of
the Department of Health Economics. He conducted
research into health care delivery systems in Japan. In
2001, he moved to the Department of Public Health.
From 1996 to 2002, Dr. Kiyoshi Kawakubo tookcharge of the Department of Health Promotion
Sciences as the associate professor.
In June 2002, Dr. Akira Akabayashi became
professor of the Department of Health Economics.
Professor Akabayashi’s area of research is biomedical
ethics. In April 2003, the Department of Health
Economics was restructured and named the Department of Biomedical Ethics. From 2007, Dr. Jung Su
Lee became the associate professor and took charge of
the Department of Health Promotion Sciences. In
2017, Dr. Yoshiyuki Takimoto acceded to the chair of
the Department of Health Promotion Sciences.
Staff members of the two departments include a
professor, an associate professor, a lecturer, anassociate, and a technical specialist. All five members,
eight project researchers, six graduate lecturers from278

other organizations, and five visiting researchers
contribute to department teaching and research
activities.
We have five department graduate students. Fourof them are doctoral program students.
In this annual report, the organization andteaching activities are reviewed followed by an
explanation of research activities.

In addition to these courses, the department operates
lectures, practical training, and joint seminars forresearch guidance on a regular basis.
Graduate level courses in Biomedical Ethics
focus on the analytical study of ethical theories and on
the review of several empirical studies within the field
and its related areas.

Research activities
Teaching activities
Our departments highly prioritize the teaching andguidance of graduate students and their research
activities. Sixteen bachelor theses, twenty-two mastertheses, and eleven doctoral dissertations werecompleted between April 2004 and March 2017. Our
departments’ staff members are also responsible forthe following undergraduate and graduate courses.
Undergraduate Courses
Required courses
1) Introduction to Biomedical Ethics (Lecture)2) Biomedical Ethics I (2 credits, lecture)3) First-Year Seminar for Natural Science Students(2 credits, seminar)
Elective courses
4) Integrated Lecture of Clinical Medicine,
Biomedical ethics (Lecture)5) Integrated Lecture of Clinical Medicine,
Biomedical ethics and Geriatric Medicine(Lecture)
6) Integrated Lecture of Clinical Medicine,
Psychosomatic Medicine and Biomedical ethics(Lecture)
7) Social Medicine (Lecture)8) Biomedical Ethics II (2 credits, lecture)9) Clinical Ethics (2 credits, lecture)10) Global Bioethics (2 credits, lecture)11) Theory of Health Care Management (1 credit,
lecture)12 Field Work for Health Care Management (1credit, practicum)
Graduate Courses
1) Biomedical Ethics I
2) Biomedical Ethics II

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279

region8) Historical analyses for the term “bioethics” in theJapanese context

References
1. Fukushi T, Isobe T, Nakazawa E, Takimoto Y,
Akabayashi A, Sakura O. Neuroethics in far east.
In Routledge Handbook of Neuroethics. (in press)
2. Maeda S, Kobayashi R, Kamishiraki E, Oikawa M,
Ishikawa E. Handling complications caused byphlebotomy for blood sampling: results of anationwide survey in Japan. Journal of Patient
Safety & Conflict Management 2018;11:14-28.
3. Nakazawa E, Yamamoto K, Akabayashi A,
Akabayashi A. Regulation of genome editing singhuman embryos: Japan's ethic of nonresolution.
Cambridge Quarterly of Healthcare thics. (inpress)
4. Takashima K, Takimoto Y, Nakazawa E, Hayashi
Y, Tsuchiya A, Fujita M, Akabayashi A. iscovery
and informing research participants of incidental
findings detected in brain agnetic resonanceimaging studies: Review and multi-institutional
study. Brain and ehavior. 2017; 00:e00676. https://doi.org/10.1002/brb3.676
5. Takimoto Y, Nakazawa E, Tsuchiya A,
Akabayashi A. Ordinary citizens' expectations foregenerative medicine and induced pluripotent
stem cells researches in Japan. Journal of linicalResearch & Bioethics 2017; 8:311. doi: 10.4172/
2155-9627.1000311
6. Toda S, Nakazawa E, Yamamoto K, Akabayashi A.
From “cannot” function to “might” unction:
Assessment of actual levels of consciousness andpotential consciousness in patient are: Japaneseexperiences. American Journal of Bioethics
Neuroscience (in press)

Health Sciences and Nursing
2. Preventive and Administrative Nursing

281

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

Lecturer
Kimie Takehara, Ph.D., R.N.

Assistant Professor
Keiko Kunie, Ph.D., R.N.

Project Assistant Professor
Naoko Ichikawa, Ph.D., R.N.

Homepage

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

Introduction and Organization

Teaching Activities

The Department of Nursing Administration/
Advanced Clinical Nursing has 60 years of history andtradition. It was first established as the Department ofFundamental Nursing in the School of Health Care andNursing in 1954. The School of Health Care andNursing was composed of two basic medical
departments and six nursing departments. When it was
reorganized as the School of Health Sciences in 1965,
only one nursing department remained, so thedepartment was renamed as Department of Nursing; it
was the department responsible for nursing education.
In 1992, the School of Health Sciences became the
School of Health Sciences and Nursing, two new
departments of nursing were established, so the
Department of Nursing became once again the
Department of Fundamental Nursing. As the result of
this shift to the chair of the Graduate School of
Medicine in 1996, two departments were established,
the Department of Nursing Administration and
Department of Advanced Clinical Nursing. Our
department is responsible for the fundamental nursing
education for undergraduate students.

Undergraduate Courses

In the undergraduate program, our department
oversees lectures and clinical practicums for
Introduction of Nursing Science, Fundamental Nursing
I, Basic nursing skills, and Nursing Administration.
Introduction of Nursing Science (1 credit, lectures)
In this course, students learn nursing concepts,
functions, theories, targets, and the practical side ofnursing.
Theory and methodology of nursing 1 (2 credits,
lectures)This course provides knowledge and nursing skills forunderstanding patients and providing care. Students
learn about the nursing process and nursing skills
necessary for knowing and caring for patients, which
are essential for providing appropriate nursing care.
Basic nursing skills (2 credits, lectures)This course provides the basics for assessing clients’
health including physical examination skills andpractices in fundamental nursing skills, which areessential for providing nursing care with physiological282

and psychosocial integrity. Students learn about thenursing process with case discussion.
Practicum:basic nursing skills(2 credits, practicum)
Under instructors’ supervision, students haveopportunities to apply their fundamental knowledge
and nursing skills in a variety of settings. Students willassess clients’ health and needs through applications of
the nursing process.
Nursing Administration (1 credit, lectures)This course introduces students to roles of nurse
administrators/managers in all types of healthcare
settings, such as institutions, organizations, communities, and politics. Students will learn fundamental
theories and practices of nursing administration/
management by analyzing current issues in healthcare
and nursing.
Practicum:nursing administration(1 credit, practicum)
Students participate in nursing administrative
practicum in units or divisions in hospitals. They willlearn care delivery systems such as staffing and patientclassification systems, nursing informatics, andbudgetary issues (e.g., cost effectiveness and quality
improvement).

Graduate Courses

In the graduate program, our department oversees
the lectures for Nursing Administration and Advance
Clinical Nursing.
Nursing Administration I, II (2 credits each)
These courses offer a critical analysis of theories innursing administration related to leadership management, organizational development/career development,
quality assurance/improvement, and cost effectiveness/
efficient care delivery systems.
Advance Clinical Nursing I (2 credits)
This course offers an overview of the environment
surrounding nursing, political decision-making processes, and public philosophy. Students develop expertiseand examine the potentialities of nurses and their legal
responsibilities. The political and administrative
functional roles of nursing are discussed.
Seminar (4 credits)
We have a department seminar every week during

which members discuss plans and topics of their own
research studies.

Research Activities
Environment and Structures to Enable Nurse
Administrators to Fulfil their Potential
We have been examining administrative issues incontemporary nursing. Our main research topic is
developing new models for nursing administration/organization development. We inquire to clarify
relationships among environmental/structural factors,
nurse administrators’ competencies/activities, efficacies, and outcome indicators. We have also been
examining the methodology for nursing administrators’
development.
Environment and Structures to Enable Nurses toFulfil their Potentials
Another main research topic is contributing to theformation of an environment in which nurses/teams
mature and succeed. We are studying careerdevelopment, team/organizational development, teamcommunication, and diversity management.
Development of Nursing Care Technology
For more effective nursing care, we have beendeveloping innovative assessment technology using
ultrasound and preventive care technology for diabetic
foot.

References
1.

2.

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 tinea pedis and feet washing behavior indiabetic patients: A cross-sectional study.
Advances in Skin and Wound Care. 2017;30(11):510-6.
Yabunaka K, Nakagami G, Komagata K, Sanada
H. Ultrasonographic follow-up of functional
chronic constipation in adults: A report of twocases. SAGE Open Med Case Rep. 2017; 5. doi:
10.1177/2050313X17694234.
Kunie K, Kawakami N, Shimazu A, Yonekura Y,
Miyamoto Y. The relationship between work
engagement and psychological distress of hospitalnurses and the perceived communication

283

4.

5.

6.

7.

8.

9.

behaviors of their nurse managers: A crosssectional survey. International Journal of Nursing
Studies. 2017; 71: 115-124.
Fujimoto Y , Mizuno H, Seto N, Nunotani M,
Ichikawa N, Shimizu Y. Examination of a way of
thinking and influence factor of the exercise for
the Crohn's disease patient. Journal of Japan
Intractable Illness Nursing Society. 2017; 21(3):181-193 [published in Japanese]
Goto T, Nakagami G, Takehara K, Nakamura T,
Kawashima M, Tsunemi Y, Sanada H. Examining
the accuracy of visual diagnosis of tinea pedis andtinea unguium in aged care facilities. J Wound
Care. 2017;26(4); 179-183.
Oe M, Hamatani M, Noguchi H, Oba M, Takehara
K, Ohashi Y, Ueki K, Kadowaki T, Mori T, Sanad
H. Factors associated with foot callus in subjects
with diabetic mellitus : a chart review. Journal ofJapanese Society of Wound, Ostomy andContinence Management 2017;20(4):426-33.
[published in Japanese]
Oe M, Takehara K, Noguchi H, Ohashi Y,
Amemiya A, Sakoda H, Suzuki R, Yamauchi T,
Ueki K, Kadowaki T, Sanada H. Thermographic
findings in a case of type 2 diabetes with foot ulcer
due to callus deterioration. Diabetology International. 2017;8(3):328-33.
Kunie K, Sasaki M, Onishi M. Managing change:
Nurse managers’ behaviors in the course of
systems redesign. The Journal of Japan Academyof Nursing Administration and Policies. 2017;21(2) 98-109. [published in Japanese]
Takehara K, Iizaka S, Oe M, Sanada H. Reliability
and validity of a portable device for measuring
stratum corneum hydration. Journal of JapaneseSociety Wound, Ostomy, and Continence Management. 2017;21(4):296-303.

284

Department of Family Nursing
Professor
Kiyoko Kamibeppu, Ph.D., R.N., P.H.N.

Lecturer
Iori Sato, Ph.D., R.N., P.H.N.

Assistant Professors
Sachiko Kita, Ph.D., R.N., M.W., P.H.N.
Takafumi Soejima, MHS., R.N., P.H.N.

Homepage

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

Introduction and Organization

Research

This department was established in 1992. Four
faculty members currently serve the department: aprofessor, a lecturer, and two assistant professors.
Enrolled at present are 8 doctoral students, 6 master’s
students, a research student, 31 visiting researchers,
and 3 administrative staff.

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

Education
1. Graduate Courses, School of Health Sciences andNursing (credit hours)
Advanced Family Nursing I (2)Advanced Family Nursing II (2)Laboratory and/or Field Work on Family Nursing(16)
Practicum in Translational Research Nursing (2)2. Undergraduate Courses for Students in the Schoolof Integrated Health Sciences (credit hours)
Family Health (2)Health Communication (1)3. Undergraduate Courses for Nursing Students in the
School of Integrated Health Sciences (credit hours)
Pediatric and Child Health Nursing (3)Clinical Practicum in Pediatric and Child HealthNursing (3)285with pediatric cancer researchers and a variety offamily support organizations across the country.
Funding for these research projects was granted
through a 2004-2006 Ministry of Education, Culture,
Sports, Science and Technology Grant-in-Aid for
Scientific Research, and currently through a Practical
Research for Innovative Cancer Control (AMED) anda 2014-2016 Ministry of Education, Culture, Sports,
Science and Technology Grant-in-Aid for Scientific
Research. Based on the department’s rich collective
research experiences, we founded the Center for
Quality of Life Research in April 2012 to study QOL
across wide developmental stages and healthconditions. Using this platform, we aim to accumulate,integrate, and disseminate scientific research andknowledge on QOL in a more systematic manner.
Additionally, the department members are conducting
research that explore the various experiences ofchildren with cancer and their families who wereextensively affected by the Tohoku Earthquake of
2011.
Studies focusing on transition such as “transferring
into adult health care” and “promoting self-care andautonomy” in patients with child chronic diseases has
been conducted since 2016. We established atransition outpatient clinic in the University of Tokyo
Hospital in June 2016 and have been providing
transitional cares for patients with congenital heartdisease, epilepsy, chromosomal abnormality, hematologic disease, and endocrine disease in the clinic. We
also developed the tool “My Health Passport” in orderfor patients to summarize the information about theirdisease and share their experiences with others (e.g.,friends and coworkers) and are now conducting a
study to evaluate it. Furthermore, we have beendeveloping newly check lists to evaluate long-term
follow ups in patients after hematopoietic stem celltransplantation and supports for school reentry inpediatric cancer survivors. Those studies and activities
have been ongoing in interdisciplinary collaboration
with health professionals in the University of Tokyo
Hospital.
In addition to our research activities, we holdbimonthly Family Care Group Supervisions, whereby
deeper understanding of family nursing practices is
promoted. In this we aim to enhance the quality ofclinical practice and research in family nursing andcontribute to the establishment of the science offamily nursing.

Publications
1. Kobayashi K, Yamaguchi E, Hayakawa A, Adachi
S, Hara J, Tokimasa S, Ohta H, Hashii Y, Rikiishi
T, Sawada M, Kuriyama K, Kohdera U,
Kamibeppu K, Kawasaki H, Oda M, Hori H.
HRQOL of Japanese children with acute lymphoblastic leukemia during and after chemotherapy.
Pediatrics International. 2017 Feb; 59(2): 145153.
2. Kita S, Haruna M, Yamaji M, Matsuzaki M,
Kamibeppu K. Association of mental andbehavioral problems among children exposed to
intimate partner violence and visits with theirfathers who perpetrated the violence. Open
Journal of Nursing. 2017 Mar; 7(3): 361-377.
3. Kita S, Haruna M, Hikita N, Matsuzaki M,
Kamibeppu K. Development of the Japaneseversion of the woman abuse screening tool-short.
Nursing and Health Sciences. 2017 Mar; 19(1):35-43.
4. Imai S, Kita S, Tobe H, Watanabe M,
Nishizono-Maher A, Kamibeppu K. Postpartum
depressive symptoms and its association withsocial support among foreign mothers in Japan at
3-4 months postpartum. International Journal of
Nursing Practice. 2017 Oct; 23(5)5. Suzuki S, Sato I, Emoto S, Kamibeppu K.
Physio-psychologicalburdensandsocialrestrictions on parents of children with technology
dependency are associated with care coordination
by nurses. Journal of Pediatric Nursing. 2017
Sep-Oct; 36: 124-131.
6. Toyama N, Kurihara K, Muranaka M, Shirai K,
Kamibeppu K. Designing a scale to assess family
nursing practice among public health nurses inJapan. Health. 2017 Jul; 9(7): 1019-1028.
7. Toyama N, Kurihara K, Muranaka M, Shirai K,
Kamibeppu K. Designing a scale to assessbreastfeeding support among public health nurses
in Japan. Health. 2017 Jun; 9(6): 964-974.
8. Toyama N, Muranaka M, Kurihara K, Kamibeppu
K. Qualitative study of breastfeeding support by
public health nurses in Japan. Health. 2017 Mar;

286

9(3): 451-458.
9. Kasahara-Kiritani M, Ikeda M, Yamamoto-Mitani
N, Kamibeppu K. Regaining my new life: Daily
lives of suicide-bereaved individuals. Death
Studies. 2017 Feb; 41(7): 447-454.
10. Kasahara-Kiritani M, Kikuchi R, Ikeda M,
Kamibeppu K. Relationships in Families After a
Member’s Death: A Qualitative Metasynthesis.
Journal of Loss & Trauma. 2017 Apr; 22(5): 396411.
11. Nishigaki K, Yoneyama A, Ishii M, Kamibeppu K.
An investigation of factors related to the use of
respite care services for children with severe
motor and intellectual disabilities (SMID) living
at home in Japan. Health & Social Care in theCommunity. 2017 Mar; 25(2): 678-689.
12. Kikuchi R, Mizuta K, Urahashi T, Sanada Y,
Yamada N, Onuma E, Ono M, Endo M, Sato I,
Kamibeppu K. Development of the Japaneseversion of the PedsQLTM transplant module.
Pediatrics International. 2017 Jan; 59(1): 80-88.
13. Takanashi S, Sakka M, Sato I, Watanabe S,
Tanaka S, Ooshio A, Saito N, Kamibeppu K.
Factors influencing mother–child communication
about fathers with neurobehavioural sequelae after
brain injury. Brain Injury. 2017 Feb; 31(3): 312318.

287

Department ofCommunity Health Nursing /Public Health Nursing
Professor (concurrent)
Noriko Yamamoto-Mitani, Ph.D., R.N., P.H.N.

Lecturer
Takashi Naruse, Ph.D., R.N., P.H.N.

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

Project Research Associate
Mahiro Fujisaki-Sakai, Ph.D., R.N., P.H.N.

Homepage

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

Introduction and Organization
Department of Community Health Nursing wasestablished in June 1992. Department of Public HealthNursing was established related to opening of mastercourse for public health nurses in 2006. In addition,
program for public health nurse license was started in2014, and our department is in charge of it. At present,
there are four faculty members introduced above and
11 graduate course students (6 in master course, 5 indoctoral course) in the department. Also, we accept
many visiting researchers from other colleges andinstitutions.

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

home health care service, and health care system.
2) Community Health Nursing (2 credits, lectures)
In this class, students learn the methodology andbasic theory of health promotion, disease
prevention and resilience toward society for
individuals, families, and groups in community.
3) Home Health Nursing Practice (2 credits, practice)This program offers opportunities to learn the basisof home nursing and understand the life of homecare patients and their family at home-visit nursing
station and hospital’s department of dischargeplanning. Basic techniques and the role of nursing
through collaboration with other profession are
mastered.
2. Graduate program, in the Graduate School of
Health Sciences and Nursing (* program for publichealth nurse curriculum)1) Advanced Community Health Nursing I(2 credits, lectures)This program is to study the health at thecommunity-level and theory and application of the288

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

10) Public Health Nursing Practice I (1 credit,
practice)*This program intends to generate understanding of
the process of public health nurses’ continuous careprovision or activity, focusing on support for theindividual/family and a specific public health issue.
In addition, students will visit a clinical setting forschool and occupational health nursing practice.
11) Public Health Nursing Practice II (4 credits,
practice)*This program is intended to help further
understanding of community assessment and thedevelopment of a community program for publichealth nurses. Students will participate in programs,
meetings, and other daily activities held by publichealth nurses. Throughout their assessment,
students are expected to foster their ability to
manage and research public health nursing practice.
We hold departmental meetings (journal reading andintroduction of research) every Tuesday and monthly
research seminars every third Friday to enhanceresearch capacity.

Research
Our research focuses on the development andevaluation of health care programs, establishment ofcommunity health care systems, and standardization ofskills among public health nurses in response to thehealth care needs of individuals, families, aggregatesand communities. Our research is supported by a Grantin-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology,
Health Science research, and other foundations.
Ongoing research projects in our department are listed
below.
1. Developing a community care system and fosteringcollaboration between home-care service providers.
Fostering collaboration between home-care service
providers is an international concern in community
care, especially elderly health care. We are conducting
a study to measure the status of collaboration between
care providers in a community setting; it also aims todevelop efficient and feasible strategies to improve this289

status.
2. Discharge planning
Discharge planning is an interdisciplinary process that
is ideally available to aid patients and their families indeveloping a feasible plan for the next step of care.
Demand for discharge planning is increasing. We areattempting to standardize discharge planning activities
and develop outcome indicators and an educational
program on discharge planning for ward nurses. We arealso conducting research on the discharge planningsystem, developing guidelines for multi-sectional andinter-agency cooperation among nurses, nurses’
support at outpatient settings.
3. Support for families with infants and children
Recently, custodial parents have faced manydifficulties and challenges. To address this, we areconducting research on children's injury prevention andsocial environments for child-rearing parents.
4. Community health care for the elderly
We are conducting research on the health of the elderly
to support favorable living conditions for thispopulation. Our research includes (1) identification ofservice needs among frail elderly persons incommunity dwellings, (2) evaluation of community
care services’ impact on the elderly and their family
caregivers, and (3) the development of an approach
aimed at providing care for the terminally ill incommunity settings (e.g., monitoring of resident
transfers).
5. Skills of public health nurses
Public health nurses use high-level support skills;
however, many of these skills have not been identified
through research. We aim to identify and standardize
the skills of public health nurses, focusing in particularon skills regarding new community diagnostic method
and group dynamics.

Publications
1.

Naruse T, Fujisaki-Sakai M, Nagata S. Home
visiting nurse service duration and factors related
to institution admission. Home Health CareManagement & Practice. 2017; 29(1): 46-52.

2.

3.

4.

5.

Naruse T, Matsumoto H, Fujisaki-Sakai M,
Nagata S. Measurement of Special Access toHome Visit Nursing Services among Japanese
Disabled Elderly People: Using GIS and Claim
data. BMC Health Serv Res. 2017; 17: 377.
Naruse T, Yamamoto N, Sugimoto T, FujisakiSakai M, Nagata S. The association between
nurses' coordination with physicians and clients'
place of death. International Journal of Palliative
Nursing. 2017; 23(3):136-42.
Iwasaki R, Arimoto A, Naruse T, Nagata S,
Murashima S. The Importance of theMaternal/Self-Role Satisfaction for Reducing
Anxiety: A Cross-Sectional Survey of Japanese
Mothers. Journal of University of Occupational
and Environmenatal Health. 2017; 39(2): 143-51.
Honda C, Nagata S. Investigation on factors
related to children’s accidental injuries in theirhome, focusing on relationship with children’s
lifestyle. Iryo no Hiroba. 2017; 57(3):18-21.

Health Sciences and Nursing
3. Clinical Nursing

291

Department of GerontologicalHome Care and Long-term Care
Nursing/Palliative Care Nursing
Professor
Noriko Yamamoto-Mitani, Ph.D., R.N.

Assistant Professor (Senior)
Ayumi Igarashi, Ph.D., R.N.

Assistant Professor (Junior)
Maiko Noguchi-Watanabe, Ph.D., R.N.
Naoko Mikoshiba, Ph.D., R.N.

Project Assistant Professor
Training Program of Oncology Specialist, The University of Tokyo
Reiko Yamahana, CNS, R.N.

Homepage

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

Introduction and Organization
The Department of Adult Health Nursing/ Palliative
Care Nursing has almost 50 years of history andtradition. Originally the department was started as the
Department of Adult Health in 1965 and it underwent
several re-organizations. The current structure with
two sub-divisions of Adult Health Nursing and
Palliative Care Nursing has started in 2006. Further,
Adult Health Nursing was renamed to GerontologicalHome Care and Long-term Care Nursing in 2016.
Noriko Yamamoto-Mitani has been responsible foradministration as a department chair since 2012.

Education
In the undergraduate program, our department is incharge of the lectures and clinical practicums for adult
health nursing. In graduate education, we aim to
educate students into independent researchers andcompetent clinicians who effectively use research. For

this purpose we respect each student’s researchinterest that they derived from their clinicalexperiences. Each student completes his/her Master’s
thesis or doctoral dissertation from developing
research question from their own scientific interests
regarding nursing practice for older people or adults inchronic stage.
In education, we emphasize critical thinking
process as a researcher who conduct unique andoriginal research: from cultivating perspectives as a
researcher to come up with original research topic,
developing research topic into unique researchquestions/ hypotheses, choosing appropriate researchmethods, and to developing valid research protocols.

Research
In research, we aim to contribute to the development of nursing science and improvement in quality ofnursing practice through collaborative research withclinicians. Especially we aim to develop new nursing

292

knowledge grounded on Japanese culture, as needed in
tomorrow’s aged society.
Faculty members conduct studies on various topics
in the field of adult and gerontological nursing.
As research methods, along with conventional
statistical methods, we often utilize qualitative
methods in order to understand experiences ofindividual patients and/or nurses and to conceptualize
and theorize them.
1) Quality assurance and improvement for long-termcare for the elderly
The goal of long-term care nursing is to allow older
adults live as high quality lives as possible, even withdiseases/disabilities; the paradigm of long-term care isdifferent from that of acute care that typically aim tohave the patients recover promptly from disease
conditions. There has not been enough attention to
long-term care nursing in today’s healthcare practice;there has been little research on quality assurance andimprovement in long-term care field in Japan. In thisdepartment, we have been conducting multiple studies
on long-term care in facilities and homecare nurse
agencies regarding care quality assurance andimprovement.
First, we attempt to develop intervention models toimprove care quality in close collaboration withclinicians, including nurses and care workers. We aim
to develop sustainable systems to improve their dailycare practice, collaborating with nurses at long-termcare facilities and homecare nurse agencies.
Second, we develop indicators to assess quality oflong-term care, including home care nursing. We havebeen developing them as a part of overall assessment
system needed for long-term care nursing.
Quality assurance and improvement for long-termcare facilities and home-care nurse agencies grow inimportance, given the educational opportunities forhealthcare provider working at long-term carefacilities and homecare nurse agencies are limited
compared to that working at critical hospital.
2) Establishing a case study method to develop
nursing science from clinical sites
We attempt to develop a new research method thatclinicians could use to conduct effective case studies.
Although case study has been used for long time, it

has not had a standardized method. We aim to develop
a protocol on conducting case study that contributes todevelop nursing science.

3) Establishment of support system for the elderly in
the integrated community care
In the Japanese aged society, it is an urgent problem
to establish a local structure supporting the life of theelderly persons by the community. As one of themeasures to solve the problem, the evaluation of theappropriateness of the public services in thecommunity is necessary. We have been examined what
combination of services the elderly persons are using
and what its related factors are. We will also examine
the outcomes affected by the combination of the used
services.
In addition, in the integrated community care, theutilization of the local resources, including
nongovernmental services, is demanded. We havediscussed the possibility of utilizing convenience
stores, which exist closely in local communities inJapan, as a hub of the elderly support. We haveconducted an action research to promote collaboration
with the convenience stores in the elderly support incommunity.
4) End-of-life care decision making in communitydwelling elderly people
We conduct a research about end of life carepreference of community dwelling elderly people(including facility for the elderly). In the Asian region,
Japan, Hong Kong, and South Korea, which are aging
society, need to promote Advanced Care Planning, andhas been designed institutional plan. By conducting
collaborate research in the three countries, we will
clarify common issues in the Asian region andproblems inherent to Japan and propose concrete
policies that the administration should do. Hence, we
aim to contribute to promotion of Advanced Care
Planning considering cultural factor.
5) Developing a clinical education program andeducational indicator to improve nurse’s clinicaljudgement competency
Education on clinical judgement is addressed inaccordance with the educational guidelines of both

293

basic education and clinical education. However, there
are no references to concrete methods on acquiring
techniques in the guidelines. For this reason, various
teaching methods were looked at, but consistenteducation for basic education and clinical education
could not be found. It can be thought that education at
nursing school do not foster the competency of actual
practice. In this study, first, the current situation ofbasic nursing education and clinical education wasinvestigated. An attempt has been made at developing
a post-graduate physical assessment training programthat aims to strengthen the clinical judgmentcompetency of nurses.
We also conduct studies on a range of topics innursing of chronic conditions, from preventive to
end-of-life phase. We have been conducting studies
which are expected to allow us to understand the stateof individuals who require nursing in those periods,
and investigate effective and efficient nursing care forsuch individuals.

Publications
1.

2.

3.

4.

Iwasaki T, Yamamoto-Mitani N, Sato K, Yumoto
Y, Noguchi-Watanabe M, Ogata Y. A purposeful
Yet Nonimposing Approach: How JapaneseHome Care Nurses Establish Relationships With
Older Clients and Their Families. J Fam Nurs.
2017 Nov;23(4):534-561.
doi: 10.1177/1074840717743247.
Horinuki F, Noguchi-Watanabe M, Takai Y,
Yamahana R, Ohno N, Okada S, Mori SI,
Yamamoto-Mitani N. The Experience of Persons
With Hematological Malignancy When Communicating With Health Care Professionals. Qual
Health Res. 2018 Feb;28(3):479-490.
doi: 10.1177/1049732317739839.
Lai CKY, Igarashi A, Lau NMY, Yu CTK.
Cancer screening for older people: To screen or
not to screen. Hong Kong Med J. 2017 Oct;23(5):503-16. doi: 10.12809/hkmj166154.
Hirao C, Mikoshiba N*, Shibuta T, Yamahana R,
Kawakami A, Tateishi R, Yamaguchi H, Koike K,
Yamamoto-Mitani N. Adherence to oral
chemotherapy medications among gastroenterological cancer patients visiting an outpatient clinic.

Jpn J Clin Oncol. 2017 Sep 1;47(9):786-794. doi:
10.1093/jjco/hyx087.
5. Go H, Tanaka M, Yamamoto-Mitani N, Suzuki
M, Kawakami A, Masaki N, Shimada M.
Medication adherence among patients withchronic hepatitis receiving antiviral treatment.
Gastroenterol Nurs. (in press)
6. Noguchi-Watanabe M, Yamamoto-Mitani N,
Arimoto A, Murashima S. Relationship between
patient group participation and self-care agency
among patients with a history of cardiac surgery:
A cross-sectional study. Heart Lung. 2017 Jul Aug;46(4):280-286.
doi: 10.1016/j.hrtlng.2017.04.006.
7. Shibuta T, Waki K, Tomizawa N, Igarashi A,
Yamamoto-Mitani N, Yamaguchi S, Fujita H,
Kimura S, Fujiu K, Waki H, Izumida Y, Sasako
T, Kobayashi M, Suzuki R, Yamauchi T,
Kadowaki T, Ohe K. Willingness of patients withdiabetes to use an ICT-based self-management
tool: A cross-sectional study. BMJ Open
Diabetes Res Care. 2017;5(1):e000322. doi: 10.
1136/bmjdrc-2016-000322.
8. Feng M, Igarashi A, Noguchi-Watanabe M,
Yoshie S, Iijima K, Yamamoto-Mitani N.
Characteristics of Care Management Agencies
Affect Expenditure on Home Help and Day Care
Services: A Population-based Cross-sectional
Study in Japan. Geriatr Gerontol Int. 2017 Jan 26.
doi: 10.1111/ggi.12969.
9. Iwato S, Ikeda M, Yoshida S, Yoshioka H,
Yamamoto-Mitani N. Nursing Practice Enabling
Discharge of Child with Severe Motor andIntellectual Disabilities who Needed Medical
Care: A Case of A Nurse Helping the MotherElicit and Actualize Her Wishes. Jpn J Fam Nurs.
2017;23(1):64-74.
10. Ohtake T, Noguchi-Watanabe M, Nohara Y,
Yamamoto-Mitani N. Decision-Making Support
by a Homecare Nurse for a Family with Dierent
Views Regarding the Place for End-of-Life Care.
Jpn J Fam Nurs. 2017;23(1):52-63.

294

Department ofMidwifery and Women's Health
Associate Professor
Megumi Haruna, Ph.D., R.N.M., P.H.N.

Assistant Professor
Emi Sasagawa, Ph.D., M.P.H., R.N.M.

Assistant Professor
Kaori Yonezawa, Ph.D., R.N.M., P.H.N.

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

Homepage

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

Introduction and Organization
The Department of Midwifery and Women’s Healthwas established in 2002.
It has 4 faculty members introduced above, 12
graduate students (7 in master’s courses, 5 in doctoral
courses), and 5 visiting researchers.

Teaching activities
We have graduate and undergraduate courses.
1. Graduate Courses, School of Health Sciences andNursing1) Advanced Midwifery and Women’s Health I(2 credits, lectures)
2) Advanced Midwifery and Women’s Health II(2 credits, lectures)

6) Midwifery VI (1 credit, lectures)
7) Clinical Practicum of Administration for
Midwifery (1 credit, practices)8) Clinical Practicum in Midwifery I(2 credits, practices)9) Clinical Practicum in Midwifery II(8 credits, practices)
3. Undergraduate Courses of Nursing, School of
Health Sciences and Nursing
1) Maternal-Newborn Nursing(2 credits, lectures)
2) First AID course(1 credit, lecture)3) Clinical Practicum in Maternal-Newborn
Nursing (2 credits, practices)

Research activities
2. Graduate Courses, School of Health Sciences andNursing for midwifery
1) Midwifery I (2 credits, lectures)
2) Midwifery II (2 credits, lectures)
3) Midwifery III (2 credits, lectures)
4) Midwifery IV (2 credits, lectures)
5) Midwifery V (2 credits, lectures)

Our research activities cover the field of maternal andchild health emphasizing on the promotion of
women’s health and quality of life at every stage oflife.
We conduct the following research projects:
1. Creating evidence of health guidance during
pregnancy

2951) Adequate maternal nutrition and weight management
This study examines the maternal body composition, lipid metabolic biomarkers, and nutritional
intake to optimize weight management and ahealthy lifestyle during pregnancy to prevent low
birth weight. Based on our investigations on the
optimal maternal nutritional status and gestational
weight gain, we propose a health guidance that canhelp lower the risk of pregnancy complications andadverse birth outcomes in pregnant women.
2) The effect of exercise during pregnancy
This study investigates the effect of exercise on
mental and physical health among pregnant
women.
3) Lifestyle factors and oxidative stress markers
during pregnancy
This study investigates the potential relationships
between lifestyle factors and oxidative stressmarkers during pregnancy to establish optimal
oxidative stress markers for predicting a healthy
lifestyle for pregnant women.
4) Secondhand smoke exposure during pregnancy andits related factors in Mongolia
This study uses biomarkers to investigate theprevalence of secondhand smoke (SHS) exposure
during pregnancy and the effects of SHS on birthoutcomes in Mongolia. Data were collected
through investigations to create an effective healtheducation.
5) Sleep apnea syndrome during pregnancy
This study investigates the prevalence and risk
factors of obstructive sleep apnea (OSA) during
pregnancy using a portable device to evaluate sleepand effects of OSA on birth outcomes.
2. Development of a support system for reliablechildbirth1) Development of assessment methods of birth canalusing transperineal ultrasonography
This study aims to develop the objective assessment methods of birth canal and the relationshipbetween birth canal and delivery mode usingtransperineal ultrasonography.
2) “Fear of childbirth” and psychosocial factors
among pregnant Japanese womenThis study aims to identify the psychosocial risk
factors of intense fear of childbirth.
3) Development of the strategy for safe delivery in El
Salvador
To reduce the maternal mortality ratio in El
Salvador, a program for humanized childbirth
based on scientific evidence that leads to maternalsafety and comfort during childbirth is developed.
3. Development of a support system for women’s
health1) Life and sleep among working mothers of infants
and toddlers
This study investigates the cadences of daily lifeand conditions of sleep such as excessive daytime
sleepiness and other related factors among working
mothers.
2) Support for continuous breastfeeding of working
mothers
This study investigates the factors related tobreastfeeding continuation among working
mothers.
3) Intimate partner violence (IPV) and its related
factors
This study clarifies associations between IPV
during pregnancy, mother-to-infant bonding failure,
and postnatal depressive symptoms.
4. Creating evidence of health guidance for neonatalskin care1) Development of an effective skin care intervention
to prevent neonatal skin problems.
This study investigates the effect of moisturizing
skin care improving skin barrier functions among
healthy neonates.
In addition, we investigate the relationshipbetween newborns’ skin problems and allergies(i.e., food allergy or atopic dermatitis).

296

Publications
1.

2.

3.

4.

5.

6.

7.

8.

Kita S, Haruna M, Hikita N, Matsuzaki M,
Kamibeppu K. Development of the Japaneseversion of the Woman Abuse Screening ToolShort. Nursing & Health Sciences. 2017;19(1):35–43.
Kita S, Haruna M, Yamaji M, Matsuzaki M,
Kamibeppu K. Associations of Mental and
Behavioral Problems among Children Exposed to
Intimate Partner Violence Previously and Visitswith Their Fathers Who Perpetrated the Violence.
Open Journal of Nursing. 2017;7(3):361–377.
Takegata M, Haruna M, Matsuzaki M, Shiraishi
M, Okano T, Severinsson E. Psychometric
Evaluation of the Japanese Wijma Delivery
Expectancy/Experience Questionnaire version B.
Open Journal of Nursing. 2017;7(1):15–27.
Takegata M, Haruna M, Matsuzaki M, Shiraishi
M, Okano T, Severinsson E. Aetiologicalrelationships between factors associated withpostnatal traumatic symptoms among Japaneseprimiparas and multiparas: A longitudinal study.
Midwifery. 2017;44:14–23.
Severinsson E, Haruna M, Rönnerhag M, Holm
AL, Hansen BS, Berggren I. Evidence of
Linkages between Patient Safety and PersonCentred Care in the Maternity and ObstetricContext—An Integrative Review. Open Journalof Nursing. 2017;7(2):378–398.
Haruna M, Matsuzaki M, Shiraishi M, Yeo S.
Physical exercise during pregnancy and its
related factors: An observational study in Japan.
Asian/Pacific Island Nursing Journal. 2017;2(4):
166–173.
Sasagawa E, Elías de Buendía L, Ortiz Avendaño
GA, Díaz de Navarro AM, Barrera Erazo HA,
Sandoval López DX, et al. A Comparison of
Blood Loss Determination After Vaginal Delivery
in El Salvador: Visual Estimation Versus Direct
Measurement. International Journal of Nursingand Health Science. 2017;4(6): 81–71.
Hikita N, Haruna M, Matsuzaki M, Sasagawa E,
Murata M, Oidovsuren O, et al. Prevalence andrisk factors of secondhand smoke (SHS) exposure
among pregnant women in Mongolia. Scientific
Reports. 2017;27;7(1):16426.

9.

Shiraishi M, Haruna M, Matsuzaki M, Murayama
R, Sasaki S. Availability of two self-administered
diet history questionnaires for pregnant Japanesewomen: A validation study using 24-hour urinary
markers. Journal of epidemiology. 2017;27(4):172–179.
10. Yonezawa K, Haruna M, Matsuzaki M.
Prevalence and risk factors for skin problems
among newborns. Journal of Japan Academy ofMidwifery. 2017;31(2):111–119.

297

Department of Psychiatric Nursing
Professor
Norito Kawakami, M.D., Ph.D.

Associate Professor
Yuki Miyamoto, R.N., P.H.N., P.S.W., Ph.D.

Project Research Associate
Ayumi Takano, R.N., P.H.N, Ph.D.

Homepage

http:// plaza.umin.ac.jp/heart/

Introduction and Organization
Our department was firstly established as Department of Fourth Clinical Medical Nursing in School of
Health Care and Nursing in 1957. When the School of
Health Care and Nursing was reorganized as the
School of Health Sciences in 1965, the department
was renamed Department of Mental Health. In 1992,
as School of Health Sciences became The School of
Health Science and Nursing, Department of Mental
Health became Department of Mental Health andPsychiatric Nursing. As the result of the shift to thechair system of the Graduate School of Medicine in
1996, two departments were established, Departmentof Mental Health and Department of PsychiatricNursing. Faculty, staff, and students of two departments have been working cooperatively ever since.
Our department currently has two faculty
members introduced above, a project research
associate, part-time lecturers, visiting research fellows,
4 doctoral course students, 8 master course students,
and research associates.
Our department’s mission comprises twoelements. One is to provide education and researchtraining in mental health and psychiatric nursing toundergraduate and graduate students in order toprepare students to assume leadership roles in nursing
clinical practice, administration, teaching, andresearch in this field. The other is to conduct clinicalresearch in the fields of psychiatric nursing andadvance knowledge and theory through research.
All activities of our department are conducted incollaboration with staff members in the Department of
Mental Health.

Education
Our department is responsible for giving lectureson psychiatric nursing to undergraduate students.
Other than lectures, our department provides students
opportunities to practice psychiatric nursing activities
in several relevant facilities.
Our department is also obliged to educate
graduate students in master and doctor programs in
psychiatric nursing. To accomplish this objective, ourdepartment has a specialized lecture course on
psychiatric nursing, and seminars on mental healthand psychiatric nursing for graduate students. These
activities are conducted and supervised by the faculty.
In collaboration with the department of mental health,
we also have the department seminar every
Wednesday evening, where members provide theactual plans for their own research and discuss the
topic.
We also have a variety of study clubs. We havepsychiatric nursing study club, study group for
multi-level analysis, qualitative research study group,and so on.

298

Research
Our research field covers mental health andpsychiatric nursing. Our department has many
research projects across diverse fields as follows:
study of self-management in mental health; recovery
in people with mental health difficulties; community
support system for the people with mental healthneeds; peer support; stigma; social inclusion; mental
health in people with substance use disorder orphysical diseases; mental health in nurses or otherworkers; disaster mental health nursing; and reducing
the use of seclusion and restraint. We are conducting
studies in collaboration with researchers in otherinstitutions and universities.

Publications
1.

2.

3.

4.

5.

Fukasawa M, Kawakami N, Umeda M,
Miyamoto K, Akiyama T, Horikoshi N, Yasumura
S, Yabe H, and Bromet EJ. Environmental
radiation level, radiation anxiety, and psychological distress of non-evacuee residents inFukushima five years after the Great East Japan
Earthquake: Multilevel analyses. SSM Popul
Health. 2017 Dec 3: 740-748.
Chiba R, Umeda M, Goto K, Miyamoto Y,
Yamaguchi S, Kawakami N. The property of theJapanese version of the Recovery Knowledge
Inventory (RKI) among mental health service
providers: a cross sectional study. International
Journal of Mental Health Systems. 2017 Dec 28;
11:71.
Kanehara A, Kotake R, Miyamoto Y, Kumakura
Y, Morita K, Ishiura T, et al. The Japanese versionof the questionnaire about the process ofrecovery: development and validity and reliability
testing. BMC Psychiatry. 2017 Nov 7;17(1):360.
Sakuraya A, Watanabe K, Kawakami N, Imamura
K, Ando E, Asai Y, Eguchi H, Kobayashi Y,
Nishida N, Arima H, Shimazu A, Tsutsumi A.
Work-related psychosocial factors and onset of
metabolic syndrome among workers: a systematic
review and meta-analysis protocol. BMJ Open.
2017 Jun 22;7(6):e016716.
Panthee B, Panthee S, Gyawali S, Kawakami N.
Prevalence and correlates of substance use among
healthcare students in Nepal: a cross sectional

study. BMC Public Health. 2017 Dec 12;17(1):950.
6. McGrath JJ, Saha S, Lim CCW, Aguilar-Gaxiola
S, Alonso J, Andrade LH, Bromet EJ, Bruffaerts R,
Caldas de Almeida JM, Cardoso G, de Girolamo
G, Fayyad J, Florescu S, Gureje O, Haro JM,
Kawakami N, Koenen KC, Kovess-Masfety V,
Lee S, Lepine JP, McLaughlin KA, Medina-Mora
ME, Navarro-Mateu F, Ojagbemi A, Posada-Villa
J, Sampson N, Scott KM, Tachimori H, Ten Have
M, Kendler KS, Kessler RC; WHO World Mental
Health Survey Collaborators. Trauma andpsychotic experiences: transnational data from theWorld Mental Health Survey. Br J Psychiatry.
2017 Dec;211(6):373-380.
7. Liu YC, Meguro K, Nakamura K, Akanuma K,
Nakatsuka M, Seki T, Nakaaki S, Mimura M,
Kawakami N. Depression and Dementia in
Old-Old Population: History of Depression May
Be Associated with Dementia Onset. The Tome
Project. Front Aging Neurosci. 2017 Oct 17;9:335.
8. Kessler RC, Aguilar-Gaxiola S, Alonso J, Benjet
C, Bromet EJ, Cardoso G, Degenhardt L, deGirolamo G, Dinolova RV, Ferry F, Florescu S,
Gureje O, Haro JM, Huang Y, Karam EG,
Kawakami N, Lee S, Lepine JP, Levinson D,
Navarro-Mateu F, Pennell BE, Piazza M,
Posada-Villa J, Scott KM, Stein DJ, Ten Have M,
Torres Y, Viana MC, Petukhova MV, Sampson NA,
Zaslavsky AM, Koenen KC. Trauma and PTSD in
the WHO World Mental Health Surveys. Eur J
Psychotraumatol. 2017 Oct 27;8(sup5):1353383.
9. McLaughlin KA, Koenen KC, Bromet EJ, Karam
EG, Liu H, Petukhova M, Ruscio AM, Sampson
NA, Stein DJ, Aguilar-Gaxiola S, Alonso J,
Borges G, Demyttenaere K, Dinolova RV, Ferry F,
Florescu S, de Girolamo G, Gureje O, Kawakami
N, Lee S, Navarro-Mateu F, Piazza M, Pennell BE,
Posada-Villa J, Ten Have M, Viana MC, Kessler
RC. Childhood adversities and post-traumaticstress disorder: evidence for stress sensitisation in
the World Mental Health Surveys. Br J Psychiatry.
2017 Nov;211(5):280-288.
10. Koenen KC, Ratanatharathorn A, Ng L,
McLaughlin KA, Bromet EJ, Stein DJ, Karam EG,
Meron Ruscio A, Benjet C, Scott K, Atwoli L,299

Petukhova M, Lim CCW, Aguilar-Gaxiola S,
Al-Hamzawi A, Alonso J, Bunting B, Ciutan M,
de Girolamo G, Degenhardt L, Gureje O, Haro JM,
Huang Y, Kawakami N, Lee S, Navarro-Mateu F,
Pennell BE, Piazza M, Sampson N, Ten Have M,
Torres Y, Viana MC, Williams D, Xavier M,
Kessler RC. Posttraumatic stress disorder in theWorld Mental Health Surveys. Psychol Med. 2017
Oct;47(13):2260-2274.
11. Tsuno K, Kawakami N, Shimazu A, Shimada K,
Inoue A, P Leiter M. Workplace incivility inJapan: Reliability and validity of the Japaneseversion of the modified Work Incivility Scale. J
Occup Health. 2017 May 25;59(3):237-246.
12. Umeda M, Kawakami N, Miller E. Effect ofsocioeconomic conditions on health careutilization in marital violence: a cross-sectional
investigation from the Japanese Study on
Stratification, Health, Income, and Neighborhood.
Int J Equity Health. 2017 Feb 28;16(1):41.
13. Watanabe K, Kawakami N. Effects of a multicomponent workplace intervention programmewith environmental changes on physical activity
among Japanese white collar employees: aprotocol for a cluster randomised controlled trial.
BMJ Open. 2017 Oct 24;7(10):e017688.
14. Watanabe K, Kawakami N, Imamura K, Inoue A,
Shimazu A, Yoshikawa A, Hiro H, Asai Y, Odagiri
Y, Yoshikawa E, Tsutsumi A. Pokemon GO andpsychological distress, physical complaints, andwork performance among adult workers: a retrospective cohort study. Sci Rep. 2017 Sep 7;7(1):10758.
15. Ali AM, Ahmed A, Sharaf A, Kawakami N,
Abdeldayem SM, Green J. The Arabic Version of
The Depression Anxiety Stress Scale-21:
Cumulative scaling and discriminant-validation
testing. Asian J Psychiatr. 2017 Dec;30:56-58.
16. Nomura S, Sakamoto H, Glenn S, Tsugawa Y,
Abe SK, Rahman MM, Brown JC, Ezoe S,
Fitzmaurice C, Inokuchi T, Kassebaum NJ,
Kawakami N, Kita Y, Kondo N, Lim SS,
Maruyama S, Miyata H, Mooney MD, Naghavi M,
Onoda T, Ota E, Otake Y, Roth GA, Saito E,
Tabuchi T, Takasaki Y, Tanimura T, Uechi M, Vos
T, Wang H, Inoue M, Murray CJL, Shibuya K.
Population health and regional variations ofdisease burden in Japan, 1990-2015: a systematic
subnational analysis for the Global Burden of
Disease Study 2015. Lancet. 2017 Sep 23;390(10101):1521-1538.
17. Yong RKFY, Inoue A, Kawakami N. The validity
and psychometric properties of the Japaneseversion of the Compulsive Internet Use Scale(CIUS). BMC Psychiatry. 2017 May 30;17(1):201.
18. Kunie K, Kawakami N, Shimazu A, Yonekura Y,
Miyamoto Y. The relationship between work
engagement and psychological distress of hospitalnurses and the perceived communication
behaviors of their nurse managers: A crosssectional survey. Int J Nurs Stud. 2017 Jun;71:
115-124.
19. Koenen KC, Ratanatharathorn A, Ng L,
McLaughlin KA, Bromet EJ, Stein DJ, Karam EG,
Meron Ruscio A, Benjet C, Scott K, Atwoli L,
Petukhova M, Lim CC, Aguilar-Gaxiola S,
Al-Hamzawi A, Alonso J, Bunting B, Ciutan M,
de Girolamo G, Degenhardt L, Gureje O, Haro JM,
Huang Y, Kawakami N, Lee S, Navarro-Mateu F,
Pennell BE, Piazza M, Sampson N, Ten Have M,
Torres Y, C Viana M, Williams D, Xavier M,
Kessler RC. Posttraumatic stress disorder in theWorld Mental Health Surveys. Psychol Med. 2017
Oct;47(13):2260-2274.
20. Global Burden of Disease Child and Adolescent
Health Collaboration. Child and Adolescent
Health From 1990 to 2015: Findings From the
Global Burden of Diseases, Injuries, and Risk
Factors 2015 Study. JAMA Pediatr. 2017 Jun 1;
171(6):573-592.
21. Kasai K, Ando S, Kanehara A, Kumakura Y,
Kondo S, Fukuda M, Kawakami N, Higuchi T.
Strengthening community mental health services
in Japan. Lancet Psychiatry. 2017 Apr;4(4):268-270.
22. Sakuraya A, Imamura K, Inoue A, Tsutsumi A,
Shimazu A, Takahashi M, Totsuzaki T, Kawakami
N. Workplace social capital and the onset of major
depressive episode among workers in Japan: a
3-year prospective cohort study. J Epidemiol
Community Health. 2017 Jun;71(6):606-612.
23. Iwanaga M, Iwanaga H, Kawakami N.
Twelve-month use of herbal medicines as a

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remedy for mental health problems in Japan: A
cross-national analysis of World Mental Health
Survey data. Asia Pac Psychiatry. 2017 Sep;9(3).
24. Asai Y, Imamura K, Kawakami N. Association ofjob stressors with panic attack and panic disorderin a working population in Japan: A crosssectional study. J Occup Environ Med. 2017 Jun;59(6):516-521.
25. Sakuraya A, Shimazu A, Eguchi H, Kamiyama K,
Hara Y, Namba K, and Kawakami N. Job crafting,work engagement, and psychological distressamong Japanese employees: a cross-sectional
study. Biopsychosoc Med. 2017 Feb 10;11:6.
26. Atwoli L, Stein DJ, King A, Petukhova M,
Aguilar-Gaxiola S, Alonso J, Bromet EJ, deGirolamo G, Demyttenaere K, Florescu S, Maria
Haro J, Karam EG, Kawakami N, Lee S, Lepine
JP, Navarro-Mateu F, O'Neill S, Pennell BE,
Piazza M, Posada-Villa J, Sampson NA, Ten Have
M, Zaslavsky AM, Kessler RC; WHO World
MentalHealthSurveyCollaborators.
Posttraumatic stress disorder associated with
unexpected death of a loved one: Cross-national
findings from the world mental health surveys.
Depress Anxiety. 2017 Apr;34(4):315-326.
27. Thornicroft G, Chatterji S, Evans-Lacko S,
Gruber M, Sampson N, Aguilar-Gaxiola S,
Al-Hamzawi A, Alonso J, Andrade L, Borges G,
Bruffaerts R, Bunting B, Caldas de Almeida JM,
Florescu S, de Girolamo G, Gureje O, Haro JM,
He Y, Hinkov H, Karam E, Kawakami N, Lee S,
Navarro-Mateu F, Piazza M, Posada-Villa J,
Torres de Galvis Y, Kessler RC. Undertreatmentof people with major depressive disorder in 21
countries. Br J Psychiatry. 2017 Feb;210(2):119124.
28. Kovess-Masfety V, Evans-Lacko S, Williams D,
Andrade LH, Benjet C, Ten Have M, Wardenaar K,
Karam EG, Bruffaerts R, Abdumalik J, Haro Abad
JM, Florescu S, Wu B, De Jonge P, Altwaijri Y,
Hinkov H, Kawakami N, Caldas-de-Almeida JM,
Bromet E, de Girolamo G, Posada-Villa J,
Al-Hamzawi A, Huang Y, Hu C, Viana MC,
Fayyad J, Medina-Mora ME, Demyttenaere K,
Lepine JP, Murphy S, Xavier M, Takeshima T,
Gureje O. The role of religious advisors in mental
health care in the World Mental Health surveys.

Soc Psychiatry Psychiatr Epidemiol. 2017 Mar;52(3):353-367.
29. Bromet EJ, Atwoli L, Kawakami N, NavarroMateu F, Piotrowski P, King AJ, Aguilar-Gaxiola
S, Alonso J, Bunting B, Demyttenaere K, Florescu
S, de Girolamo G, Gluzman S, Haro JM, de JongeP, Karam EG, Lee S, Kovess-Masfety V, MedinaMora ME, Mneimneh Z, Pennell BE, Posada-Villa
J, Salmeron D, Takeshima T, Kessler RC. Posttraumatic stress disorder associated with naturaland human-made disasters in the World Mental
Health Surveys. Psychol Med. 2017 Jan;47(2):227-241.
30. Suzuki Y, Yabe H, Horikoshi N, Yasumura S,
Kawakami N, Ohtsuru A, Mashiko H, Maeda M;
Mental Health Group of the Fukushima HealthManagement Survey..Diagnostic accuracy ofJapanese posttraumatic stress measures after acomplex disaster: The Fukushima Health Management Survey. Asia Pac Psychiatry. 2017 Mar;9(1).
31. Watanabe K, Tabuchi T, Kawakami N.
Improvement of the work environment andwork-related stress: a cross-sectional multilevelstudy of a nationally representative sample ofJapanese workers. J Occup Environ Med. 2017
Mar;59(3):295-303.
32. Imamura K, Kawakami N, Tsuno K, Tsuchiya M,
Shimada K, Namba K, Shimazu A. Effects ofweb-based stress and depression literacy intervention on improving work engagement among
workers with low work engagement: An analysisof secondary outcome of a randomized controlled
trial. J Occup Health. 2017 Jan 24;59(1):46-54.
33. Watanabe K, Kawakami N, Adachi H, Inoue S,
Umstattd MR. Internal consistency, convergent
validity, and structural validity of the Japaneseversion of the Physical Activity Self-Regulation
scale (PASR-12) among Japanese workers: avalidation study. J Occup Health. 2017 Jan 24;59(1):24-32.
34. Arai K, Takano A, Nagata T, Hirabayashi N.
Predictive accuracy of the Historical-ClinicalRisk Managemant-20 for violence in forensic
psychiatric wards in Japan. Crim Behav Ment
Health. 2017 Dec;27(5):409-420.

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Department ofGerontological Nursing /Wound Care Management
Professor
Hiromi Sanada, R.N., P.H.N., W.O.C.N., Ph.D.

Associate Professor
Gojiro Nakagami, R.N., Ph.D.

Associate
Aya Kitamura, R.N., Ph.D., Yuko Mugita, R.N., Ph.D.

Project Research Associate
Kenneth Scott Barton, M.A.

Homepage

http://www.rounenkango.m.u-tokyo.ac.jp/index-e.html

Introduction and Organization
The Department of Gerontological Nursing wasestablished in June 2003, followed by theestablishment of the Department of Wound CareManagement in April 2006. These two departments
are currently headed by one professor and assisted byan associate professor, two research associates, aproject research associate, two part-time lecturers forundergraduate courses, and seven part-time lecturers
for graduate courses. The student body consists of fivedoctoral course students, eight master course students,
one undergraduate, and two research students. The
goal of our department is to achieve “evidence-based
practice and development of gerontological nursing
and wound care management.”

Teaching activities
1. Undergraduate course
For undergraduate education, our department takes
part in lectures of Health Support Practice, Overview
of Clinical Medicine, and Observation of Human
Anatomy, as well as lectures, exercises, and clinicalpractice about gerontological nursing.
1) Health Support Practice (W in 2nd yr; 1 credit)
Nursing is a science of searching for ways to support
health and the achievement of self-actualization, and it
is practiced in various social situations, including
hospitals, healthcare centers or medical facilities. The
aim of this practice is for students to understand thevariety and wide potential of nursing, and to learn themethods and practices for health support throughexperiential learning of various types of nursing fromthe earliest stages of their nursing course. In 2017, ourprogram included themes related to:a) Policy creation for solving the problems confronted in nursingb) Health support servicesc) Hospital management based on nursingd) Creation of a nursing body of knowledge based on
nursing research.
2) Overview of Clinical Medicine (S2 in 3rd yr; 2credits)
The aim of this series of lectures is to learn the basic

302

knowledge and thought process for understanding
clinical medicine, and to learn the pharmaceutics
required for nursing practice. The main content
themes in the 2017 session included:a) Introduction to surgical treatmentb) Introduction to radiologyc) Surgical anesthesiad) Perioperative managemente) Clinical conditionsf) Natural history and treatment of diseasesg) Nursing pharmaceutics
The above lectures were provided through cooperationfrom the departments at The University of Tokyo
Hospital.
3) Observation of Human Anatomy (A1 in 3rd yr; 1
credit)
The aim of a series of the lectures is to gain a deeper
understanding of life and learn about human anatomy
through a careful examination of “death” and“disease,” as conceptual opposites of “life” and“health.” The main themes in the 2017 curriculum
included:a) Introduction to anatomical pathologyb) Case studyc) Introduction to anatomicopathological researchd) Approaches to anatomical pathologye) Autopsy room practicef) Medical specimen room visit
4) Gerontological Nursing (A2 in 3rd yr; 2 credits)
The aim of a series of the lectures is to understand thephysical, psychological, and social characteristics ofthe elderly population, to learn fundamental theories
of gerontological nursing, and to promote anunderstanding of the ailments and conditions required
to provide proper care to the elderly. The main themes
covered in the 2017 session were as follows:a) Practical simulation for gerontological nursingb) Physical, psychological, and social characteristicsof the elderly from a nursing standpointc) Geriatric syndrome and nursing (i.e., dementia,
feeding and swallowing difficulty, malnutrition,pressure ulcer and incontinence)d) Age-related changes in the physiological systeme) Aging and dementiaf) Aging and osteoporosisg) Aging and renal function, hypertension, and strokeh) Aging and cardiovascular disordersi) Aging and respiratory disordersj) Pharmacological management of the elderlyk) Support of walking and movementl) Relationship-building and communication skills
with the elderlym) Group work
A portion of the above lectures was provided throughcooperation from the Department of GeriatricMedicine and other departments at The University ofTokyo Hospital.
5) Clinical Practice in Gerontological Nursing (S2in 4th yr; 2 credits)
The aim of this practicum is to learn about the current
state of gerontological nursing through practice (orpractical training) in a long-term care facility. The
program in 2017 was supported by the long-term carefacility owned by Medical Corporation Tatsuoka.
6) Bachelor’s thesis
The research theme in 2017 was “Developing apressure ulcer severity estimation algorithm via
machine learning.”
2. Graduate course
1) Gerontological Nursing I (S1; 2 credits)
The main theme of Gerontological Nursing I in 2017
was to understand the latest research related to thecare of elderly persons and to discuss future perspectives of gerontological nursing from three viewpoints:
basic biology, engineering, and clinical nursing
research. Recent research papers were selected fromthese three fields and critically evaluated.
2) Gerontological Nursing II (A1; 2 credits)
Gerontological Nursing II provided lectures regarding
recent topics around gerontological medicine andnursing from broad viewpoints, including biological,
individual, and social aspects, by part-time lecturers
and specialists from each research field. The aim of
this course was to understand and learn scientificways of thinking for gerontological considerations of
the future Japanese community. The main themes in2017 were as follows:a) Gerontological nursing and law

303b) Assessment and treatment of defecation disorderc) Nutrition management in the elderly and cancer
patients; physiological activity and deficiency of
micronutrientsd) Nursing care for dementiae) Medical imaging ― recent image processing
techniques and image operations using biosignalsf) Biomedical engineering for ER patients andrehabilitation for hemiplegia patients
3) Wound Care Management I (S2; 2 credits)
The main topic of Wound Care Management I in 2017
was the acquisition of the basic knowledge (i.e., basic
biology, clinical research, and engineering), necessary
to understand wound management studies. The topics
were as follows:a) Structure and function of skin; wound healing andmanagementb) Basics of clinical nursing researchc) Principles of measurement and data organization;
application of measurement devices to medical,
care, and welfare researchd) Application of ultrasound technology in woundcare managemente) Basics and application of biological nursingf) Nursing translational research in the creation of
new nursing techniquesg) Basics of pressure ulcer management and related
nursing science research4) Wound Care Management II (A2; 2 credits)
The main theme of Wound Care Management II in2017 was to obtain deeper insight in our own researchknowledge through lectures and discussion by
specialists from various basic and advanced research
fields. The topics were as follows:a) Pressure ulcer management in home-visit caresettingsb) Leading-edge wound care managementc) Advanced wound care―in cooperation with thediagnosis and treatment department; activities ofWound, Ostomy and Continence Nursesd) Efforts in advanced wound caree) Pressure ulcer care: support surfacesf) Wound assessment using molecular biology
techniquesg) Basic and advanced wound healing

5) Master’s theses
In 2017, the following research themes were
submitted:
 “Development of a mattress sensor system toestimate desire to void for elderly patients withphysical and cognitive impairment”
 “Fecal distribution changes using colorectal
ultrasonography in elderly patients with physicaland cognitive impairment at long-term carefacilities: A longitudinal observational study”
 “Prediction of healing in Category I pressure ulcers
by skin blotting with a lymphangiogenesis marker,
vascular endothelial growth factor C: A pilot
study”
 “Validity of biofilm detection by wound blotting
on chronic wounds”
6) Doctoral theses
The following were research themes in 2017:
 “Development of a biomarker for adrenocorticotropic hormone-induced mechanical hypersensitivity using a full-thickness cutaneous woundmodel”
 “Healing process of incontinence-associateddermatitis and promoting effects of acylated
homoserine lactone on its healing in rats”

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
regularly participate in 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 to304

promote team nursing intervention and research
involving the clinical division, the nursing department,
and the nursing departments of the Graduate School of
Medicine. Through this program, nurses canscientifically study the subject of nursing, including
research in epidemiological surveys and molecularand gene-level topics. Furthermore, the technology
and medical equipment developed by companies canbe evaluated in the hospital, offering new nursing
technologies suitable for needs in clinical sites.
In April 2017, the Global Nursing Research Center(GNRC) was established. Professor Sanada has been
the director, and faculty staff members in our
department have been involved in the Division of Care
Innovation in GNRC. GNRC aims to create a transdisciplinary research and educational environment that
fosters young leaders in nursing research in order topromote care innovation.
In July 2017, we organized the 5th introductory
seminar for bioengineering nursing research involving
many nursing researchers and clinical nurses. In thisseminar, a new research framework “Bioengineering
Nursing” which consists of nursing biology (whichinvestigates, in detail, the mechanism of a target
phenomenon), nursing engineering (which develops
technologies for the clarified target), and nursing
translational
research(whichevaluatesthetechnologies in the clinical field and further explores
new clinical problems) was introduced. Furthermore,
we organized an advanced hands-on seminar of
bioengineering nursing research methodologies for
those who attended the introductory seminar and wereinterested in this research framework.
Regarding international activities, we participatedin the International Research and Development
Summer School held at the University of Nottingham,
the UK, in September 2017. Participants, researchersand graduate students from five countries discussed
chronic wounds and lymphoedema. We introduced
ultrasonographic and thermographic assessment
methods for pressure ulcers and shared thetechnologies used for nursing assessment in Japan
with researchers from other countries. Additionally,
our department has been promoting collaborative
research with researchers in universities around theworld. Our counterparts include: University ofCalifornia, Los Angeles (USA), Florida University(USA), Curtin University (Australia), and The
University of Nottingham (UK). Professor Sanada has
been working as Continental Board for World Union
of Wound Healing Societies and a member of theInternational Board of Directors for International
Lymphoedema Framework.
In April 2017, the Department of Imaging Nursing
Science was established. This department aims topromote nursing skills based on advanced imaging
technologies related to clinical nursing fields andcreate innovative technologies that advance nursing
activities in order to realize a “safe, secure, andcomfortable recuperation environment.”
2. Research fields and themes in 2017
1) Basic experimental studies
・Development of a novel method for controllingwound infection focusing on gene expression ofbacteria and hosts
・Evaluation of wound condition using exudates
・Skin blotting for analyzing physiological status of
the skin・ Development of a new technique for detecting
wound biofilm
・Cutaneous wound healing and diabetes mellitus
・Research on scalp care science・Research on the mechanisms of wound pain
2) Nursing engineering
・Development of a new air mattress equipped withinterface pressure-sensing system and automaticpressure control
・Non-invasive detection of tissue injury and preinjury status using ultrasonography and thermography
・Early detection of complications of peripheral intravascular catheter by thermography
・Development of insole-type measurement system forthe simultaneous measurement of plantar pressure
and shear force during gait・Development of a fitting device for non-invasive
positive pressure ventilation oral-nasal mask usinga three-dimensional solution
・Development of apps using communication robots
for the elderly
・Development of an absorbent pad for the preventionof incontinence-associated dermatitis
3) Clinical studies

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・Novel assessment technologies for pressure ulcers
・Cross-sectional study of diabetic foot (e.g., ulcers,
callus, fissures, onychomycosis) and its risk factors
・Cross-sectional study of malignant wounds in breast
cancer patients and their risk factors
・Survey and international comparison of lymphoedema
・Methods for predicting skin tear development
・Establishment of a novel diagnosis method of latentdysphagia
・Establishment of a novel assessment method of
malnutrition using ultrasonography
・Establishment of a novel assessment method of
constipation using ultrasonography
・Cross-sectional study of the skin of elderly people ina nursing home・Cross-sectional study of the skin of obese people
・Survey of the skin condition of wheelchair basketball athletes・Survey on the relationship between the microbiota
in the bed environment and the development ofpressure ulcer infections
Several awards were given for our research, as
follows:
・Incentive award from the 47th Annual Congress ofJapanese Society for Wound Healing.
Yamane T, Konno R, Nakagami G, Iwatsuki K,
Sanada H, Oishi Y. Effect of the hydrocellular foam
dressing on leptin signal-mediated wound healing
and its molecular mechanism.
・Incentive award from the 5th Annual Congress of
Nursing Science and Engineering.
Matsumoto M, Ogai K, Nemoto T, Kurita T,
Sugama J. Sleep evaluations for 24h and monitoringof vital signs in a bedridden elderly patient withdisorder of consciousness. Journal of Nursing
Science and Engineering, 2015;2(1):47-53.
・Incentive award from the 5th Annual Congress of
Nursing Science and Engineering.
Nitta S, Matsumoto M, Sugama J, Nakagami G,
Okuwa M, Nakatani T, Sanada H. New quantitative
indicators of evaluating the skin care regimen for
older adults with dry skin by using the digital image
analysis, Journal of Nursing Science andEngineering, 2016;3(2):93-100.
・ Young researcher presentation award from

LIFE2017.
Araki D, Noguchi H, Kawaguchi T, Sanada H,
Mori T. Comparison of the learning method of theclassification of posture and movement on bed byinterface pressure sensor inside the mattress.
・President award from the 26th Annual Congress ofJapanese Society of Wound, Ostomy, and Continence Management.
Oya M, Murayama R, Oe M, Tanabe H,
Yabunaka K, Komiyama C, Sanada H. Characteristics of the subcutaneous tissue around the
peripheral intravenous catheters in patients withpaclitaxel-carboplatin combination therapy.
・Article award from the Japanese Society of Wound,
Ostomy, and Continence Management 2017.
Hori N, Tamai N, Noguchi H, Nakagami G,
Sugama J, Mori T, Sanada H．Development andassessment of air mattress with independent air cellpressure control responsive to interface pressure
distribution. Journal of Japanese Society of Wound,
Ostomy, and Continence Management. 2017;20(3):300-9.
・Award from the Japan Society for the Promotion of
Science.
Sanada H. S

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and Urodynamics. 2017;36(1):98-103.
12. Goto T, Nakagami G, Nakai A, Noyori S, Sasaki S,

Hayashi C, Miyagaki T, Akamata K, Sanada H.
Utility of a three-dimensional wound measurement device in pressure ulcers. Chronic Wound
Care Management and Research. 2017;2017(4):129-33.
13. Matsui Y, Murayama R, Tanabe H, Oe M, Motoo
Y, Wagatsuma T, Michibuchi M, Kinoshita S,
Sakai K, Konya C, Sugama J, Sanada H.
Evaluation of the predictive validity ofthermography in identifying extravasation withintravenous chemotherapy infusions. Journal of
Infusion Nursing. 2017;40(6):367-74.
14. Yabunaka K, Nakagami G, Kitamura A, Sanada H.
Pocket-sized versus laptop type ultrasonography
devices for imaging normal subcutaneous tissue.
Journal of Nursing Science and Engineering.
2017;4(1):21-6.
15. Uehata Y, Yoshida M, Yabunaka K, Minematsu T,
Tamai N, Sugama J, Sanada H. Relationship ofskin hardness of the temporal region to nutritional
status. Journal of Nursing Science andEngineering. 2017;4(1):49-57.
16. Nakagami G, Mori M, Yoshida M, Kitamura A,
Hayashi A, Miyagaki T, Sasaki S, Sugama J,
Sanada H. Inter-rater and intra-rater reliability
outcomes of a rapid bacteria counting system withpressure ulcer samples. Journal of Wound Care.
2017;26(Sup2):S27-S31.
17. Goto T, Nakagami G, Takehara K, Nakamura T,
Kawashima M, Tsunemi Y, Sanada H. Examining
the accuracy of visual diagnosis of tinea pedis andtinea unguium in aged care facilities. J Wound
Care. 2017;26(4):179-83.
18. Noyori S, Nakagami G, Noguchi H, Yabunaka K,
Mori T, Sanada H. A new ultrasonographic image
displaying system to support vein detection.
Journal of Robotics and Mechatronics. 2017;29(2):306-16.
19. Koyano Y, Nakagami G, Sanada H. Reliability
and validity of the Japanese version ofIncontinence-Associated Dermatitis and its
Severity (IADS). Journal of Japanese Society ofWound, Ostomy, and Continence. 2017;21(1):1-9.
20. Nozawa K, Tamai N, Minemtsu T, Kitamura A,
Saegusa M, Amaike K, Sanada H. Situation of
occurrence and morphological characteristics ofpressure ulcers among inpatients with mental

307

illness. Journal of Japanese Society of Wound,
Ostomy, and Continence. 2017;21(1):10-24.
21. Oya M, Murayama R, Oe M, Yabunaka K, Tanabe
H, Takahashi T, Matsui Y, Otomo E, Komiyama C,
Sanada H. Continuous thermographic observation
may predict extravasation in chemotherapytreated patients. European Journal of Oncology
Nursing. 2017;28:56-61.
22. Yamanaka H, Okada S, Sanada H. A multicenter,randomized, controlled study of the use ofnutritional supplements containing collagen
peptides to facilitate the healing of pressure ulcers.
Journal of Nutrition and Intermediary Metabolism.
2017;8(2017):51-9.
23. Shiraishi M, Haruna M, Matsuzaki M, Murayama
R, Sasaki S. Availability administered diet history
questionnaires for pregnant Japanese women: A
validation study using 24-hour urinary markers.
Journal of Epidemiology. 2017;27(4):172-9.
24. Yoshida M, Igawa Y, Higashimura S, Suzuki M,
Niimi A, Sanada H. Translation and reliability andvalidity testing of a Japanese version of theIntermittent Self-Catheterization Questionnaire
among disposable and reusable catheter users.
Neurourology and Urodynamics. 2017;36(5):1356-62.
25. Haryanto H, Arisandi D, Suriadi S, Imran I, Ogai
K, Sanada H, Okuwa NM. Relationship between
maceration and wound healing on diabetic footulcers in Indonesia: a prospective study.
International Wound Journal. 2017;14(3):516-22.
26. Takehara K, Iizaka S, Oe M, Sanada H. Reliability
and validity of a portable device for measuring
stratum corneum hydration. Journal of JapaneseSociety Wound, Ostomy, and ContinenceManagement. 2017;21(4):296-303.
27. Higashiguchi T, Ohara H, Kamakura Y, Kikutani T,
Kuzuya M, Enoki H, Sanada H, Matsuzaki M,
Murayama M. Efficacy of a new post-mouthwash
intervention (wiping plus oral nutritional
supplements) for preventing aspiration pneumonia
in elderly people: a multicenter, randomized,
comparative trial. Annals of Nutrition andMetabolism. 2017;71(3-4):253-60.
28. Tsunemi Y, Takehara K, Miura Y, Nakagami G,
Sanada H, Kawashima M. Specimens processedwith an extraction solution of the Dermatophyte

Test Strip can be used for direct microscopy.
British Journal of Dermatology. 2017;177(3):e50e51.
29. Yabunaka K, Nakagami G, Kitamura A, Miyagaki
T, Hayashi A, Sasaki S, Sanada H. Visualizationof blood flow in an undermined pressure ulcer
revealed by sonographic imaging and clutter
suppression post-processing: A case report.
Journal of Diagnostic Medical Sonography. 2017;
33(1):33-6.
30. Yabunaka K, Nakagami G, Komagata K, Sanada
H. Ultrasonographic follow-up of functional
chronic constipation in adults: A report of twocases. SAGE Open Medical Case Reports. 2017;5:
1-4.
31. Oe M, Takehara K, Noguchi H, Ohashi Y,
Amemiya A, Sakoda H, Suzuki R, Yamauchi T,
Ueki K, Kadowaki T, Sanada H. Thermographic
findings in a case of type 2 diabetes with footulcer due to callus deterioration. Diabetology
International. 2017;8(3):328-33.

International Health
1. International Social Medicine

309

Department of
Global Health Policy
Professor
Kenji Shibuya, MD, DrPH

Assistant Professor
Sarah Abe, MSc, PhD
Shuhei Nomura, MSc

Project Assistant Professor
Md. Mizanur Rahman, MSc, PhD

Homepage

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

Introduction and Organization
Our mission is to improve population health byenhancing accountability and improving the evidencebase for global health programs, through the provisionof the best possible information and rigorous
monitoring and evaluation. The department's members
generate knowledge and ideas through their research,strengthen technical and leadership skills througheducational programs, and enhance national capacities
through collaborative projects, especially in thedeveloping world. As of March 2018 the department,
headed by Professor Kenji Shibuya, included thefollowing staff complement; two assistant professors(Sarah Abe, Shuhei Nomura); one project assistantprofessors (Md. Mizanur Rahman); three post-doctoral
fellows; 12 adjunct lecturers; 10 doctoral students; andnine master’s students.
The priority areas of research are:
- Health outcome research (mortality, morbidity anddisability; health service research; health technology
assessment and cost-effectiveness; disease modeling; and comparative risk factor analysis);- Health system performance assessment, including
the analysis of health system inputs, outputs, andimpact;- Health and foreign policy (e.g. global healtharchitecture and governance, the 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 presentation
skills are held to an international standard. Furthermore,through the Global Health Entrepreneurship Program(GHE) students are able to develop skills andexperience to become future leaders in global health.
Master's program
The Master's program is a demanding, interdisciplinary
program emphasizing student-directed learning,problem-solving, and the acquisition of fundamental
public health skills required for global health practices(health policy, statistics, epidemiology, and social
sciences). Students are required to complete aminimum of 30 course credits and a master’s thesis.
Beyond the program and concentration requirements,

310

students are encouraged to consult with faculty
advisers to choose elective courses best suited to theirneeds.

A guest speaker or a master or doctoral student presents
his/her research. There is a 15-minute presentationfollowed by a 30-minute discussion.

PhD program
The PhD program is designed to train the next
generation of leaders in global health. PhD students are
required to complete a minimum of 24 course credits
and a doctoral thesis with which needs to be publishedin a peer-reviewed journal. PhD students without MPH
degree should take the lectures to acquire fundamental
public health skills such as health policy, biostatistics
and epidemiology.

Research

Global Health Policy I and IIThis course introduces the principles and theories ofglobal health problems, as well as practical applicationsof quantitative methods (demography, statistics,
epidemiology and econometrics) to analyze andinterpret issues and challenges for policy.
The followings are the topics covered in the academic
year 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- Health system performance assessment- Health service quality- Monitoring and evaluation- Financing health systems
GHP Monday seminar
Every Monday, 13:00-15:00 pm
1) Journal clubStudents present a brief summary of research articles
from the major medical, social science, economics
journals, which are relevant for global health policy.
The major objective is to share knowledge, evoke
debates and facilitate discussions.
2) Research seminar

A comprehensive assessment of the burden of diseasein Japan. Ministry of Education, Culture, Sports,
Science and Technology, Grants-in-Aid for Scientific
Research (A). PI: Kenji Shibuya.
An evidence-based assessment of the Japanese healthsystem. Ministry of Health, Labour, and Welfare Healthand Labour Science Research Grants. PI: Kenji
Shibuya
AXA Chair on Health and Human Security, AXA
Research Fund
Analysis of the time-dependent trend of internal
exposure examination after Fukushima Nuclear Power
Plant accident and factors related to consultation
behavior. Program of the network-type Joint
Usage/Research Center for Radiation Disaster Medical
Science of Hiroshima University, Nagasaki University,and Fukushima Medical University. PI: Shuhei Nomura
Assessment of the mid- to long-term health effects ofJapan's 2011 Fukushima nuclear disaster―towarddisaster-resilient health care systems. Toyota
Foundation Research Grant Program. PI: Shuhei
Nomura.

Publications
1.

2.

Toda H, Nomura S, Gilmour S, Tsubokura M,
Oikawa T, Lee K, Kiyabu GY, Shibuya K.
Assessment of medium-term cardiovasculardisease risk after Japan’s 2011 Fukushima Daiichi
nuclear accident: a retrospective analysis. BMJ
Open. 2017; 7(12): e018502.
Tsubokura M, Nomura S, Yoshida I, Sawano T,
Miyazaki M, Tomita S, Oikawa T, Watanabe M.
Comparison of external doses between radiocontaminated areas and areas with high natural
terrestrial background using the individual
dosimeter "D-shuttle" 75 months after the
Fukushima Daiichi nuclear power plant accident.

311

3.

4.

5.

6.

7.

8.

9.

Journal of Radiological Protection. 2017; Online
first.
Tokiwa S, Shimmura H, Nomura S, Watanabe R,
Kurita M, Yoshida N, Yamashita K, Nishikawa Y,
Kouzmenko A, Kato S. Degarelix treatment iscompatible with diabetes and antithrombotic
therapy in patients with prostate cancer. Researchand Reports in Urology. 2017; 9: 225-232.
Shichijo S, Nomura S, Aoyama K, Nishikawa Y,
Miura M, Shinagawa T, Takiyama H, Tanimoto T,
Ishihara S, Matsuo K, Tada T. Application of
convolutional neural networks in the diagnosis ofhelicobacter pylori infection based on endoscopic
images. EBioMedicine. 2017; 25:106-111.
Tsubokura M, Murakami M, Nomura S, Morita T,
Nishikawa Y, Leppold C, Kato S, Kami M.
Individual external doses below the lowest
reference level of 1 mSv per year five years after
the 2011 Fukushima nuclear accident among all
children in Soma City, Fukushima: a retrospective
observational study. PLoS One. 2017; 12(2):e0172305.
Nomura S, Tsubokura M, Ozaki A, Murakami M,
Hodgson S, Blangiardo M, Nishikawa Y, Morita T,
Oikawa T. Towards a long-term strategy forvoluntary-based internal radiation contamination
monitoring: a population-level analysis ofmonitoring prevalence and factors associated with
monitoring participation behavior in Fukushima,
Japan. International Journal of Environmental
Research and Public Health. 2017; 14(4):397.
Morita T, Nomura S, Tsubokura M, Leppold C,
Gilmour S, Ochi S, Ozaki A, Shimada Y,
Yamamoto K, Inoue M, Kato S, Shibuya K, Kami
M. Excess mortality due to indirect health effectsof the 2011 triple disaster in Fukushima, Japan: aretrospective observational study. J Epidemiol
Community Health. 2017; Online first.
Nomura S, Tsubokura M, Murakami M, Ono K,
Nishikawa Y, Oikawa T. Towards a long-term
strategy for voluntary-based internal radiation
contamination monitoring: representativeness ofthe monitoring results in Fukushima, Japan.
International Journal of Environmental Researchand Public Health. 2017; 14(6):656.
Nomura S, Sakamoto H, Glenn S, Tsugawa Y, Abe
SK, Rahman MM, Brown JC, Ezoe S, Fitzmaurice

10.

11.

12.

13.

14.

15.

C, Inokuchi T, Kassebaum NJ, Kawakami N, Kita
Y, Kondo N, Lim SS, Maruyama S, Miyata H,
Mooney MD, Naghavi M, Onoda T, Erika O,
Otake Y, Roth GA, Saito E, Tabuchi T, Takasaki Y,
Taimura T, Uechi M, Vos T, Wang H, Inoue M,
Murray CJL, Shibuya K. Population health andregional variations of disease burden in Japan,
1990–2015: a systematic subnational analysis for
the Global Burden of Disease Study 2015. The
Lancet. 2017; 390:1521-38.
Ozaki A, Nomura S, Leppold C, Tsubokura M,
Tanimoto T, Yokota T, Saji S, Sawano T, Tsukada
M, Morita T, Ochi S, Kato S, Kami M, Nemoto T,
Kanazawa Y, Ohira H. Breast cancer patient delay
in Fukushima, Japan following the 2011 triple
disaster: a long-term retrospective study. BMC
Cancer 2017; 17(1): 423.
Leppold C, Nomura S, Sawano T, Ozaki A,
Tsubokura M, Hill S, Kanazawa Y, Anbe H. Birthoutcomes after the Fukushima Daiichi Nuclear
Power Plant Disaster: a long-term retrospective
study. International Journal of Environmental
Research and Public Health 2017, 14(5): 542.
Ozaki A, Yokota T, Nomura S, Tsubokura M,
Leppold C, Tanimoto T, Miura T, Yamamoto K,
Sawano T, Tsukada M, Kami M, Ohira H.
Decontamination work and the long-term increasein hospital visits for hymenopteran stings
following the Fukushima nuclear disaster: aretrospective observational study. Disaster
Medicine and Public Health Preparedness 2017;11(5): 545-51.
Murakami M, Tsubokura M, Ono K, Nomura S,
Oikawa T. Additional risk of diabetes exceeds theincreased risk of cancer caused by radiation
exposure after the Fukushima disaster. Plos One
2017; 12(9): e0185259.
Ezoe S, Noda H, Akahane N, Sato O, Hama T,
Miyata T, Terahara T, Fujishita M, Sakamoto H,
Abe SK, Gilmour S, Shobayashi T. Trends inpolicy on the prevention and control of noncommunicable diseases in Japan. Health Systems& Reform. 2017; 3(4): 268-277.
Rahman MM, Karar A, Rahman MS, Parsons A,
Abe SK, Bilano V, Gilmour S, Shibuya K.
Progress toward universal health coverage: acomparative analysis in 5 South Asian countries.

312

16.

17.

18.

19.

20.

21.

22.

23.

JAMA Intern Med. 2017; 177(9): 1297-1305.
Song H, Saito E, Sawada N, Abe SK, Hidaka A,
Shimazu T, Yamaji T, Goto A, Iwasaki M,
Sasazuki S, Ye W. Body mass index change during
adulthood and risk of oesophageal squamous-cellcarcinoma in a Japanese population: the Japan
Public Health (JPHC)-based prospective study.
British Journal of Cancer. 2017; 117(11):1715.
Huang HL, Leung CY, Cheng CJ. Mass-like
Dieulafoy's lesion associated with advanced
gastric cancer at the antrum of stomach: a casereport and literature review. Diagnostic Pathology.
2017; 12(1): 73.
Song H, Saito E, Sawada N, Abe SK, Hidaka A,
Shimazu T, Yamaji T, Goto A, Iwasaki M,
Sasazuki S, Ye W. Perceived stress level and riskof cancer incidence in a Japanese population: theJapan Public Health Center (JPHC)-based Prospective Study. Scientific Reports. 2017; 7(1):12964.
Babamuradova K, Sidikov Z, Ichikawa M,
Regional disparities in human resources andinfrastructure in public eye care services in
Uzbekistan. Public Health Panorama. 2017; 3(3):398-407.
GBD 2016 Risk Factors Collaborators. Global,
regional, and national comparative risk
assessment of 84 behavioural, environmental andoccupational, and metabolic risks or clusters ofrisks, 1990–2016: a systematic analysis for the
Global Burden of Disease Study 2016. The Lancet.
2017; 390: 1345-1422.
GBD 2016 DALYs and HALE Collaborators.
Global, regional, and national disability-adjusted
life-years (DALYs) for 333 diseases and injuries
and healthy life expectancy (HALE) for 195
countries and territories, 1990–2016: a systematic
analysis for the Global Burden of Disease Study
2016. The Lancet. 2017; 390: 1260–1344.
GBD 2016 Causes of Death Collaborators. Global,
regional, and national age-sex specific mortality
for 264 causes of death, 1980–2016: a systematic
analysis for the Global Burden of Disease Study
2016. The Lancet. 2017; 390: 1151–1210.
GBD 2016 Mortality Collaborators. Global,
regional, and national under-5 mortality, adultmortality, age-specific mortality, and life

24.

25.

26.

27.

28.

29.

30.

31.

expectancy, 1970–2016: a systematic analysis for
the Global Burden of Disease Study 2016. The
Lancet. 2017; 390: 1084–1150.
GBD 2016 SDG Collaborators. Measuring
progress and projecting attainment on the basis ofpast trends of the health-related Sustainable
Development Goals in 188 countries: an analysis
from the Global Burden of Disease Study 2016.
The Lancet. 2017; 390: 1423–59.
Narita S, Saito E, Sawada N, Shimazu T, Yamaji T,
Iwasaki M, Sasazuki S, Noda M, Inoue M,
Tsugane S. Coffee consumption and lung cancer
risk: the Japan Public Health Center-based
Prospective Study. Journal of Epidemiology. 2017.
Online first.
Kita Sugai M, Gilmour S, Ota E, Shibuya K.
Trends in perinatal mortality and its risk factors inJapan: Analysis of vital registration data, 1979–
2010. Scientific Reports. 2017; 46681.
Shin S, Saito E, Sawada N, Ishihara J, Takachi R,
Nanri A, Shimazu T, Yamaji T, Iwasaki M,
Sasazuki S, Inoue M et al. Menstrual andreproductive factors in the risk of thyroid cancer
in Japanese women: the Japan Public HealthCenter-based Prospective Study (JPHC study).
European Journal of Cancer Prevention. 2017;27(4):361-369.
Chen Y, Fen W, Saito E, Lin Y, Song M et al.
Association between type 2 diabetes and risk ofdeath from cancer: a pooled analysis of over 771
000 individuals in the Asia Cohort Consortium.
Diabetologia. 2017; 60(6): 1022-1032.
Narita S, Inoue M, Saito E, Abe SK et al. Dietaryfiber intake and risk of breast cancer defined by
estrogen and progesterone receptor status: theJapan Public Health Center-based Prospective
Study. Cancer Causes & Control. 2017; 28: 569.
Teng Y, Saito E, Abe SK, Sawada N, Iwasaki M,
Yamaji T, Shimazu T, Sasazuki S, Inoue M et al.
Female reproductive factors, exogenous hormone
use, and pancreatic cancer risk: The Japan Public
Health Center-based Prospective Study. European
Journal of Cancer Prevention. 2017; 26(5): 378384.
Islam MR, Rahman MS, Islam Z, Zhang C,
Sultana P, Rahman MM. Inequalities in financial
risk protection in Bangladesh: an assessment of

313

universal health coverage. International Journal
for Equity in Health. 2017; 16: 59.
32. Khan MN, Rahman MM, Shariff AA, Rahman
MM, Rahman MS, Rahman MA. Maternal
undernutrition and excessive body weight and riskof birth and health outcomes. Archives of Public
Health. 2017; 75: 12.
33. Rahman MM, Akter S, Jung J, Rahman MS,
Sultana P. Trend, projection, and appropriate bodymass index cut-off point for diabetes andhypertension in Bangladesh. Diabetes Researchand Clinical Practice. 2017; 126:43-53.

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Department of Community andGlobal HealthProfessor, Academic Leader
Masamine Jimba, MD, PhD, MPH

Assistant Professors
Akira Shibanuma, MID
Junko Kiriya, PhD

Website: http://www.ich.m.u-tokyo.ac.jp/en/index.html
Introduction and Organization
The Department of Community and Global Health(formerly Department of International Community
Health) has been headed by four professors since
1993: Professors Gen Ohi (1993-1996), Som-Arch
Wongkhomthong (1996-1999), Susumu Wakai (19992006), and Masamine Jimba (2006-present).
The mission of the department is to seek equity andsocial justice in health within and across nations. To
achieve this, we aim toward:
1. Investigating how to improve health status of themost vulnerable people, in particular, in developing
countries
2. Undertaking research on the influence of globalization on health and social development
3. Investigating mechanisms to reduce inequalities
between and within nations on health and development
Our research focuses on how to promote
community-based activities and how to link abottom-up approach to national and international
policies. As of April 2017, the members of thedepartment include department chair and professor, 2assistant professors, 4 secretaries, 13 visiting lecturers,
15 doctoral students, 19 master's degree students, 2
research students, and 30 visiting scientists. Morethan half of the students in this department areinternational students.

International Cooperation
Activities
As part of our international cooperation activities,
we provided technical assistance of developing thematernal and child health handbook in China throughParent and Child Health Handbook Promotion
Association of Japan. As Regional Vice-President for
Northern Part of Western Pacific of International
Union for Health Promotion and Education, Professor
Jimba contributed to enhancing health promotion at
the global and regional level. In addition, as the
President of Asia-Pacific Academic Consortium for
Public Health, Professor Jimba takes a leading role in
improving public health research and practices in theregion.

Education
The main objectives of our teaching activities are
the following two:1) To train researchers who understand and complement the wise activities of practitioners in thefield.
2) To train practitioners who can also wisely carryout research in the field.
The postgraduate curriculum is composed mainly

315of community and global health advanced courses,
exercises and practical work. All curricula focus oncommunity health. Our main educational activities
other than the curriculum include technical assistancein writing Master’s and doctoral theses. We always
encourage students to publish their theses ininternational journals. In addition, we urge students togain experiences in the field and learn about real
global health from their experiences.
Because we have many international students, alllectures, practices, and discussions are carried out inEnglish. For those who do not have health/medical
background, we provide a wide variety of curriculafrom basics to advanced level.
We also provide training run by JICA and lecturesin different universities to young leaders fromoverseas.

Our research has been conducted in various
countries, including Nepal, Myanmar, Thailand,
Bangladesh, Viet Nam, Lao PDR, Cambodia,
Indonesia, Ghana, Tanzania, Kenya, Zambia, andPeru.

Publications
1.

2.

Research
The major objectives of our research activities are
the following two:3.

1) To promote research which has a significant
impact on international and local societies

2) To promote research which contributes toendogenous development

We aim to demonstrate research findings based oncommunity-based data directly collected from thefield. Therefore, we consider fieldwork is very important. At the same time, our department aims tocontribute to policy making and promoting actions forbetter health by making the most of community-based
research. We carry out research by working incollaboration with different research institutes, international organizations, JICA, NGOs, and universities
in developing countries. We conduct research mainly
in developing countries, but we are also involved inresearch in Japan.
The major directions of current research haveencompassed 1) health, nutrition, and development, 2)
health, human rights and human security, 3)
ecological approach in infectious disease control, 4)
health promotion, 5) disaster and health, 6) humanresources for health worldwide, and 7) maternal andchild health.

4.

5.

6.

Okawa S, Mwanza-Kabaghe S, Mwiya M,
Kikuchi K, Jimba M, Kankasa C, Ishikawa N.
Adolescents' Experiences and Their Suggestionsfor HIV Serostatus Disclosure in Zambia: A
Mixed-Methods Study. Front Public Health. 2017
Dec 15;5:326.
Fujimura MS, Komasa Y, Kimura S, Shibanuma
A, Kitamura A, Jimba M. Roles of children andtheir parents in the reduction of radiation risk
after the 2011 Fukushima Daiichi Nuclear Power
Plant accident. PLoS One. 2017 Dec;13;12(12):e0188906.
Ong KIC, Kosugi H, Thoeun S, Araki H, Thandar
MM, Iwagami M, Hongvanthong B, Brey PT,
Kano S, Jimba M. Systematic review of theclinical manifestations of glucose-6-phosphate
dehydrogenase deficiency in the Greater Mekong
Subregion: implications for malaria elimination
and beyond. BMJ Glob Health. 2017 Aug 19;
2(3):e000415.
Sakeah E, Okawa S, Rexford Oduro A,
Shibanuma A, Ansah E, Kikuchi K, Gyapong M,
Owusu-Agyei S, Williams J, Debpuur C, Yeji F,
Kukula VA, Enuameh Y, Asare GQ, Agyekum
EO, Addai S, Sarpong D, Adjei K, Tawiah C,
Yasuoka J, Nanishi K, Jimba M, et al.
Determinants of attending antenatal care at least
four times in rural Ghana: analysis of a crosssectional survey. Glob Health Action. 2017;10(1):1291879.
Pokhrel KN, Sharma VD, Shibanuma A, Pokhrel
KG, Mlunde LB, Jimba M. Predicting
health-related quality of life in people living with
HIV in Nepal: mental health disorders andsubstance use determinants. AIDS Care. 2017
Sep;29(9):1137-1143.
Shakya P, Kunieda MK, Koyama M, Rai SS,
Miyaguchi M, Dhakal S, Sandy S, Sunguya BF,
Jimba M. Effectiveness of community-based

316

7.

8.

9.

10.

11.

12.

13.

peer support for mothers to improve theirbreastfeeding practices: A systematic review andmeta-analysis. PLoS One. 2017 May 16;12(5):e0177434.
Saw YM, Saw TN, Yasuoka J, Chan N, Kham
NPE, Khine W, Cho SM, Jimba M. Genderdifference
inearly
initiationofmethamphetamine use among current methamphetamine users in Muse, Northern Shan State,
Myanmar. Harm Reduct J. 2017 May 8;14(1):21.
Hongo H, Green J, Nanishi K, Jimba M.
Development of the revised Japanese Maternal
Breastfeeding Evaluation Scale, short version.
Asia Pac J Clin Nutr. 2017 May;26(3):392-395.
Sunguya BF, Mlunde LB, Urassa DP, Poudel KC,
Ubuguyu OS, Mkopi NP, Leyna GH, Kessy AT,
Nanishi K, Shibanuma A, Yasuoka J, Jimba M.
Improving feeding and growth of HIV-positive
children through nutrition training of frontline
health workers in Tanga, Tanzania. BMC Pediatr.
2017 Apr 4;17(1):94.
Kikuchi K, Poudel KC, Rwibasira JM,
Majyambere A, Mutabazi V, Nyonsenga SP,
Muhayimpundu R, Jimba M. Caring forperinatally HIV-infected children: call for mental
care for the children and the caregivers. AIDS
Care. 2017 Oct;29(10):1280-1286.
Kamiya Y, Akpalu B, Mahama E, Ayipah EK,
Owusu-Agyei S, Hodgson A, Shibanuma A,
Kikuchi K, Jimba M; Ghana EMBRACE
Implementation Research Project Team. The
gender gap in relation to happiness andpreferences in married couples after childbirth:
evidence from a field experiment in rural Ghana.
J Health Popul Nutr. 2017 Mar 15;36(1):8.
Vorasane S, Jimba M, Kikuchi K, Yasuoka J,
Nanishi K, Durham J, Sychareun V. An
investigation of stigmatizing attitudes towards
people living with HIV/AIDS by doctors andnurses in Vientiane, Lao PDR. BMC Health Serv
Res. 2017 Feb 10;17(1):125.
Sunguya BF, Mlunde LB, Ayer R, Jimba M.
Towards eliminating malaria in high endemic
countries: the roles of community health workers
and related cadres and their challenges in
integrated community case management formalaria: a systematic review. Malar J. 2017 Jan

3;16(1):10.

International Health
2. International Biomedical Sciences

318

Department of Human Genetics
Professor
Katsushi Tokunaga, Ph.D.

Associate Professor
Akihiko Mabuchi, M.D., Ph.D.

Assistant professor
Yuki Hitomi, Ph.D.,

Hiromi Sawai, Ph.D.

Project Assistant professor
Hiromi Toyoda, Ph.D., Yosuke Kawai, Ph.D.,

Yosuke Omae, Ph.D.,

Seik-Soon Khor, 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, 6 assistant professors,
1 research associate, 6 graduate students, and 6
research assistants/technicians. We also accept a few
graduate students from clinical departments for their
PhD studies.

Teaching activities
For students at the Graduate School of International
Health, courses that cover basic principles as well as
the clinical application of human genetics areprovided.
As to undergraduate students, a series of lectures isgiven to each of the sophomore (Human Genetics I,
compulsory) and junior (Human Genetics II, elective)classes at the School of Health Sciences. A series oflectures is also provided to the first year (M0) students
at the School of Medicine (compulsory).

Research activities
The Department of Human Genetics is broadlyinterested in the human genome diversity, especiallyin the Asian populations. Specifically, we are using

genomic research tools including SNP and microsatellite 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 in319Japan.

References
1. Ueta M*, Sawai H* (equal contribution), Shingaki
R, Kawai Y, Sotozono C, Kojima K, Yoon K-C,
Kim MK, Seo KY, Joo C-K, Nagasaki M,
Kinoshita S, and Tokunaga K. Genome-wide
association study using the ethnicity-specific
Japonica array: Identification of new susceptibility loci for cold medicine-related StevensJohnson syndrome with severe ocular complications. J. Hum. Genet. 62(4): 485-489, 2017.
2. Shimada-Sugimoto M, Otowa T, Miyagawa T,
Umekage T, Kawamura Y, Bundo M, Iwamoto K,
Tochigi M, Kasai K, Kaiya H, Tanii H, Okazaki Y,
Tokunaga K, and Sasaki T. Epigenome-wide
association study of DNA methylation in panic
disorder. Clin. Epigenet. 9: e6, 2017.
3. Kawashima M*, Hitomi Y*, Aiba Y*, Nishida N*,
Kojima K* (equal contribution), Kawai Y,
Nakamura H, Tanaka A, Zeniya M, Hashimoto E,
Ohira H, Yamamoto K, Abe M, Nakao K,
Yamagiwa S, Kaneko S, Honda M, Umemura T,
Ichida T, Seike M, Sakisaka S, Harada M,
Yokosuka O, Ueno Y, Senju M, Kanda T, Shibata
H, Himoto T, Murata K, Miyake Y, Ebinuma H,
Taniai M, Joshita S, Nikami T, Ota H, Kouno H,
Kouno H, Nakamuta M, Fukushima N, Kohjima
M, Komatsu T, Komeda T, Ohara Y, Muro T,
Yamashita T, Yoshizawa K, Nakamura Y, Shimada
M, Hirashima N, Sugi K, Ario K, Takesaki E,
Naganuma A, Mano H, Yamashita H, Matsushita
K, Yamauchi K, Makita F, Nishimura H, Furuta K,
Takahashi N, Kikuchi M, Masaki N, Tanaka T,
Tamura S, Mori A, Yagi S, Shirabe K, Komori A,
Migita K, Ito M, Nagaoka S, Abiru S, Yatsuhashi
H, Yasunami M, Shimoda S, Harada K, Egawa H,
Maehara Y, Uemoto S, Kokudo N, Takikawa H,
Ishibashi H, Chayama K, Mizokami M, Nagasaki
M, Tokunaga K, and Nakamura M. Genome-wide
association studies identify PRKCB as a novel
genetic susceptibility locus for primary biliary
cirrhosis in the Japanese population. Hum. Mol.
Genet. 26(3): 650-659, 2017.
4. Matsuura K, Sawai H, Ikeo K, Ogawa S, Iio E,
Isogawa M, Shimada N, Komori A, Toyoda H,

5.

6.

7.

8.

Kumada T, Namisaki T, Yoshiji H, Sakamoto N,
Nakagawa M, Asahina Y, Kurosaki M, Izumi N,
Enomoto N, Kusakabe A, Kajiwara E, Itoh Y, Ide
T, Tamori A, Matsubara M, Kawada N, Shirabe K,
Tomita E, Honda M, Kaneko S, Nishina S,
Suetsugu A, Hiasa Y, Watanabe H, Genda T,
Sakaida I, Nishiguchi S, Takaguchi K, Tanaka E,
Sugihara J, Shimada M, Kondo Y, Kawai Y,
Kojima K, Nagasaki M, Tokunaga K, and Tanaka
Y. Genome-wide association study identifies a
TLL1 variant associated with developing hepatocellular carcinoma after eradication of hepatitis C
virus. Gastroenterol. 152(6): 1383-1394, 2017.
Wakamatsu TH, Ueta M, Tokunaga K, Okada Y,
Loureiro RR, Costa KA, Sallum JM, Milhomens
JA, Inoue C, Sotozono C, Gomes JÁ, andKinoshita S. Human leukocyte antigen class I
genes associated with Stevens-Johnson syndrome
and severe ocular complications following use ofcold medicine in a Brazilian population. JAMA
Ophthalmol. 135(4): 355-360, 2017.
Ohigashi I, Ohte Y, Setoh K, Nakase H, Maekawa
A, Kiyonari H, Hamazaki Y, Sekai M, Sudo T,
Tabara Y, Sawai H, Omae Y, Yuliwulandari R,
Tanaka Y, Mizokami M, Inoue H, Kasahara M,
Minato N, Tokunaga K, Tanaka K, Matsuda F,
Murata S, and Takahama Y. A human PSMB11
variant affects thymoproteasome processing andCD8+ T cell production. JCI Insight 2(10):e93664, 2017.
Nagao Y, Nishida N, Toyo-Oka L, Kawaguchi A,
Amoroso A, Carrozzo M, Sata M, Mizokami M,
Tokunaga K, and Tanaka Y. Genome-wide
association study identifies risk variants for lichen
planus in patients with hepatitis C virus infection.
Clin. Gastroenterol. Hepatol. 15(6): 937-944,
2017.
Ikeda M, Takahashi A, Kamatani Y, Okahisa Y,
Kunugi H, Mori N, Sasaki T, Ohmori T, Okamoto
Y, Kawasaki H, Shimodera S, Kato T, Yoneda H,
Yoshimura R, Iyo M, Matsuda K, Akiyama M,
Ashikawa K, Kashiwase K, Tokunaga K, Kondo
K, Saito T, Shimasaki A, Kawase K, Kitajima T,
Matsuo K, Itokawa M, Someya T, Inada T,
Hashimoto R, Inoue T, Akiyama K, Tanii H, Arai
H, Kanba S, Ozaki N, Kusumi I, Yoshikawa T,
Kubo M and Iwata N. A genome-wide association

320

study identifies two novel susceptibility loci andtrans population polygenicity associated withbipolar disorder. Mol. Psychiatry 23(3): 639-647,
2018. (Jan 2017, Epub ahead of print)
9. Trinks J, Nishida N, Hulaniuk ML, Caputo M,
Tsuchiura T, Marciano S, Haddad L, Blejer J,
Bartoli S, Ameigeiras B, Frías SE, Vistarini C,
Heinrich F, Remondegui C, Ceballos S,
Echenique G, Charre Samman M, D'Amico C,
Rojas A, Martínez A, Ridruejo E, Fernández RJ,
Pratx LB, Salamone H, Nuñez F, Galdame O,
Gadano A, Corach D, Sugiyama M, Flichman D,
Tokunaga K, and Mizokami M. Role of HLA-DP
and HLA-DQ on the clearance of hepatitis B virus
and the risk of chronic infection in a multiethnic
population. Liver Int. 37(10): 1476-1487, 2017.
10. Sugiura-Ogasawara
M*,
Omae
Y*(equal
comtribution), Kawashima M, Toyo-Oka L, Khor
S-S, Sawai H, Horita T, Atsumi T, Murashima A,
Fujita D, Fujita T, Morimoto S, Morishita E,
Katsuragi S, Kitaori T, Katano K, Ozaki Y, andTokunaga K. The first genome-wide association
study identifying new susceptibility loci for
obstetric antiphospholipid syndrome. J. Hum.
Genet. 62(9): 831-838, 2017.
11. Hitomi Y, Kojima K, Kawashima M, Kawai Y,
Nishida N, Aiba Y, Yasunami M, Nagasaki M,
Nakamura M, and Tokunaga K. Identification of
the primary functional variant in an extended
linkage disequilibrium block of human chromosome 17q12-21 in primary biliary cholangitis Sci.
Rep. 7(1): e2904, 2017.
12. Toyo-Oka L, Mahasirimongkol S, Yanai H,
Mushiroda T, Wattanapokayakit S, Wichukchinda
N, Yamada N, Smittipat N, Juthayothin T,
Palittapongarnpim P, Nedsuwan S, Kantipong P,
Takahashi A, Kubo M, Sawanpanyalert P, andTokunaga K. Strain based HLA association
analysis identified HLA-DRB1*09:01 associatedwith modern strain tuberculosis. HLA 90(3): 149156, 2017.
13. Jinam TA, Phipps ME, Aghakhanian F, Majumder
PP, Datar F, Stoneking M, Sawai H, Nishida N,
Tokunaga K, Kawamura S, Omoto K and Saitou N.
Discerning the origins of the Negritos, first
Sundaland peoples: Deep divergence and archaic
admixture. Genome Biol. Evol. 9(8): 2013-2022,

2017.
14. Omae Y, Toyo-oka L, Yanai H, Nedsuwan S,
Wattanapokayakit S, Satproedprai N, Smittipat N,
Palittapongarnpim P, Sawanpanyalert P, Inunchot
W, Pasomsub E, Wichukchinda N, Mushiroda T,
Kubo M, Tokunaga K, and Mahasirumongkol S.
Pathogen lineage-based genome-wide association
study identified CD53 as susceptible locus in
tuberculosis. J. Hum. Genet. 62(12): 1015-1022,
2017.
15. Yasunami M, Nakamaura H, Tokunaga K,
Kawashima M, Nishida N, Hitomi Y, andNakamura M. Principal contribution of HLA-DQ
alleles, DQB1*06:04 and DQB1*03:01, to disease
resistance against primary biliary cholangitis in a
Japanese population. Sci. Rep. 7(1): e11093,
2017.
16. Lee MH, Hwang YH, Chen HY, Khor CS, Chang
YH, Lin YJ, Jen CL, Lu SN, Nishida N,
Mizokami M, Yuan Y, L’Italien G, Tokunaga K,
and Chen CJ; REVEAL-HCV Cohort. Humanleukocyte antigen Variants and risk of hepatocellular carcinoma modified by HCV genotypes:
A genome-wide association study. Hepatology(Sep 2017, Epub ahead of print)
17. Kannabiran C, Ueta M, Sangwan V, Rathi V, Basu
S, Tokunaga K, and Kinoshita S. Association ofhuman leukocyte antigens class 1 genes with
Stevens Johnson Syndrome with severe ocularcomplications in Indian population. Sci. Rep.
7(1): e15960, 2017.
18. Toyoda H, Honda Y, Tanaka S, Miyagawa T,
Honda M, Honda K, Tokunaga K, and Kodama T.
Narcolepsy susceptibility gene CCR3 modulates
sleep-wake patterns in mice. PLoS One 12(11):e0187888, 2017.
19. Saitou N, Jinam TA, Kanzawa-Kiriyama H, andTokunaga K. Initial Movements of Modern
Humans in East Eurasia. Terra Austraris 45.
Australian National University. 43-50, 2017.
20. Hitomi Y and Tokunaga K. Significance of thefunctional disease-causal/susceptible variants
identified by whole-genome analyses for theunderstanding of human diseases. Proc. Japan
Acad. Series. Phys. Biol. Sci. 93(9): 657-676,
2017.

321

Department of Developmental
Medical Sciences
Professor
Masashi Mizuguchi, M.D., Ph.D.

Associate Professor
Teruyuki Tanaka, M.D., Ph.D.

Research Associate
Sayaka Takanashi, M.D., Ph.D.

Homepage

Ai Hoshino, M.D., Ph.D.

http://www.sih.m.u-tokyo.ac.jp/devt.html

Introduction and Organization
Founded in 1966 as the Department of Maternal andChild Health, our department was the first one
established in Japan. With the subsequent expansionof research activities and the foundation of the
Graduate School of Medicine, it was renamed in 1998
as the Department of Developmental Medical
Sciences. Up to now, it has been engaged in experimental and epidemiologic studies to provide thescientific bases for all the activities to promote thephysical and mental health of mothers and children.
The experimental studies include those on the nervousand endocrine systems, infection, immunity andmetabolism, whereas the epidemiologic studies deal
with development, mother-to-child relationship,vaccination and health promotion. In 2007, joined by
new members, the department has entered a new era,putting more emphasis than ever on the research on
developmental disorders of the human nervous
system.
At present, our department consists of one professor,
one associate professor, two research associates, one
assistant clerk, one technical assistant, seventeen
visiting lecturers, fifteen visiting researchers, andeight graduate students, including two 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, Brazil, Italy, Greece, China,
Taiwan, Korea, Thailand, Viet Nam, Laos, Malaysia,
Indonesia, Bangladesh, Pakistan, Sri Lanka andAustralia, in order to promote the mothers’ andchildren’s health all over the world. We also haveaccepted many young students from these countries,
for the purpose of bringing up professionals whoeither perform medical research or lead local healthpolicies.

Teaching activities
1. Undergraduate course, Faculty of Medicine, Schoolof Integrated Health Sciences
1) Human growth and development
2) Immunity and defense mechanism3) Infectious diseases
4) Topics in life and environmental sciences
5) Maternal and child health6) School health7) International health8) Experiments in life sciences
9) Exercises in life sciences

32210) Introduction to general health science
2. Graduate course, the Graduate School of Medicine,
School of International HealthIn addition to lectures and laboratory courses by ourown staff, special lectures are given by experts both
inside and outside the University.

Research activities(1) Clinical, genetic and pathologic studies of acuteencephalopathy: Acute necrotizing encephalopathy, acute encephalopathy with biphasic seizures
and late reduced diffusion, acute encephalitis
with refractory, repetitive partial seizures, andmild
encephalitis/encephalopathy
withareversible splenial lesion.
(2) Pharmacological studies on the pathogenesis andtreatment of developmental disorders, such as
autism spectrum disorder and attention deficit/
hyperactivity disorder, using genetically engineered animals.
(3) Medical genetic studies on congenital anomalies
caused by abnormal intracellular signal transduction, such as tuberous sclerosis, Noonan
syndrome and Ellis-van Creveld syndrome.
(4) Molecular pathologic studies on childhood
intractable epilepsy and developmental disorders,such as West syndrome and Rett syndrome, using
genetically engineered animals.
(5) Molecular genetic and cell biologic studies
combined with post-genomic approaches on molecules regulating neuronal migration, such as
Doublecortin and Cdk5.
(6) Studies on the nutrition, immunity, brain andepigenetics of human fetuses and neonates.
(7) International studies on the maternal and childhealth.
(8) Studies on the virulence, drug resistance andvaccines of herpesviruses and poxviruses.
(9) Molecular epidemiology of pediatric viral
infections, in particular gastrointestinal diseases(rotavirus, norovirus, sapovirus and bocavirus),
respiratory infections (influenza, RS virus andrhinovirus), exanthematous diseases (rubella) andHIV infection.

References
1. Iizuka I, Ami Y, Suzaki Y, Nagata N, Fukushi S,
Ogata M, Morikawa S, Hasegawa H, Mizuguchi
M, Kurane I, Saijo M. A single vaccination of
nonhuman primates with highly attenuatedsmallpox vaccine, LC16m8, provides long-term
protection against monkeypox. Japanese Journalof Infectious Diseases 2017; 70(4): 408-415.
2. Kakiuchi S, Tsuji M, Nishimura H, Yoshikawa T,
Wang L, Takayama-Ito M, Kinoshita H, Lim CK,
Fujii H, Yamada S, Harada S, Oka A, Mizuguchi
M, Taniguchi S, Saijo M. Association of theemergence of acyclovir-resistant herpes simplex
virus 1 with prognosis in hematopoietic stem celltransplantation patients. The Journal of Infectious
Diseases 2017; 215(6): 865-873.
3. Kaneko M, Takanashi S, Thongprachum A, Hanaoka N, Fujimoto T, Nagasawa K, Kimura H,
Okitsu S, Mizuguchi M, Ushijima H. Identification of vaccine-derived rotavirus strains in children with acute gastroenteritis in Japan, 20122015. PLoS One. 2017;12(9): e0184067.
4. Kodachi T, Matsumoto S, Mizuguchi M, Osaka H,
Kanai N, Nanba E, Ohno K, Yamagata T. Severe
demyelination in a patient with a late infantile
form of Niemann-Pick disease type C. Neuropathology 2017; 37(5): 426-430.
5. Okuda K, Kobayashi S, Fukaya M, Watanabe A,
Murakami T, Hagiwara M, Sato T, Ueno H, Ogonuki N, Komano-Inoue S, Manabe H, Yamaguchi
M, Ogura A, Asahara H, Sakagami H, Mizuguchi
M, Manabe T, Tanaka T. CDKL5 controls
postsynaptic localization of GluN2B-containing
NMDA receptors in the hippocampus and regulates seizure susceptibility. Neurobiology of Disease 2017; 106: 158-170.
6. Shimoda K, Mimaki M, Fujino S, Takeuchi M,
Hino R, Uozaki H, Hayashi M, Oka A, Mizuguchi
M. Brain edema with clasmatodendrosis complicating ataxia telangiectasia. Brain and Development 2017; 39(7): 629-632.
7. Takanashi S, Thongprachum A, Okitsu S, Nishimura S, Kobayashi M, Kikuta H, Yamamoto A,
Sugita K, Baba T, Hayakawa S, Mizuguchi M,
Ushijima H. Molecular epidemiological traits ofgroup A rotavirus in Japanese children during

323

transitional period of rotavirus implementation,
2011- 2014. Clinical Laboratory 2017; 63(5):961-970.
8. Thongprachum A, Khamrin P, Pham NT, Takanashi S, Okitsu S, Shimizu H, Maneekarn N,
Hayakawa S, Ushijima H. Multiplex RT-PCR for
rapid detection of viruses commonly causing diarrhea in pediatric patients. Journal of Medical
Virology 2017; 89(5): 818-824.
9. Ushijima H, Thongprachum A, Khamrin P, Takanashi S, Okitsu S, Maneekarn N, Hayakawa S.
Evaluation of immunochromatography tests andnew enzyme immunoassay for detection of novel
GII.17 norovirus in stool samples. Japanese Journal of Infectious Diseases 2017; 70(3): 326-328.

324

Department of Human Ecology
Associate Professor
Masahiro UMEZAKI, Ph.D. (until December 31, 2017)

Research Associate
Satoko KOSAKA, Ph.D.
Shoko KONISHI, Ph.D.

Homepage

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

Introduction and Organization
Department of Human Ecology was founded when
Kenji Uraguchi was appointed to the professorship of
Human Ecology course on April 1, 1965. Following
retirement of professor Uraguchi as of March 31, 1966,
professor Haruo Katsunuma (appointed also as
professor of Public Health course, School of
Medicine) became a joint professor of the Human
Ecology course. Tsuguyoshi Suzuki was appointed as
an associate professor and worked in the department
until August 31, 1971 when he was transferred toFaculty of Medicine, Tohoku University as a professor.
After professor Katsunuma left the department on
March 31, 1972, professor Akira Koizumi became thehead of the Human Ecology course on April 1, 1972.
Professor Koizumi was transferred to Public Healthcourse, School of Medicine on March 31, 1976, andassociate professor Shosuke Suzuki served as adepartment head from April 1 1976 to March 1979.
Tsuguyoshi Suzuki was appointed as a professor of
the Human Ecology course as of April 16, 1979. He
founded theoretical framework of the current humanecology which is based on studying adaptation
mechanisms of humans to environment. Afterassociate professor Shosuke Suzuki was transferred toFaculty of Medicine, Gunma University, as professor
on July 31, 1981, Ryutaro Ohtsuka was appointed as
an associate professor on September 1. Associate
professor Ohtsuka established the methodology ofcollecting quantitative information on demography,
nutrition, and subsistence targeting small-scale

populations based on extensive fieldwork, which
methodology is still utilized by the current department
members. Following the retirement of professor
Tsuguyoshi Suzuki on March 31, 1992, Ryutaro
Ohtsuka was appointed as a professor as of April 1 inthe same year.
Chiho Watanabe was appointed as an associate
professor on December 1997. He expanded
methodologies that examine relationships between
environment and health by utilizing various tools suchas measuring biomarkers in biological specimens
collected in the field, and animal experiments.
Professor Ohtsuka retired on March 31, 2005 andChiho Watanabe was appointed as a professor as ofApril 1, 2005. Masahiro Umezaki was appointed as an
associate professor in August 2005. While relying thequantitative research based on fieldwork, he has also
been exploring new research topics including
relationship between gut microflora (internal
environment) and health. Professor Chiho Watanabe
was transferred from the University of Tokyo to the
National Institute of Environmental Studies as of April
1, 2017. Masahiro Umezaki was appointed as aprofessor as of January 1, 2018.
In fiscal year 2017 the department had threefaculties; Dr. Umezaki, Dr. Konishi, and Dr. Kosaka.
There were 11 extra-university lecturers delivering
lectures in either graduate or undergraduate course.
Professor Umezaki held additional roles in the
Integrated Research System for Sustainability Science(IR3S) as well as in the Earth Observation Data

325

Integration&(EDITORIA).

FusionResearch

Initiative

Teaching activities
The department is one of the six departments of the
School of International Health. Human Ecology
Special Lecture I focused on the basic components of
Human Ecology such as demography, nutrition, andenvironment and introducing the notion of humanecosystem. In “Human Ecology Special Lecture II”,emphases were on recent topics and ongoing
researches in the field of Human Ecology and relatedareas. With these classes for the Graduate Students,
we tried to describe Human Ecology as a basic
component of International Health, and gave examplesof the recent issues that have been dealt with andapproaches used in this field. The lectures for the
Graduate Course were given in English.
In the undergraduate course, the department is incharge of a part of the School of Integrated Health
Sciences, providing the lectures on “Human Ecology”,“Environment and Health”, “Demography”, “International Health”, and “Medical Anthropology”. We
were also responsible for organizing “Pharmacology
and Toxicology”, “Physiology”, as well as“Environmental Engineering/ Human Engineering”.
At the undergraduate level, our emphases are in
introducing global-scale issues such as population
explosion, food security, and environmental issues inrelation to the problems that Asia-Pacific region(including Japan) has been facing. Another emphasis
was on the relation between human activities andchemical contamination of the environment.

Research activities
Human ecology is literally the understanding of
human population in the context of their respective
ecology as well as in the global context. Most of ourresearch tackles the tasks that have been dealt in thefield of “Environmental Health” and/or “Population
Ecology [of human]”, but with more comprehensive
and broader context. Therefore, we need to adopt
different approaches including fieldwork, experiment,
as well as GIS/GPS analyses. Our study fields include
Asian-Oceanian (including Japan) rural as well urban
communities, focusing on population, nutrition,

growth, environment, and sustainability. Experimental
studies focusing on the effects of perinatal exposures
to heavy metals have been conducted, emphasizing thefactors that modify the effects. Almost all the studies
require “transdisciplinary” approach, hence, we arecollaborating with various domestic and overseas
research institutes. The following is a list of major
activities conducted in the past year.
In recent years we also use secondary data forresearch aiming to elucidate potential effects ofenvironmental exposure (such as air pollution) on
health.
1. Environmental contamination by metals and its
health impacts in South Asia
In the As-contaminated area in Myanmar, we
recruited pregnant mothers at clinics and collectedbiological specimens. We investigated potential
effect of arsenic and cadmium exposure on healthof mothers and newborns.
2. Adaptation to low-protein dietPrevious studies reported that Papua New Guinea
Highlanders show masculine body and do not show
clinical symptoms of protein deficiency, although
their main diet is sweet potatoes and their protein
intake levels is low. To elucidate the biologicalmechanisms underlying this, we conducted fieldand experimental studies.
3. Adaptive strategy to aging and depopulation
The population issues (low fertility, aging,
population decrease) that Japanese people are now
facing are the first problem that humans face at a
global scale. Targeting Japanese rural communities,
the front-runners of this global issue, we conducted
population projection and studies on their food
habit, nutritional intake, and subjective perceptionof health. At the mean time, we also conducted astudy to categorize original strategies against aging
and depopulation that were used in each local
community.
4. Double-burden of malnutrition in Indonesia
To elucidate background and mechanisms of the
double-burden of malnutrition (coexistence ofundernutrition and overweight within the same

326

household), we conducted a survey in rural andurban communities in West Java, Indonesia. The
prevalence of double-burden households was higher
in the urban than in the rural community. It was alsosuggested that differential nutrient intakes among
members of the same household may be one of thefactors contributing to double-burden of malnutrition.
5. Study on Fecundity in Japan
Using an internet-based survey we estimatedage-pattern of time to pregnancy (duration between
discontinuing contraception and conception, used asa measure of fecundity) on which we havepublished a paper. We also conducted another study
on time to pregnancy with a prospective cohort with
2-year follow-up.
6. Health effects of air pollution exposure
Using methodologies of environmental epidemiology, we studied potential effect of air pollution
and airborne pollen on health (e.g. mortality,
number of clinical visits).

References
1. Tomitsuka E, Igai K, Tadokoro K, Morita A, Baba J,
Suda W, Greenhill AR, Horwood PF, Soli KW, Siba
PM, Odani S, Natsuhara K, Morita H, Umezaki M(2017) Profiling of faecal water and urine metabolites among Papua New Guinea highlanders believed to be adapted to low protein intake. Metabolomics, 13:105.
2. Chen SM, Qiu L, Du ZH, Jin YM, Du JW, Chen Y,
Watanabe C, Umezaki M (2017) Spatial clusteringof severe hand-foot-mouth disease cases in Hainan
Island, China. Japanese Journal of Infectious Diseases., 70(6) 604-608.
3. Horwood P, Soli KW, Maure T, Naito YI, Morita A,
Natsuhara K, Tadokoro K, Baba J, Odani S, Tomitsuka E, Igai K, Larkins JA, Siba PM, McBryde E,
Umezaki M, Greenhill AR. (2017) A high burden of
asymptomatic gastrointestinal infections in traditional communities in Papua New Guinea. American
Journal of Tropical Medicine and Hygiene, 97(6)1872-1875.
4. Hamamatsu Y, Goto C, Nishitani M, Shimadate R,

Ueno J, Kusakari Y, Umezaki M (2017) Associations between neighborhood food environments anddeficient protein intake among elderly people in a
metropolitan suburb: a case study in Kisarazu City,
Japan. American Journal of Human Biology, 29(6).
5. Wai KM, Mar O, Kosaka S, Umemura M, Watanabe
C. Prenatal Heavy Metal Exposure and Adverse
Birth Outcomes in Myanmar: A Birth-Cohort Study.
Int Journal of Environ Res Public Health, 14(11):1339.
6. Kosaka S, Umezaki M (2017) A systematic reviewof the prevalence and predictors of the double burden of malnutrition within households. British Journal of Nutrition, 117(8):1118-1127.
7. Phosri A, Ueda K, Tasmin S, Kishikawa R, Hayashi
M, Hara K, Uehara Y, Phung VLH, Yasukouchi S,
Konishi S, Honda A, Takano H (2017) Interactive
effects of specific fine particulate matter compositions and airborne pollen on frequency of clinic visits for pollinosis in Fukuoka, Japan. Environmental
Research, 156:411-419.
8. Sakata S, Konishi S, Ng CFS, Kishikawa R,
Watanabe C (2017) Association of Asian Dust withdaily medical consultations for pollinosis in Fukuoka City, Japan. Environmental Health and Preventive Medicine, 22:25.
9. Stickley A, Ng CFS, Konishi S, Koyanagi A,
Watanabe C (2017) Airborne pollen and suicidemortality in Tokyo, 2001–2011. Environmental Research, 155:134-140.
10. Ser PH, Omi S, Shimizu-Furusawa H, Yasutake A.,
Sakamoto M, Hachiya N, Konishi S, Nakamura M,
Watanabe C (2017) Differences in the responses ofthree plasma selenium-containing proteins in relation to methylmercury-exposure through consumption of fish/whales. Toxicology Letters, 267:53-58.
11. Rarau P, Vengiau G, Gouda H, Phuanukoonon S,
Kevau IH, Bullen C, Scragg R, Riley I, Marks G,
Umezaki M, Morita A, Oldenburg B, McPake B,
Pulford J (2017) Prevalence of non-communicabledisease risk factors in three sites across Papua New
Guinea: a cross-sectional study. BMJ Global Health,2:e000221.

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Department of
Biomedical Chemistry
Professor
Tomoyoshi Nozaki, Ph.D., MD

Associate Professor
Yoh-ichi Watanabe, Ph.D.

Assistant Professor
Jeelani Ghulam, Ph.D.

Homepage

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

Introduction and Organization
Aim of our department is to contribute to global
health and welfare from basic research. Our department, formerly named Biochemistry and Nutrition
was renamed on April 1st, 1996 to The Department of
Biomedical Chemistry as newly affiliating with
Biomedical Science Division of International Health,Graduate School of Medicine, The University ofTokyo. Former Prof. Kiyoshi Kita (Professor
Emeritus) has been retired in March 2016, and Dr.
Tomoyoshi Nozaki, National Institute of Infectious
Diseases, has been assigned as a new professor in
October, 2016, and became a full-time processor in
August, 2017.

Teaching activities
Teaching activities in our department cover a broad
spectrum of biochemistry-oriented life sciences frompremise to frontiers and in either conceptual orexperimental point of view
Graduate Course: Biomedical Chemistry I, IIThis course is comprised of lectures and seminars toprovide basic concepts and newer vistas for understanding biomedical chemistry with special reference
to biochemistry and molecular biology. These include
the structure and function of biomolecules, metabo-lism, its regulation, and underlying mechanism ateither molecular, cellular and systemic level.
Undergraduate Course: Basic Life Science, Life
Science and Genome Science I & II, Nutrition,
Laboratory Practice for Life Science Ⅰ& II, Seminarin Environmental and Human Life Sciences,
Microbiology II (Parasitology).

Research activities
Our major research interests include virulencemechanisms and metabolism of protozoa, particularly
Plasmodium spp. causing malaria and Entamoeba
histolytica causing amebic dysentery. We mainly focus
on vesicular trafficking, phagocytosis, autophagy,proteases, amino acid metabolisms, RNA maturation,translation, drug development, and organellogenesis.
Our research approaches are very robust, and include
biochemistry, molecular and cell biology, live imaging,
multi-omics including metabolomics, and reverse
genetics. Our present research themes include: Molecular elucidation of pathogenesis of parasites
 Biochemical and biological analyses of metabolism and organelles unique to parasites
 Analysis of vesicular traffic, protein secretion, andphagocytosis/trogocytosis in parasites
 Genome wide analysis and comparison of parasite
strains

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 Drug discovery and development against protozoan
infections such as malaria and amebiasis
 Elucidation of divergence of RNA maturation andtranslation

References
1. Behavior of DNA-lacking mitochondria in
Entamoeba histolytica revealed by organelletransplant. Kazama, M., Ogiwara, S., Makiuchi,T., Yoshida, K., Nakada-Tsukui, K., Nozaki, T.,& Tachibana H. (2017) Sci Rep. 7, 44273
2. X-Ray snapshots of a pyridoxal enzyme: acatalytic mechanism involving concerted [1,5]hydrogen sigmatropy in methionine γ-lyase. Sato,D., Shiba, T., Karaki, T., Yamagata, W., Nozaki,T., Nakazawa, T. & Harada, S. (2017) Sci Rep. 7,4874
3. AGC family kinase1 participates in trogocytosis
but not in phagocytosis in Entamoeba histolytica.
Somlata, Nakada-Tsukui, K., & Nozaki, T. (2017)
Nat Commun 8, 101
4. Genetic diversity of Entamoeba: novel ribosomal
lineages from cockroaches. Kawano, T., Imada,M., Chamavit, P., Kobayashi, S., Hashimoto, T., &Nozaki, T. (2017) PLoS One 12, e0185233
5. Structural and thermodynamic characterization of
metal binding in Vps29 from Entamoeba
histolytica: Implication in retromer function.
Srivastava, V.K., Yadav, R., Watanabe, N., Tomar,P., Mukherjee, M., Gourinath, S., Nakada-Tsukui,K., Nozaki, T. & Datta, S. (2017) Mol Microbiol.
106, 562-581
6. Complete sequence and characterization of themitochondrial genome of Diphyllobothrium
stemmacephalum, the type species of genus
Diphyllobothrium (Cestoda: Diphyllobothriidae),using next generation sequencing. Yamasaki, H.,
Izumiyama, S., & Nozaki, T. (2017) Parasitol Int.
66, 573-578
7. Hetero-oligomer of dynamin-related proteinsparticipates in the fission of highly divergent
mitochondria from Entamoeba histolytica.
Makiuchi, T., Santos, H., Tachibana, H. & Nozaki,
T. (2017) Sci Rep 7, 13439
8. Genetic, metabolomic and transcriptomic analysesof the de novo L-cysteine biosynthetic pathway inthe enteric protozoan parasite Entamoeba
histolytica. Jeelani, G., Sato, D., Soga, T., &Nozaki, T. (2017) Sci Rep. 7, 15649
9. Glycerol kinase of African trypanosomes
possesses an intrinsic phosphatase activity.
Balogun, E.O., Inaoka, D.K., Shiba, T., Tokuoka,
S.M., Tokumasu, F., Sakamoto, K., Kido, Y.,
Michels, P.A.M., Watanabe, Y., Harada, S. & Kita,
K. (2017) Biochim Biophys Acta. 1861, 28302842
10. Expression, purification, and crystallization oftype 1 isocitrate dehydrogenase from Trypanosoma brucei brucei. Wang, X., Inaoka, D.K.,
Shiba, T., Balogun, E.O., Allmann, S., Watanabe,Y., Boshart, M., Kita, K. & Harada, S. (2017)
Protein Expr Purif. 138, 56-62
11. DuplicationofDrosophilamelanogastermitochondrial EF-Tu: pre-adaptation to T-arm
truncation and exclusion of bulky aminoacyl
residues. Sato, A., Suematsu, T., Aihara, K., Kita,
K., Suzuki, T., Watanabe, K., Ohtsuki, T. &Watanabe, Y. (2017) Biochem J. 474, 957-969

School of Public Health
1. Epidemiology and Health Sciences

330

Department of Social andPreventive Epidemiology
Professor
Satoshi Sasaki, M.D., Ph.D.

Associate
Kentaro Murakami, Ph.D.

Homepage

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

Introduction and Organization
The Department of Social and Preventive Epidemiology is a new department which was established at
the same time of the establishment of the School of
Public Health, the University of Tokyo (April 2007).
Epidemiology is a study of quantitatively assessing
health status and disease development in populations
and statistically analyzing the relationship of risk
factors with the development of certain disease. In
addition to traditional risk factors including alcohol
drinking, smoking, nutrition, and physical activity,
gene and factors controlling gene and socioeconomic
factors are also important topics in epidemiologic
research. Epidemiologic data are needed for
conducting the assessment of certain treatment
including medicine and estimating situation of diseasedevelopment.
Epidemiology not only provides research methodology in the field of public health but also is
considered a practical study for public health and thus
a central field of health science. However, botheducation and research systems have long been
insufficient in Japan.
Social and preventive epidemiology is a study of
epidemiologically clarifying the relationship between
various phenomena in human society (including
individual lifestyle) and certain disease.
The Department of Social and Preventive Epidemiology particularly focuses on nutrition, which isessential for individual and population health, as amain research topic and epidemiologically researches
various issues related to nutrition (nutritional epidemiology), playing a central role in this research field inJapan.
The Department currently consists of one professor
and one associate.

Teaching activities
We have the following two lectures in the School of
Public Health.
Epidemiological research and practice
Practice and assessment in public health
Both are strongly associated with practical tasks inpublic health field, aiming at giving students opportunities for acquiring abilities of conducting publichealth activities and tasks based on theory of
epidemiology.
We have also several lectures for students in otherschools.

Research activities
Our main topic is basic research for development andapplication of research methodology in the field of
nutritional epidemiology. Based on this basic research,
we also conduct a wide range of epidemiologic
research for investigating the relationship of nutrition
with health and disease. As a characteristic of thisresearch field, we conduct many multi-center studies

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with various kinds of disease.
Another characteristic is collection of researchfindings (scientific papers) derived from epidemiologic research all over the world on the association ofnutrition with health and disease, which is applied for
health control through nutrition improvement anddisease control.

References
1. Asakura K, Masayasu S, Sasaki S. Dietary intake,physical activity, and time management areassociated with constipation in preschool children in
Japan. Asia Pac J Clin Nutr 2017; 26(1): 118-29.
2. Uechi K, Asakura K, Sasaki Y, Masayasu S, Sasaki
S. Simple questions in salt intake behavior
assessment: comparison with urinary sodium
excretion in Japanese adults. Asia Pac J Clin Nutr
2017; 26(5): 769-80.
3. Kobayashi S, Asakura K, Suga H, Sasaki S and theThree-generation Study of Women on Diets and
Health Study Group. Living status and frequency ofeating out-of-home foods in relation to nutritional
adequacy in 4017 Japanese female dietetic students
aged 18-20 years: a multicenter cross-sectional study.
J Epidemiol 2017; 27(6): 287-93.
4. Asakura K, Todoriki H, Sasaki S. Relationshipbetween nutrition knowledge and dietary intake
among primary school children in Japan: combined
effect of children's and their guardians' knowledge. J
Epidemiol 2017; 27: 483-91.
5. Uechi K, Asakura K, Masayasu S, Sasaki S.
Within-country variation of salt intake assessedwith urinary excretion in Japan: a multilevel
analysis in all 47 prefectures. Hypertens Res
2017; 40(6): 598-605.
6. Asakura K, Sasaki S. School lunches in Japan:
their contribution to healthier nutrient intake
among elementary-school and junior high-school
children. Public Health Nutr 2017; 20(9):1523-33.
7. Murakami K, Livingstone MB, Okubo H, Sasaki
S. Energy density of the diets of Japanese adults
in relation to food and nutrient intake and generaland abdominal obesity: a cross-sectional analysis
from the 2012 National Health and Nutrition
Survey, Japan. Br J Nutr 2017; 117(1): 161-9.

8. Inomaki R, Murakami K, Livingstone MB, Okubo
H, Kobayashi S, Suga H, Sasaki S; Threegeneration Study of Women on Diets and HealthStudy Group. A Japanese diet with low glycaemic
index and glycaemic load is associated with bothfavourable and unfavourable aspects of dietaryintake patterns in three generations of women.
Public Health Nutr 2017; 20(4): 649-59.
9. Uechi K, Sugimoto M, Kobayashi S, Sasaki S.
Urine 24-Hour sodium excretion decreased
between 1953 and 2014 in Japan, but estimatedintake still exceeds the WHO recommendation. J
Nutr 2017; 147(3): 390-97.
10. Osawa Y, Arai Y, Takayama M, Hirata T,
Kawasaki M, Abe Y, Iinuma T, Sasaki S, Hirose N.
Identification of dietary patterns and theirrelationships with general and oral health in thevery old. Asia Pac J Clin Nutr 2017; 26(2):262-70.
11. Tanaka K, Miyake Y, Fukushima W, Kiyohara C,
Sasaki S, Tsuboi Y, Oeda T, Shimada H,
Kawamura N, Sakae N, Fukuyama H, Hirota Y,
Nagai M, Nakamura Y; Fukuoka Kinki
Parkinson’s Disease Study Group. Vitamin D
receptor gene polymorphisms, smoking, and riskof sporadic Parkinson's disease in Japan. Neurosci
Lett 2017; 643: 97-102.
12. Miyake Y, Tanaka K, Okubo H, Sasaki S,
Furukawa S, Arakawa M. Manganese intake isinversely associated with depressive symptoms
during pregnancy in Japan: Baseline data from the
Kyushu Okinawa Maternal and Child HealthStudy. J Affect Disord 2017; 211: 124-9.
13. Shiraki K, Murakami K, Okubo H, Livingstone
MBE, Kobayashi S, Suga H, Sasaki S;
Three-Generation Study of Women on Diets and
Health Study Group. Nutritional correlates ofmonetary diet cost in young, middle-aged, andolder Japanese women. J Nutr Sci 2017; 6: e22.
14. Kobayashi S, Suga H, Sasaki S; Three-generation
Study of Women on Diets and Health Study
Group. Diet with a combination of high protein
and high total antioxidant capacity is strongly
associated with low prevalence of frailty among
old Japanese women: a multicenter cross-sectional
study. Nutr J 2017; 16(1): 29.
15. Sakai H, Murakami K, Kobayashi S, Suga H,

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Sasaki S, the Three-generation Study of Womenon Diets and Health Study Group. Food-based
diet quality score in relation to depressive
symptoms in young and middle-aged Japanesewomen. Br J Nutr 2017; 117: 1674-81.
16. Murakami K, Livingstone MB, Okubo H, Sasaki
S. Higher dietary acid load is weakly associatedwith higher adiposity measures and bloodpressure in Japanese adults: the National Healthand Nutrition Survey. Nutr Res 2017; 44: 67-75.
17. Murakami K, Livingstone MBE, Sasaki S.
Establishment of a meal coding system for thecharacterization of meal-based dietary patterns inJapan. J Nutr 2017; 147: 2093-101.
18. Asakura K, Sasaki S. SFA intake among Japanese
schoolchildren: current status and possible
intervention to prevent excess intake. Public
Health Nutr 2017; 20(18): 3247-56.
19. Murakami K. Nutritional quality of meals andsnacks assessed by the Food Standards Agency
nutrient profiling system in relation to overall dietquality, body mass index, and waist circumferencein British adults. Nutr J 2017; 16(1): 57.
20. Okubo H, Miyake Y, Sasaki S, Tanaka K, Hirota Y.
Rate of eating in early life is positively associatedwith current and later body mass index among
young Japanese children: the Osaka Maternal andChild Health Study. Nutr Res 2017; 37: 20-8.
21. Okubo H, Inagaki H, Gondo Y, Kamide K, Ikebe
K, Masui Y, Arai Y, Ishizaki T, Sasaki S,
Nakagawa T, Kabayama M, Sugimoto K, Rakugi
H, Maeda Y; SONIC Study Group. Association
between dietary patterns and cognitive function
among 70-year-old Japanese elderly: a crosssectional analysis of the SONIC study. Nutr J
2017; 16(1): 56.
22. Kashino I, Li YSh, Kawai K, Nanri A, Miki T,
Akter S, Kobayashi S, Kasai H, Mizoue T. Dietarynon-enzymatic antioxidant capacity and DNA
damage in a working population. Nutrition 2017;47: 63-68.
23. Okuda M, Asakura K, Sasaki S. Placing Salt/Soy
Sauce at Dining Tables and Out-Of-Home
Behavior Are Related to Urinary Sodium
Excretion in Japanese Secondary School Students.
Nutrients 2017; 9: 12.
24. Sakurai M, Yoshita K, Nakamura K, Miura K,Takamura T, Nagasawa SY, Morikawa Y, Kido T,
Naruse Y, Nogawa K, Suwazono Y, Sasaki S,
Ishizaki M, Nakagawa H. Skipping breakfast and5-year changes in body mass index and waist
circumference in Japanese men and women. Obes
Sci Pract 2017; 3(2): 162-70.

333

Department of Clinical
Epidemiology and
Health Economics
Professor
Hideo Yasunaga, MD, PhD.

Assistant Professor
Hiroki Matsui, MPH.

Homepage

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

Introduction and Organization
The Department of Clinical Epidemiology and Health
Economics was established in April 2007, as a part ofMaster of Public Health (MPH) program under the
new School of Public Health (SPH). The Department
is also affiliated with the Division of Social Medicine
for doctoral education.
The mission of the Department is two folds; to help
health professionals obtain scientifically sound basis
and skills for evidence-based practice, and toempirically evaluate the clinical practice, health caresystem/policy for further improvement of the qualityof health care. For this purpose, the Department puts aunique emphasis on quantitative analytic methods andinter-disciplinary theories across clinical epidemiology, health service research, health economics andhealth policy.

Teaching activities
Under the MPH program, the Department is responsible for 6 courses, one on introduction to clinicalmedicine for non-MD students, two on clinicalepidemiology, two on health economics, and one on
healthcare organization management.
The lecture course on clinical epidemiology provides
a quick review on elementary to intermediate levels of
epidemiology such as research design, bias and error,

and causal inference.
Health economics course provides an intermediatelevel of micro-economics and health economics
theories of consumer choice, insurance, and humancapital, and enhances discussion to apply these
theories to behaviors of providers and consumers. The
3-day intensive course offers students an opportunity
for hands-on training of actual cost-effectivenessanalysis of health care and technologies.
The applied course of clinical epidemiology supports
the students to build a research hypothesis, design a
study, and prepare a study protocol for fund proposal.
The course on health care organization management
provides basics of financial accounting, and management frameworks on human resource, strategy, information, and risk, helping the students deepen theknowledge through in-class discussion over real-casescenarios.
The Department accepted 10 master students for the
fiscal years of 2017.

Research activities
Current activities in this Department cover a broad
range of health services research, including 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.

7.

8.

References
1.

2.

3.

4.

5.

6.

Aso S, Matsui H, Fushimi K, Yasunaga H.
Resuscitative endovascular balloon occlusion of
the aorta or resuscitative thoracotomy with aortic
clamping for non-compressible torso hemorrhage: a retrospective nationwide study. Journalof Trauma and Acute Care Surgery 2017;
82(5) :910–914
Hasegawa W, Yamauchi Y, Yasunaga H,
Takeshima H, Sakamoto Y, Jo T, Sasabuchi Y,
Matsui H, Fushimi K, Nagase T. Prognostic
nomogram for inpatients with asthma exacerbation. BMC Pulmonary Medicine 2017;17:108
Ishimaru M, Ono S, Suzuki S, Matsui H, Fushimi
K, Yasunaga H. Artificial nutrition dependence
after cetuximab vs. cisplatin combined withradiotherapy for advanced head and neck cancer:
A propensity score matched analysis. Head &Neck 2017;39(2):320-325
Isogai T, Matsui H, Tanaka H, Fushimi K,
Yasunaga H. Factors affecting in-hospitalmortality and likelihood of undergoing surgicalresection in patients with primary cardiac tumors.
Journal of Cardiology 2017;69(1):287-292.
Isogai T, Matsui H, Tanaka H, Fushimi K,
Yasunaga H. Treatments and in-hospital mortality in acute myocardial infarction patients withrheumatoid arthritis: a nationwide retrospective
cohort study in Japan. Clinical Rheumatology
2017;36(5):995-1004
Isogai T, Matsui H, Tanaka H, Fushimi K,
Yasunaga H. In-hospital management andoutcomes in patients with peripartum cardiomyopathy: a descriptive study using a national
inpatient database in Japan. Heart and Vessels

9.

10.

11.

12.

13.

14.

2017;32(8):944-951
Isogai T, Matsui H, Tanaka H, Fushimi K,
Yasunaga H. Seasonal variation in patientcharacteristics and in-hospital outcomes of
Takotsubo syndrome: a nationwide retrospective
cohort study in Japan. Heart and Vessels 2017;32:1271–1276
Isogai T, Matsui H, Tanaka H, Fushimi K,
Yasunaga H. Clinical characteristics of patientswith Takotsubo syndrome diagnosed withoutcoronary artery evaluation: A retrospective
nationwide study. Journal of Cardiology 2017;
71(3):268-276.
Iwagami M, Yasunaga H, Matsui H, Horiguchi
H, Fushimi K, Noiri E, Nangaku M, Doi K.
Impact of end-stage renal disease on hospitaloutcomes among patients admitted to intensive
care units: A retrospective matched-pair cohort
study. Nephrology 2017;22(8):617-623.
Jo T, Yasunaga H, Sasabuchi Y, Michihata N,
Morita K, Yamauchi Y, Hasegawa W, Takeshima
H, Sakamoto Y, Matsui H, Fushimi K, Nagase T.
Association between dementia and discharge
status in patients hospitalized with pneumonia.
BMC Pulmonary Medicine 2017;17(1):128
Kawata M, Sasabuchi Y, Inui H, Taketomi S,
Matsui H, Fushimi K, Chikuda H, Yasunaga H,
Tanaka T. Annual trends in knee arthroplasty andtibial osteotomy: Analysis of a national databasein Japan. Knee 2017;24(5):1198-1205
Kikuchi H, Hamanaga C, Yasunaga H, Matsui H,
Hashimoto H. Privacy-preserving multiple linear
regression of vertically partitioned real medical
datasets. Advanced Information Networking andApplications (AINA), 2017 IEEE 31st International Conference
Kishimoto M,Yamana H, Inoue H, Noda
T,Myojin T, Matsui H, Yasunaga H, Kawaguchi
M, Imamura T. Sivelestat sodium and mortality inpneumonia patients requiring mechanical ventilation: propensity score analysis of a Japanesenationwide database. Journal of Anesthesia 2017;31(3):405-412
Koike S, Matsumoto M, Ide H, Kawaguchi H,
Shimpo M, Yasunaga H. Internal medicine board
certification and career pathways in Japan. BMC
Med Educ. 2017;17(1):83.

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15. Maeda T, Sasabuchi Y, Matsui H, Ohnishi Y,
Miyata S, Yasunaga H. Safety of tranexamic use
during pediatric cardiac surgery: a nationwide
database study. Journal of Cardiothoracic and
Vascular Anesthesia 2017;31(2):549-553
16. Matsui H, Jo T, Fushimi K, Yasunaga H.
Outcomes after early and delayed rehabilitationfor exacerbation of chronic obstructive
pulmonary disease: a nationwide retrospective
cohort study in Japan. Respiratory Research
2017;21;18(1):68.
17. Morita K, Matsui H, Fushimi K, Yasunaga H.
Association between nurse staffing andin-hospital bone fractures: A retrospective cohort
study. Health Services Research 2017;52(3):1005-1023
18. Morita K, Matsui H, Fushimi K, Yasunaga H.
Association between advanced practice nursing
and 30-day mortality in mechanically ventilated
critically ill patients: a retrospective cohort study.
Journal of Critical Care 2017;41:209-215
19. Nagano M, Ichinose J, Sasabuchi Y, Nakajima J,
Yasunaga H. Surgery versus percutaneoustranscatheter embolization for pulmonary
arteriovenous malformation: Analysis of anational inpatient database in Japan. J Thorac
Cardiovasc Surg. 2017;154(3):1137-43.
20. Odagiri H, Yasunaga H, Matsui H, Matsui S,
Fushimi K, Kaise M. Hospital volume andadverse events following esophageal endoscopic
submucosal dissection: analysis of a national
inpatient database in Japan. Endoscopy 2017;
49(4):321-326
21. Odagiri H, Yasunaga H. Complications
following endoscopic submucosal dissection for
gastric, esophageal, and colorectal cancer: areview of studies based on nationwide large-scale
databases. Ann Transl Med. 2017;5(8):189.
22. Ohya J, Oshima Y, Chikuda H, Oichi T, Matsui H,
Fushimi K, Tanaka S, Yasunaga H. Seasonal
Variations in the Risk of Reoperation for SurgicalSite Infection Following Elective Spinal Fusion
Surgery: A Retrospective Study Using theJapanese Diagnosis Procedure Combination
Database. Spine 2017;42(14):1068-1079
23. Oichi T, Chikuda H, PhD, Ohya J, Ohtomo R,
Morita K, Matsui H, Fushimi K, Tanaka S,

24.

25.

26.

27.

28.

29.

30.

31.

Yasunaga H. Mortality and morbidity after
spinal surgery in patients with Parkinson’s
disease: a retrospective matched-pair cohort study.
Spine Journal 2017;17(4):531-537
Okubo Y, Michihata N, Yoshida K, Morisaki N,
Matsui H, Fushimi K, Yasunaga H. Impact ofpediatric obesity on acute asthma exacerbation in
Japan. Pediatr Allergy Immunol. 2017;28(8):763767.
Okubo Y, Michihata N, Morisaki N, Kinoshita N,
Miyairi I, Urayama KY, Yasunaga H. Recent
patterns in antibiotic use for children with group
A streptococcal infections. Journal of Global
Antimicrobial Resistance 2017;13;13:55-59.
Ono S, Ono Y, Matsui H, Yasunaga H. Impact ofclinic follow-up visits on body weight control inpeople with prediabetes or diabetes mellitus:
Japanese nonelderly cohort study. Family
Practice 2017;34(5):552-557
Ono S, Ono Y, Matsui H, Yasunaga H. Enhanced
Oral Care and Health Outcomes among Nursing
Facility Residents: Analysis Using the National
Long-term Care Database in Japan. Journal of theAmerican Medical Directors Association 2017;18(3):277.e1-277.e5
Ono Y, Ono S, Yasunaga H, Matsui H, Fushimi
K, Tanaka Y. Clinical characteristics andoutcomes of myxedema coma: analysis of anational inpatient database in Japan. J Epidemiol
2017;27:117-122
Ono Y, Ono S, Yasunaga H, Matsui H, Fushimi
K, Tanaka Y. Clinical Features and PracticePatterns of Treatment for Adrenal Crisis: A
Nationwide Cross-Sectional Study in Japan.
European Journal of Endocrinology 2017:176,
329–337
Sakamoto Y ， Yamauchi Y ， Yasunaga H ，
Takeshima H, Hasegawa W，Jo T，Matsui H，Fushimi K, Nagase T. Guidelines-concordant
empiric antimicrobial therapy and mortality inpatients with severe community-acquired
pneumonia requiring mechanical ventilation.
Respiratory Investigation 2017;55(1):39-44
Sakamoto Y ， Yamauchi Y ， Yasunaga H ，
Takeshima H, Hasegawa W，Jo T，Matsui H，Fushimi K, Nagase T. Development of anomogram for predicting in-hospital mortality of

336

32.

33.

34.

35.

36.

37.

38.

39.

patients with exacerbation of chronic obstructive
pulmonary disease. International Journal of
Chronic Obstructive Pulmonary Disease 2017;12:
1605-1611.
Sako A, Yasunaga H, Matsui M, Fushimi K,
Hamasaki H, Katsuyama H, Tsujimoto T, Goto A,
Yanai H. Hospitalization with hypoglycemia inpatients without diabetes mellitus: a retrospective
study using a national inpatient database in Japan,
2008-2012. Medicine 2017;96(25):e7271
Sasabuchi Y, Matsui H, Yasunaga H, Fushimi K.
Increase in Avoidable Hospital Admissions after
the Great East Japan Earthquake. Journal of
Epidemiology & Community Health 2017;71(3):248-252.
Sasabuchi Y, Matsui H, Yasunaga H, Fushimi K.
Epidural analgesia is infrequently used in patientswith acute pancreatitis: a descriptive study. Acta
Gastro-enterologica Belgica 2017;80(3)Sato M, Tateishi R, Yasunaga H, Matsui H,
Fushimi K, Ikeda H, Yatomi Y, Koike K.
Association between hospital volume andin-hospital mortality following radiofrequency
ablation for hepatocellular carcinoma: A national
survey of 36,675 patients. BJS Open 2017;1:
50–54
Sato M, Tateishi R, Yasunaga H, Horiguchi H,
Matsui H, Yoshida H, Fushimi K, Koike K. The
ADOPT-LC Score: A Novel Predictive Index of
In-hospital Mortality of Cirrhotic Patients
Following Surgical Procedures. Hepatology
Research 2017;47(3):E35-E43.
Sato M, Tateishi R, Yasunaga H, Matsui H,
Horiguchi H, Fushimi K, Koike K. Mortality andhemorrhagic complications associated with radiofrequency ablation for treatment of hepatocellular
carcinoma in patients on hemodialysis forend-stage renal disease: A nationwide survey. J
Gastroenterol Hepatol. 2017;32(11):1873-1878.
Shakya S, Matsui H, Fushimi K, Yasunaga H.
In-hospital complications after implantation ofcardiac implantable electronic devices: analysis
of a national inpatient database in Japan. Journalof Cardiology 2017;70(5):405-410.
Sugihara T, Yasunaga H, Matsui H, Nagao G,
Ishikawa A, Fujimura T, Fukuhara H, Fushimi K,
Ohori M, Homma Y. Accessibility to surgical

40.

41.

42.

43.

44.

45.

46.

robot technology and prostate-cancer patient
behavior for prostatectomy. Jpn J Clin Oncol.
2017;47(7):647-651
Tagami T, Matsui H, Moroe Y, Fukuda R, Shibata
A, Tanaka C, Unemoto K, Fushimi K, Yasunaga
H. Antithrombin use and 28-day in-hospitalmortality among severe burns patients: anobservational nationwide study. Annals of
Intensive Care 2017;7(1):18.
Tagami T, Yasunaga H, Yokota H. Antiarrhythmic drugs for out-of-hospital cardiac arrestwith refractory ventricular fibrillation. Critical
Care 2017;21:59.
Takeuchi T, Yasunaga H, Matsui H, Fushimi K.
Pediatric urolithiasis associated with acutegastroenteritis: an inpatient database study inJapan. European Journal of Pediatrics 2017;
176(4):501-507
Tomio J, Yamana H, Matsui H, Yamashita H,
Yoshiyama T, Yasunaga H. Tuberculosis
screening prior to anti-tumor necrosis factor
therapy among patients with immune-mediatedinflammatory diseases in Japan: a study using alarge-scale health insurance claims database.
International Journal of Rheumatic Diseases 2017
Nov;20(11):1674-1683
Urushiyama H, Jo T, Yasunaga H, Yamauchi Y,
Matsui H, Hasegawa W, Takeshima H, Hiraishi Y,
Mitani A, Fushimi K, Nagase T. Adjuvant
chemotherapy versus chemoradiotherapy forsmall cell lung cancer with lymph nodemetastasis: a retrospective observational study
with use of a national database in Japan. BMC
Cancer 2017;17(1):613
Wada T, Yasunaga H, MD, Yamana H, Matsui H,
Matsubara T, Fushimi K, Nakajima S.
Relationship between Hospital Volume andOutcomes in Patients with Traumatic Brain
Injury: A Retrospective Observational Study
using a National Inpatient Database in Japan.
Injury 2017;48(7):1423-1431
Wada T, Yasunaga H, MD, Yamana H, Matsui H,
Matsubara T, Fushimi K, Nakajima S.
Development and validation of a new ICD-10–
based trauma mortality prediction scoring systemusing a Japanese national inpatient database.
Injury Prevention 2017;23(4):263-267.

337

47. Yagi M, Yasunaga H, Matsui H, Fushimi K,
Fujimoto M, Koyama T, Fujitani J. Impact ofRehabilitation on Outcomes in Patients with
Ischemic Stroke: A Nationwide Retrospective
Cohort Study in Japan. Stroke 2017;48(3):740746
48. Yamana H, Moriwaki M, Horiguchi H, Kodan M,
Fushimi K, Yasunaga H. Validity of diagnoses,
procedures, and laboratory data in Japaneseadministrative data. J Epidemiology 2017;27(10):476-482

338

Department of HealthCommunication
Professor
Takahiro Kiuchi, M.D., Ph.D.

Associate Professor
Hirono Ishikawa, Ph.D.

Homepage

http://www.umin.ac.jp/hc/

Introduction and Organization
The Department of Health Communication wasestablished as a part of the newly developed School of
Public Health (professional graduate school) in April
2007, which was derived from the University Hospital
Medical Information Network (UMIN) Center. It
consists of two faculty members: a professor and an
associate professor.
Health communication is a major discipline in schoolof public health, especially in the US, and there aremany graduate programs and research centers forhealth communication. On the other hand, there havebeen few such departments in Japan, although theimportance of the health communication discipline has
gradually been recognized among the academic
society as well as among general public. Our department was established one of the few departments
specialized in health communication in Japan.

Teaching Activities
The Department of Health Communication, within the
School of Public Health, is a professional graduate
program that aims to foster the development of
medical and public health professionals as well as
researchers. We strive to make the most of our
professional activities and experience at UMIN Center.
We provide lectures and practical instruction in the
program. The following is the current curriculum:[Health Communication Lectures]
1. Introduction to health communication
2. Patient-provider communication (1): Patient perspective
3. Patient-provider communication (2): Healthcare
professional education
4. Communication in group and organization
5. Interpersonal communication skills for behavioral
changes
6. Public health communication skills for behavioral
changes
7. Evaluation and research in health communication
8. How to write persuasive health materials
9. Media and communication (1): Television
10. Media and communication (2): News paper
11. Media and communication (3): Internet
12. Entertainment education
13. Communicating for policy and advocacy
14. Group discussion[Health Communication Practice]
1. How to write persuasive health materials
2. Coaching
3. Manners in interpersonal relationship4. MBTI (Myers-Briggs Type Indicator) (1)(2)(3)5. Mass communication: Media doctor
6. Internet communication (1)(2)[Medical research and CDISC standards]
1. Introduction to CDISC standards
2. Introduction to data management in clinical

339

3.
4.
5.
6.
7.

research
Data and metadata – Define.xml
Standardization of case report form – CDASH
Standardization of data format – SDTM
Standardization of dataset for analysis – AdaM
Electronic application by CDISC standards

In the undergraduate program, Professor Kiuchi
presents a lecture entitled “Medical Literature
Informatics” and associate professor Ishikawa
presents a lecture entitled “health communication.”

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 on MediaWe have analyzed contents and suitability of healthinformation delivered by mass media and social media.
We also have conducted researches to increaseinfluence of small media such as leaflets, and held
seminars for health professionals.

(5) Research Related to UMIN Activities
Most systems developed at the UMIN Center havebeen subjects for research. In particular, we publishedand reported systems utilizing advanced technologies
and having scientifically meaningful concepts at
academic conferences.
(6) Information Systems for Clinical Epidemiologic
Studies

340

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.
(7) Research Regarding the Security of an Information
Network
The study addresses a Virtual Private Network (VPN),
and secure transactions with electronic mail(encryption), which have been also utilized for systemmanagement at the UMIN Center.

References
1. Ishikawa H.,Yamaguchi I., Nutbeam D., Kato M.,
Okuhara T., Okada M., Kiuchi T. Improving
health literacy in a Japanese community
population: A pilot study to develop an
educational program. Health Expect. 2018;00:1–8.
2. Okuhara T., Ishikawa H., Okada M., Kato M.,
Kiuchi T. Contents of Japanese pro- and anti-HPV
vaccination websites: A text mining analysis.
Patient Educ Couns. 2017;101(3):406-413.
3. Okuhara T., Ishikawa H., Okada M., Kato M.,
Kiuchi T. Readability comparison of pro- andanti-HPV-vaccination online messages in Japan.
Patient Educ Couns. 2017; 10(10): 1859-1866.
4. Kato, M., Ono, N., Ishikawa, H., Okuhara, T.,
Okada, M., & Kiuchi, T. Lessons learned fromprevious environmental health crises: Narrativesof patients with Minamata disease in TV
documentaries as the main media outlet. Cogent
Arts & Humanities. 2017; 5(1), 1447780.
5. Kato M., Ishikawa H., Okuhara T., Okada M.,
Kiuchi T. Mapping research on health topics
presented in prime-time TV dramas in ‘developed’
countries: A literature review. Cogent Social
Science. 2017; 3(1).
6. Goto, E., Ishikawa, H., Okuhara, T., Kato, M.,
Okada, M., & Kiuchi, T. Factors associated withadherence to recommendations to visit a physician
after annual health checkups among Japaneseemployees: a cross-sectional observational study.

Ind Health,

2018; 56(2), 155-159.

School of Public Health
2. Behavioral Health Sciences

342

Departments ofHealth and Social Behavior &Health Education and HealthSociology
Professor in health and social behavior
Hideki Hashimoto, M.D., D.PH.

Associate Professor in health education and health sociology
Naoki Kondo, M.D., Ph.D.

Lecturer
Daisuke Takagi, Ph. D.

Associates

Homepage http://webpark1166.sakura.ne.jp/
Introduction and Organization
The department originated as one of the firstdepartments dedicated to health education andbehavioral science in Japan, led by former Prof.
Emeritus Tadao Miyasaka, who had double degrees of
M.D. from the University of Tokyo and MPH in healtheducation from Harvard School of Public Health in1950s. He was succeeded by a sociologist, former
Prof. Kyoichi Sonoda who founded the first healthsociology department affiliated with the medical
school in Japan. Since then, the program has beenleading research focusing on socio-behavioral aspectsof health in this country. The legend was extended by
Prof. Chieko Kawada who raised academic andpractical attention on the concept of empowerment
and adult pedagogy in health education. Since 1997,
the department was further evolved by Prof. Ichiro
Kai who integrated diverse health and social science
disciplines into social gerontology program, and by
Associate Prof. Yoshihiko Yamazaki who ledsociological research projects on salutogenesis, social
stigma, power, and agency in health settings. The

departments were reorganized under the newly
established School of Public Health since 2007. In
2012, the Department of Social Gerontology has beenrenamed the Department of Health and Social
Behavior to apply a life-course perspective to a wider
range of social conditions and human well-being.
The new department intends to further integrate
health science (medicine and public health) and social
science (economics, sociology, and psychology) toreveal a causal mechanism linking social structure andindividual health for realizing health equity as afundamental goal to human security.

Teaching activities
The departments offer four courses in the master
degree program for public health, and seven courses
in the undergraduate program for the Integrated
Health Sciences track.
1. Graduate Courses, School of Public Health
1) Health and Society I & II: The course highlights
the significance of social determinants of health(SDH) as a key exposure causing social gradient343

of health. A series of omnibus lectures, each ofwhich focusing a specific topic of SDH (e.g.
income distribution, gender, job stress, anddiscrimination), are provided by invitedlecturers specialized in the field. The course isfollowed by course II which offers application ofconcepts into practice through in-classdiscussion and group works.
2) Health Education: The course provides basic
knowledge on relevant behavioral theories forhealth promotion and behavioral modification,
followed by case method learning on healtheducational intervention in community, school,
and work places. The case discussion was
facilitated by invited lecturers to reach practicallessons for effective communication.
3) Health Sociology: Sociology in medicine andsociology applied to health issues are treated in
the systemic course of lectures, covering social
model of health, medical gaze and socializationof health professionals, phenomenology ofchronic ills, and culture and health.
Hospital management practicum, jointly
organized with the Department of Health
Economics and Clinical Epidemiology, was notprovided in the FY2017.
2. Undergraduate Courses, School of Integrated
Health Sciences
1) Introduction to social survey and practice: This
course was not provided in the FY2017 due tocurriculum change. It will be provided as“Introduction of health science survey” in
FY2018.
2) Health and Society (former 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) Integrated Lectures of Public Health Sciences I(jointly offered by the faculty of Health
Sciences)
6) Scientific writing
7) Critical reading/writing of epidemiologicalstudies“Occupational health and nursing” was closed dueto the curriculum change, and has been partiallycovered by newly offered “Integrated Lectures of
Public Health Sciences II” coordinated by the
Department of Mental Health. However, somethemes, e.g. risk assessment and mission-based
health management in worksite, was missing, andneed to be covered in future curriculum amendment.
The department contributed to extend educational
environment in the new frame of School curriculum
policy, and management of educational duties withlimited resources became a challenge.

Research activities
The Department has contributed to an ongoing
research of socioeconomic status and health/functions
among elderly population in the collaboration with the
School of Economics of the University of Tokyo andthe Research Institute of Economic, Industry, andTechnology. The Japanese Study of Ageing andRetirement (J-STAR) is a sister study with the U.S.
Health and Retirement Study, Study of Health,Ageing, and Retirement in Europe (SHARE), EnglandLongitudinal Survey of Ageing (ELSA), and theirglobal sisters in Asian countries. The scope of JSTAR
is diverse; contribution of health for successful ageing,social economic conditions and access to health care,household economy and its impact on life styles suchas eating habits and nutrition, impact of retirement
onto cognitive function, etc..
Since 2010, the Department has launched anotherpanel study of younger generation, the Japanese studyof Stratification, Health, Income, and Neighborhood(J-SHINE) in collaboration with researcher groups on
neuroscience, economics, sociology, and social
psychology. The aim of this comprehensive panel
study is to identify a mechanism how socio-economic
environments get to “under-skin” to cause social
gradient of health across socio-economic positions. In
the year of 2011, the JSHINE conducted a
supplemental survey to respondent’s spouse andchildren. Main and supplement surveys were followedin 2012 and 2013, respectively. Obtained panel data
are made open to a broader range of researchers under
the data-control committee, to share analytic scheme

344

and to enhance inter-disciplinary studies so as tobetter identify common factors as well as uniquefactors affecting health inequality in Japanese context.
Following third follow-up for children conducted in
2015-2016, FY2017 was the year for third panel forthe original adult cohort after 5 year interval.
Otherwise, the department joined with Departments of
Public Health, Medical Informatics, and Health
Economics and Clinical Epidemiology the management of National claim Data Base and onsite research
center under the contract with the Ministry of Health,Welfare, and Labour to extend empirical healthcare
research using a representative big administrative data.
Dr. Kondo also is an active and leading coreresearcher in another large cohort for social epidemiology in gerontology, called Japan Gerontological
Evaluation Study (JAGES) that covers more than 30
municipalities and approximately 200,000 participating old people in the community. The project purports
to reveal social relationship and its impact on healthin later life. The team has been developing community
diagnosis tool using JAGES data to support
participating municipalities to effectively findleverage population for policy intervention, withsupport from AMED and other funding sources. The
developed tools are expected to be disseminated andstandardized for wider use in municipalities.
Dr. Takagi, in collaboration with Niigata University,
is preparing for a social epidemiological survey ofcommunity-dwelling older adults in Myanmar andMalaysia. In these countries that have distinctive
stage of economic development, culture, and ageing
rate, this study aims at verifying applicability of theexisting social models of health and building new
theories based on each country’s context. A
probability proportionate sampling of sites andselection of local investigators have been completed
in 2017, and interview surveys will be conducted in
2018.

Publications
1.

2.

Anezaki H, Hashimoto H. Process value of caresafety: women’s willingness to pay for perinatal
services. Int J Qual Health Care. 2017; 29(4):484-489.
Kato A, Fujimaki Y, Fujimori S, Isogawa A,

Onishi Y, Suzuki R, Yamauchi T, Ueki K,
Kadowaki T, Hashimoto H. Psychological andbehavioural patterns of stigma among patientswith type 2 diabetes: a cross-sectional study.
BMJ Open. 2017; 7(3): e013425.
3. Tokunaga M, Hashimoto H. The socioeconomic
within-gender gap in informal caregiving among
middle-aged women: Evidence from a Japanesenationwide survey. Soc Sci Med. 2017; 173: 4853.
4. Ikari Y, Awata M, Mitsudo K, Akasaka T, Saito
S, Ishihara T, Fujii T, Hashimoto H, Terashima
M, Ikemoto T, Hibi K, Tazaki J, Nakamura A,
Nishikawa H, Sato T, Nakagawa Y. Efficientdistal tip size of primary guidewire for antegrade
percutaneous coronary intervention in chronic
total occlusion: The G-FORCE study. Int J
Cardiol. 2017; 227: 94-99.
5. Murakami K, Ohkubo T, Hashimoto H. Distinct
association between educational attainment andoverweight/obesity in unmarried and married
women: evidence from a population-based study
in Japan. BMC Public Health. 2017; 17(1): 903.
6. Gero K, Kondo K, Kondo N, Shirai K, Kawachi
I. Associations of relative income and subjective
social status with favorable cardiovascular health.
European Journal of Public Health 2017; 27:
ckx187.083.
7. Okada Y, Ito YM, Tani Y, Sasaki Y, Saito J,
Haseda M, Kondo N, Kondo K, Tamakoshi A,
Ukawa S. Social participation patterns and theincidence of functional disability: The JAGES.
European Journal of Public Health 2017; 27:
ckx189.059.
8. Haseda M, Kondo N, Ashida T, Tani Y, Takagi
D, Kondo K. Community social capital, built
environment, and income-based inequality indepressive symptoms among older people inJapan: An ecological study from the JAGES
Project. Journal of Epidemiology 2017:
JE20160216.
9. Shiba K, Kondo N, Kondo K, Kawachi I.
Retirement and mental health: does social
participation mitigate the association? A fixedeffects longitudinal analysis. BMC Public Health
2017;17:526.
10. Nomura S, Sakamoto H, Glenn S, Tsugawa Y,

345

11.

12.

13.

14.

15.

16.

Abe SK, Rahman MM, Brown JC, Ezoe S,
Fitzmaurice C, Inokuchi T, Kassebaum NJ,
Kawakami N, Kita Y, Kondo N, Lim SS,
Maruyama S, Miyata H, Mooney MD, Naghavi
M, Onoda T, Ota E, Otake Y, Roth GA, Saito E,
Tabuchi T, Takasaki Y, Tanimura T, Uechi M,
Vos T, Wang H, Inoue M, Murray CJL, Shibuya
K. Population health and regional variations ofdisease burden in Japan, 1990–2015: asystematic subnational analysis for the Global
Burden of Disease Study 2015. Lancet 2017;
390(10101): 1521-1538.
Shrestha S, Aihara Y, Bhattarai AP, Bista N,
Rajbhandari S, Kondo N, Kazama F, Nishida K,
Shindo J. Dynamics of domestic water consumption in the urban area of the Kathmandu Valley:
Situation analysis pre and post 2015 Gorkha
Earthquake. Water 2017;9:222.
Tani Y, Kondo N, Noma H, Miyaguni Y, Saito
M, Kondo K. Eating alone yet living with others
is associated with mortality in older men: The
JAGES Cohort Survey. The Journals ofGerontology. Series B, Psychological Sciences
and Social Sciences 2017.
Tabuchi T, Kondo N. Educational inequalities insmoking among Japanese adults aged 25–94
years: Nationally representative sex- and agespecific statistics. Journal of Epidemiology 2017;27:186-92.
Saito M, Kondo N, Aida J, Kawachi I, Koyama
S, Ojima T, Kondo K. Development of an
instrument for community-level health relatedsocial capital among Japanese older people: The
JAGES Project. Journal of Epidemiology 2017;27:221-7.
Yokobayashi K, Kawachi I, Kondo K, Kondo N,
Nagamine Y, Tani Y, Shirai K, Tazuma S, group
J. Association between Social Relationship andGlycemic Control among Older Japanese:
JAGES Cross-Sectional Study. PLOS ONE
2017;12:e0169904.
Morikawa S, Takagi D, Komatsuzaki S. Attitude
toward the construct of radioactive waste
disposal facilities and spiral of silence: Resultsfrom online survey experiment. International
Journal of Management and Applied Science.
2017; 3(5): 74-82.

School of Public Health
3. Health Services Sciences

347

Department of Clinical
Information Engineering
Professor
Hiroshi Oyama, M.D., Ph.D.

Research Associate
Toki Saito, Ph.D.
Ayako Kohyama-Koganeya

Homepage:

http://park.itc.u-tokyo.ac.jp/CIEMedUTokyo/wp/

Introduction and Organization
Information engineering in Japan places a great dealof weight on computer hardware, software, and dataprocessing. It is a discipline that seeks objective dataand emphasizes the conception of new methods ofdata transfer, storage, processing, and input/output. It
also targets research on developing computer devices
and systems.
Reviewing the history of the application ofcomputers in medicine, calculating machines forsupporting scientists and technologists first appearedin the 1950s. In the 1960s, computers were used foraccounting and various statistics. The personal
computer appeared in the 1980s and was adopted for
personal use in many professions. The systematizationof large hospitals, such as university hospitals, pushedahead rapidly.
In the 1990s, the computer began to be used as atool to help human thinking, such as in presentations,design, and discovery. When computers became
connected to each other through the internet, thedistribution of information became very easy andrapid, not only within organizations, but alsointernationally.
In 2003, a high-quality, "finished" sequence of thehuman genome was completed. At the dawn of thetwenty-first century, bioinformatics appeared as a new
discipline, one that uses applied mathematics,
informatics, statistics, computer science, and bio-chemistry to solve biological problems. In medicine,advanced information technologies have been applied
to health information infrastructures, electrical clinicalguidelines, and knowledge navigation systems.
In response to the needs of the time, the Departmentof Clinical Information Engineering (CIE) wasestablished at the School of Public Health in April
2007. Its predecessor was the clinical informationengineering division of clinical bioinformatics, using
Special Coordination Funds for Promoting Scienceand Technology from the Ministry of Education,
Culture, Sports, Science, and Technology, of Japan.

Teaching activities
The purpose of the Department of Clinical
Information Engineering is to nurture talented people
who have special knowledge and skills at aninternational level in order to apply advanced
information technologies to practical projects inclinical medicine and the health sciences. It offers
courses on information system design, development
methodology, evaluation and project management inbiomedicine, health care and public health in the
School of Public Health, and data mining and virtual
reality for clinical decision-making in social medicine.
Famous visiting lecturers and researchers from the
National Cancer Center and other universities havegiven lectures here, furthering our hope of becoming aworld leader in this field.

348

The education of graduate students is based on
weekly conferences at which the students present the
progress on their own research projects and discuss
their future directions.

References
1.

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:2.

3.
(1) Computer Graphics & Virtual Reality (VR) for
Medical Science: Our research has three goals:(1) to improve the living conditions of in-patientswith limited physical activity by providing virtual
experiences; (2) to develop new diagnostic
methods using medical imaging; and (3) todevelop a surgical edutainment and preoperative
surgical planning support system in virtual space.
The advantages of simulating surgical procedures
using VR techniques include: (1) practicing thesurgical procedure and image-based training; (2)planning the surgical procedure for individual
patients preoperatively using VR images modeledfrom the patient's preoperative computed tomography (CT) or magnetic resonance (MR) images,
in collaboration with the Department of Neurosurgery; (3) allowing supervisors to evaluate aprocedure objectively; and (4) helping patientsand their families to better understand the surgicalprocedure before and after the operation.
(2) Social Information Engineering for Public Health(Public Health Informatics): Our laboratory
researches new tools and methodologies for
applying information and computer science andtechnology to public health practice, research,and learning.
At present, we are studying
differences in the computerization of publichealth in the US and Japan.

4.

5.

6.

Hiroyasu Kobayashi, Mai Hagiwara, Toki Saito,
Daisuke Ichikawa, Naoyuki Shono, Taichi Kin,
Naoto Kunii, Nobuhito Saito, Hiroshi Oyama. A
Four-dimensional Virtual Brain Application for
Visualization and Explanation of Abnormal
Neural Activity and Medication Efficacy. Journalof Medical Virtual Reality, 2017, 15(1): 1-7.
Shimoda, A., Ichikawa, D., & Oyama, H.
Prediction models to identify individuals at riskof metabolic syndrome who are unlikely toparticipate in a health intervention program.
International Journal of Medical Informatics,
2017,111: 90-99. doi: https://doi.org/10.1016/j.
ijmedinf.2017.12.009
Ujita W., Kohyama-Koganeya A., Endo N.,
Oyama H. Mice lacking a functional NMDA
receptor exhibit social subordination in agroup-housed environment. FEBS J. 2017 Nov
18. doi: 10.1111/febs.14334.
Ichikawa, D., Saito, T., & Oyama, H. Impact ofpredicting health-guidance candidates using
massive health check-up data: A data-driven
analysis. International journal of medical
informatics, 2017, 106: 32-36.
KIN, T., NAKATOMI, H., SHONO, N.,
NOMURA, S., SAITO, T., OYAMA, H., &SAITO, N. Neurosurgical Virtual Reality
Simulation for Brain Tumor Using Highdefinition Computer Graphics: A Review of the
Literature. Neurologia medico-chirurgica,2017,57.10: 513-520. doi: https://doi.org/10.2176/nmc.
ra.2016-0320
Shono, N., Kin, T., Nomura, S., Miyawaki, S.,
Saito, T., Imai, H., Nakatomi H., Oyama H. &Saito, N. Microsurgery Simulator of Cerebral
Aneurysm Clipping with Interactive Cerebral
Deformation Featuring a Virtual Arachnoid.Oper
Neurosurg (Hagerstown). 2017, Aug 1. doi: 10.
1093/ons/opx155.

Endowed Department

350

Department of Ubiquitous
Preventive Medicine
Associate Professor
Yuichi Ikeda, M.D., Ph.D.

Assistant Professor
Kazutaka Ueda, M.D., Ph.D.

Introduction and Organization
As an official department in the Graduate School of
Medicine of the University of Tokyo, the Departmentof Ubiquitous Preventive Medicine was established inAugust 1st, 2007, with a donation from threepharmaceutical companies, Toa-Eiyo Ltd., Shionogi &Co., Ltd. and NEC Corporation to the University(since August 2010, from Shionogi & Co.). Its
predecessor is the Clinical Bio-Informatics Research
Unit, which was established in 2002 as a governmentfunded program (Bio-Informatics Training Programsupported by the Ministry of Education, Culture,
Sports, Science and Technology [MEXT] throughSpecial Coordination Funds for Promoting Scienceand Technology). When the Clinical Bio-Informatics
Research Unit completed its program tenure in 2007,
its academic services were succeeded by our department and the Department of Clinical Epidemiology
and Systems, both affiliated with the Department of
Cardiovascular Medicine in the Graduate School of
Medicine of the University of Tokyo.
Our department provides clinical as well as
academic support for the Department of Epidemiology
and Preventive Medicine, which was established in2007 within the University of Tokyo Hospital. In
collaboration with our department, the Department ofClinical Epidemiology and Systems also support the
management of the Department of Epidemiology andPreventive Medicine.

Research Activities
Our goal is to create diagnostic and therapeutic basis
for prevention and early detection of cardiovasculardiseases by utilizing advanced techniques ofbiochemistry and molecular pharmacology.
Weespecially focus on the discovery of bioactive
molecules and diagnostic biomarkers in order topromote translational research, which connects basic
scientific findings to tangible clinical application.
One of our achievements is the establishment of anovel technique for detecting post-translational
modification and degradation of B-type natriuretic
peptide, one of the most important biomarkers in
cardiovascular pathologies such as ischemic heartdisease and heart failure. This unique technique wasdeveloped in collaboration with Shimadzu Corporation. We have already confirmed and published its
utility in clinical practice (Clin Chem, in press),further, issued press-release from the University ofTokyo Hospital.
In addition to the development of diagnostic
techniques, we have also established several screening
systems towards the discovery of bioactive substancesthat are involved in the pathogenesis of cardiovasculardiseases. Utilizing these newly developed systems,
we will screen tissue extracts and a small-moleculecompound library to identify novel bioactive
molecules.
In this way, Ubiquitous Preventive Medicine is anapplied science, based on which a comprehensive
system is to be developed in an effort to promote
preventive medicine for health promotion.

Clinical activities
The Department of Ubiquitous Preventive Medicine
is involved in the management of the Department of351

Epidemiology and Preventive Medicine in the
University of Tokyo Hospital and provides clinical aswell as academic support for the department.

Teaching activities
The Department of Ubiquitous Preventive Medicine
offers education and research supervision to graduate
students and post-doctoral fellows in the affiliate
Department of Cardiovascular Medicine.

Publications
1.

2.

3.

4.

5.

Sato H, Suzuki J, Aoyama N, Watanabe R,
Kaneko M, Shiheido Y, Yoshida Y, Wakayama K,
Kumagai H, Ikeda Y, Akazawa H, Komuro I,
Isobe M, Izumi Y: A periodontal pathogen porphyromonas gingivalis deteriorates isoproterenolinduced myocardial remodeling in mice.
Hypertens Res. 40:35-40, 2017
Watanabe R, Suzuki J, Wakayama K, Maejima Y,
Shimamura M, Koriyama H, Nakagami H,
Kumagai H, Ikeda Y, Akazawa H, Morishita R,
Komuro I, Isobe M. A peptide vaccine targetingangiotensin II attenuates the cardiac dysfunction
induced by myocardial infarction. Sci Rep. 7:43920, 2017
Takanashi M, Taira Y, Okazaki S, Takase S,
Kimura T, Li CC, Xu PF, Noda A, Sakata I,
Kumagai H, Ikeda Y, Iizuka Y, Yahagi N,
Shimano H, Osuga J, Ishibashi S, Kadowaki T,
Okazaki H. Role of hormone-sensitive lipase inleptin-promoted fat loss and glucose lowering. J
Atheroscler Thromb. 24(11):1105, 2017
Kamo T, Akazawa H, Suda W, Saga-Kamo A,
Shimizu Y, Yagi H, Liu Q, Nomura S, Naito AT,
Takeda N, Harada M, Toko H, Kumagai H, Ikeda
Y, Takimoto E, Suzuki JI, Honda K, Morita H,
Hattori M, Komuro I. Dysbiosis and compositional alterations with aging in the gut
microbiota of patients with heart failure. PLoS
One 12(3): e0174099, 2017
Nagata N, Iwanari H, Kumagai H, Kusano-AraiO, Ikeda Y, Aritake K, Hamakubo T, Urade Y.
Generation and characterization of an antagonistic monoclonal antibody against an extracellular domain of mouse DP2 (CRTH2/GPR44)
receptors for prostaglandin D2. PLoS One 12(4):e0175452, 2017
6. Aoyama N, Suzuki J, Kobayashi N, Hanatani T,
Ashigaki N, Yoshida A, Shiheido Y, Sato H,
Kumagai H, Ikeda Y, Akazawa H, Komuro I,
Izumi Y, Isobe M. Periodontitis deteriorates
peripheral arterial disease in Japanese population
via enhanced systemic inflammation. Heart
Vessels 32(11):1314-1319, 2017
7. Aoyama N, Suzuki J, Kumagai H, Ikeda Y,
Akazawa H, Komuro I, Minabe M, Izumi Y,
Isobe M. Specific periodontopathic bacterial
infection affects hypertension in male cardiovascular disease patients. Heart Vessels 32(2):198-204, 2017
8. Aoyama N, Suzuki J, Kobayashi N, Hanatani T,
Ashigaki A, Yoshida A, Shiheido Y, Sato H,
Kumagai H, Ikeda Y, Akazawa H, Komuro I,
Minabe M, Izumi Y, Isobe M. Detrimental effectsof specific periodontopathic bacterial infection
on tachyarrhythmia compared to bradyarrhythmia.
BMC Cardiovasc Disord. 17(1):267, 2017
9. Lu Q, Schnitzler GR, Vallaster CS, Ueda K,
Erdkamp S, Briggs CE, Iyer LK, Jaffe IZ, Karas
RH. Unliganded estrogen receptor alpharegulates vascular cell function and gene expression. Molecular and Cellular Endocrinology.
442:12-23, 2017
10. Adachi Y, Kinoshita O, Hatano M, Shintani Y,
Naito N, Kimura M, Nawata K, Nitta D, Maki H,
Ueda K, Amiya E, Takimoto E, Komuro I, Ono
M. Successful bridge to recovery in fulminant
myocarditis using a biventricular assist device: acase report. J Med Case Rep. 11(1):295, 2017

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Division of Chronic Kidney Disease(CKD) Pathophysiology
Division Chief (Associate Professor)
Reiko Inagi, Ph.D.

Assistant Professor
Tzu-Ming Jao, Ph.D.

Postdoctoral fellow
Kumi Shoji, M.D., Ph.D. (Division of Nephrology and Endocrinology)
Yu Ishimoto, M.D., Ph.D. (Division of Nephrology and Endocrinology)
Akira Okada, M.D. (Division of Nephrology and Endocrinology)

PhD Students
Hiroshi Maekawa, M.D. (Division of Nephrology and Endocrinology)
Mari Aoe, M.D. (Division of Nephrology and Endocrinology)
Chia-Hsien Wu, Msc. (Division of Nephrology and Endocrinology)

Visiting Researcher
Maria Ponce Nava, MSc.
(Faculty of Medicine, National Autonomous University of Mexico Mexico City, Mexico)
Yen-Chen Liu, Msc.
(Department of Life Science, National Taiwan Normal University Taipei, Taiwan)

Lab Technician
Ikumi Okuaki, B.S.

Homepage

http://www.todai-ckd.com

Introduction and Organization
In Japan, more than 13 million people suffer fromchronic kidney disease (CKD), or roughly one inevery eight adults. Why has the number of CKD
patients increased so remarkably? One major cause is
the sharp increase in the number of people withdiabetic nephropathy, which is a complication ofdiabetes; since 1998, this has been the most importantcause among diseases which require incipient dialysis
in Japan. Additional causes include the aging ofsociety and other social factors. The kidney is called asilent organ, and CKD progresses without subjective
symptoms. It is now evident, however, thatasymptomatic CKD which progresses over time
carries a number of risks.
One risk is the possible progression of CKD to
end-stage renal disease (ESRD), which requires renal
replacement therapy. A second risk is the development
and progression of lifestyle-related diseases, such asheart attack and arteriosclerosis. The kidneys work

353

closely with the heart and other organs, and a decrease
in renal function causes dysfunction of the heart andblood vessels. This adverse impact of the progressionof CKD on other organs underlines the importance of
the kidneys in maintaining general health. Further,many researchers have also focused on the vicious
spiral of aging and CKD: aging worsens the
progression of CKD, while CKD accelerates aging.
With our modern lifestyles and the super-aging society,
CKD cannot be separated from lifestyle-relateddiseases, and senility cannot be separated from CKD.

identification of the mechanism of development
and progress of renal anemia.
3) Clarifying the impact of kidney aging on CKD
progression in super-aging society4) Identifying factors in the exacerbation of CKD inpatients with diabetes, and developing diagnostic
and therapeutic drugs targeting such factors.
5) Pathophysiology of uremic toxins on organcrosstalk and impact of uremia management in
CKD

Research Funds (PI)
Creating a healthy, long-lived society full of energy
and vigor requires that the quality of life (QOL) of theelderly be improved. In turn, total medical
expenditures will also be decreased. These are important issues requiring urgent solutions. Against thisbackground, the Division of CKD Pathophysiology
was newly established in November 2013 withsupport from Kyowa Hakko Kirin Co., Ltd. The aimof the Division is to aid and support the CKD control
and the creation of a healthy and long-lived society.
The Division takes an innovative approach toidentifying the pathophysiology of CKD, and works todevelop more effective CKD preventive andtherapeutic strategies. Through these research
activities, our goal is to contribute to the creation of ahealthy, long-lived society in which the elderly canlive a happy and independent life.

Major Research Projects
The Division of CKD Pathophysiology works incollaboration with the Division of Nephrology and
Endocrinology, a part of The University of Tokyo
Graduate School of Medicine (Professor Masaomi
Nangaku) to conduct basic and clinical research on
CKD pathophysiology, including:1) Identifying the mechanism of destruction ofadaptive signals to various stresses (endoplasmic
reticulum stress, ischemia, glycative stress,
oxidative stress) in CKD; and using the findings
obtained to establish new CKD treatment
strategies.
2) Clarifying the mechanism of functional change inrenal erythropoietin (EPO)- producing cells, alongwith the mechanisms of CKD progression and Japan Society for the Promotion of Science, Grantsin-Aid for Scientific Research
15KT0088 (to Reiko Inagi, Analysis of epigenetic
regulation of endoplasmic reticulum stress signals
on kidney aging),
16K15465 (to Reiko Inagi, Analysis of pathophysiological significance of D-amino acid in
kidney disease)
16K09604 (to Tzu-Ming Jao, Development of
Noveltherapeutic
approaches
targeting
ATF-6-mediated metabolic alteration)AwardsDr. Tzu-Ming Jao received the Investigators Awardof Nagoya Chronic Kidney Disease Frontier.
Dr. Tzu-Ming Jao received the Highest Asian Session
Oral Award of the 60th annual meeting of JapaneseSociety of Nephrology.
Dr. Akira Okada received the Travel grant Award of
the 3rd International Conference of D-amino acidResearch (IDAR2017, Varese, Italy).

References
1. Ishimoto Y, Inagi R, Yoshihara D, Kugita M,
Nagao S, Shimizu A, Takeda N, Wake M,
Honda K, Zhou J, Nangaku M. Mitochondrial
Abnormality Facilitates Cyst Formation in
Autosomal Dominant Polycystic Kidney Disease.
Mol Cell Biol. 2017 Oct 9. pii: MCB.00337-17.
doi: 10.1128/MCB.00337-17.

354

2. Inagi R, Ishimoto Y, Jao TM. Foreseeing thefuture of glomerular disease through slits: miRNPNT axis. Kidney Int. 2017 Oct ;92(4):782-784.
doi:10.1016/j.kint.2017.04.036.
3. Okada A, Nangaku M, Jao TM, Maekawa H,
Ishimono Y, Kawakami T, Inagi R. D-serine, anovel uremic toxin, induces senescence in humanrenal tubular cells via GCN2 activation. Sci Rep.
2017 Sep 11;7(1):11168. doi:10.1038/s41598-01711049-8.
4. Sasaki M, Sasako T, Kubota N, Sakurai Y,
Takamoto I, Kubota T, Inagi R, Seki G, Goto M,
Ueki K, Nangaku M, Jomori T, Kadowaki T. Dual
Regulation of Gluconeogenesis by Insulin and
Glucose in the Proximal Tubules of the Kidney.
Diabetes. 2017 Sep;66(9):2339-2350. doi: 10.
2337/db16-1602.
5. Nangaku M, Hirakawa Y, Mimura I, Inagi R,
Tanaka T. Epigenetic Changes in the Acute
Kidney Injury-to-Chronic Kidney Disease
Transition. Nephron. 2017 Jun 9. doi: 10.1159/
000476078.
6. Hirakawa Y, Jao TM, Inagi R. Pathophysiology
and therapeutics of premature ageing in chronic
kidney disease, with a focus on glycative stress.
Clin Exp Pharmacol Physiol. 2017 May 3. doi:
10.1111/1440-1681.
7. Hasegawa S, Jao TM, Inagi R. Dietary
Metabolites and Chronic Kidney Disease.
Nutrients. 2017 Apr 4;9(4). pii: E358. doi: 10.
3390/nu9040358. Review.
8. Tanaka S, Tanaka T, Kawakami T, Takano H,
Sugahara M, Saito H, Higashijima Y, Yamaguchi J,
Inagi R, Nangaku M. Vascular adhesion protein-1
enhances neutrophil infiltration by generation ofhydrogen peroxide in renal ischemia/reperfusion
injury. Kidney Int. 2017 Jul;92(1):154-164. doi:
10.1016/j.kint.2017.01.014.
9. Maekawa H, Inagi R. Stress Signal Network
between Hypoxia and ER Stress in Chronic
Kidney Disease. Front Physiol. 2017 Feb 8;8:74.
10. Hirakawa Y, Inagi R. Glycative Stress and Its
Defense Machinery Glyoxalase 1 in Renal
Pathogenesis. Int J Mol Sci. 2017 Jan 17;18(1).
pii: E174.
11. Yamaguchi J, Tanaka T, Inagi R. Effect of
AST-120 in Chronic Kidney Disease Treatment:

Still a Controversy. Nephron. 2017;135(3):201206.

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Department of Molecular Structure
and Dynamics
Project Professor
Nobutaka Hirokawa, M. D.

Project Associate
Tadayuki Ogawa, Ph. D.

Home page

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

Teaching activities
We are involved in teaching medical students andMaster course and Ph. D. course students in thefollowing lectures and laboratory courses together
with the Department of Cell Biology and Anatomy.
I.
1) Lecture on Cell Bilogy, Developmental Biology,
Histology and Neurocytology.
2) Lecture on Gross Anatomy and Neuroanatomy. to
medical students and students of other facultiesII.
1) Laboratory course of Gross Anatomy and
Neuroanatomy.
2) Laboratory course of Histology and Histology of
the Cenrtral Nervous System.
to medical students and students of other faculties.
In addition we offer a special training course (freequarter) of various kinds of molecular cell biology
techniques such as immunocytochemistry, electron
microscopy, biochemistry, molecular biology, biophysics, and cellular and molecular neurobiology
technique to medical students.
Especially we devote ourselves for the teaching of the
cutting edge approaches of new light microscopy suchas the Photoactivated Localization Microscopy (PALM),
cryo-electron microscopy and X-ray crystallography.

Research activities
Our laboratory studies molecular motors and rail
microtubules and the mechanisms of intracellulartransport. To study these molecular mechanisms we
use new molecular cell biological approaches
including cutting edge light microscopies, cryoelectron microscopy of molecular resolution, X-ray
crystallography, biophysics, molecular biology andmolecular genetics. We aim to study the structure anddynamics of the molecular motors in vitro and in vivo
at the highest special and temporal resolution and onthese bases try to elucidate functions of molecularmotors in vivo combining molecular genetics.

References
1. Ogawa, T., S. Saijo, N. Shimizu, X. Jiang and N.
Hirokawa. Mechanism of Catalytic Microtubule
Depolymerization via KIF2-tubulin Transitional
Conformation.. Cell Rep. 20: 2626–2638, 2017.
2. Ogawa, T., and N. Hirokawa. Multiple analysesof protein dynamics in solution. Biophy. Rev..
https://doi.org/10.1007/s12551-017-0354-7 2017
3. Homma, N. R., Zhou, M. I. Naseer, A. G.
Chaudhary, M. H. Al-Qahtani, and N. Hirokawa.
KIF2A regulates the development of dentate
granule cells and postnatal hippocampal wiring.
eLife 7: e30935. DOI: https://doi.org/10.7554/
eLife. 30935, 2018
4. Morikawa, Mo., Y. Tanaka, H. –S. Cho, M.
Yoshihara, and N. Hirokawa. The molecularmotor KIF21B mediates synaptic plasticity andfear extinction by terminating Rac1 activation.
Cell Rep. 23: 3864-3877, 2018.

356

5. Xu, F., H. Takahashi, Y. Tanaka, S. Ichinose, S.
Niwa, M. P. Wicklund, and N. Hirokawa. KIF1B
beta mutations detected in hereditary neuropathy
impair IGF1R transport and axon growth. J. Cell
Biol. 217:3480-3496. 2018
6. Wang, L., Y. Tanaka, D. Wang, R. Zhou, N.
Homma, Y. Miyamoto and N. Hirokawa. The
atypical kinesin KIF26A facilitates termination ofnoticeptive responses by sequestering focal adhesion
kinase. Cell Rep. 24:2894-2907. 2018
7. Shima, T., M. Morikawa, J. Kaneshiro, T. Kambara,
S. Kamimura, T. Yagi, H. Iwamoto, S. Uemura, H.
Shigematsu, M. Shiromizu, T. Ichimura, T.
Watanabe, R. Nitta, Y. Okada, N. Hirokawa.
Kinesin-binding triggered conformation switchingof microtubules contributes to polarized transport.
J. Cell Biol. 2018 https://doi.org/10.1083/jcb.
201711178

357

Department of Continence
Medicine
Project Professor
Yasuhiko Igawa, M.D.,Ph.D.

Project Assistant Professor
Naoki Aizawa, Ph.D.

Homepage: http://cont-med.umin.jp/
Introduction and Organization

Clinical activities

Our department has been established as anendowment department supported by Astellas Pharma
Inc. in close collaboration with the Department ofUrology on July 1st 2010 to facilitate researches
specially focusing on continence medicine. Since July,
2013, this department has been received kind
donations from six pharmaceutical companies(Astellas Pharma Inc., Asahi-kasei Pharma Corp., Ono
Pharmaceutical Co., Ltd, Kissei Pharmaceutical Co.,
Ltd, Kyorin Pharmaceutical Co., Ltd, and Taiho
Pharmaceutical Co., Ltd).
The aim of our department is to contribute to theadvancement of continence medicine through basic
and clinical researches on regulation mechanisms oflower urinary tract (LUT) function and pathphysiology of LUT dysfunction, as well as function/
dysfunction of lower bowel and pelvic floor.
We believe that a multi-disciplinary professionalteam consisted of physicians, surgeons, nurses,
physiotherapists, bio-engineers, social workers andscientists is necessary to achieve greater advancementof continence medicine and care. We hope many
researchers with different specialties are interested inour research themes and collaborate with us for the
purpose of supporting patients with continence
problems by providing them better treatment andmanagement strategies.

Professor Igawa offers clinical services specialized
for patients with intractable lower urinary tract
dysfunction as well as for children with urogenital
disorders in conjunction with the Department ofUrology.

Teaching activities
We take part in providing systematic urologicallectures for second year medical students, and bed
side teaching for third and fourth year medical
students.

Research activities
We are currently investigating regulation mechanisms of lower urinary tract (LUT) function, andpathophysiological mechanisms of various LUT dysfunction, including overactive bladder (OAB), bladderoutlet obstruction (BOO), interstitial cystitis/bladderpain syndrome(IC/BPS), and underactive bladderdysfunction, especially focusing on:
1. To elucidate bladder sensory transduction mechanisms
2. To disclose pathophysiology of development of
detrusor overactivity/OAB
3. To find useful biomarkers for IC/BPS
4. To evaluate the effects of metabolic syndrome on
LUT function

358

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, Ito H, Sugiyama R, Fujimura T,
Fukuhara H, Kume H, Homma Y, Igawa Y. Effectsof Sildenafil, a phosphodiesterase type 5 inhibitor,
on the primary single afferent activity of the rat
bladder. LUTS. 2017 Jan;9(1):57-61.
2. Aizawa N, Wakamatsu D, Kida J, Otsuki T, Saito
Y, Matsuya H, Homma Y, Igawa Y. Inhibitory
effects of retigabine, a Kv7 channel activator, on
mechanosensitive primary bladder afferent
activities and nociceptive behaviors in rats.
Neurourol Urodyn. 2017 Feb;36(2):280-285.
3. Ito H, Pickering, AE, Igawa Y, Kanai, AJ, Fry, CH,
Drake, MJ. Muro-Neuro- Urodynamics; a Reviewof the Functional Assessment of Mouse Lower
Urinary Tract Function. FRONTIERS IN
PHYSIOLOGY. 2017 Feb 6;8:49.
4. Sugiyama R, Aizawa N, Ito H, Fujimura T, Suzuki
M, Nakagawa T, Fukuhara H, Kume H, Homma Y,
Igawa Y. Synergic Suppressive Effect of Silodosin
and Imidafenacin on Non-Voiding Bladder
Contractions in Male Rats with Subacute Bladder
Outlet Obstruction. LUTS. 2017 May; 9(2):94101.
5. Yoshida M, Igawa Y, Higashimura S, Suzuki M,
Niimi A, Sanada H. Translation and reliability andvalidity testing of a Japanese version of theIntermittent Self-Catheterization Questionnaire
among disposable and reusable catheter users.
Neurourol Urodyn. 2017 Jun;36(5): 1356-1362.
6. Igawa Y, Aizawa N. Incontinence: How do
β3-adrenoceptor agonists work in the bladder? Nature
Reviews Urology 2017 Jun;14(6): 330-332.
7. Ichihara K, Aizawa N, Akiyama Y, Kamei J,
Masumori N, Andersson KE, Homma Y, Igawa Y.
Toll-like receptor 7 is overexpressed in the
bladder of Hunner-type interstitial cystitis, and its
activation in the mouse bladder can induce cystitis
and bladder pain. Pain. 2017 Aug; 158(8):15381545.

8. Aizawa N, Ichihara K, Fukuhara H, Fujimura T,
Andersson KE, Homma Y, Igawa Y.
Characteristics of the mechanosensitive bladderafferent activities in relation with microcontractions in male rats with bladder outlet
obstruction. Sci Rep. 2017 Aug 9;7(1):7646..
9. Yamada Y, Fujimura T, Fukuhara H, Sugihara T,
Miyazaki H, Nakagawa T, Kume H, Igawa Y,
Homma Y. Overactive bladder is a negative
predictor of achieving continence after robotassisted radical prostatectomy. Int J Urol. 2017
Oct;24(10):749-756.
10. Aizawa N, Igawa Y. Pathophysiology of theunderactive bladder. Investig Clin Urol. 2017
Dec;58(Suppl 2):S82-S89.

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Department of Medical Genomics
Associate Professor
Masahito Kawazu, M.D., Ph.D.

Assistant Professor
Shinji Kohsaka, M.D., Ph.D., Satoshi Inoue, Ph.D.

Introduction and Organization

Teaching activities

Department of Medical Genomics was establishedwith Professor Hiroyuki Mano in September 2009
with the goal to identify essential growth drivers inevery cancer, by taking advantage of our functional
screening system coupled with the next generation
sequencing technologies. Department of Medical
Genomics had been settled by the tight support from
Department of Molecular Pathology (Professor Kohei
Miyazono) and by the donation from Astellas Pharma
Inc. and Illumina, Inc. Starting as of September 2012,
Department of Medical Genomics had been run onlyby the donation from Astellas Pharma Inc. In April
2013, Professor Hiroyuki Mano was promoted to be
the Professor of Department of Cellular Signaling
which then co-supported this Department. Instead,
Associate Professor Yoshihiro Yamashita led thisDepartment. Starting from September 2014,
Department of Medical Genomics has entered thesecond 5-year term by the support from Eisai Co., Ltd.
In September 2014, Dr. Yoshihiro Yamashita waspromoted to become Associate Professor at Department of Cellular Signaling, and this Department was
run by the leadership of Associate Professor Eirin Sai.
Since the retirement of Dr. Sai in 2017, Dr. Masahito
Kawazu has managed Department of Medical
Genomics as Associate 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
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 a360

constitutively 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 found that copy number alterations in oncogenes
and tumor-suppressor genes are significantly lessfrequent in 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.
(3) High-throughput functional evaluation method
Numerous variants of unknown significance(VUS) have been identified through large-scale cancer
genome projects, although their functional relevanceremains uninvestigated. The L858R substitution orexon 19 deletions are, for instance, known to confer
activation of epidermal growth factor receptor (EGFR)
kinase, but there are more than one thousand of
nonsynonymous mutations within EGFR reported in
the COSMIC database. It is still obscure whether suchmutations have some relevance to EGFR kinase
activity or are merely passenger mutations. To
drastically increase the speed of functional annotation,
here we have developed a mixed-all-nominatedmutants-in-one (MANO) method to evaluate thetransforming potential and drug sensitivity of
oncogene VUS in a high-throughput manner. To
validate its usefulness, we applied this method to 101
nonsynonymous EGFR mutants, and successfully
evaluated clinical relevance of each mutations.

References
1. Takamochi K, Takahashi F, Suehara Y, Sato E,
Kohsaka S, Hayashi T, Kitano S, Uneno T,
Kojima S, Takeuchi K, Mano H & Suzuki K.
DNA mismatch repair deficiency in surgicallyresected lung adenocarcinoma: Microsatellite
instability analysis using the Promega panel.
Lung Cancer 110, 26-31, 2017.
2. Soh SX, Siddiqui FJ, Allen JC, Kim GW, Lee JC,
Yatabe Y, Soda M, Mano H, Soo RA, Chin TM,
Ebi H, Yano S, Matsuo K, Niu X, Lu S, Isobe K,
Lee JH, Yang JC, Zhao M, Zhou C, Lee JK, Lee
SH, Lee JY, Ahn MJ, Tan TJ, Tan DS, Tan EH,
Ong ST & Lim WT. A systematic review andmeta-analysis of individual patient data on theimpact of the BIM deletion polymorphism on
treatment outcomes in epidermal growth factor
receptor mutant lung cancer. Oncotarget 8,41474-41486, 2017.
3. Seki M, Kimura S, Isobe T, Yoshida K, Ueno H,
Nakajima-Takagi Y, Wang C, Lin L, Kon A,
Suzuki H, Shiozawa Y, Kataoka K, Fujii Y,
Shiraishi Y, Chiba K, Tanaka H, Shimamura T,
Masuda K, Kawamoto H, Ohki K, Kato M,
Arakawa Y, Koh K, Hanada R, Moritake H,
Akiyama M, Kobayashi R, Deguchi T, Hashii Y,
Imamura T, Sato A, Kiyokawa N, Oka A, Hayashi

361

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Y, Takagi M, Manabe A, Ohara A, Horibe K,
Sanada M, Iwama A, Mano H, Miyano S, Ogawa
S & Takita J. Recurrent SPI1 (PU.1) fusions inhigh-risk pediatric T cell acute lymphoblastic
leukemia. Nat Genet 49, 1274-1281, 2017.
Nakamura T, Yamashita S, Fukumura K,
Nakabayashi J, Tanaka K, Tamura K, Tateishi K,
Kinoshita M, Fukushima S, Takami H, Fukuoka K,
Yamazaki K, Matsushita Y, Ohno M, Miyakita Y,
Shibui S, Kubo A, Shuto T, Kocialkowski S,
Yamanaka S, Mukasa A, Sasayama T, Mishima K,
Maehara T, Kawahara N, Nagane M, Narita Y,
Mano H, Ushijima T & Ichimura K. Genome-wide
DNA methylation profiling identifies primarycentral nervous system lymphoma as a distinct
entity different from systemic diffuse large B-cell
lymphoma. Acta Neuropathol 133, 321-324,
2017.
Matsubara D, Soda M, Yoshimoto T, Amano Y,
Sakuma Y, Yamato A, Ueno T, Kojima S,
Shibano T, Hosono Y, Kawazu M, Yamashita Y,
Endo S, Hagiwara K, Fukayama M, Takahashi T,
Mano H & Niki T. Inactivating mutations andhypermethylation of the NKX2-1/TTF-1 gene in
non-terminal respiratory unit-type lung adenocarcinomas. Cancer Sci 108, 1888-1896, 2017.
Kohsaka S, Nagano M, Ueno T, Suehara Y,
Hayashi T, Shimada N, Takahashi K, Suzuki K,
Takamochi K, Takahashi F & Mano H. A methodof high-throughput functional evaluation of EGFR
gene variants of unknown significance in cancer.
Sci Transl Med 9, eaan6556, 2017.
Kawazu M, Kojima S, Ueno T, Totoki Y,
Nakamura H, Kunita A, Qu W, Yoshimura J, Soda
M, Yasuda T, Hama N, Saito-Adachi M, Sato K,
Kohsaka S, Sai E, Ikemura M, Yamamoto S,
Ogawa T, Fukayama M, Tada K, Seto Y,
Morishita S, Hazama S, Shibata T, Yamashita Y& Mano H. Integrative analysis of genomic
alterations in triple-negative breast cancer inassociation with homologous recombination
deficiency. PLoS Genet 13, e1006853, 2017.

362

Department of Life Support
Technology (Molten)
Project Professor
Taketoshi Mori, Ph.D.

Project Lecturer
Hiroshi Noguchi, Ph.D.

Project Assistant Professor
Daichi Araki, Ph.D.

Homepage

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

Introduction and Organization
Department of Life Support Technology (Molten) was
founded Oct. 1, 2010 as a laboratory in Graduate
School of Medicine of the University of Tokyo.
The aim of the department is to establish life support
technology, which include not only pathophysiology
investigation of diseases and symptoms caused bydaily life activities but also development of directintervention method based on nursing approach andmethodology establishment for supporting daily life
widely.
First, Prof. Hiromi Sanada, who drives translational
research in nursing research area, and Molten Corp.,
which is one of Japanese welfare device development
companies, planned to establish this department. After
planned, Prof. Takeyoshi Dohi, leading person in
welfare and medical device engineering, recommended Taketoshi Mori, Ph.D. as a leader of thedepartment. He arrived at his post and the department
was established.
From Oct 1, 2015, the second term of the department
started. On Feb 20, 2016, the celebration party for
department continuation and promotion of Prof. Mori
was held at Gakushi-Kaikan, which is the same placeas the celebration party for department establishment.

Many people including president of Molten Corp.
Kiyoshi Tamiaki, Prof. Noriko Yamamoto and Prof.
Takeyoshi Dohi attended the party. Both nursing
researchers and engineering researches congratulate
the department continuation and promotion of Prof.
Mori.
Our department contributed to establishment of thesociety for nursing science and engineering from 2012.
The first annual meeting of nursing science andengineering was hold at 5th Oct 2013. Our department
played a great important role for management of themeeting as a host.
From Apr 1, 2017, global nursing research center was
established in Graduate School of Medicine of the
University of Tokyo. In the center, Project Prof Mori
held the addition concurrent post of Robotic Nursing
in Division of Care innovation.
Current members include a project professor, a project
lecturer and a project assistant professor. We accept
students from Division of Health Science and Nursing.
Accepted two master course students were graduatedat the end of 2013. The supportive department is the
Department of Gerontological Nursing / Wound CareManagement. We also accept foreign students. In 2013,
we accepted a Ph.D. student from Mexico. In 2017,363

we accepted a research student from Korea.

Teaching activities
As for lectures, our department assisted the lectures ofthe supportive department, the Department ofGerontological Nursing/Wound Care Management. In
a part of Wound Care Management, I for graduate
course, Taketoshi Mori taught electric engineering,which is closely related to development of medical
and nursing devices. Hiroshi Noguchi taught
measurement engineering. We invited Prof. Hiroyasu
Iwata, Waseda University and other speakers related
to engineering to lecture for Gerontological Nursing II
for graduate course. In a part of GerontologicalNursing I for graduate course, the members in thedepartment lectured the features and reading methodof journal papers of engineering research based on
typical publications.
As for the other education activity, our department
supported management of the fifth seminar for nursing
science and engineering, which was organized by
global nursing research center. The staffs in our
department had engineering-related lectures. In
addition, our departments hold advanced lecture
course about 3D scanner and printer.
From establishment of global nursing research center,the laboratory have accepted training or visitation in
our laboratory 19 times (8 from foreigners, and 11
from domestic visitors)

Research activities
Our research themes are to investigate causes of
diseases and/or wounds due to daily life activity, andto develop instrument for effective monitoring andpreventing diseases and/or wounds. We study scienceand technology of natural human monitoring, nursing
engineering, and human behavior sensing thoroughly.
We are seeking a new interdisciplinary researchdomain between engineering and nursing, and willing
to realize comfortable daily life through theseresearches.
We are developing the methodology to support healthy

and comfortable daily life by 1) monitoring daily life
naturally, 2) understanding the typical behaviors, and
3) predicting diseases, injuries, and accidents using
various sensing technology.
Main themes of our department are the following:a) Development of monitoring systems for patient on
a bed and vital sign measurement system using
mattressb) Construction of behavior measurement in dailyliving environment using simple sensors andalgorithm for typical behavior pattern extraction
and transition estimation of human behavior
patternc) Three-dimensional leg movement measurement
and spatiotemporal 3D leg state measurement for
prevention of foot ulcerd) Clinical research and image processing technology
development for current status and management ofincontinencee) Human position measurement and behavior
estimation using laser range scannersf) Design and construction of human behavior
database
As for the clinical field, we attend the Foot Care
Outpatient Clinic held by Department of Metabolic
Diseases. In this school year, we started the researchat the University hospital using communication
robots.
We started a new research theme collaborating with
Department of Gerontological Nursing/Wound CareManagement. The research aim is to measure desire to
void using load cell sensors in mattressunconstrainedly. The mattress system contains 5
panels with 4 load cell sensors. The sensors can detectslight body movement. A master course student, who
was belonging to Department of GerontologicalNursing/Wound Care Management developed andevaluated new algorithm to detect desire to void using
this system. In addition, he conducted case study
using the mattress system. He wrote master course
thesis “Development of a mattress sensor system toestimate desire to void for elderly patients withphysical and cognitive impairment” and graduated.

364

We started another new research theme. As asupportive method for validation of qualitative
research, introduction of text mining were tried. A partof this research was used in the master course thesis“Fecal distribution changes using colorectal
ultrasonography in elderly patients with physical andcognitive impairment at long-term care facilities: A
longitudinal observational study”, which is describedby a master course student who was belonging to
Department of Gerontological Nursing/Wound CareManagement.
We achieved the following award in this year.
1. Noriko Hori, Papar award of Japanese Society ofWound, Ostomy, and Continence Management．
Hori N, Tamai N, Noguchi H, Nakagami G, Sugama J,
Mori T, Sanada H．Development and assessment of
air mattress with independent air cell preessure
control responsive to interface pressure distribution.
Journal of Japanese Society of Wound, Ostomy, andContinence Management．2017；20(3)：300-309.
2. Daichi Araki. Life 2017 young presentation award(domestic conference).
Daichi Araki, Hiroshi Noguchi, Takayasu Kawaguchi,
Hiromi Sanada, Taketoshi Mori. “Comparison of
movement discrimination method using aircell
mattress including pressure distribution sensor”
proceedings of LIFE2017, p.22. OS5-3. 2017.
(LIFE2017, Tokyo 2017/9/15)

References
1.

2.

3.

Miura Y, Nakagami G, Yabunaka K, Tohara H,
Noguchi H, Mori T, Sanada H. A Randomized
Controlled Trial to Investigate the Effectivenessof the Prevention of Aspiration Pneumonia Using
Recommendations for Swallowing Care Guided
by Ultrasound Examination. Healthcare (Basel).
2018;6(1):E15.
Watanabe A, Noguchi H, Oe M, Sanada H, Mori
T. Development of a Plantar Load Estimation
Algorithm for Evaluation of Forefoot Load of
Diabetic Patients during Daily Walks Using a
Foot Motion Sensor. Journal of Diabetes
Research. 2017;2017:1-8.
Noyori S, Nakagami G, Noguchi H, Yabunaka K,
Mori T, Sanada H. A New Ultrasonographic

4.

5.

Image Displaying System to Support Vein
Detection. Journal of Robotics and Mechatronics.
2017;29(2):306-16.
Mori T, Kobayashi Y. Innovative Technology for
Nursing Care and Nosotrophy. Journal of
Robotics and Mechatronics. 2017;29(2):287.
Oe M, Takehara K, Noguchi H, Ohashi Y,
Amemiya A, Sakoda H, Suzuki R, Yamauchi T,
Ueki K, Kadowaki T, Sanada H. Thermographic
findings in a case of type 2 diabetes with footulcer due to callus deterioration. Diabetology
International. 2017;8(3):328-33.

365

Department of Youth Mental
HealthAssociate Professor
Tsuyoshi Araki, M.D., Ph.D.

Lecturer
Mio Masaoka, Ph.D.

Homepage

http:// plaza.umin.ac.jp/~youth-mh/

Introduction and Organization
The Department of Youth Mental health wasestablished May 2011. This department is supported
by Otsuka Pharmaceutical Co., Ltd. and keeps close
relationship with the department of neuropsychiatry.
Youth means the period of time when someone isyoung, especially the period when someone is ateenager. This period includes the period of puberty
and adolescence. This period is unique to human andis very important for developing the ego function. If
some critical event happens at this time, thedevelopment might be inhibited and this inhibition
may cause mental illness. In order to keep thisdevelopment safely, the close care for teenagers isvery useful. Although the importance of mental healthof children and adult is emphasized in the history ofneuropsychiatry, youth mental health did not attract a
lot of attention of psychiatrists and researchers. Fromthe late 20th century, psychiatrists began to notice theimportance of youth mental health.
This department has a focus on youth mental healthand combines the biological aspect and social aspectof psychiatry. We are trying to create the new conceptof the social psychiatry including early intervention
and education.

Clinical activities
We have outpatient clinics especially for the youth.
This clinic is a part of neuropsychiatry clinics but
treats young people especially suffering from earlystage of psychosis. We try to use cognitive and social
therapy for those patients and to minimize the use of
medication.
Psychiatrists and co medical staffs go to highschools and are engaged in educational activities.
School teachers often need some advises about mental
health problems happening in schools, we try to assist
those teachers as well.
Just after the Great East Japan Earthquake, staffs ofthe department of neuropsychiatry went to Miyagi
prefecture and support the staffs working at
Higashimatsushima City. This department also sends
staffs and meets the needs of staffs working at
Higashimatsushima City.

Educational activities
Staffs are participating in several kinds of lectureswith the staffs of the department of psychiatry. We
also manage the mental health research course which
is one of the courses of clinical research training
program in the University of Tokyo.

Research activities
Our research field covers Integrative neuroimaging
studies for schizophrenia targeting early intervention
and prevention (IN-STEP), Tokyo teen cohort study,
and the cohort-subsample brain imaging study.

366

References
1. Ando S, Kuwabara H, Araki T, Kanehara A,
Tanaka S, Morishima R, Kondo S, Kasai K:
Mental Health Problems in a Community Afterthe Great East Japan Earthquake in 2011: A
Systematic Review. Harv Rev Psychiatry 25(1):15-28, 2017
2. Kanehara A, Ando S, Araki T, Usami S,
Kuwabara H, Kano Y and Kasai K: Trends inpsychological distress and alcoholism after The
Great East Japan Earthquake of 2011. SSM –Population Health 2: 807-812, 2016
3. Sakakibara E, Homae F, Kawasaki S, Nishimura Y,Takizawa R, Koike S, Kinoshita A, Sakurada H,
Yamagishi M, Nishimura F, Yoshikawa A, Inai A,
Nishioka M, Eriguchi Y, Matsuoka J, Satomura Y,
Okada N, Kakiuchi C, Araki T, Kan C, Umeda M,
Shimazu A, Uga M, Dan I, Hashimoto H,
Kawakami N and Kasai K: Detection of restingstate functional connectivity using partial
correlation analysis: A study using multi-distanceand whole-head probe near-infrared spectroscopy.
Neuroimage 142: 590-601, 2016
4. Araki T, Kirihara K, Koshiyama D, Nagai T, Tada
M, Fukuda M and Kasai K: Intact neural activity
during a Go/No-go task is associated with highglobal functioning in schizophrenia. Psychiatry
Clin Neurosci 70(7): 278-285, 2016

367

Department of Immunotherapy
Management
Project Associate Professor
Hiroko Kanda, M.D., Ph.D.

Project Associate
Mariko Inoue, M.D., PhD, Shoko Tateishi, M.D., PhD

Home page: http://ryumachi.umin.jp/immu.html
Introduction and Organization
Recently, biologic agents targeting cytokines or cellsurface molecules and small molecules targeting
intracellular pathways relevant to cytokine production
or cytokine signaling, play an important role in thetreatment of autoimmune diseases. Both of them are
named as molecularly targeted drugs. In Japan, thesemolecularly targeted drugs are available for thetreatment of rheumatoid arthritis, psoriasis, Behcet
disease and inflammatory bowel diseases. Thesediseases are treated in the Department of Allergy &Rheumatology, Dermatology, Orthopedics Gastroenterology, Surgical oncology & vascular surgery, andOphthalmology. The Department of Immunotherapy
Management was established in April 2013, andrenewed through donations from new seven pharmaceutical companies (Mitsubishi-Tanabe, Chugai,
Ayumi, Taishotoyama, Nipponkayaku, UCB Japan,
Abbvie) in June 2016. The Department of Allergy &Rheumatology, Dermatology and Orthopedics work incollaboration.
Biologics agents include infliximab, infliximab BS,
adalimumab, golimumab, certolizumab pegol,etanercept, tocilizumab, abatacept, ustekinumab,
secukinumab, ixelizumb, brodulumab, guselkumab,
rituximab, mepolizumab and belimumab. The Jakkinase inhibitors include tofacitinib and baricitinib.
These molecularly targeted drugs have beendeveloped in succession. However, it is difficult topredict the efficacy and toxicity of these agents by the

background characteristics of patients withrheumatoid arthritis. The aims of this department are
to propose an optimal treatment strategy for eachpatient and to establish a platform to investigate novel
biologics through analyses of immunological changes
by molecularly targeted therapy and the relationshipbetween biologics response and biomarkers or genetic
information.

Clinical activities
We established a new booth for outpatients withrheumatoid arthritis who are receiving molecularly
targeted drugs which is available every morning from
Monday to Friday. We focus on total rheumatoid
arthritis care with molecularly targeted drugs.
Moreover, we examine outpatients with psoriasis,
spodyloarthritis and Behcet’s disease before
molecularly targeted therapy and judge whether thesetreatments can be used safely. In every Friday
afternoons, we evaluate for outpatient with psoriatic
arthritis including accurate diagnosis and monitoringdisease activity by clinical and imaging examinations.

Teaching activities
As for education, we take part in providing
information of molecularly targeted drugs for patients
who are the candidates to receive biologics, including
necessity, benefits, safety, complications, procedures
and costs. Every time when a new molecularly
targeted drug becomes available for prescription, we368

provide information of the agent for medical staffs.
Moreover, we are giving lectures about molecularly
targeted therapy for medical students at bed-side
learning programs or at systematic lecture courses.

Research activities
As for research, we are investigating novel
molecularly targeted drugs through analyses of
immunological changes by molecularly targeted
therapy and the relationship between biologics
response and biomarkers or genetic information.

References
1.

2.

3.

Nakachi S, Sumitomo S, Tsuchida Y, Tsuchiya H,
Kono M, Kato R, Sakurai K, Hanata N,
Nagafuchi Y, Tateishi S, Kanda H, Okamura T,
Yamamoto K, Fujio K. Interleukin-10-producing
LAG3+ regulatory T cells are associated withdisease activity and abatacept treatment inrheumatoid arthritis. Arthritis Res Ther. 2017;19(1) :97-107
Nagafuchi Y, Shoda H, Sumitomo S, Nakachi S,
Kato R, Tsuchida Y, Tsuchiya H, Sakurai K,
Hanata N, Tateishi S, Kanda H, Fujio K,
Yamamoto K. Enhanced gut homing receptor
expression of unswitched memory B cells in
rheumatoid arthritis. Clin Exp Rheumatol. 2017;35(2):354-5
Kanda H: Biologics treatments for psoriatic
arthritis. Orthopaedic Surgery and Traumatology
2017; 60(3): 315-23

369

Department of medical researchand the management ofmusculoskeletal pain
Professor
Koh Matsudaira, M.D,Ph.D.

Associate Professor
Hiroyuki Oka, M.D,Ph.D.

Researcher
Tomoko Fujii, M.D,Ph.D

Homepage

http://www.h.u-tokyo.ac.jp/research/center22/contribute/undouki_toutu.html

Introduction and Organization
The department of medical research and the
management of musculoskeletal pain was establishedat the 22nd Century Medical and Research Centre
thanks to donations from Ono Pharmaceutical Co. Ltd.,Showa Yakuhin Kako Co., Ltd., Nippon Zoki
Pharmaceutical Co., Ltd., MTG Co., Ltd., Sompo
Holdings, Inc, NUVASIVE Japan, and Shionogi & Co.,
Ltd..The department is a collaboration among the
Department of Orthopaedics, the Department of
Rehabilitation Medicine, and the Department ofAnaesthesiology and Pain Medicine. Currently, ouraims are to design an algorithm for diagnosing andtreating most types of musculoskeletal pain that do nothave established treatment guidelines and to elucidate
evidence for the possibility of developing causal
therapies.
In the “Comprehensive Survey of Living Conditions” and the “Survey on the Status of Occurrence of
Diseases at Work,” which were published by the
Health, Labour, and Welfare Ministry, the issues
affecting the locomotive apparatus over the years,
particularly low back pain and joint pain, have beenranked as the top complaints among citizens and as acause of absence from work. Musculoskeletal pain,
mainly low back pain and joint pain, is an issue with ahigh complaint rate that causes tremendous social
loss.
In April 2014, the course on medical research andthe management of musculoskeletal pain was madeavailable to provide more knowledge on highly
prevalent musculoskeletal pain and to become a coreprogramme in leading multidisciplinary clinicalresearch.
To achieve these goals, We will closely collaborate
with the Department of Orthopaedics, Department of
Spinal Surgery, Department of Rehabilitation, andAnaesthesiology and Pain Relief Centre (University ofTokyo Hospital). On the basis of an extensive
epidemiological survey, we will identify risk factorsthat contribute to determining the therapeutic strategy
for treating musculoskeletal pain as well as the
prognosis. In addition, on the basis of these
determined risk factors, we will develop and propose
diagnostic tools/algorithms as well as prevention andtreatment programmes. Then we will collect andanalyse clinical data and systematise the diagnosis,
prevention, and treatment of chronic pain – mainly
musculoskeletal pain.

370

Research activities
In 2014 the first year after the course’s inauguration– we will explore the risk factors that contribute todetermining the therapeutic strategy for treatingmusculoskeletal pain and the prognosis through thefollowing methods:
1) Identify risk factors associated with the onset andexacerbation of musculoskeletal pain through anapproach that integrates physical and psychosocial
factors as well as biomechanics;
2) Verify the validity of the standard values ofscreening tools recommended worldwide for their use
in Japan; and3) Evaluate the brain function of people who are on
administrative leave due to low back pain, since thisphenomenon is a major social problem.
Specifically, we will conduct the following research:fluoro-2-deoxyglucose positron emission tomography
images of the brain taken before and after therapeuticinterventions (e.g. exercise and cognitive behaviouraltherapy, which are highly recommended worldwide)
on approximately 15 cases of refractory low back painthat led to a leave of absence from work.
Prospects for future research
We plan to train clinicians with skills in musculoskeletal pain rehabilitation, including specialised
exercise therapy and cognitive behavioural therapy fornonspecific low back pain, which is the most frequent
type of musculoskeletal pain. By collaborating with
the Department of Nursing, we plan to develop simple
tools to prevent low back pain, which will be useful inthe clinical settings and for industrial hygiene.
Moreover, we plan to verify and diagnose the tools’
utility and conduct further research on preventive
tools and therapeutic programmes.

References
1.

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

2.

3.

Matsudaira K, Oka H, Kikuchi N, Haga Y,
Sawada T, Tanaka S. The Japanese version of the
STarT Back Tool predicts 6-month clinicaloutcomes of low back pain. J Orthop Sci 22:
224-229, 2017
Isomura T, Sumitani M, Matsudaira K,
Kawaguchi M, Inoue R, Hozumi J, Tanaka T,
Oshima H, Mori K, Taketomi S, Inui H, Tahara K,
Yamagami R, Hayakawa K. Development of theJapanese Version of the Leeds Assessment of the
Neuropathic Symptoms and Signs Pain Scale(LANSS-J): Diagnostic Utility in a ClinicalSetting. Pain Pract 17 :800-807, 2017
Coggon D, Ntani G, Walker-Bone K, Palmer KT,
Felli VE, Harari R, Barrero LH, Felknor SA,
Gimeno D, Cattrell A, Vargas-Prada S, Bonzini
M, Solidaki E, Merisalu E, Habib RR, SadeghianF, Kadir MM, Warnakulasuriya SS, Matsudaira K,
Nyantumbu B, Sim MR, Harcombe H, Cox K,
Sarquis LM, Marziale MH, Harari F, Freire R,
Harari N, Monroy MV, Quintana LA, Rojas M,
Harris EC, Serra C, Martinez JM, Delclos G,
Benavides FG, Carugno M, Ferrario MM,
Pesatori AC, Chatzi L, Bitsios P, Kogevinas M,
Oha K, Freimann T, Sadeghian A, Peiris-John RJ,

371

Sathiakumar N, Wickremasinghe AR, Yoshimura
N, Kelsall HL, Hoe VC, Urquhart DM, Derrett S,
McBride D, Herbison P, Gray A, Salazar Vega
EJ.: Epidemiological differences between
localised and non-localised low back pain.Spine
42 :740-747, 2017
4. Tonosu J, Oka H, Matsudaira K, Higashikawa A,
Okazaki H, Tanaka S. The relationship between
the findings on magnetic resonance imaging andprevious history of low back pain. J Pain Res 10:
47-52, 2017
5. Matsudaira K, Oka H, Kawaguchi M, Murakami
M, Fukudo S, Hashizume M, Löwe, B. Development of a Japanese Version of the Somatic
Symptom Scale-8: Psychometric Validity andInternal Consistency. Gen Hosp Psychiatry 45:
7-11, 2017
6. Wakaizumi K, Yamada K, Oka H, Kosugi S,
Morisaki H, Shibata M, Matsudaira K. Fearavoidance beliefs are independently associatedwith the prevalence of chronic pain in Japanese
workers. J Anesth 31:255-262, 2017
7. Yamada K, Matsuadira K, Tanaka E, Oka H,
Katsuhira J, Iso H. Sex-specific impact ofearly-life adversity on chronic pain: A large
population-based study in Japan. J Pain Res 10:427-433, 2017
8. Fukushima M, Oka H, Hara N,Oshima Y,
Chikuda H, Tanaka S, Takeshita K , Matsudaira
K. Prognostic factors associated with the surgicalindication for lumbar spinal stenosis patients lessresponsive to conservative treatments. J Orthop
Sci 22:411-414, 2017
9. Oka H, Matsudaira K, Fujii T, Kikuchi N, Haga Y,
Sawada T, Katsuhira J, Yoshimoto T, Kawamata
K, Tonosu J, Sumitani M, Kasahara S, Tanaka S.
Estimated risk for chronic pain determined using
the generic STarT Back 5-item screening tool. J
Pain Res 10: 461-467, 2017
10. Yoshimoto T, Oka H, Katsuhira J, Fujii T,
Masuda K, Tanaka S, Matsudaira K. Prognostic
Psychosocial Factors for Disabling Low Back
Pain in Japanese Hospital Workers. PLoS One
12: e0178694, 2017
11. Asai Y, Tsutsui S, Oka H, Yoshimura N,
Hashizume H, Yamada H, Akune T, Muraki S,
Matsudaira K, Kawaguchi H, Nakamura K,

12.

13.

14.

15.

16.

17.

18.

19.

Tanaka S, Yoshida M. Sagittal spino-pelvicalignment in adults: The Wakayama Spine Study.
PLoS One 12: e0178697, 2017
Hashimoto Y, Matsudaira K, Sawada S, Gondo Y,
Kawakami R, Kinugawa C, Okamoto T,
Tsukamoto K, Miyachi M, Naito H, Brair SN.
Obesity and Low back pain: A retrospective
cohort study of Japanese males. J Phys Ther Sci
29: 978-983, 2017
Tanaka Y, Oka H, Nakayama S, Ueno T,
Matsudaira K, Miura T, Tanaka K, Tanaka S.
Improvement of walking ability during postoperative rehabilitation with the hybrid assistive
limb after total knee arthroplasty: A randomized
controlled study. SAGE Open Med 5: 1-6, 2017
Izawa S, Matsudaira K, Miki K, Arisaka M,
Tsuchiya M. Psychosocial correlates of cortisol
levels in fingernails among middle-aged workers.
Stress 20:386-389, 2017
Oka H, Kadono Y, Ohashi S, Yasui T, Ono K,
Matsudaira K, Nishino J, Tanaka S. Assessing
joint destruction in the knees of patients withrheumatoid arthritis by using a semi-automatedsoftware for magnetic resonance imaging:therapeutic effect of methotrexate plus etanercept
compared with methotrexate monotherapy. Mod
Rheumatol. 2017 Aug 2:1-7 [Epub ahead of print]
Kawaguchi M, Matsudaira K, Sawada T, Koga T,
Ishizuka A, Isomura T, Coggon D. Assessment ofpotential risk factors for new onset disabling low
back pain in Japanese workers: findings from the
CUPID (cultural and psychosocial influences on
disability) study. BMC Musculoskelet Disord
18 :334, 2017
Kasahara S, Okamura Y, Matsudaira K, Oka H,
Suzuki Y, Murakami Y, Tazawa T, Shimazaki H,
Niwa S, Yamada Y. Diagnosis and Treatment ofAttention-Deficit Hyperactivity Disorder inPatients with Chronic Pain. Open Journal of
Psychiatry 7: 261-275, 2017
Oka H, Matsudaira K, Fujii T, Okazaki H,
Kitagawa T. Epidemiology and psychologicalfactors of whiplash associated disorders inJapanese population. J Phys Ther Sci 29: 15101513, 2017
Tonosu J, Oka H, Higashikawa A, Okazaki H,
Tanaka S, Matsudaira K. The associations be-372

tween magnetic resonance imaging findings andlow back pain: A 10-year longitudinal analysis.
PLoS One 12(11):e0188057, 201720. Sasaki T, Yoshimura N, Hashizume H, Yamada H,
Oka H, Matsudaira K, Iwahashi H, Shinto K,
Ishimoto Y, Nagata K, Teraguchi M, Kagotani R,
Muraki S, Akune T, Tanaka S, Kawaguchi H,
Nakamura K, Minamide A, Nakagawa Y, Yoshida
M. MRI-defined paraspinal muscle morphology
in Japanese population: The Wakayama Spine
Study. PLoS One 12(11):e0187765, 2017
21. Ishikura H, Ogihara S, Oka H, Maruyama T,
Inanami H, Miyoshi K, Matsudaira K, Chikuda H,
Azuma S, Kawamura N, Yamakawa K, Hara N,
Oshima Y, Morii J, Saita K, Tanaka S, Yamazaki
T. Risk factors for incidental durotomy during
posterior open spine surgery for degenerative
diseases in adults: A multicenter observational
study. PLoS One 12(11): e0188038, 2017

373

Department of Molecular Sciences
on Diabetes
Project Associate Professor
Hironori Waki, M.D.,Ph.D.

Project Research Associate
Masatoshi Kobayashi, M.D.,Ph.D.

Introduction and Organization
The prevalence of diabetes is rising to epidemic
proportions worldwide. There is urgent need fordevelopment of the treatment for diabetes and relateddiseases.
Advances in molecular biology had
successfully led to elucidation of various mechanisms
at a cellular level and at a tissue level in thephysiological condition and in the disease states. In
order to understand the precise mechanism underlying
the development of diabetes, it is critical to reveal
systemic connections between the cells and the tissues
in the body.
The specific aims of our department are (1) todeepen and expand the investigations on metabolic
tissues involved in glucose and lipid homeostasis,such as pancreatic endocrine cells, skeletal muscle,
liver and adipose tissue and (2) to reveal the essential
causes of diabetes from the perspective of thesystemic network among the metabolic tissues.

Teaching activities
As for the under-graduate education, ourdepartment takes a part in systemic lectures. We train
graduate and post-graduate students in Nutrition andMetabolism, Internal Medicine, Graduate School of
Medicine, The University of Tokyo.

Research activities
Adipocyte and Energy Metabolism
Brown fat dissipates energy in the form of heat.
Increasing the mass or activity of brown fat is an

attracting strategy for the treatment of obesity. We
analyzed open chromatin genomic regions in brown
fat and identified NFIA as a new transcription factor
that controls brown-fat-specific gene program. NFIA
binds to enhancers near brown-fat-specific genes andfacilitates the binding of PPARγ—the adipocyte
master regulator—to these enhancers. We further
demonstrated its role by conducting experiments using
culture cells, gene knock out animals, and epigenetic
analysis using next generation sequencer.
We also found that RNA N6-adenosine methyltransferase complex consisting of Wilms’ tumor
1-associating protein (WTAP), methyltransferase like3 (METTL3), and METTL14 positively controls
adipogenesis by promoting cell cycle transition in the
mitotic clonal expansion phase during adipogenesis.
WTAP heterozygous knockout mice exhibited smaller
adipocytes and were resistant to diet-induced obesity.
CDK5 Regulatory Subunit-Associated Protein
1-like 1 (CDKAL1) was identified as a susceptibility
gene for type 2 diabetes and body mass index ingenome-wide association studies. We found that
CDKAL1 is expressed in adipose tissue and its
expression is increased during differentiation. Stable
overexpression of CDKAL1, however, inhibited
adipocyte differentiation of 3T3-L1 cells, whereas
knockdown of CDKAL1 promoted differentiation.
CDKAL1 increased protein levels of β-catenin and its
active unphosphorylated form in the nucleus, thereby
promoting Wnt target gene expression, suggesting that
CDKAL1 activated the Wnt/β-catenin pathway—a
well-characterized inhibitory regulator of adipocyte
differentiation Our results identify CDKAL1 as novel374

negative regulator of adipocyte differentiation andprovide insights into the link between CDKAL1 andmetabolic diseases such as type 2 diabetes and obesity.
We expect further investigation on thepathophysiological roles of these factors will provide
insights into better understanding of pathophysiologyof obesity and development of treatment for obesity.
Impact of inflammatory responses in adipose tissue on
obesity-induced insulin resistance
Inflammatory responses in adipose tissue caused byobesity change secretion of adipokines and metabolites, leading to systemic insulin resistance. To clarify
the mechanism of these changes, we have extensively
investigated expression of genes in human adipose
tissues taken from those with a wide range of BMI.
We have identified several adipokines, which may
initiate the inflammatory responses and subsequent
insulin resistance. We are now exploring the role ofthese adipokines using animal models.
We expect further investigation on thepathophysiological roles of these factors will provide
insights into better understanding of pathophysiologyof obesity and development of treatment for obesity.
Mechanisms regulating pancreatic β cell function andmass
Progressive decline in pancreatic β cell function andmass has been implicated in the development of type 2
diabetes. We have found that insulin signaling in β
cells plays a key role in maintaining β cell mass
through insulin receptor (IR)/insulin receptor
substrate-2 (IRS-2)/Phosphoinositide-3 kinase (PI3K)
by autocrine/paracrine mechanisms using knockout
animal models. More recently we have also shownthat this pathway contributes to maintaining normal
insulin secretion in response to glucose by controlling
intra islet communication and exocytotic machinery.
Thus, we propose that once insulin secretion isdecreased, reduced insulin signaling in b cells causes
decreased β cell mass and insulin secretion, leading todecreased β cell mass and subsequent further
hypoinsulinemia and hyperglycemia. We seek to
identify the strategies for correcting this vicious cycle
to cure type 2 diabetes.

Impact of cellular responses in liver to feeding andtheir disorders on insulin resistance
We have found that feeding transiently promotes
endoplasmic reticulum (ER) stress in liver underphysiologic condition, and in obesity the ER stress issustained, leading to inhibition of insulin signaling
and insulin resistance. We have also found that insulin
signaling suppresses ER stress after feeding and theinsulin resistant state decreases insulin signaling andup-regulates ER stress and subsequent further insulin
resistance. Recently, we have also shown that IRS-2 is
up-regulated in the fasted state to maintain fasting
glucose homeostasis and appropriate and prompt
metabolic responses to feeding. This is partly
regulated by insulin, but we have unraveled that
adiponectin contributes to this IRS-2 up-regulation
through communicating with adipose tissue-derived
substance.

References
1. NFIAco-localizes
with
PPARγ
and
transcriptionally controls the brown fat geneprogram. Hiraike Y, Waki H, Yu J, Nakamura M,
Miyake K, Nagano G, Nakaki R, Suzuki K,
Kobayashi H, Yamamoto S, Sun W, Aoyama T,
Hirota Y, Ohno H, Oki K, Yoneda M, White AP,
Tseng YH, Cypess AM, Larsen TJ, Jespersen NZ,
Scheele C, Tsutsumi S, Aburatani H, Yamauchi T,
Kadowaki T. Nature cell biology 19(9) 1081-1092,
2017
2. CDK5 Regulatory Subunit-Associated Protein
1-like 1 Negatively Regulates Adipocyte
Differentiation through Activation of Wnt
Signaling Pathway. Take K, Waki H, Sun W, Wada
T, Yu J, Nakamura M, Aoyama T, Yamauchi T,
Kadowaki T. Scientific reports 7(1) 7326, 2017
3. Echinomycin inhibits adipogenesis in 3T3-L1
cells in a HIF-independent manner. Yamaguchi J,
Tanaka T, Saito H, Nomura S, Aburatani H, Waki
H, Kadowaki T, Nangaku M. Scientific reports
7(1) 6516, 2017

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Department of Integrated
Molecular Sciences on Metabolic
Diseases
Project Associate Professor
Masato Iwabu, M.D., Ph.D.

Project Lecturer
Miki Okada-Iwabu, Ph.D. (〜2017. Aug.)

Introduction and Organization
The Department of Integrated Molecular Sciences on
Metabolic Diseases (DIMSMD) is devoted toclarifying the mechanisms of onset of lifestyle-relateddiseases resulting from interactions between genetic
and environmental factors in the Japanese population
as well as to contributing to the prophylaxis, diagnosis
and treatment of these diseases, in response to thedrastic increase in the number of diabetic patients
which is becoming a major social issue of current
interest. In this regard, the DIMSMD strives toestablish an accurate method through which to predictrisk for the onset of lifestyle-related diseases bytapping into a comprehensive database for genetic andenvironmental factors for these diseases which is
being developed to integrate “Informatics on Genetic
Predisposition to Lifestyle-related Diseases” asgenerated by cutting-edge advances such as single
nucleotide polymorphism analyses with “Informatics
on Environmental Factors for Lifestyle-relatedDiseases” that draw on surveys including detailed
questionnaires on diet intake. The DIMSMD istherefore expected to make significant scientific andsocial contributions by providing effective modalities
for primary prevention of diabetes, moleculardiagnosis of onset of diabetes and its pathology, andoptimal treatment of diabetes, and to play a major role
in reducing the number of newly onset diabetes aswell as in raising the treatment standard for diabetes.

The DIMSMD also aims to develop a system thatallows formulas to be developed to predict therapeutic
response to drugs as well as their safety to be
developed based on information available onenvironmental and genetic factors including gene
expression from patients being treated at University ofTokyo Hospital, and which allows safe and effective
use of drugs being developed in patients withlifestyle-related diseases.
The DIMSSMD has set as its final goal the
installment of a human metabolic disease tissue bankat University of Tokyo Hospital, which draws on an“integrated database” that offers comprehensive
information on gene expression in human hepatic andadipose tissue samples, electronic charts, SNP andlifestyle habits, which will allow validation ofmolecular targets in actual human diseases, design ofa clinical trial system based on SNP and gene
expression profiles, development of models forprediction of therapeutic response based on
environmental and genetic interactions, identificationof molecular targets, discovery of novel therapeutic
agents and safe and effective use of drugs thus
developed in time.
The DIMSMD is thus engaged in daily research
activities and clinical care aimed at contributing to theadvancement of health and medical care in the future.

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Research activities
The DIMSMD Research Laboratory aims to elucidate
the molecular mechanisms of lifestyle-related diseases
such as the metabolic syndrome, diabetes andcardiovascular disease associated with obesity and to
put relevant molecular targets identified in the process
to effective use in the treatment of these diseases. Of
note, the DIMSMD Research Laboratory has animpressive track record in research in this area,
including identification of multiple “key molecules”
implicated in lifestyle-related diseases, such as
adiponectin receptors, which led to an elucidation ofsome of the processes through which lifestyle-relateddiseases develop and progress, based on functional
analyses that tap into developmental engineering and
RNA engineering. The DIMSMD ResearchLaboratory has also been credited with discoveringthat adiponectin is highly active in its high molecularweight form as a ligand to the adiponectin receptors
and that its quantitative measurement is useful in the
diagnosis of insulin resistance and the metabolic
syndrome. Not only that, the DIMSMD ResearchLaboratory has found that, via the adiponectin
receptors, the plant-derived peptide osmotin activates
the AMPK pathway which has a critical role inprotecting against lifestyle-related diseases. Currently,
the DIMSMD Research Laboratory is proactively
engaged in the development of definitive treatments
for lifestyle-related diseases that draw on ligands
specific for the adiponectin receptors.

References
1. Okada-Iwabu M, Yamauchi T, Iwabu M,
Kadowaki T. Aging and homeostasis. Development of novel AdipoR-targeted drugs with
exercise-mimicking and anti-aging properties.
Clin Calcium. 27(7): 975-981, 2017
2. Iwabu M, Yamauchi T, Okada-Iwabu M,
Kadowaki T. Developing Exercise-mimicking
Drugs toward Realization of Preemptive Medicine
for Lifestyle-related Diseases. Clin Calcium.
28(1): 73-80, 2018

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Department of Osteoimmunology
Project Associate Professor
Kazuo Okamoto, Ph.D.

Project Assistant Professor
Asuka Terashima, Ph.D.

Introduction and Organization
Bone is a key component of the skeletal-locomotor
system and serves as a calcium reservoir regulated by
the endocrine system in vertebrates. Bone also acts
as the “primary lymphoid organ” that harbors andmobilizes hematopoietic stem cells (HSCs) andimmune progenitor cells. Furthermore, the bone andimmune systems are closely related through a numberof shared regulatory molecules including cytokines,
receptors and signaling molecules.
Osteoimmunology is an interdisciplinary research field thatinvestigates the shared mechanisms and crosstalks
between the bone and the immune systems. Studies
on bone destruction associated rheumatoid arthritis(RA) have highlighted regulation of bone by the
immune cells and promoted this field. As seen in theclinical benefits of anti-TNF antibody, anti-IL-6
antibody and CTLA4-Ig on inflammation andosteoclast differentiation for the treatment of RA, theosteoimmunological insight is now of growing
importance in clinical applications. It is necessary tocomprehensively understand the interplay betweenbone and immune systems for elucidation of themolecular mechanisms underlying the pathogenesis ofvarious bone diseases (osteoporosis, osteoarthritis,
periodontal disease etc.) and immune diseases(autoimmune diseases, infectious diseases etc.).
Osteoimmunology is now emphasized by not only
the academic but also clinical sides, and theinternational competition has intensified in both basic
and pharmaceutical researches. This department was
founded as a new department focusing on the osteoimmunology in May 2016, with the support of Noevir
Co., Ltd., Chugai Pharmaceutical Co., Ltd. andAYUMI Pharmaceutical Corporation. We aim tounderstand the mechanisms underlying the pathogenesis of various skeletal and immune diseases, andto provide the molecular basis for novel drug
discovery in the field.

Teaching activities
As for under-graduate education, our department takes
a part in systemic lectures. We train post-doctoral
fellows, graduate and post-graduate students in
Department of Immunology, Graduate School of
Medicine and Faculty of Medicine, The University ofTokyo.

Research activities
By extending the concept of osteoimmunology tovarious skeletal and immune diseases, we aim tocomprehensively elucidate the crosstalks between thebone and immune systems involved in the pathogenesis of the diseases, and provide the molecularbasis for novel therapeutic strategies. Our achievement would help to improve the welfare and raise thelevel of medical treatment in the world.
Main research achievements
Osteoclast differentiation and RANKL signaling
Bone is a dynamic organ that continuously undergoes
a process involving resorption and formation (boneremodeling), which are mediated by osteoclasts andosteoblasts, respectively. An imbalance of bone
resorption and formation is often central to metabolicbone diseases, including bone destruction in RA,
postmenopausal osteoporosis, bone tumors and378

osteopetrosis. Osteoclasts are large, multinucleatedcells formed by the fusion of precursor cells of
monocyte/macrophage lineage. Mature osteoclasts
degrade bone matrix proteins by secreting proteolytic
enzymes and decalcify the inorganic components ofbone by releasing hydrochloric acid. RANKL is an
essential cytokine for osteoclast differentiation.
RANKL, which are produced by the supporting
mesenchymal cells including osteoblasts, osteocytes
and synovial fibroblasts, binds to its receptor RANK
expressed on osteoclast precursor cells. Mice with adisruption of either Rank or Rankl exhibit severe
osteopetrosis accompanied by a tooth eruption defectresulting from a complete lack of osteoclasts.
Mutations in the RANK and RANKL genes have been
identified in human patients with bone disorders suchas autosomal recessive osteopetrosis. These genetic
findings clearly demonstrate that RANK/RANKL
signaling is essential for osteoclastogenesis in vivo.
Recently, a fully human anti-RANKL neutralizing
antibody has been introduced for the treatment of
osteoporosis and skeletal-related events by bonetumors, and has been approved in Japan for thetreatment of bone erosion associated with RA. On
the other hand, certain reports have suggested that
osteoclasts can differentiate independently of RANKL.
It has been recently reported that lysyl oxidase (LOX),
the collagen cross-linking enzyme, promotes breast
cancer bone metastasis by potently inducing osteoclastdifferentiation in a RANKL-independent manner (Coxet al., Nature, 2015). However, it lacks sufficientexperimental evidence for the RANKL-independence.
By using RANKL-deficient mice, we demonstrated
that LOX alone fails to induce osteoclastogenesis, but
has the capacity to promote osteoclastogenesis
indirectly via induction of endogenous RANKL
expression on the mesenchymal cells (Tsukasaki et al.,J Bone Miner Res, 2016). These findings not only
deepened the understanding of the mechanisms
underlying bone metastasis, but also led to thereconsideration of the concept of RANKLindependent osteoclastogenesis.
Roles of T cells in bone destruction associated with
inflammation
The bone destruction in RA is the result of theenhanced osteoclast activity due to the inflammatory

responses triggered by the activation of pathogenic
helper T cells. We previously reported using amouse model of autoimmune arthritis that a subset of
Foxp3+ T cells loses Foxp3 expression under arthritic
conditions and converts into IL-17-prodcing T cells(called exFoxp3Th17 cells).
exFoxp3Th17 cells
display a greater capacity for inducing both synovitis
and osteoclastic bone resorption (Komatsu et al, Nat
Med, 2014). The conversion of Foxp3+ T cells into
effector T cells has also been observed in various
diseases such as diabetes and multiple sclerosis. We
have recently demonstrated that exFoxp3Th17 cells
also act as osteoclastogenic T cells in alveolar bone
destruction in periodontitis.
exFoxp3Th17 cells
accumulate in periodontitis tissues in response to oral
bacteria, and stimulate mesenchymal cells including
osteoblastic cells and periodontal ligament cells to
induce RANKL. In addition, exFoxp3Th17 cells
protect against bacteria by evoking mucosal immune
responses as well as removing the tooth (Tsukasaki etal, Nat Commun. 2018). Our findings introduce a
new concept that bone destruction contributes to thehost defense against oral bacteria in periodontitis.
Immune regulation by osteoblast in the bone marrow
HSCs have the capacity to differentiate into all
immune cells, and their activities require extrinsic
signals from the microenvironments (niches) in thebone marrow. Various cell types including CXCL12abundant reticular (CAR) cells, leptin receptorexpressing perivascular stromal cells, Nestin+
perivascular cells and neural cells have been shown to
be important for HSC maintenance. Although osteoblasts were first reported to function as the HSC niche
about 10 years ago, the significance of the osteoblastic
niche has remained unclear. In order to clarify therole of osteoblasts in the hematopoiesis in the bonemarrow, we generated an inducible deletion system ofosteoblasts in adult mice. We found that inducible
ablation of osteoblast had no effect on the HSCs but
reduced the number of both common lymphoidprogenitors in the bone marrow and lymphocytes in
the periphery. Osteoblast-derived IL-7 is requiredfor development of common lymphoid progenitors inthe bone marrow (Terashima et al., Immunity, 2016).
Moreover, we showed that sepsis reduces theosteoblast number, which induces lymphopenia

379

through IL-7 downregulation. Our study identified anovel mechanism by which bone cells regulate theimmune system.

References
1. Tsukasaki M, Komatsu N, Nagashima K, Nitta T,
Pluemsakunthai W, Shukunami C, Iwakura Y,
Nakashima T, Okamoto K, Takayanagi H. Hostdefense against oral microbiota by bone-damaging
T cells. Nat Commun, 9: 701, 2018
2. Kazuo Okamoto and Hiroshi Takayanagi,
Osteoimmunology, Genetics of Bone Biology andSkeletal Disease, Second Edition, 261-282, 2017
3. Okamoto K, Nakashima T, Shinohara M,
Negishi-Koga T, Komatsu N, Terashima A, Sawa
S, Nitta T, Takayanagi H. Osteoimmunology: theconceptual framework unifying the immune andskeletal systems. Physiol Rev, 97: 1295-1349,
2017

380

Department of Medical andPharmaceutical Community
Healthcare
Project Professor
Hirohisa Imai, M.D., Ph.D.

History and Organization Overview
In health care today, there needs to be morecooperation among doctors and other medical
professionals in order to provide patients with an
optimal level of care. Specifically, doctors andpharmacists need to have a common understanding of
the disease being treated in order to be able to provide
appropriate drug therapy and follow the patient andaccurately evaluate their treatment. The delivery of
optimal drug therapy involves multiple interconnected
processes, from investigating what drugs should be
used to planning the treatment regimen, assessing
treatment compliance and effectiveness, and managing
adverse reactions, and only a multidisciplinary, teamoriented approach to health care will make it possible
to provide patients with efficient, effective drug therapy.
Unfortunately, there are currently few examples of such
“multidisciplinary approaches to delivering optimal
drug therapy.” Japan is becoming a super-aging society
in which the number of elderly patients receiving
multiple drug products is increasing sharply, and theappropriate delivery of drug treatments has therefore
become an extremely important issue. Because optimal
drug therapy delivery cannot be accomplished throughthe traditional health care system or through regional
health care systems, the construction of a new healthcare system for the delivery of drug therapy is required.
The interfaces between the systems used in the fieldsof medicine and pharmacology, and the working
relationships between doctors and pharmacists, havegaps; these systems function independently of eachother, rendering the design of the overall systeminefficient. To date, it has not been possible toformulate measures for solving these problems becauseof a lack of evidence.
For example, although dispensing limits for patientswith long-term prescriptions have been discussed incancer therapy and primary care settings, no theoreticalor empirical research has been conducted to study thisissue. Nor have any systems been put in place tomanage drug therapies based on predetermined
protocols for patients with chronic diseases who are instable condition. In addition, not enough empiricalresearch has been conducted on the development of
optimal treatment methods (e.g., optimal patient
selection, efficient treatment procedures) based on
postmarketing surveillance of expensive drug products.
Against the aforementioned background, theobjective of this program is to conduct theoretical andempirical research on the development of new healthcare and collaborative systems for doctors(hospitals/clinics) and pharmacists (both hospital andnon-hospital pharmacists) in order to try to construct a
new collaborative system for doctors and pharmacists
to optimize the drug therapies that are provided topatients.
In this program, we will plan theoretical research toformulate measures that will support the constructionof efficient and effective regional medical care andempirical research using large-scale data, and we will
use statistical and epidemiological procedures toanalyze medical record data and prescription drug(including medical history) data as well as data fromour own epidemiological research in order to381

investigate systems for delivering effective drug
therapy through a multidisciplinary approach, startingwith the attending physician and the pharmacist, andfocusing specifically on dispensing limits for patientswith long-term prescriptions, the introduction ofregional formularies, and the introduction ofmultidisciplinary interventions in the treatment ofcancer and cognitive disorders.
This program consists of 1 program professor and 1
assistant program professor. The former is Dr. Hirohisa
Imai, a lecturer in social medicine who is a specialist in
public health and welfare and epidemiology, and thelatter was until just recently Setsuko Kinoshita, apharmacist whose specialty is epidemiology (and who
has resigned her post for family reasons, and for whom
a replacement is being sought). The program also has 2
full-time and 1 part-time administrative staff. In
addition, graduate students in the professional degree
course of the School of Public Health as well as
students in the University of Tokyo’s School ofIntegrated Health Sciences have been involved in thisprogram’s research activities. Starting at the end of July
2018, this department is moving from the 22nd Century
Medical and Research Center on the 8th floor of the
University of Tokyo Hospital to the Clinical Research
Building (North) (formerly the Center for Advanced
Clinical Research), a quieter setting better suited to thebasic research that forms the core of this department
and that will make it possible for program researchers
to concentrate more on the research at hand.

Education
The objective of this program is to develop healthcare specialists who can implement medical
collaborations that are suited to a super-aging society.
The era when a single doctor is capable of handling allof the care for a single patient is over. The coming age
will see physicians, pharmacists, nurses, public healthand welfare workers, etc. use a multidisciplinary
approach, and collaborate with the government as well,to implement regional, comprehensive health caresystems. This program will train the health carespecialists that will be needed for this coming age. In
addition, in order to help train the next generation ofresearchers, this program will be responsible forteaching specialist and general courses at the School of

Medicine. In the Epidemiology courses, we will focus
on identifying issues and formulating responses in thefield of regional health care as one example of theapplication of epidemiological techniques. We willattempt to convey the significance and fundamentals of
epidemiology to students with no field experience by
exposing them to common scenarios in regional healthcare. In addition, as their graduating thesis, graduate
students will teach undergraduate students directly andwill this year provide 4th-year students in the School ofIntegrated Health Services with instruction in“Estimating the Effectiveness of Interventions Basedon Specific Health Guidance” and “Using Prescribing
Data to Investigate the Status of the Prescribing of
Dabigatran to Elderly Patients.”
In the School of Public Health (professional degree
course), this program will offer courses in connection
with the School of Medicine in, for example,
Pharmaceutical Epidemiology and Drug Product
Delivery Systems. Graduate students in the latter stagesof obtaining their doctorate degrees will receive
instruction in creating themes for research papers,
analyzing data, the handling of literature references,and other basic and critical skills, and will also receive
guidance when writing their dissertations on how todevelop a consistently logical argument throughout
their dissertation as well as on how to properly cite
literature references.

Research
This program will utilize primarily prescription drug
data (including prescribing histories) and medical
record data to conduct theoretical and empiricalresearch focusing on the biostatistical andepidemiological methodologies involved in “thedevelopment of new methods of multidisciplinary
collaboration for optimizing physician-directed drug
therapies.”
1. Research on prescription drug dispensing limits forpatients with long-term prescriptions
1) “Dispensing limits for patients with long-termprescriptions” refers to the practice of having
patients who have, for example, received a 90day prescription go to the pharmacy every 30
days to receive 30 days’ worth of medicine. The

382

pharmacist submits a tracking report to theprescribing doctor when the patient picks up his
medicine. This has many benefits in the case ofpatients with chronic conditions, including
making it possible to manage the patient’s drug
therapy appropriately and to control health carecosts more appropriately. This program willconduct theoretical and empirical research
aimed at establishing a model system that
doctors and pharmacists can use in both primarycare and oncology to implement dispensing
limits for patients with long-term prescriptions.
2) A pilot study on dispensing limits for patientswith long-term prescriptions is currently
underway(in
hypertension,
diabetes,
dyslipidemia, osteoporosis, and breast cancer
hormone therapy). In the future, this programplans to conduct a larger-scale research with thehelp of the Ministry of Health, Labour andWelfare.
2. Research on multidisciplinary interventions in drug
therapy in regional health care1) This program will cooperate with regional
metropolitan
doctors’ andpharmacists’associations, national health insurance regional
branch offices, Japan Health Association branch
offices, prefectural health and welfare agency
pharmaceutical affairs bureaus, and the like toconduct research on optimal drug therapy
interventions for elderly patients. The patients
who should receive interventions will beidentified by a patient selection board comprisedof doctors and pharmacists, and saidinterventions will be implemented.
2) This program will use prescribing data fromhealth insurance societies to conduct research on
implementing notification interventions for
optimizing drug therapy in the elderly. The
program is conducting research on interventions
that attempt to improve drug therapies bysendingprescribing
physicians
andcompounding pharmacists written notices
informing them of inappropriate prescriptions.
The results of such notification interventions
will be evaluated after half a year.

3. Research on the development of methodologies for
implementing regional formularies
1) The cost effectiveness of the use of drug
products has been called into serious question
in recent years, and the efficient use of drug
products is being required within theframework of regional comprehensive healthcare systems. Although formularies may be one
effective method of accomplishing this,“Hospital Formularies” and “Regional
Formularies” are very different, although they
may appear alike, because the latter has many
stakeholders, and the implementation of suchformularies is therefore extremely difficult.
Although regional formularies have not yet
been implemented in Japan, this program isconducting research on their introduction.
2) This program is using certain “Regional HealthCare Collaboration Promotion Foundations”
themes to research the development of themethodologies thereof. We will conduct
research that includes quantitative analyses toinvestigate incentives and inducements forpromoting data collection and analysis and thescreening and use of listed drug products.
4. The development of systems for optimizing drug
therapies that utilize artificial intelligence
1) This research is being conducted with funds
provided by AMED and NEDO. A collaborative
research project is underway with the Social
ICT Research Center of the University ofTokyo’s Graduate School of Information
Science and Technology that is aimed at
utilizing artificial intelligence to optimize thedelivery of drug therapies.
2) Adverse reactions have many causes, includinginteractions between different drugs andinteractions with the metabolites of certain
drugs, and the identification and prevention ofadverse reactions requires tremendous effort.
Because a tremendous amount of work is
required to investigate the causes of adverse
reactions and prevent them from occurring,systems are being developed that utilize
artificial intelligence to identify safer and more
effective drug therapies. A research team is in

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the process of collecting and managing a vast
amount of data, and working to develop
innovative interfaces that will allow doctors andpharmacists to easily make use of artificial
intelligence.

Publications
1. Imai H. New Functions of Pharmacists Illustratedby Pharmacy KPIs The Journal of Community
Pharmacy and Pharmaceutical Sciences. 2018; Vol.
10 (No.1): 96-101
2. Imai H. Examples of Interventions That Can
Reduce Polypharmacy. Credentials. 2018; No. 116:
34-37
3. Imai H, Kumazawa R. Precautions for Treating
Elderly Patients – Prescribing Cautions. Rinsho
Derma. 2018; Vol. 60 (No. 6)
4. Fukatsu S, Ikemi Y, Yonezawa A, Ozaki J, Asano
M, Sakurai K, Uesugi M, Yoshida Y, Denda M,
Otani Y, Omura T, Imai S, Nakagawa S, Nakagawa
T, Imai H, Matsubara K．Health Care Economic
Effects of Prescriptions with “Management of
Unused Medicines” Pre-Printed as an Instruction
from the Prescribing Physician. Journal ofJapanese Society of Hospital Pharmacists. 2018;
Vol. 54 (No. 3): 307-312

384

Health Economy and Society
PolicyProject Professor
Tomoyuki Takura, Ph.D, MEng.

Assistant Professor
Rei Ishiki, Ph.D, MD. Yoshiaki Shintani, MD

Homepage

http://plaza.umin.ac.jp/hehp/

Introduction and Organization
Health Economy and Society policy is a donatedfund course established in 22nd Century Medical andResearch Center in February 2017, which is donated by
10 companies, Development Bank of Japan Inc.,
Chugai Pharmaceutical Co., Ltd., Baxter Limited,
Nihon Medi-Physics Co., Ltd., Medibrain Corporation,
Asahi Kasei Medical Co., Ltd., NIPRO Corporation,
Toray Medical Co., Ltd., JMS Co., Ltd., and Terumo
Corporation, and is cooperating with Department of
Cardiac Surgery, Division of Nephrology and Endocrinology, and Department of Clinical Epidemiology &Health Economics as cooperating course.
The social structure has been changing over recent
years and it can be assumed that policies related to the
medical system and medical industry are at a
crossroads in Japan and may undergo dramatic changes
in the future. Our department was established to discuss
future healthcare systems (medical practices andsystems, economy and industry), particularly in termsof theory construction and validation studies pertaining
to the "evaluation of the value of the healthcare field"
and other topics. Concretely, we promote theoreticaland methodological research on health technology
assessment, cost effectiveness analysis, and thehealthcare industry structure, and aim to evaluate thevalue of healthcare technologies and healthcare
systems. We also promote manpower training programs(Program for “The movements of medical value“) inhealth technology assessment with collaboration

departments.

Research activities
We are engaging in the following research in orderto promote rational and evidence-based medical
resource investment, to support medical practice, andto promote advances in medical technology.
1) The evaluation of the cost effectiveness of various
therapies, including (but not limited to) VAD therapy
for severe heart failure, hemodialysis therapy forend-stage renal failure and radiological diagnostics.
2) A study of the socioeconomic impact of chronic painon the disease burden in Japan.
3) Testing and developing methods for evaluating laborproductivity (e.g., the productivity of cardiology
doctors) by applying data envelopment analysis(DEA) techniques.
Moreover, we are also working on a project todevelop a forecasting model for health technology
assessment (HTA) that makes use of big data. We also
have a plan to start a study that applies computational
finance to forecast the market value of research anddevelopment projects.

References
1.

Tomoyuki Takura, Takashi Takei, Kosaku Nitta.
Cost-Effectiveness of Administering Rituximab
for Steroid-Dependent Nephrotic Syndrome andFrequently Relapsing Nephrotic Syndrome: A
Preliminary Study in Japan. Sci. Rep. 7,46036;

385

doi: 10.1038/srep46036 (2017).
2. Tomoyuki Takura. An Evaluation of Clinicaleconomics and Cases of Cost-effectiveness. Intern
Med. 2017 Dec 27. doi: 10.2169.
3. Takura T, Yoshimatsu M, Sugimori H, Takizawa K,
Furumatsu Y, Ikeda H, Kato H, Ogawa Y,
Hamaguchi S, Fujikawa A, Satoh T, Nakajima Y.
Cost-Effectiveness Analysis of Percutaneous
Vertebroplasty for Osteoporotic Compression
Fractures. Clin Spine Surg. 2017 Apr;30(3):E205E210.
4. Takura T, Tachibana K, Isshiki T, Sumitsuji S,
Kuroda T, Mizote I, Ide S, Nanto S. Preliminary
report on a cost-utility analysis of revascularization by percutaneous coronary intervention forischemic heart disease. Cardiovasc Interv Ther.
2017 Apr;32(2):127-136.
5. Shiroiwa T, Fukuda T, Ikeda S, Takura T. New
decision-making processes for the pricing ofhealth technologies in Japan: The FY 2016/2017
pilot phase for the introduction of economic
evaluations. Health Policy. 2017 121(8):836-841.
6. Takura T. Health economic valuation of renaltransplantation. Journal of Japanese Society for
Clinical Renal Transplantation. 2017; 5: 113-121.
7. Takura T. Trends in national medical expenduter(Chapter 1, Part 3). Pharmacy and Society Clinical Pharmacy and Therapeutics. Tokyo,
Nakayama shoten. 2017; 26-32.
8. Takura T. Current status and issues of medical
economics in Japan (Part 7, Chapter 4). Global andInnovative Medicine. Osaka, Osaka University.
2017; 368-388.
9. Takura T. Medical economics of medication
adherence - Part 4: Adherence of phosphorus
adsorbent. Dialysis therapy Next XXII. Tokyo,
Igakutosho shuppan. 2017; 136-140.
10. Takura T. Cost-effectiveness of complete physicalexamination (Ningen Dock) (Chapter 8). Actual ofcomplete physical examination. Tokyo, Bunkodo.
2017; 316-318.

386

Department of Biostatistics andBioinformatics
Project Professor
Daisuke Koide, R.Ph., HIM, Ph.D.

Project Associate Professor
Akihiro Hirakawa, Ph.D.

Project Lecturer
Kentaro Sakamaki, Ph.D.

Project Assistant Professor
Sachiko Ono, DDS, MPH.

Homepage

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

Introduction and Organization
Biostatistics is an applied statistics in the fields of
medical and health sciences and contributes to thesefields through developments of statistical methodologies for clinical trials and epidemiological researches.
Biostatisticians who work at an organization for
conducting and coordinating clinical researches (e.g.,
academic research organization) in hospitals andinstitutions are few in Japan. To this end, the Japanfunding agency, Agency for Medical Research andDevelopment (AMED), started the Support Programfor Biostatisticians from 2016.
The AMED selected the Graduate School of the
University of Tokyo and the Graduate school of the
Kyoto University, as 2 centers for training
biostatisticians, which function as core facilities,
respectively. Each graduate school establishes a new
biostatistics course, forms a training center uponcollaboration with a hospital, and performs on-the-job
training.
This program improves the environment that leads
to higher quality in clinical research and trials, withthe collaboration of industry, academia, and thegovernment, based upon the donations from drug
companies and national research funding. Collabora-

tive projects of industry, academia, and the government through the flow of funds in this program, arethe first of their kind in Japan.
On March 1, 2017, the Deparment of Biostatistics
and Bioinformation was established in the Graduate
School of Medicine. In the Graduate School ofInterdisciplinary Information Studies in the Universityof Tokyo, the Biostatistics and Bioinformatics course
will be established on April 1, 2018. This course
provides specialized education to acquire not only
statistical methodologies, but also practical skills (e.g.,
design and analysis of clinical researh, programming,
reporting) for conducting clinical research. We willtrain biostatisticians with high communication skill
and ethics that can promote high quality research incollaboration with health care professionals byteaching and on-the-job -training (OJT).

Teaching activities
1) Education in the Biostatistics and Bioinformatics
courseIn the Biostatistics and Bioinformatics course,
through the following teachings, we educate a wide
range of knowledge and skills required to biostatisticians. Its curriculum is made up of 28 subjects

387

including 42 credits. For students who have taken over
38 credits, we will issue a certificate along with the
Master degree.
Biostatistics
Statistical inference, categorical data analysis,
survival analysis, longitudinal data analysis, Bayesianstatistics, multiple comparison prcedure, multivariate
analysis, causal inference, missing data analysis,
stochastic process and time series analysis,
pharmacometrics, statistical programming, genomic
data analysis
Clinical research and epidemiology
Clinical trial methodology, design and analysis of
epidemiological research, research ethics andguidelines, medical research and CDISC standards,
general clinical medicine, regulatory science, medical
writing, medical technology evaluation exercises
In addition, the student receive the OJT at
University of Tokyo Hospital and the National Cancer
Center. The OJT programs are dveloped by thebiostatisticians of each institution. In the first year of
master's program, the students learn the basic practiceof biostatistician through the training at the Universityof Tokyo Hospital. In the second year, at the National
Cancer Research Center, students receive advanced
training in how to plan the design and analysis ofclinical researches.
2) Seminars and symposiums for the healthcare
professionals and biostatisticians
We give seminars about clinical trial methodologies
and biostatistics for physician, nurse, clinical researchcoordinator, monitor, and other healthcare professionals. We also hold a symposiumu for biostatisticians inacademia and pharmaceutical companies in order toshare and discuss the “state-of-the-arts” of statisticalmethodolgies. We had the 1st basic seminar Randomized clinical trial and latest design”(80 people wereregistred) on October 25 in 2017, the Biostatistical
Symposium “Multiple tests in clinical trials” (83people were registred) on Nobember 29 in 2017, the
2nd basic seminar “Design and confounding adjustment of observational research”(78 people wereregistred) on December 18 in 2017, the 3rd basic

seminar “Frequently used test method in medical
research” (71 people were registred) on February 21 in2018, and the Biostatistical Symposium “Biostatist’s
success in clinical research” (133 people wereregistred) on March 14 in 2018.

Research activities
In the department of biostatistics and bioinformatics,
the main reaeach areas are as follows:
1) Statistical methodology and design of clinical trials
and epidelimiology
We study on the statistical methodologies and design
for streamlining clinical trial and estimating treament
effect precisely. The research area includes Bayesian
design in oncology, clinical trial design using
biomarkers, adaptive design, study on the use ofBayesian statistics in clinical trials, causal inference,and multiple comparison method.
2) Epidemiological methodology
Epidemilogy deals with health or disease related
incidence quantitatively in large populations,evaluates cause and effective factors, and ultimately
finds the measures of prevention. It starts fromepidemics (such as infectious diseases) and now its
focus is on lifestyle related diseases, such as cardiovascular disorders. Also, several kinds of medical
databases are developed rapidely in Japan. It is
important to conduct epidemiological, pharmacoepidemiological and clinical epidemiological studies
using such databases.
3) Pharmacoepidemiology
Pharmacoepidemiology is a study to investigate drug
use and its effects in a population. We are engaged inresearch on effectiveness, risk, and cost using dataobtained from hospital information system andelectronic medical record.
4) Clinical Epidemiology
Clinical epidemiology is the application of theprinciples and methods of epidemiology to conductclinical research studies focusing on prevention,
diagnosis, prognosis, and treatment of disease. As thebasic science of Evidence-based Medicine, the impor-388tance of clinical epidemiology has been increasing.
5) Medical informatics
Medical informatics is a science of studying how to
use data, information and knowledge in the all
medical fields, such as clinical, medical studies,
education and government. Recently, the area of
medical informatics is much expanding because of the
progress of genomic studies or bioinformatics, andintroduction of new technologies, such as virtual
reality and artificial intelligence (AI).
6) Algebraic statistics
The focus of research is on developing and applying
methods of algebraic statistics to specific statisticalproblems. In statistical inference, the computation ofcomplicated integrals or summation sometimes makes
the problem intractable. When a statistical model
has algebraic structure, techniques from algebraic
statistics are useful. I currently work on the topics
related to Groebner basis theory and the holonomic
gradient method.

References
1.

2.

3.

4.

Kishi A, Uchida I, Koide D, Imamura K.
Japanese Initiative for Education in Pharmaceutical Medicine and Clinical Research Training.
J Med Dev Sci. 3(1);1-10, 2017. doi: 10.18063/
JMDS.2017.01.166
Hirakawa A, Sato H, Daimon T, Matsui S.
Modern Dose-Finding Designs for Cancer Phase
I Trials: Drug Combinations and Molecularly
Targeted, Springer. 2017.
Hirakawa A, Hiroyuki Sato. A comparative studyof model-based dose-finding methods for twoagent combination trials. Frontiers of Biostatistical Methods and Applications in ClinicalOncology, Springer. 2017.
Hirakawa A, Nishikawa T, Yonemori K, Shibata
T, Nakamura K, Ando M, Ueda T, Ozaki T,
Tamura K, Kawai A, Fujiwara Y. Utility ofBayesian single-arm design in new drug application for rare cancers in Japan: a case study ofphase 2 trial for sarcoma. Therapeutic Innovation& Regulatory Science, 2017; DOI: 10.1177/
2168479017728989.

5.

Sakamaki K, Kito Y, Yamazaki K, Izawa N,
Tsuda T, Morita S, Boku N. Exploration of time
points and cut-off values for early tumour
shrinkage to predict survival outcomes of patientswith metastatic colorectal cancer treated with
first-line chemotherapy using a biexponential
model for change in tumour size. ESMO Open;2(5): e000275. 2017.
6. Takeuchi H, Sugimoto K, Oshiro H, Iwatsuka K,
Kono S, Yoshimasu Y, Kasai Y, Furuichi Y,
Sakamaki K, Itoi T. Liver fibrosis: noninvasive
assessment using supersonic shear imaging and
FIB4 index in patients with non-alcoholic fatty
liver disease. Journal of Medical Ultrasonics; 1-7.
2017.
7. Ono S, Ono Y, Matsui H, Yasunaga H. Impact ofclinic follow-up visits on body weight control inpeople with prediabetes or diabetes mellitus:
Japanese nonelderly cohort study. Family
Practice; 34(5): 552-557. 2017.
8. Ono Y, Ono S, Yasunaga H, Matsui H, Fushimi K,
Tanaka Y. Clinical Features and Practice Patternsof Treatment for Adrenal Crisis: A Nationwide
Cross-Sectional Study in Japan. Eur J
Endocrinol; 176 (3): 329-337. 2017.
9. Ono S, Ishimaru M, Yamana H, Morita K, Ono Y,
Matsui H, Yasunaga H. Enhanced oral care andhealth outcomes among nursing facility residents:
analysis using the national long-term care
database in Japan. J Am Med Dir Assoc; 18: 277.
e1-277.e5. 2017.
10. Ono Y, Ono S, Yasunaga H, Matsui H, Fushimi K,
Tanaka Y. Clinical characteristics and outcomesof myxedema coma: analysis of a national
inpatient database in Japan. J Epidemiol; 27(3):117-122. 2017.
11. Ono Y, Ono S, Hinata T, Ito T, Yasuda H, Tanaka
Y. Usefulness of urinary glucose excretion after
oral glucose tolerance testing to detect insulin
secretion failure before the onset of diabetes
mellitus. Endocr J; 64(1):75-81. 2017.database inJapan. J Am Med Dir Assoc 18(3):277.e1-5,
2017.

389

Department of Preventive Medicine
for Locomotive Organ Disorders
Project Professor
Noriko Yoshimura, M.D., Ph.D.

Project Research Associate
Toshiko Iidaka, M.D.

Homepage

http:// www.h.u-tokyo.ac.jp/research/center22/index.html

Introduction and Organization
The department of department of Preventive Medicine
for Locomotive Organ Disorders in 22nd Century
Medical and Research Center on March 1st, 2017,
which is an endowment department supported by
Chugai Pharmaceutical Co., Ltd., Fujifilm Corporation, Ajinomoto Co., Inc., ASAHI KASEI PHARMACORPORATION, ALCARE Co., Ltd., Inter Reha
Co.,Ltd., Anima Corporation, TEIJIN PHARMALIMITED, Suntory Holdings Limited and in close
collaboration with departments of Orthopaedic
Surgery and Rehabilitation Medicin. Our department
has been established for the epidemiological study toclarify the frequencies and risk factors for locomotive
organ disorders including osteoarthritis (OA),
osteoporosis (OP) and sarcopenia (SP).

Research activities
Although locomotive organ disorders are major causesof disability and require support, little information isavailable regarding their epidemiology. The Research
on Osteoarthritis/Osteoporosis Against Disability(ROAD) study, which started in 2005-7, is a
prospective cohort study that aims to elucidate theenvironmental and genetic background for bone andjoint diseases. It was designed to examine the extent
to which risk factors for these diseases are related toclinical features, laboratory and radiographic findings,
bone mass and geometry, lifestyle, nutritional factors,
anthropometric and neuromuscular measures, and fall

propensity. In addition, the study’s aim was also to
determine how these diseases affect activities of dailyliving and quality of life in Japanese men and women.
We have completed the baseline study in 2005-2007,
then, 2nd, 3rd and 4th follow-ups were performed in
2008-2010, 2012-2013, and 2015-2016, respectively.
We will conduct further follow-up surveys.

References
1. Yoshimura N, Muraki S,Nakamura K, Tanaka S:
Epidemiology of the locomotive syndrome: The
Research on Osteoarthritis/Osteoporosis Against
Disability study 2005-2015. Mod Rheumatol
27(1):1-7, 2017
2. Yoshimura N, Muraki S, Oka H, Iidaka T,
Kodama R, Kawaguchi H, Nakamura K, Tanaka S,
Akune T: Is osteoporosis a predictor for futuresarcopenia, or vice-versa? Four-year observations
between the second and third ROAD study
surveys. Osteoporos Int 28(1):189-199, 2017
3. Ishimoto Y, Yoshimura N, Muraki S, Yamada H,
Nagata K, Hashizume H, Takiguchi N, Minamide
A, Oka H, Tanaka S, Kawaguchi H, Nakamura K,
Akune T, Yoshida M: Association of lumbar
spondylotisthesis with back pain and symptomatic
lumbar spinal stenosis in the general population:
the Wakayama Spine Study. Spine (Phila Pa 1976),
42: E666-E671, 2017
4. Teraguchi M, Yoshimura N, Hashizume H, Yamada
H, Oka H, Minamide A, Nagata K, Ishimoto Y,

390

5.

6.

7.

8.

9.

Kagotani R, Kawaguchi H, Tanaka S, Akune T,
Nakamura K, Muraki S, Yoshida M: Progression,
incidence and risk factors for intervertebral discdegeneration in a longitudinal population- based
cohort: the Wakayama Spine Study. Osteoarthritis
Cartilage 25: 1122-1131, 2017
Narumi K, Funaki Y, Yoshimura N, Muraki S,
Omori G, Nawata A, Seki R: Quadriceps muscle
strength reference value as index for functional
deterioration of locomotive 3 organs: Data from3617 men and women in Japan. J Orthop Sci 22:
765-770, 2017
Asai Y, Tsutsui S, Oka H, Yoshimura N,
Hashizume H, Yamada H, Akune T, Muraki S,
Matsudaira K, Kawaguchi H, Nakamura K,
Tanaka S, Yoshida M. Sagittal spino-pelvicalignment in adults: The Wakayama Spine Study.
PLoS One 12: e0178697, 2017
Sasaki T, Yoshimura N, Hashizume H, Yamada H,
Oka H, Matsudaira K, Iwahashi H, Shinto K,
Ishimoto Y, Nagata K, Teraguchi M, Kagotani R,
Muraki S, Akune T, Tanaka S, Kawaguchi H,
Nakamura K, Minamide A, Nakagawa Y, Yoshida
M: MRI-defined paraspinal muscle morphology inJapanese population: The Wakayama Spine Study.
PLoS One. 2017 Nov 8;12(11):e0187765. doi:
10.1371/journal.pone.0187765. eCollection 2017
Coggon D, Ntani G, Walker-Bone K, Palmer KT,
Felli VE, Harari R, Barrero LH, Felknor SA,
Gimeno D, Cattrell A, Vargas-Prada S, Bonzini M,
Solidaki E, Merisalu E, Habib RR, Sadeghian F,
Kadir MM, Warnakulasuriya SS, Matsudaira K,
Nyantumbu B, Sim MR, Harcombe H, Cox K,
Sarquis LM, Marziale MH, Harari F, Freire R,
Harari N, Monroy MV, Quintana LA, Rojas M,
Harris EC, Serra C, Martinez JM, Delclos G,
Benavides FG, Carugno M, Ferrario MM, Pesatori
AC, Chatzi L, Bitsios P, Kogevinas M, Oha K,
Freimann T, Sadeghian A, Peiris-John RJ,
Sathiakumar N, Wickremasinghe AR, Yoshimura
N, Kelsall HL, Hoe VC, Urquhart DM, Derrett S,
McBride D, Herbison P, Gray A, Vega EJ:
Epidemiological differences between localised
and non-localised low back pain. Spine (Phila Pa
1976), 740-747, 2017
Nagata K, Yoshimura N, Hashizume H, IshimotoY, Muraki S, Yamada H, Oka H, Kawaguchi H,

Akune T, Tanaka S, Nakamura K, Yoshida M: Theprevalence of tandem spinal stenosis and its
characteristics in a population-based MRI study:
The Wakayama Spine Study. Eur Spine Journal 26,2529-2535, 2017
10. Iidaka T, Muraki S, Oka H, Kodama R, Tanaka S,
Kawacughi H, Nakamura K, Akune T, Yoshimura
N: Radiographic measurements of hip joint andtheir association with hip pain in Japanese men
and women: The ROAD study. Osteoarthritis
Cartilage 25, 2072-2079, 201711. Shioji M, Yamamoto T, Ibata T, Tsuda T, Adachi
K, Yoshimura N: Artificial neural networks topredict future bone mineral density and bone loss
rate in Japanese menopausal women. BMC
Research Notes, 2017 Nov 10;10(1):590.
12. Kodama R, Muraki S, Iidaka T, Oka H, Teraguchi
M, Kagotani S, Asai Y, Hashizume H, Yoshida M,
Kawaguchi H, Nakamura K, Akune T, Tanaka S,
Yoshimura N: Serum levels of inflammatory
indices, matrix metalloproteinase-3, and autoantibodies related to rheumatoid arthritis in general
Japanese population and their association withosteoporosis and osteoarthritis: The ROAD study.
Bone Miner Metabol 36: 246-253, 2018
13. Wang K, Kim HA, Felson DT, Xu L, Kim DH,
Nevitt MC, Yoshimura N, Kawaguchi H, Lin J,
Kang X, Zhang Y: Radiographic Knee Osteoarthritis and Knee Pain: Cross-sectional study
from five different racial/ethnic populations.
Scientific Reports, #SREP-17-27711A, in press
14. Yamada K, Satoh S, Hashizume H, Yoshimura N,
Ryohei Kagotani R, Yuyu Ishimoto Y, Abe Y,
Toyoda H, Terai H, Masuda T, Muraki S,
Nakamura H, Yoshida M: Diffuse idiopathic
skeletal hyperostosis is associated with lumbar
spinal stenosis requiring surgery. J Bone Miner
Metab, in press
15. Leyland KM, Gates LS, Nevitt M, Felson D,
Bierma-Zeinstra SM, Conaghan PG, Engebretsen
L, Hochberg M, Hunter D, Jones G, Jordan JM,
Judge A, Lohmander S, Roos EM, SanchezSantos MT , Yoshimura N, van Meurs JBJ, Batt
ME, Newton J, Cooper C, Arden NK: Harmonising measures of osteoarthritis in population-based
cohortstudies:aninternational
study.
Osteoarthritis Cartilage, in press

391

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

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

Assistant professor
Takashi Matsukawa, M.D., Ph.D.

Homepagehttps://molecular-nuerology.org/

Introduction and Organization
Department of Molecular Neurology wasestablished on April 1, 2017 to elucidate the molecularmechanisms based on detailed clinical information
and research that integrates comprehensive genome
analysis, furthermore, to develop new therapies that
can intervene in pathophysiological mechanisms ofthe neurological diseases and to conduct new clinical
trials for the neurological diseases.

Clinical activities
We have outpatient clinic specialized in multiple
system atrophy (MSA) cooperating with Departmentof Neurology. We have started a registry for MSA toestablish the natural history of MSA, and, furthermore,
to recruit patients to the clinical trial which we arepreparing. We also take care of patients in theinpatient’s’ ward cooperating with Department of
Neurology. We provide clinical sequencing forpatients with neurological diseases to help clinicaldiagnosis of these patients. We also provide clinicalsequencing on referral basis from other hospitals.

Teaching activities
In under-graduate education, we offer opportunities ofresearch experience on molecular genetics ofneurological disorders during the period of the“free–quarter program”. In the post-graduate
education, we offer programs for graduate students
including molecular genetics, neurobiology andtranslational researches.

Research activities
Multiple system atrophy (MSA) is a progressive
neurodegenerative disease which is characterized byvarious combinations of cerebellar ataxia andparkinsonism in addition to autonomic failure. No
effective therapeutic measures are available. We havebeen conducting extensive researches on MSA
including comprehensive genome analysis on familial
as well as sporadic MSA. We have found that a
homozygous mutation and compound heterozygous
mutations of COQ2 gene are associated with anincreased risk of MSA in multiplex families, andheterozygous mutations of COQ2 gene are associatedwith an increased risk of MSA in patients withsporadic disease (Mitsui J, et al. N Engl J Med. 2013;
369:233-44). Based on these findings, we consideredthat supplementation of coenzyme Q10 to patients with
MSA could benefit patients because COQ2 encodes
the enzyme essential for the biosynthesis of coenzyme
Q10. Recent studies have reported decreased coenzyme
Q10 levels in blood, cerebral spinal fluid, and the
cerebellum even in MSA patients without COQ2

392

mutations (Mitsui J, et al. JAMA Neurol. 2016;73:
977-80, Kasai T, et al. PLoS One. 2016;11:e0147574,
Schottlaender LV, et al. PLoS One. 2016;11:e0149557,
Barca E, et al. J Neuropathol Exp Neurol. 2016;75:
663-72, Compta Y, Parkinsonism Relat Disord. 2018;46:16-23.). Based on these studies, we planned amulticenter-based (13 institutions) phase II clinical
trial to evaluate the clinical efficacy of a high-dose
ubiquinol (reduced form of coenzyme Q10) supplementation for suppressing progression of symptoms ofpatients with MSA. To facilitate recruitment of MSA
patients into the clinical trial, and, to establish adetailed natural history of MSA, we started a registry
for MSA.
To standardize the rating of patients based on
Unified Multiple System Atrophy Rating Scale(UMSARS) among the 13 institutions in the phase II
clinical trial, we translated the original UMSARS into
Japanese with generous help by Dr. Gregor Wenning,
the original author of UMSARS. We also prepared a
training video focusing on items of UMSARS, where
rating tends to vary among raters to reduce thevariance of rating among raters.

References
1. Tsuji S, Mitsui J. Letter re: A genome-wide
association study in multiple system atrophy.
Neurology. 2017 Mar 28;88(13):1296.
2. Mitsui J, Koguchi K, Momose T, Takahashi M,
Matsukawa T, Yasuda T, Tokushige SI, Ishiura H,
Goto J, Nakazaki S, Kondo T, Ito H, Yamamoto Y,
Tsuji S. Three-Year Follow-Up of High-Dose
Ubiquinol Supplementation in a Case of Familial
Multiple System Atrophy with Compound
Heterozygous COQ2 Mutations. Cerebellum.
2017 Jun;16(3):664-672.
3. Edaravone (MCI-186) ALS 19 Study Group.
Safety and efficacy of edaravone in well defined
patients with amyotrophic lateral sclerosis: arandomised, double-blind, placebo-controlled trial.
Lancet Neurol. 2017 Jul;16(7):505-512.
4. Writing group on behalf of the edaravone(mci-186) als 18 study group.Exploratory doubleblind, parallel-group, placebo-controlled study ofedaravone (MCI-186) in amyotrophic lateralsclerosis (Japan ALS severity classification:

Grade 3, requiring assistance for eating, excretionor ambulation). Amyotroph Lateral Scler Frontotemporal Degener. 2017 Oct;18(sup1):40-48.
5. Writing group on behalf of the edaravone (mci186) als 17 study group. Exploratory double-blind,parallel-group, placebo-controlled extension studyof edaravone (MCI-186) in amyotrophic lateralsclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2017 Oct;18(sup1):20-31.
6. Writing group on behalf of the edaravone(mci-186) als 19 study group. Open-label 24-weekextension study of edaravone (MCI-186) inamyotrophic lateral sclerosis. Amyotroph Lateral
Scler Frontotemporal Degener. 2017 Oct;18(sup1):55-63.
7. Kimura M, Yabe I, Hama Y, Eguchi K, Ura S,
Tsuzaka K, Tsuji S, Sasaki H. SCA42 mutation
analysis in a case series of Japanese patients withspinocerebellar ataxia. J Hum Genet. 2017 Sep;
62(9):857-859.
8. Yamashita T, Mitsui J, Shimozawa N, Takashima
S, Umemura H, Sato K, Takemoto M, Hishikawa
N, Ohta Y, Matsukawa T, Ishiura H, Yoshimura J,
Doi K, Morishita S, Tsuji S, Abe K. Yamashita T,
Mitsui J, Shimozawa N, Takashima S, Umemura
H, Sato K, Takemoto M, Hishikawa N, Ohta Y,
Matsukawa T, Ishiura H, Yoshimura J, Doi K,
Morishita S, Tsuji S, Abe K. J Neurol Sci. 2017
Apr 15;375:424-429.
9. Harigaya Y, Matsukawa T, Fujita Y, Mizushima K,
Ishiura H, Mitsui J, Morishita S, Shoji M, Ikeda Y,
Tsuji S. Novel GBE1 mutation in a Japanesefamily with adult polyglucosan body disease.
Neurol Genet. 2017 Feb 24;3(2):e138.
10. Matsukawa T, Koshi KM, Mitsui J, Bannai T,
Kawabe M, Ishiura H, Terao Y, Shimizu J,
Murayama K, Yoshimura J, Doi K, Morishita S,
Tsuji S, Goto J. Slowly progressive d-bifunctional
protein deficiency with survival to adulthood
diagnosed by whole-exome sequencing. J Neurol
Sci. 2017 Jan 15;372:6-10.
11. Ikeda T, Nakahara A, Nagano R, Utoyama M,
Obara M, Moritake H, Uechi T, Mitsui J, Ishiura
H, Yoshimura J, Doi K, Kenmochi N, Morishita S,
Nishino I, Tsuji S, Nunoi H. TBCD may be acausal gene in progressive neurodegenerative
encephalopathy with atypical infantile spinal

393

muscular atrophy. J Hum Genet. 2017 Apr;62(4):473-480.
12. Kodama S, Mano T, Masuzawa A, Hirata Y,
Nagasako Y, Mano K, Hamada M, Terao Y,
Hayashi T, Ono M, Tsuji S. Tacrolimus-induced
reversible cerebral vasoconstriction syndrome
with delayed multi-segmental vasoconstriction. J
Stroke Cerebrovasc Dis. 2017 May;26(5):e75e77.
13. Yoshimura A, Yuan J.-H., Hashiguchi A,
Hiramatsu Y, Ando M, Higuchi Y, Nakamura T,
Okamoto Y, Matsumura K, Hamano T, Sawaura N,
Shimatani Y, Kumada S, Okumura Y, Miyahara J,
Yamaguchi Y, Kitamura S, Haginoya K, Mitsui J,
Ishiura H, Tsuji S, Takashima H. Clinical andmutational spectrum of Japanese patients with
Charcot-Marie-Tooth disease caused by GDAP1
variants, Clin Genet. 2017 Sep;92(3):274-280.
14. Eriguchi Y, Kuwabara H, Inai A, Kawakubo Y,
Nishimura F, Kakiuchi C, Tochigi M, Ohashi J,
Aoki N, Kato K, Ishiura H, Mitsui J, Tsuji S, Doi
K, Yoshimura J, Morishita S, Shimada T,
Furukawa M, Umekage T, Sasaki T, Kasai K,
Kano Y. Identification of candidate genes
involved in the etiology of sporadic TouretteSyndrome by exome sequencing. Am J Med
Genet B Neuropsychiatr Genet. 2017 Oct;174(7):712-723.
15. Hosoe J, Kadowaki H, Miya F, Aizu K,
Kawamura T, Miyata I, Satomura K, Ito T, Hara K,
Tanaka M, Ishiura H, Tsuji S, Suzuki K, Takakura
M, Boroevich KA, Tsunoda T, Yamauchi T,
Shojima N, Kadowaki T. Structural Basis andGenotype-phenotype Correlations of INSR
Mutations Causing Severe Insulin Resistance.
Diabetes. 2017 Oct;66(10):2713-2723.
16. Ando M, Hashiguchi A, Okamoto Y, Yoshimura A,
Hiramatsu Y, Yuan J, Higuchi Y, Mitsui J, Ishiura
H, Umemura A, Maruyama K, Matsushige T,
Morishita S, Nakagawa M, Tsuji S, Takashima.
Clinical and genetic diversities of Charcot-MarieTooth disease with MFN2 mutations in a largecase study. J Peripher Nerv Syst. 2017 Sep;22(3):191-199.
17. Ando M, Okamoto Y, Yoshimura A, Yuan J-H,
Hiramatsu Y, Higuchi A, Hashiguchi a, Mitsui J,
Ishiura H, FukumuracS, Matsushima M, Ochi N,

Tsugawa J, Morishita S, Tsuji S, Takashima H.
Clinical and mutational spectrum of Charcot–
Marie–Tooth disease type 2Z caused by MORC2
variants in Japan. Eur J Neurol. 2017 Oct;24(10):1274-1282.

394

Laboratory for Advanced Researchon Pathophysiology of Metabolic
Diseases
Project Associate Professor
Miki Okada-Iwabu, Ph.D.

Introduction and Organization
Laboratory for Advanced Research on Pathophysiology of Metabolic Diseases was launched in2017 to promote cutting-edge research aimed at
unraveling the underlying pathophysiology of diabetes
and related metabolic diseases thereby contributing to
the development of effective preventive measuresagainst these diseases.
“Individuals at risk of diabetes”, i.e., thosestrongly suspected of having diabetes and those inwhom the possibility of diabetes cannot be denied, arecurrently estimated to account for 28.5% of males and21.4% of females in Japan, thus making it an urgent
task not only for metabolic science but for society atlarge to fully elucidate the underlying pathophysiology of diabetes. Diabetes is defined as a hyperglycemic condition resulting from decreased secretion
and/or action of insulin from the pancreas andencompasses a wide disease spectrum from such rare
conditions as mitochondrial diabetes and lipoatrophic
diabetes to diabetes mellitus as a common disease.
Diabetes occurs not only through genetic susceptibility to the disease but due to disorderly living habits,
such as overeating, lack of physical activity andobesity. Therefore, the Laboratory is intended topromote wide-ranging research into human tissues
from patients with diabetes mellitus as a common
disease but from those with rare forms of diabetes bydrawing on state-of-the-art genomic, epigenomic,
metabolomic, metagenomic and iPS-cell technologies
and to bring resulting research insights to bear on thedevelopment of innovative diagnostic, preventive andtherapeutic modalities for diabetes.
Within the research milieu that the Laboratoryoffers, therefore, the research currently being
promoted is expected to lead to the elucidation of thepathophysiology of diabetes and related metabolic
diseases, where rare disease-derived tissue- and iPS
cell-based investigations are expected to provide
invaluable insights into the pathophysiology ofdiabetes as a common disease. Thus, the Laboratory is
devoted to promoting relevant research leading to thedevelopment of innovative diagnostic, preventive andtherapeutic modalities, thereby contributing to theeffective prevention and treatment of diabetes.

Teaching activities
Working in collaboration with its closely related
Laboratory, Departments of Diabetes and Metabolic
Disease, Division of Nephrology and Endocrinology,
the Laboratory aims to foster internationally-oriented
young talents in both an academic and social sensewith the focus on graduate students, through theLaboratory’s mentoring program for academic
dissertations and conference presentations to develop
and enhance their science capabilities and skills.
The Laboratory has also had an active role in theclinical researcher development program by the
University of Tokyo, the main aim of which is to
impart not only the importance of clinical research but
the rudiments of clinical thinking to medical students
and clinical researchers in training. As part ofMetabolism Research Course on the clinicalresearcher development program, the Course holds up

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and pursues, as its research theme, exploration of key
molecules involved in the onset/progression ofobesity/ type 2 diabetes, given that radical preventive/
therapeutic modalities remain yet to be established forthe so-called lifestyle-related diseases, which include
the metabolic syndrome, type 2 diabetes, obesity,
dementia, and frailty, as well as for age-relateddiseases, all of which are known to occur and progress
through interactions between individuals’ genetic andenvironmental factors. Thus, the aim of the program is
to explore these key molecules by drawing on theanalysis of integrated genomic, epigenomic, transcriptomic, metabolomic and clinical data.
Metabolism Research Course is widely open to
medical students and clinicians in training alike toprovide support not only for designated themes but forthemes of interest to course participants and to foster
an infrastructure/environment that would facilitate thepresentation of research results at conferences inJapan and overseas as well as their publication as
peer-reviewed papers in a timely fashion

Research activities
Diabetes occurs due not only to genetic factors but tothe influence of environmental factors, such as
overeating, lack of physical activity, and obesity.
Therefore, while diabetes represents a disease
condition with a wide spectrum from inherited rare
forms of diabetes to diabetes as a common disease, its
pathophysiology remains yet to be fully elucidated.
The Laboratory thus focuses on the analysis of
the physiological functions of organs and systems thatplay a key role in the onset of diabetes, i.e., pancreatic
endocrine cells, liver, adipose tissue, skeletal muscle,
nervous system, immune system and intestinal tract,
as well as diseases resulting from disruption of theirfunctions by drawing fully on state-of-the-art omic
(genomic, epigenomic, metabolomic, and metagenomic) and iPS-cell technologies and genetic celland animal engineering.
Research themes also being pursued at theLaboratory include the onset/progression of chronic
diseases associated with aging and rare diseases, suchas mitochondrial diabetes and lipoatrophic diabetes, tofacilitate the development of innovative diagnostic,
preventive and therapeutic modalities for these

diseases, based on resulting research findings andinsights.

References
1. Okada-Iwabu M, Yamauchi T, Iwabu M,
Kadowaki T. Aging and homeostasis. Development of novel AdipoR-targeted drugs with
exercise-mimicking and anti-aging properties.
Clin Calcium. 27(7): 975-981, 2017
2. Iwabu M, Yamauchi T, Okada-Iwabu M,
Kadowaki T. Developing Exercise-mimicking
Drugs toward Realization of Preemptive Medicine
for Lifestyle-related Diseases. Clin Calcium.
28(1): 73-80, 2018

Endowed Department(22nd Century Medical and Research Center)397

Department of
Immunotherapeutics
Project Professor
Kazuhiro Kakimi, M.D., Ph.D.

Project Lecturer
Hirokazu Matsushita, M.D., Ph.D.

Homepage

http://immunoth.umin.jp/

Introduction and Organization
The aim of our Department is to execute basic andclinical research on cancer immunology and immunotherapy and to establish its role in the treatment ofcancer. Cancer immunotherapy requires the expansionof functional T cells and/or dendritic cells (DC) thatare responsible for the anti-tumor immune response invivo. The GMP-level Cell Processing Center (CPC)
was installed in the Department. Peripheral bloodmononuclear cells (PBMC) are isolated from thepatients and processed in the CPC to ensure that they
maintain optimal functionality, or for triggering new
functions in vitro prior to clinical application.
Autologous cells derived from cancer patients are processed for therapeutic use in our CPC in accordancewith all current regulations and ethical obligations.
To perform reliable high quality translational
research, we designed our Department’s facilities
literally from the bench to the bedside. The Department consists of three divisions, (1) laboratory forbasic and pre-clinical research (2); Cell Processing
Center and (3) outpatient clinic. Because these threedivisions are situated side-by-side on the same floor,
close cooperation between the members of each groupcan be more easily and better organized. As soon as
blood is drawn from the patient at the outpatient clinic,
it is directly transferred to the CPC through the
pass-box between the two. The cells processed andcultured in the CPC are scrutinized in the laboratorynext door to the clinic and CPC regarding their quality

and function. Those cultured cells which are approved
following this examination are transferred back to theclinic and administered to the patient. The patients arefollowed-up at regular intervals by the research staff
at the laboratory to monitor their immune responses toevaluate the impact of the immunotherapy.
All protocols for cancer immunotherapy performed in our Department are submitted to theinstitutional review board (IRB). Once approved, theprotocols are registered in the UMIN clinical researchregistration system to provide open access to any
interested parties. Because the cells used for treatment
are derived from each individual patient; it is difficult
to guarantee consistent quality. However, we doeverything possible to provide the cultured cells withthe best conditions, by means of well-trained specialist staff following standard operating procedures. All
these efforts allow us to reliably perform cancer
immunotherapy clinical trials in cooperation withmany clinical departments of the University of Tokyo
Hospital.
Since “The Act on the Safety of Regenerative
Medicine” and the “Pharmaceuticals, Medical Devices
and Other Therapeutic Products Act” came into effective on November 25, 2014, we registered our cellprocessing facility and got approved (DC3140011).
All the protocols for cell therapy was also reviewed
and approved by institutional committee for theregenerative medicine.

398

Clinical activities
We provide outpatient services for cancer patients.
All interventions performed in the department are
defined by the protocols based on the Act on
Securement of Safety of Regenerative Medicine(Approved on Nov 20, 2013). The following clinical
trials are underway in our department:γδ T cell therapy for advanced cancer
1. UMIN registration number ： UMIN000006128
active, recruiting. Adoptive immunotherapy using
zoledronate-expanded autologous γδ T cells forpatients with non-small cell lung cancer refractory
to standard treatment.
2. UMIN registration number ： UMIN000001419
active, recruiting. The efficacy and safety ofautologous γδ T cell transfer therapy foresophageal cancer
3. UMIN registration number ： UMIN000008097
active, recruiting. Combination of chemotherapy
with docetaxel / cisplatin / fluorouracil (DCF) andautologous γδ T cell transfer therapy foresophageal cancer.
Dendritic cell therapy
1. UMIN registration number：UMIN000014703
active,recruiting.
Safety,efficacyandimmunogenicity of concomitant molecular target
drug or cytokine therapy and autologous tumor
lysate-pulsed dendritic cell therapy in patients withadvanced renal cell carcinoma
Immunomodulator(anti-CCR4 mAb+anti-PD-1mAb)
1. UMIN-CTR Clinical Trial ID：UMIN000021480.
ClinicalTrials.gov ID ： NCT02946671. Study ofPre-operative
Combination
Therapy
with
Mogamulizumab and Nivolumab Against Solid
Cancer Patients

Teaching activities
Research guidance in molecular immunology isprovided to postgraduate students. Because knowledge
and techniques for evaluation of immune response areimportant for clinicians and medical researchers, we
also provide many opportunities to postgraduate

students to learn how to analyze in vivo immune
responses by means of experiments using animalmodels and by the immunological monitoring of thepatients themselves in clinical research.

Research activities
All our research activities are directed atunderstanding the dynamics of the immune response
in vivo at the molecular, cellular and organismal levels
and to develop more effective immunotherapy against
cancer. To this end, we perform both clinical immunology in humans and basic preclinical immunology
using animal models. We especially focus on thespatiotemporal analysis of anti-tumor immunity inboth humans and experimental animals. During thecourse of each trial, many samples from the clinic aredelivered to the research laboratory to monitor
immune responses in patients. Tumor-specific immunity is evaluated using standardized immunologicalassays, such as ELISA, ELISPOT and flow cytometry.
To develop novel immunological interventions,tumor-bearing mice are used to confirm principles
believed to be the basis for the new immunotherapy.
Using many different TCR-transgenic and human
MHC class I-bearing mice we can provide clear
answers regarding the antigen-specific immune
response. As described above, we pursue a researchstrategy of going back and forth from the bench to thebedside and from basic to clinical immunology inorder to maximize benefit to patients via the rapid
application of new knowledge to clinical practice.

List of Publications
1. Aoki T, Matsushita H, Hoshikawa M, Hasegawa
K, Kokudo N, Kakimi K. Adjuvant combination
therapy with gemcitabine and autologous γδ
T-cell transfer in patients with curatively resectedpancreatic cancer. Cytotherapy. 2017 Apr;19(4):473-485.
2. Karasaki T, Nagayama K, Kuwano H, Nitadori JI,
Sato M, Anraku M, Hosoi A, Matsushita H,
Morishita Y, Kashiwabara K, Takazawa M, Ohara
O, Kakimi K, Nakajima J. An Immunogram for
the Cancer-Immunity Cycle: Towards Personalized Immunotherapy of Lung Cancer. J Thorac
Oncol. 2017 May;12(5):791-803.

399

3. Ando K, Fujita H, Hosoi A, Ma L, Wakatsuki M,
Seino KI, Kakimi K, Imai T, Shimokawa T,
Nakano T. Intravenous dendritic cell administration enhances suppression of lung metastasis
induced by carbon-ion irradiation. J Radiat Res.
2017 Jul 1;58(4):446-455
4. Matsushita H, Hasegawa K, Oda K, Yamamoto S,
Nishijima A, Imai Y, Asada K, Ikeda Y, Karasaki
T, Fujiwara K, Aburatani H, Kakimi K. The
frequency of neoantigens per somatic mutation
rater than overall mutational load or number ofpresicted neoantigens per se is a prognostic factor
in ovarian clear cell carcinoma. Oncoimmunology.
2017 Jul 14;6(8):e1338996.
5. Nagaoka K, Hosoi A, Iino T, Morishita Y,
Matsushita H, Kakimi K. Dendritic cell vaccine
induces antigen-specific CD8+Tcells that are
metabolically distinct from those of peptide
vaccine and is well-combined with PD-1 checkpoint blockade. Oncoimmunology. 2017 Nov 20;
7(3): e1395124.
6. Hoshikawa M, Aoki T, Matsushita H, Karasaki T,
Hosoi A, Odaira K, Fujieda N, Kobayashi Y,
Kambara K, Ohara O, Arita J, Hasegawa K,
Kakimi K, Kokudo N. NK cell and IFN signatures
are positive prognostic biomarkers for resectablepancreatic cancer. Biochemical and BiophysicalResearch Communications 495(2018)2058-2065
7. Hosoi A, Takeda K, Nagaoka K, Iino T,
Matsushita H, Ueha S, Aoki S, Matsushima K,
Kubo M, Morikawa T, Kitaura K, Suzuki R,
Kakimi K. Increased diversity with reduced“diversity evenness” of tumor infiltrating T-cells
for the successful cancer immunotherapy.
SCIENITIFIC REPORTS. 2018 Jan 18;8(1):1058.

Presentation at International
conference
1. 2017/4/3, AACR (American Association forCancer Research) Annual Meeting 2017,
Washington Convention Center, Hirokazu
Matsushita, Kosei Hasegawa, Katsutoshi Oda,
Shogo Yamamoto, Akira Nishijima, Yuichi Imai,
Kayo Asada, Yuji Ikeda, Takahiro Karasaki,
Keiichi Fujiwara, Hiroyuki Aburatani, Kazuhiro
Kakimi, Neoantigen frequency as an independent

2.

3.

4.

5.

6.

7.

prognostic factor in patients with clear ovariancarcinoma(CCOC)
2017/4/4, AACR (American Association forCancer Research) Annual Meeting 2017,
Washington Convention Center, Koji Nagaoka,
Akihiro Hosoi, Tamaki Iino, Hirokazu Matsushita,
Kazuhiro Kakimi, Advantage of dendrituc cells
for the therapeutic cancer vaccine
2017/6/23, The 36th sapporo Internatonal Cancer
Symposium, Sapporo, Japan (Royton Sapporo),
Kazuhiro Kakimi, An Immunogram for theCancer-Immunity Cycle
2017/9/22, Cold Spring Harbor Asia conferences,Suzhou, China(Suzhou Dushu Lake ConferenceCenter), Kazuhiro Kakimi, An immunogram forthe cancer-immunity cycle-Towards personalized
immunotherapy
2017/10/13, JDDW (Japan Digestive DiseaseWeek) 2017 FUKUOKA, Fukuoka, The Best
Presenter Award in International Session, I. Wada,
K. Odaira, K. Kakimi, Immunological analysis of
the tumor infiltrating lymphocytes of theadvanced gastric cancer
2017/10/16, IASLC (INTERNATIONAL ASSOCIATION FOR THE STUDY OF LUNGCANCER) 18TH WORLD CONFERENCE ON
LUNG CANCER、Yokohama, Japan, T. Karasaki,
K. Nagayama, K. Fukumoto, K. Kitano, J.
Nitadori, M. Sato, M. Anraku, A. Hosoi, H.
Matsushita, K. Kakimi, J. Nakajima, ASSESSMENT OF CANCER IMMUNITY STATUS IN
EACH PATIENT USING IMMUNOGRAM
2018/2/23, The 2nd workshop on Microscopic
Simulation and Cell Experiments for Biological
Systems, Kashiwa-shi, Chiba, JAPAN, K. Kakimi,
Development of Cancer Immunotherapy

400

Department of Advanced Clinical
Science and Therapeutics
Project Associate Professor
Jun-ichi Suzuki, M.D., Ph.D.

Project Assistant Professor
Kouji Wakayama, M.D., Ph.D.
Hidetoshi Kumagai, Ph.D.

Homepage

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

Introduction and Organization
The Department of Advanced Clinical Science andTherapeutics, established at the University of Tokyo in
2004, aims to develop new clinical strategies andtherapy in cardiovascular medicine and other areas.
This department hopes to develop not only basic
research, but also applications to devise new clinicalstrategies.

Research activities
Followings are our recent basic and clinical research
activities.
Basic Research• New strategies to regulate acute rejection and graftarterial diseases in cardiac transplantation.
• New strategies to regulate acute/chronic myocarditis.
• New strategies to regulate acute myocardial infarction and ischemia/reperfusion injury.
• New strategies to regulate restenosis after coronary
angioplasty.
• New strategies to regulate atherosclerosis andaneurism.
• New strategies to regulate systolic/diastolic heart
failure.
• New strategies to regulate sleep apnea syndromeand circadian rhythm abnormality.
• New strategies to regulate cardio-kidney syndrome.

• New strategies to regulate oral-pathogen induced
cardiovascular diseases.
• Development of gene therapies (anti-inflammationetc.).
• Development of new growth factor treatments(hepatocyte growth factor, etc.).
• Development of new anti-adhesion molecule
treatments (anti-inflammation, etc.).
• Development of new anti-extracellular treatments(anti-inflammation, anti-oxidation, etc.).
• Development of new chemical compounds (antiinflammation, anti-coagulation, etc.).
• Expanding the use of foods and natural extracts.
• Expanding the application of existing drugs anddevices.
• Analysis of angiogenesis using in situ hybridization.
Clinical Research• Gene therapies to prevent restenosis and thrombosis
after coronary intervention.
• Pathophysiology of oral disorder and cardiovasculardiseases.
• Pathophysiology of sleep apnea syndrome andcardiovascular diseases.
• Pathophysiology of renal dysfunction and cardiovascular diseases.

401

References
1.

2.

3.

4.

5.

6.

7.

Wakayama K, Shimamura M, Suzuki J, Watanabe
R, Koriyama H, Akazawa H, Nakagami H,
Mochizuki H, Isobe M, Morishita R. Angiotensin
II peptide vaccine protects ischemic brain
through reducing oxidative stress. Stroke. 48(5):1362-1368, 2017.
Watanabe R, Suzuki J (corresponding author),
Wakayama K, Maejima Y, Shimamura M,
Koriyama H, Nakagami H, Kumagai H, Ikeda Y,
Akazawa H, Morishita R, Komuro I, Isobe M. A
peptide vaccine targeting angiotensin II
attenuates the cardiac dysfunction induced bymyocardial infarction. Sci Rep. 7:43920, 2017.
Kamo T, Akazawa H, Suda W, Saga-Kamo A,
Shimizu Y, Yagi H, Liu Q, Nomura S, Naito A,
Takeda N, Harada M, Toko H, Kumagai H, Ikeda
Y, Takimoto E, Suzuki J, Honda K, Morita H,
Hattori M, Komuro I. Dysbiosis andCompositional Alterations with Aging in the Gut
Microbiota of Patients with Heart Failure.
PlosOne. 12(3):e0174099, 2017.
Nagata N, Iwanari H, Kumagai H, Kusano-AraiO, Ikeda Y, Aritake K, Hamakubo T, Urade Y.
Generation
andcharacterizationofanantagonistic monoclonal antibody against an
extracellular domain of mouse DP2 (CRTH2/
GPR44) receptors for prostaglandin D2. PLoS
One. 2017 Apr 10;12(4):e0175452.
Takanashi M, Taira Y, Okazaki S, Takase S,
Kimura T, Li CC, Xu PF, Noda A, Sakata I,
Kumagai H, Ikeda Y, Iizuka Y, Yahagi N,
Shimano H, Osuga JI, Ishibashi S, Kadowaki T,
Okazaki H. Role of Hormone-sensitive Lipase in
Leptin-Promoted Fat Loss and Glucose Lowering.
J Atheroscler Thromb. 2017 Nov 1;24(11):1105-1116.
Aoyama N, Suzuki J (corresponding author),
Kobayashi N, Hanatani T, Ashigaki A, Yoshida A,
Shiheido Y, Sato H, Kumagai H, Ikeda Y,
Akazawa H, Komuro I, Minabe M, Izumi Y,
Isobe M. Detrimental effects of specificperiodontopathic
bacterial
infectionontachyarrhythmia compared to bradyarrhythmia.
BMC Cardiovasc Disord. 17(1): 267, 2017.
Aoyama N, Suzuki J (corresponding author),

8.

9.

10.

11.

12.

13.

Kobayashi N, Hanatani T, Ashigaki N, Yoshida A,
Shiheido Y, Sato H, Kumagai H, Ikeda Y,
Akazawa H, Komuro I, Izumi Y, Isobe M.
Periodontitis deteriorates peripheral arterial
disease in Japanese population via enhanced
systemic inflammation. Heart Vessels. 32(11):1314-1319, 2017.
Aoyama N, Suzuki J, Sato H, Yoshida A,
Shiheido Y, Izumi Y. Japanese workers with longleisure time have deteriorated periodontal
condition: a cross-sectional study. J Oral Biosci.
59: 104–107, 2017.
Aoyama N, Suzuki J (corresponding author),
Kumagai H, Ikeda Y, Akazawa H, Komuro I,
Minabe M, Izumi Y, Isobe M. Specificperiodontopathic bacterial infection affects
hypertension in male cardiovascular disease
patients. Heart Vessels. 2017 Aug 12. doi: 10.
1007/s00380-017-1042-z. [Epub ahead of print]
Aoyama N, Suzuki J (corresponding author),
Kobayashi N, Hanatani T, Ashigaki N, Yoshida A,
Shiheido Y, Sato H, Minabe M, Izumi Y, Isobe M.
Associations among tooth loss, systemic
inflammation and antibody titers to periodontal
pathogens in Japanese cardiovascular disease
patients. J Periodontal Res. 2017 Nov 15. doi:
10.1111/jre.12494. [Epub ahead of print]
Aoyama N, Suzuki J (corresponding author),
Kobayashi N, Hanatani T, Ashigaki N, Yoshida A,
Shiheido Y, Sato H, Kumagai H, Ikeda Y,
Akazawa H, Komuro I, Minabe M, Izumi Y,
Isobe M. Diabetes Mellitus Patients Lost Many
Teeth among Japanese Cardiovascular Diseases
Patients –A Cross-sectional Study. Internal Med.
2017 Nov 20. doi: 10.2169/internalmedicine.
9578-17. [Epub ahead of print]
Kaneko M, Suzuki J (corresponding author),
Aoyama N, Watanabe R, Yoshida A, Shiheido Y,
Izumi Y, Isobe M. A critical role of toll-likereceptor-2 in periodontal pathogen-induced myocardial fibrosis in pressure overloaded murine
hearts. Hypertens Res. 40(2): 110-116, 2017.
Sato H, Suzuki J (corresponding author), Aoyama
N, Watanabe R, Kaneko M, Shiheido Y, YoshidaY, Wakayama K, Kumagai H, Ikeda Y, Akazawa
H, Komuro I, Isobe M, Izumi Y. A periodontal
pathogen Porphyromonas gingivalis deteriorates

402

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16.

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isoproterenol-induced myocardial remodeling in
mice. Hypertens Res. 40(1):35-40, 2017.
Srisuwantha R, Shiheido Y, Aoyama N, Sato H,
Kure K, Laosrisin N, Izumi Y, Suzuki J.
Porphyromonas gingivalis elevated high-mobility
group box 1 levels after myocardial infarction in
mice. Int Heart J.;58(5):762-768, 2017.
Hosomichi J, Kuma Y, Oishi S, Nagai H, Maeda
H, Usumi-Fujita R, Shimizu Y, Kaneko S,
Shitano C, Suzuki J, Yoshida K, Ono T.
Intermittent hypoxia causes mandibular growth
retardation and macroglossia in growing rats. Am
J Orthod Dentofac Orthop. 151(2): 363-371,
2017.
Yamaguchi H, Ishida Y, Hosomichi J, Suzuki J,
Hatano K, Usumi-Fujita R, Shimizu Y, Kaneko S,
Ono T. Ultrasound microbubble-mediatedtransfection of NF-κB decoy oligodeoxynucleotide into gingival tissues inhibits periodontitis inrats in vivo. PlosOne 12(11): e0186264.
Yamaguchi H, Ishida Y, Hosomichi J, Suzuki J,
Usumi-Fujita R, Shimizu Y, Kaneko S, Ono T.
New approach to transfect NF-kappaB decoy
oligodeoxynucleotides into the periodontal tissue
using ultrasound-microbubble method. Int J
Oral Sci. 9(2):80-86, 2017.
Hatano K, Ishida Y, Yamaguchi H, Hosomichi J,
Suzuki J, Usumi-Fujita R, Shimizu Y, Shibutani
N, Kaneko S, Ono T. The chemokine receptor
type 4 antagonist, AMD3100, interrupts experimental tooth movement in rats. Arch Oral Biol.
11;86:35-39, 2017.
Tamura N, Maejima Y, Tezuka D, Takamura C,
Yoshikawa S, Ashikaga T, Hirao K, Isobe M.
Profiles of serum cytokine levels in Takayasu
arteritis patients: Potential utility as biomarkers
for monitoring disease activity. J Cardiol. Sep;
70(3):278-285, 2017.
Ueshima D, Ashikaga T, Yoshikawa S, Sasaoka T,
Hatano Y, Kurihara K, Maejima Y, Isobe M.
Effect of over-2-year dual antiplatelet therapy on
the rate of major adverse cardiac and cerebral
events for everolimus-eluting stent implantation:
The landmark analysis from Tokyo-MD PCI
registry. J Cardiol. Jun;69(6):815-822, 2017.
Ohigashi H, Tamura N, Ebana Y, Harigai M,
Maejima Y, Ashikaga T, Isobe M. Effects ofimmunosuppressive and biological agents on
refractory Takayasu arteritis patients unresponsive to glucocorticoid treatment. J Cardiol.
May;69(5):774-778, 2017.
22. Akimoto S, Suzuki J (corresponding author),
Aoyama N, Ikeuchi R, Watanabe H, Tsujimoto H,
Wakayama K, Kumagai H, Ikeda Y, Akazawa H,
Komuro I. A novel bioabsorbable sheet which
delivers NF-κB decoy oligonucleotide restrains
abdominal aortic aneurysm development in rats.
Int Heart J. in press
23. Aoyama N, Suzuki J (corresponding author),
Kobayashi N, Hanatani T, Ashigaki N, Yoshida Y,
Shiheido Y, Sato H, Izumi Y, Isobe M. Increased
oral Porphyromonas gingivalis prevalence in
cardiovascular patients with uncontrolled
diabetes mellitus. Int Heart J. in press
24. Ikeya K, Aoki J, Ikeda N, Ninomiya T, Tashiro T,
Okamura T, Suzuki J (corresponding author). Useof a human-type communication robot to evaluate
the categorized communicative ability ofdemented elderly people. Geriatr Gerontol Int.
in press
English Review
1. Suzuki J (corresponding author), Sato H, Kaneko
M, Yoshida A, Aoyama N, Akimoto S, Wakayama
K, Kumagai H, Ikeda Y, Akazawa H, IzumiY,
Isobe M, Komuro I. Periodontitis and myocardial
hypertrophy. Hypertens Res. 40(4):324-328,
2017.
2. Kamo T, Akazawa H, Suzuki J, Komuro I. Novel
concept of a heart-gut axis in the pathophysiology of heart failure. Korean Circ J. 2017
Sep;47(5):663-669. doi: 10.4070/kcj.2017.0028.
Epub 2017 Aug 23.

403

Department of Computational
Diagnostic Radiology andPreventive Medicine
Project Professor
Naoto Hayashi, M.D.,Ph.D.

Project Associate Professor
Kansei Uno, M.D.,Ph.D., Takeharu Yoshikawa, M.D.,Ph.D.

Project Research Associate
Kensuke Asaba, M.D.,Ph.D., Eriko Maeda, M.D.,Ph.D., Soichiro Miki, M.D., Ph.D., Aya
Watanabe, M.D.,Ph.D., Junichi Ishida, M.D.,Ph.D., Katsuhiro Koyama, M.D., Ph.D.

Project researcher
Yukihiro Nomura, Ph.D., R.T., Tomomi Takenaga, Ph.D., R.T., Masaki Murata, Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/research/center22/contribute/computer.html

Introduction and Organization
The Department of Computational Diagnostic
Radiology and Preventive Medicine (CDRPM) wasestablished in May 2005. It is under the supervision of
the Department of Radiology.
The aim of our research project is as follows: (1) 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 (PET), 3-teslamagnetic resonance imaging (3T-MRI) system, multidetector CT (MDCT), ultrasound imaging system, anddigital mammography.

Teaching Activities
At present, CDRPM does not accept students.
However, CDRPM participates in the education of
students and residents in the Department of Radiology.
CDRPM endeavors to help students whose research
themes include image analysis such as computerassisted detection, or epidemiologic studies employing
health-screening data.

Research Activities
1) Health screening database
We have developed a unique health screening information system to facilitate daily management of the404

health screening activities and to input healthscreening data. This information system is still underconstant revision. The medical images acquired in thehealth screenings are stored in the hospital picturearchiving and communication system (PACS) for
clinical use. Medical images used solely for research
purposes are stored in an independent PACS installedinside the CDRPM department.
2) Image processing software development
We have structured an integrated software developing
system to facilitate the production of image processing
software. The system is divided into the clinical partand the research part, with the data in the latter being
anonymized. The clinical part consists of case entry
for software development, and clinical application of
the developed software. The research part consists ofan interface to obtain images of the representative
cases to develop the software, and an interface to test
the developed software with the accumulated cases.
3) Clinical evaluation, application of software, andepidemiological studies
Researches based on the health-screening database arecarried out in collaboration with other researchers ofvarious specialties. Images are analyzed using thedeveloped software.

References(1) Nomura Y, Higaki T, Fujita M, Miki S, Awaya Y,
Nakanishi T, Yoshikawa T, Hayashi N, Awai K.
Effects of Iterative Reconstruction Algorithms on
Computer-assisted Detection (CAD) Software forLung Nodules in Ultra-low-dose CT for Lung
Cancer Screening. Acad.Radiol. 2017 Feb;24(2):124-130.
(2) Yasaka K, Furuta T, Kubo T, Maeda E, Katsura M,
Sato J, Ohtomo K. Full and hybrid iterative
reconstruction to reduce artifacts in abdominal
CT for patients scanned without arm elevation.
Acta Radiol. 2017 Sep;58(9):1085-1093.
(3) Maeda E, Tomizawa N, Kanno S, Yasaka K,
Kubo T, Ino K, Torigoe R, Ohtomo K. Subjective
and objective evaluation of 10–30% dose reduced
coronary artery phantom scans reconstructed with
Forward projected model-based Iterative Reconstruction SoluTion (FIRST). Data in brief

2017;10:210-214.
(4) Saitoh M, Dos Santos MR, Emami A, Ishida J,
Ebner N, Valentova M, Bekfani T, Sandek A,
Lainscak M, Doehner W, Anker SD, vonHaehling S. Anorexia, functional capacity, andclinical outcome in patients with chronic heart
failure: results from the Studies Investigating
Co-morbidities Aggravating Heart Failure (SICAHF). ESC.Heart Fail. 2017 Nov;4(4):448-457.
(5) Ishida J, Konishi M, Saitoh M, Anker M, Anker
SD, Springer J. Myostatin signaling is
up-regulated in female patients with advanced
heart failure. Int.J.Cardiol. 2017 Jul 1;238:37-42.
(6) Ishida J, Saitoh M, Doehner W, von Haehling S,
Anker M, Anker SD, Springer J. Animal models
of cachexia and sarcopenia in chronic illness:
Cardiac function, body composition changes andtherapeutic results. Int.J.Cardiol. 2017 Jul 1;238:
12-18.
(7) Saitoh M, Ishida J, Doehner W, von Haehling S,
Anker MS, Coats AJS, Anker SD, Springer J.
Sarcopenia, cachexia, and muscle performance inheart failure: Review update 2016. Int.J.Cardiol.
2017 Jul 1;238:5-11.
(8) Hanaoka S, Nakano Y, Nemoto M, Nomura Y,
Takenaga T, Miki S, Yoshikawa T, Hayashi N,
Masutani Y, Shimizu A. Automatic detection ofvertebral number abnormalities in body CT
images. International Journal of Computer
Assisted Radiology and Surgery 2017 May;12(5):719-732.
(9) Hanaoka S, Masutani Y, Nemoto M, Nomura Y,
Miki S, Yoshikawa T, Hayashi N, Ohtomo K,
Shimizu A. Landmark-guided diffeomorphic
demons algorithm and its application to automatic
segmentation of the whole spine and pelvis in CT
images. Int.J.Comput.Assist.Radiol.Surg. 2017
Mar;12(3):413-430.
(10) Kumamaru KK, Murayama S, Yamashita Y, Nojo
T, Watanabe Y, Goto M, Maeda E, Echigo J, Soga
S, Fujii S. Appropriate imaging utilization in
Japan: a survey of accredited radiology training
hospitals. Japanese journal of radiology 2017;35(11):648-654.
(11) Saitoh M, Ishida J, Ebner N, Anker SD, vonHaehling S. Myostatin inhibitors as pharmacological treatment for muscle wasting and405

muscular dystrophy. JCSM Clinical Reports
2017;2(1).
(12) Ishida J, Saitoh M, Springer J. Single‐nucleotide
polymorphisms in cachexia‐related genes: Can
they optimize the treatment of cancer cachexia?
Journal of cachexia, sarcopenia and muscle 2017;8(3):516-517.
(13) Ishida J, Saitoh M, Springer J. Is cardiac wastingaccompanied by skeletal muscle loss in breast
cancer patients receiving anticancer treatment?
Journal of cachexia, sarcopenia and muscle 2017;
8(5):851-852.
(14) Saitoh M, Ishida J, Springer J. Physical activity
for the prevention and treatment of sarcopenic
obesity. Journal of cachexia, sarcopenia andmuscle 2017;8(3):518-519.
(15) Saitoh M, Ishida J, Springer J. Considering
technique of assessment and method fornormalizing skeletal muscle mass. Journal ofcachexia, sarcopenia and muscle 2017;8(5):853-854.
(16) Maeda E, Tomizawa N, Kanno S, Yasaka K,
Kubo T, Ino K, Torigoe R, Ohtomo K. The
feasibility of Forward-projected model-based
Iterative Reconstruction SoluTion (FIRST) for
coronary 320-row computed tomography angiography: A pilot study. J.Cardiovasc. Comput.
Tomogr. 2017 Jan - Feb;11(1):40-45.
(17) Nemoto M, Hayashi N, Hanaoka S, Nomura Y,
Miki S, Yoshikawa T. Feasibility study of ageneralized framework for developing computeraided detection systems—a new paradigm. J.
Digital Imaging 2017;30(5):629-639.
(18) Nakao T, Hanaoka S, Nomura Y, Sato I, Nemoto
M, Miki S, Maeda E, Yoshikawa T, Hayashi N,
Abe O. Deep neural network‐based computer‐assisted detection of cerebral aneurysms in MR
angiography. Journal of Magnetic ResonanceImaging 2017.
(19)Dos Santos MR, Saitoh M, Ebner N, Valentova M,
Konishi M, Ishida J, Emami A, Springer J,
Sandek A, Doehner W, Anker SD, von Haehling S.
Sarcopenia and Endothelial Function in Patients
With Chronic Heart Failure: Results From theStudies Investigating Comorbidities Aggravating
Heart Failure (SICA-HF). J.Am.Med.Dir.Assoc.
2017 Mar 1;18(3):240-245.

(20) Hanaoka S, Shimizu A, Nemoto M, Nomura Y,
Miki S, Yoshikawa T, Hayashi N, Ohtomo K,
Masutani Y. Automatic detection of over 100
anatomical landmarks in medical CT images: A
framework with independent detectors andcombinatorial optimization. Med.Image Anal.
2017 Jan;35:192-214.
(21) Naganawa S, Yoshikawa T, Yasaka K, Maeda E,
Hayashi N, Abe O. Role of delayed-time-point
imaging during abdominal and pelvic cancer
screening using FDG-PET/CT in the general
population. Medicine (Baltimore) 2017 Nov;
96(46):e8832.
(22) Mizuno S, Isayama H, Nakai Y, Yoshikawa T,
Ishigaki K, Matsubara S, Yamamoto N, Ijichi H,
Tateishi K, Tada M, Hayashi N, Koike K.
Prevalence of Pancreatic Cystic Lesions Is
Associated With Diabetes Mellitus and Obesity:
An Analysis of 5296 Individuals Who Underwent
a Preventive Medical Examination. Pancreas
2017 Jul;46(6):801-805.
(23) Shirota G, Maeda E, Namiki Y, Bari R, Ino K,
Torigoe R, Abe O. Pediatric 320-row cardiac
computed tomography using electrocardiogramgated model-based full iterative reconstruction.
Pediatr. Radiol. 2017;47(11):1463-1470.

406

Department of Health Care Safety
Management (Tokio Marine &Nichido)Project Adjunct Assoc. Professor
Masaki Anraku, M.D., Ph.D.

Project Assistant Professor
Maiko Mizuki, MPH.

Project Researcher
Yuri Asano, MPH. Shintaro Hara, Ph.D.

Project Academic Support Specialist
Yuriko Kobashi

Visiting Researcher
Tomoko Matsuura, M.S., Shinji Nagakawa, M.D., Ph.D.,
Reiko Segawa, R.N., M.S. Keiko Katsui,Ph.D.

Homepage http://www.h.u-tokyo.ac.jp/research/center22/contribute/iryou_anzen.html
http://hcsm.m.u-tokyo.ac.jp/
Introduction and Organization
The Department of Health Care Safety Management
was established in December, 2005 within the “22ndCentury Medical and Research Center” at the
University of Tokyo Hospital based upon contributions by the Tokio Marine & Nichido Fire InsuranceCo., Ltd.
Public concern regarding malpractice and the medical
related disputes has risen in developed countries
accompany several publicized cases such as the public
inquiry into children’s heart surgery at the Bristol
Royal Infirmary and the accidental chemotherapy
overdoses occurring at the Dana-Farber Cancer
Institute at the end of the 20th century. Reports of themedia in our country concerning malpractice and the
medical related disputes increased suddenly from1999. Fears also rose regarding possible criminal

prosecutions through the mandatory reporting to thepolice provided in the Medical Practitioners Law
Article 21. Some incidents become targets ofinvestigations although several verdicts resulted inacquittals. Nonetheless, there exist various discussions
and some confusion over the intervention of the police
authority and criminal procedures into the process of
medical treatment.
On another front, in medical related disputes
involving civil claims for compensation for damages,
many cases have been dealt with and resolved throughvarious measures such as explanation and reconciliation settlement before becoming a lawsuit. In spite ofsuch efforts, the number of civil health care lawsuits
has kept increasing from the 1970s (about 100 new
cases received per year) to 2004 (1110 new cases peryear), with the pace that has doubled every ten years.
Though the number of civil health care lawsuits shows407

a trend for decrease after 2004, many medical
treatment disputes resulted in lawsuits in 2017, with
857 new cases received and 782 cases resolved.
In our department, while looking straight at therealities of malpractice and the medical related
disputes, we aim, from each aspect of the patient, thehealth care provider, and society, for a healthy
rebuilding of the health care system and the recoveryof confidence in medical treatment via thinking about
the ideal ways to build a better legal system. Together
therewith, we are establishing an approach that
promotes mutual understanding by conversations
between the patient and the health care provider,improves the quality and safety of medical care inorder to facilitate future medical care.

Research activities
Basic researches concerning both the prevention of
malpractice and the honest resolution of medical
accidents (including the preventing of disputes andlawsuits) are urgent issues. In addition, we conducted
research for the Patient Safety Support Cente as
Health & Labour Sciences Research since 2012. In
addition, we started Development of long-term
oxygenator for chronic lung disease patient (AMED
under grant) since 2017.
Such research activities are vigorously carried out inour department to return the results widely in societyby the development of educational activities.

Teaching activities
We promote education based on the research results
described above for the purpose of training
researchers and graduate students in the university.

Clinical activities
Based on the research results described above,
department is creating a system to identify issues incare settings, to examine those issues, to inform
personnel in care settings of those issues, and tocontinually assist personnel in those settings. Lectures
and talks to legal professionals, the medical
establishment, welfare providers, and personnel in
related fields regarding topics such as patient
education, education to improve counseling, andinformation about advanced medical care.
*Patient Safety Support Center Comprehensive
Support Project
Training and related activities are carried our targetingthe personnel of the “Patient Safety Support Centers”
established in each prefecture of Japan pursuant to theprovisions of the Medical Care Law (a Ministry of
Health, Labor and Welfare commissioned project).

References
Conference Presentations
1. Shintaro Hara, Takashi Isoyama, Terumi Yurimoto,
Xin-Yang Li, Itsuro Saito, Masaki Anraku, Yusuke
Abe, Development of the Sequential flow pump:Principle of the sequential pressurization andhemolysis results in secondary model. ASAIO,
2017. Chicago

408

Department of Clinical Trial DataManagement
Project Assistant Professor
Tempei Miyaji, M.Sc.

Project Researcher
Takuhiro Yamaguchi, Ph.D.

Registered Researcher
Satoru Fukimbara, Ph.D.
Hideki Suganami, Ph.D.
Yukikazu Hayashi, M.Sc.

Project Academic Support Staff
Kimiyo Terada
Miyuki Kurosaki

Homepage

http://ctdm.umin.jp/

Introduction and Organization
Why we discuss Clinical Data Management (CDM)?
The reason why the concept of CDM is important has
not been fully discussed and educated in Japan. Our
department was established to answer this question.
The Department of Clinical Trial Data Management
was established in 2007 and carries out educationaland research activities on CDM in collaboration withThe Department of Biostatistics and The ClinicalResearch Support Center in University of Tokyo.
As compared to the situation of CDM in the UnitedStates and Europe, technical aspects (data collection,
entry, check…) have been mainly focused in Japan but
the essence of CDM is to ensure quality of clinicaldata to appropriate level for fair and scientificevaluation. This has not been recognized in manyeducational activities. CDM should be defined as atechnical system to conduct clinical trials scientifically,
ethically and efficiently and to draw correctconclusion and also as a research discipline withtheory and practice that applies statistics, quality

control and clinical knowledge. It can optimize thewhole clinical trial process, keep the level of data
quality appropriately and calculate the trial cost.
One of our missions is to activate researches on CDM
aimed at improving the quality of clinical trials. The
other is to produce data managers trained under the
new education system which can look around all theclinical trial process to adapt rapid change of medical
environment and recent increase of e-clinical trials in
the world.

Teaching activities
1. Development of systematic educational programsof CDM and holding of seminars, which include; Design of clinical trials
 CDM
 Risk-based Monitoring Protocol development
 Regulatory science Ethics
 IT

409

 Safety information and PMS
 Translational research methodology
2. Acceptance of clinical trial staffs from other sites,that is, conducting an on-the-job training (OJT)
3. Support to clinical researchers, especially those in
the University of Tokyo Hospital, in collaboration
with the Clinical Research Support Center and theDepartment of Clinical Epidemiology and Systems;
 Consultation works on medical statistics andresearch methodology
 Functioning as a data center and stuffs
participate in projects as biostatisticians or
clinical data managers.

2.

Research activities
In addition to activities described above, we areconducting the research on methodology of Riskbased monitoring and developing ePRO in collaboration with other universities, pharmaceutical industries,
CRO and venders.
We are also supporting several clinical studies which
are conducted in the University of Tokyo Hospital.
Moreover, we also have collaborative works outsideof University of Tokyo Hospital for several clinicalresearches. For example, our department support“Exploratory Clinical Trial on Methods and Effects ofTojisha-Kenkyu for Autism Spectrum Disorder” which
conducted at Research Center for Advanced Scienceand Technology, The University of Tokyo and“Psychometric Property of Japanese version of Patient
Reported Outcome - Common Terminology Criteria
for Adverse Event”, “Feasibility study of collecting
patient – generated health data using mobile health”
which conducted at Department of Pharmacy, Tokyo
Medical University Hospital. Finally, as thecollaborative department of the Clinical Research
Support Center (CresCent), we also involved in theirprojects as biostatisticians and clinical data mangers.

3.

4.

5.

6.

References
1. Ishigami H, Fujiwara Y, Fukushima R, Nashimoto
A, Yabusaki H, Imano M, Imamoto H, Kodera Y,
Uenosono Y, Amagai K, Kadowaki S, Miwa H,
Yamaguchi H, Yamaguchi T, Miyaji T, andKitayama J, for the Japan Intraperitoneal
Chemotherapy Study Group. Phase III Trial

7.

Comparing Intraperitoneal and Intravenous
Paclitaxel Plus S-1 Versus Cisplatin Plus S-1 in
Gastric Cancer Patients with Peritoneal Metastasis: PHOENIX-GC Trial. J Clin Oncol 2018 (inpress)
Kawaguchi T, Azuma K, Sano M, Kim S,
Kawahara Y, Sano Y, Shimodaira T, Ishibashi K,
Miyaji T, Basch E, Yamaguchi T. The Japaneseversion of the National Cancer Institute's patientreported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE):
The psychometric validation and discordance
between clinician and patient assessments ofadverse events. Journal of Patient-Reported
Outcomes. 2018;2:2.
Ishiyama K, Sato T, Yamaguchi T, Taguma Y:
Efficacy of low-density lipoprotein apheresis
combined with corticosteroids for cholesterol
crystal embolism. Clinical and Experimental
Nephrology 21(2): 228-235, 2017.
Nakane T, Nakamae H, Yamaguchi T, Kurosawa S,
Okamura A, Hidaka M, Fuji S, Kohno A, Saito T,
Aoyama Y, Hatanaka K, Katayama Y, Yakushijin
K, Matsui T, Yamamori M, Takami A, Hino M,
Fukuda T. Use of mycophenolate mofetil and a
calcineurin inhibitor in allogeneic hematopoietic
stem-cell transplantation from HLA-matchedsiblings or unrelated volunteer donors: Japanesemulticenter phase II trials. International Journalof Hematology 105(4): 485-496, 2017.
Koretsune Y, Yamashita T, Yasaka M, Oda E,
Matsubayashi D, Ota K, Kobayashi M, Matsushita
Y, Kaburagi J, Ibusuki K, Takita A, Iwashita M,
Yamaguchi T:
Usefulness of a healthcare
database for epidemiological research in atrial
fibrillation. Journal of Cardiology 70(2): 169179, 2017.
Watanabe T, Yamaguchi T, Tsunoda H, Kaoku S,
Tohno E, Yasuda H, Ban K, Hirokaga K, Tanaka
K, Umemoto T, Okuno T, Fujimoto Y, Nakatani S,
Ito J, Ueno E: Ultrasound Image Classificationof Ductal Carcinoma In Situ (DCIS) of the Breast:
Analysis of 705 DCIS Lesions. Ultrasound in
Medicine and Biology 43(5): 918-925, 2017.
Nakamura M, Yamada N, Oda E, Matsubayashi D,
Ota K, Kobayashi M, Matsushita Y, Kaburagi J,
Ibusuki K, Takita A, Iwashita M, Yamaguchi T:410

Predictorsofvenousthromboembolism
recurrence and the bleeding events identified
using a Japanese healthcare database. Journal of
Cardiology 70(2): 155-162, 2017.
8. Maeda T, Shimo Y, Chiu SW, Yamaguchi T,
Kashihara K, Tsuboi Y, Nomoto M, Hattori N,
Watanabe H, Saiki H; J-FIRST group: Clinicalmanifestations of nonmotor symptoms in 1021
Japanese Parkinson's disease patients from 35
medical centers.
Parkinsonism and Related
Disorders 38: 54-60, 2017.
9. Fuji S, Yamaguchi T, Inoue Y, Utsunomiya A,
Moriuchi Y, Uchimaru K, Owatari S, Miyagi T,
Taguchi J, Choi I, Otsuka E, Nakachi S,
Yamamoto H, Kurosawa S, Tobinai K, Fukuda T:
Development of a modified prognostic index forpatients with aggressive adult T-cell leukemialymphoma aged 70 years or younger: possiblerisk-adapted management strategies including
allogeneic transplantation. Haematologica 102(7): 1258-1265, 2017.
10. Hatano Y, Aoyama M, Morita T, Yamaguchi T,
Maeda I, Kizawa Y, Tsuneto S, Shima Y,
Miyashita M: The relationship between cancer
patients' place of death and bereaved caregivers'
mental health status. Psychooncology 26(11):1959-1964, 2017.
11. Fuji T, Akagi M, Abe Y, Oda E, Matsubayashi D,
Ota K, Kobayashi M, Matsushita Y, Kaburagi J,
Ibusuki K, Takita A, Iwashita M, Yamaguchi T:
Incidence of venous thromboembolism andbleeding events in patients with lower extremity
orthopedic surgery: a retrospective analysis of aJapanese healthcare database.
Journal of
Orthopaedic Surgery and Research 12(1): 55,
2017.
12. Kunimatsu-Sanuki S, Iwase A, Araie M, Aoki Y,
Hara T, Fukuchi T, Udagawa S, Ohkubo S,
Sugiyama K, Matsumoto C, Nakazawa T,
Yamaguchi T, Ono H: The role of specificvisual subfields in collisions with oncoming cars
during simulated driving in patients withadvanced glaucoma.
British Journal of
Ophthalmology 101(7): 896-901, 2017.
13. Yamaguchi T, Maeda I, Hatano Y, Mori M, Shima
Y, Tsuneto S, Kizawa Y, Morita T, Yamaguchi T,
Aoyama M, Miyashita M:
Effects of

End-of-Life Discussions on the Mental Health of
Bereaved Family Members and Quality of Patient
Death and Care. Journal of Pain and Symptom
Management 54(1): 17-26, 2017.
14. Kako J, Morita T, Yamaguchi T, Sekimoto A,
Kobayashi M, Kinoshita H, Ogawa A, Zenda S,
Uchitomi Y, Inoguchi H, Matsushima E:
Evaluation of the Appropriate Washout Period
Following Fan Therapy for Dyspnea in Patients
With Advanced Cancer: A Pilot Study.
American Journal of Hospice and Palliative Care2017 Jan 1:1049909117707905. doi: 10.1177/
1049909117707905. [Epub ahead of print]
15. Kurosawa S, Oshima K, Yamaguchi T,
Yanagisawa A, Fukuda T, Kanamori H, Mori T,
Takahashi S, Kondo T, Kohno A, Miyamura K,
Umemoto Y, Teshima T, Taniguchi S, Yamashita T,
Inamoto Y, Kanda Y, Okamoto S, Atsuta Y:
Quality of Life after Allogeneic Hematopoietic
Cell Transplantation According to Affected Organand Severity of Chronic Graft-versus-Host
Disease.
Biology of Blood and Marrow
Transplantation 23(10): 1749-1758, 2017.
16. Shimada S, Saito H, Kawasaki Y, Yamashita S,
Adachi H, Kakoi N, Namima T, Sato M, Kyan A,
Mitsuzuka K, Ito A, Yamaguchi T, Arai Y:
Clinical predictors of the estimated glomerular
filtration rate 1 year after radical nephrectomy inJapanese patients. Investigative and Clinical
Urology 58(4): 228-234, 2017.
17. Okuyama J, Funakoshi S, Tomita H, Yamaguchi T,
Matsuoka H: School-Based Interventions Aimedat the Prevention and Treatment of Adolescents
Affected by the 2011 Great East Japan Earthquake: A Three-Year Longitudinal Study.
Tohoku Journal of Experimental Medicine 242(3):203-213, 2017.
18. Kanno T, Nakamura K, Ishiyama K, Yamada Y,
Shirato M, Niwano Y, Kayaba C, Ikeda K, Takagi
A, Yamaguchi T, Sasaki K:
Adjunctive
antimicrobial chemotherapy based on hydrogen
peroxide photolysis for non-surgical treatment ofmoderate to severe periodontitis: a randomized
controlled trial. Scientific Reports 7(1): 12247,
2017.
19. Fujimura T, Hidaka T, Kambayashi Y, Furudate S,
Kakizaki A, Tono H, Tsukada A, Haga T,411

Hashimoto A, Morimoto R, Yamaguchi T, Takano
T, Aiba S: Phase I study of nivolumab combinedwith IFN-β for patients with advanced melanoma.
Oncotarget 8(41): 71181-71187, 2017.
20. Kido R, Akizawa T, Fukagawa M, Onishi Y,
Yamaguchi T, Fukuhara S: Interactive Effectiveness of Angiotensin-Converting Enzyme
Inhibitors and Angiotensin Receptor Blockers orTheir Combination on Survival of Hemodialysis
Patients.
American Journal of Nephrology
46(6): 439-447, 2017.
21. Yasaka M, Koretsune Y, Yamashita T, Oda E,
Matsubayashi D, Ota K, Kobayashi M, Matsushita
Y, Kaburagi J, Ibusuki K, Takita A, Iwashita M,
Yamaguchi T: Recurrent Stroke and Bleeding
Events after Acute Cardioembolic StrokeAnalysis Using Japanese Healthcare Databasefrom Acute-Care Institutions. Journal of Stroke
and Cerebrovascular Diseases 2017 Dec 12.
pii: S1052-3057(17)30606-7. doi: 10.1016/j.
jstrokecerebrovasdis.2017.11.002. [Epub ahead ofprint]
22. Miyaji T, Iioka Y, Kuroda Y, Yamamoto D, Iwase
S, Goto Y, Tsuboi M, Odagiri H, Tsubota Y,
Kawaguchi T, Sakata N, Basch E, Yamaguchi T.
Japanese translation and linguistic validation of
the US National Cancer Institute's PatientReported Outcomes version of the Common
Terminology Criteria for Adverse Events (PROCTCAE). Journal of Patient-Reported Outcomes.
2017;1:8.
23. Matsuoka H, Ishiki H, Iwase S, Koyama A,
Kawaguchi T, Kizawa Y, Morita T, Matsuda Y,
Miyaji T, Ariyoshi K, Yamaguchi T. Study
protocol for a multi-institutional, randomised,double-blinded, placebo-controlled phase III trial
investigating additive efficacy of duloxetine forneuropathic cancer pain refractory to opioids andgabapentinoids: the DIRECT study. BMJ Open2017;7:e017280.
24. Tantsyura V, Mitchel J, Kim YJ, Miyaji T,
Yamaguchi T, McCanless Dunn. Risk-BasedApproaches to Data Management and Data
Quality: Double Standards or Is It Just Common
Sense and Intelligence Taking Over?. Data Basics.
2017; 23: 1

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Department of
Therapeutic Strategy forHeart Failure
Research Associate Professor
Masaru Hatano, M.D.

Research Assistant Professor
Seitaro Nomura, M.D

Project Researcher
Naoko Kato

Homepage

http: http://plaza.umin.ac.jp/~heart-f/

Introduction and Organization

Clinical Activities

The Department of Therapeutic Strategy for Heart
Failure (TSHF) in the University of Tokyo Hospital
was established by the support of the Department of
Cardiac Surgery and the Department of Cardiovascular
Medicine of the University of Tokyo Hospital in May
2008. The purpose to establish the department of TSHF
is to promote surgical and medical innovative treatment
for end-stage heart failure in the University of Tokyo
Hospital, which includes heart transplant, pediatricheart transplant, ventricular assist device, andregenerative therapy. The Department has been also
supported by nine companies.
Recently, right heart failure (RHF) gains recognition
as well as left heart failure (LHF). RHF developed after
left ventricular assist devise (LVAD) is a critical issue
remains to be elucidated. Pulmonary hypertension (PH)is also an important cause of RHF. Now a lot of patientswith severe PH are referred to our hospital because theUniversity of Tokyo Hospital has been approved as alung transplantation center since 2014. We pursue
optimal treatment strategy for not only LHF but also
RHF.

1. Heart Transplant (HTx)Patients who performed heart transplant in our
hospital or in abroad transferred from our hospital arefollowed up once a month in the out-patient clinic, andundergo myocardial biopsy once a month in the firstyear and once a year afterwards. When some symptom
or findings which suggest rejection are detected,
patients will undergo in-hospital treatment.
2. Ventricular Assist Device (VAD) Therapy
We recently implant not only extracorporeal
pulsatile but also implantable ventricular assist device(VAD). All candidates fell into end-stage heart failure
before VAD implantation, and a significant number ofthem were rescued with heart transplantation or bridge
to recovery. We implant centrifugal VAD (EVAHEART
and DuraHeart) or axial VAD (HeartMate II and Jarvik
2000) considering patients’ physics and clinical status).
We also assisted VAD implantation in affiliate orcooperative hospital in 2012 to establish VAD networkin Shinsyu University Hospital, Saku General Hospital,
Shinsyu University Hospital, Akita University Hospital,
Gunma Prefectural Cardiovascular Center, and Nagoya
Tokusyukai Hospital.

413

3. Treatment of PH
Although pulmonary arterial hypertension (PAH)
was a disease of poor prognosis, the treatment outcomeof PAH significantly improved in this decade attributed
to a number of newly approved drugs. Now we can use
ten agents for PAH including oral, inhaled, subcutaneous and intravenous drugs. Combination therapyof these drugs is increasingly prevalent for the management of PAH. We join the nationwide PH registry toestablish optimal treatment strategy for PAH .

Teaching Activities
We have the chair of systematic review of cardiovascular surgery in the spring term at the 2nd grade of
medical course. We also take charge in clinical practiceon diagnosis of cardiovascular disease in the autumn
term at the 2nd grade. We expose the students to dailyclinical works as well as research works during thecourse of “Free Quarter” and “Research Lab Visit”,
which are scheduled in the summer and springvacations at 1st and 2nd grade. Joint lectures with the
Cardiology Department are scheduled 3rd through 4th
grades. Each student is assigned one or two
cardiovascular surgical cases in the Bed Side Learning,in which he/she is required to learn preoperative patient
evaluation and management, surgical treatment andpostoperative care, based on participatory practice.
There are also twelve small key-lectures on
cardiovascular surgery. Hands-on practice is provided
during the “Clinical clerkship” one-month course in thelast months of 3rd grade.
We take charge in core surgical curriculum in the“Super-rotation” postgraduate training. We offer a
program in which each resident can learn basic
knowledge of cardiovascular disease and surgery, andhemodynamic and respiratory evaluation as well asbasic surgical techniques and patient management.
Residents who take the course of cardiovascularsurgery are required three-year general surgicaltraining for General Surgery Board certification. We
have well-developed specialty/ subspecialty training
programs to allow the residents to pass Cardiovascular
Board Examination by 10th postgraduate year.

Research Activities
In order to achieve excellent clinical results and toseek for new possibilities of surgical treatments forheart failure, it is essential for our department of the
University to have active research programs in clinicaland basic subjects related to assisted circulations andheart transplantation. We created highly active research
programs in the every field of medical and surgicalheart failure treatment, played an internationallyleading role and contributed to its development. A
research meeting is held every Saturday on a research
project with Department of Cardiothoracic Surgery.
Basic and/or clinical research activities are focusedon 1) development of new driving method of rotary
blood pump, 2) development of Compact CP externalcounterpulsation, 3) basic and clinical research on
regenerative therapy, 4) establishment of social support
system for patients with implantable LVAD. We haveorganized 4series of clinical trial of implantable rotary
blood pump LVAD, EVAHEART, DuraHeart, Jarvik
2000, and HeartMate II since 2007.

References
1. Kubota K, Soma K, Uehara M, Inaba T, Saito A,
Takeda N, Hatano M, Morita H, Inuzuka R, Hirata
Y, Yao A, Komuro I. Combined Surgical andMedical Therapy for Candida Prosthetic
Endocarditis in a Patient with Repaired Tetralogy
of Fallot. Int Heart J. 2018 (In press)
2. Minatsuki S, Kiyosue A, Saito A, Maki H, Hatano
M, Komuro I. Effectiveness of Nitroglycerin in
Managing Subacute Lung Bleeding Induced by
Balloon Pulmonary Angioplasty. Int Heart J. 2018
(In press)
3. Sato T, Hatano M, Iwasaki Y, Maki H, Saito A,
Minatsuki S, Inaba T, Amiya E, Fujio K, Watanabe
M, Yamamoto K, Komuro I. Prevalence of primary
Sjögren's syndrome in patients undergoingevaluation for pulmonary arterial hypertension.
PLoS One. 2018; 13(5):e0197297
4. Asano Y, Jinnin M, Kawaguchi Y, Kuwana M,
Goto D, Sato S, Takehara K, Hatano M, FujimotoM, Mugii N, Ihn H. Diagnostic criteria, severity
classification and guidelines of systemic sclerosis.
J Dermatol. 2018;45(6):633-691.
5. Yonenaga A, Hasumi E, Fujiu K, Ushiku A, Hatano
M, Ando J, Morita H, Watanabe M, Komuro I.
Prognostic Improvement of Acute Necrotizing

414

Eosinophilic Myocarditis (ANEM) Through a
Rapid Pathological Diagnosis and Appropriate
Therapy. Int Heart J. 2018;59(3):641-646.
6. Taya M, Amiya E, Hatano M, Maki H, Nitta D,
Saito A, Tsuji M, Hosoya Y, Minatsuki S,
Nakayama A, Fujiwara T, Konishi Y, Yokota K,
Watanabe M, Morita H, Haga N, Komuro I. Highintensity aerobic interval training can lead to
improvement in skeletal muscle power among inhospital patients with advanced heart failure. Heart
Vessels. 2018;33(7):760-761.
7. Tobita T, Nomura S, Fujita T, Morita H, Asano Y,
Onoue K, Ito M, Imai Y, Suzuki A, Ko T, Satoh M,
Fujita K, Naito AT, Furutani Y, Toko H, Harada M,
Amiya E, Hatano M, Takimoto E, Shiga T,
Nakanishi T, Sakata Y, Ono M, Saito Y, Takashima
S, Hagiwara N, Aburatani H, Komuro I. Genetic
basis of cardiomyopathy and the genotypes
involved in prognosis and left ventricular reverse
remodeling. Sci Rep. 2018;8(1):1998.
8. Saito A, Amiya E, Hatano M, Hosoya Y, Maki H,
Nitta D, Minatsuki S, Watanabe M, Komuro I.
Newly developed atrial fibrillation progresses to amore severe INTERMACS score in a patient withadvanced heart failure due to dilated cardiomyopathy. Clin Case Rep. 2017;5(12):2028-2033.
9. Numata G, Kodera S, Kiriyama H, Nakayama A,
Amiya E, Kiyosue A, Hatano M, Takimoto E,
Watanabe M, Komuro I. Usefulness of central
venous saturation as a predictor of thiamine
deficiency in critically ill patients: a case report. J
Intensive Care. 2017;5:61
10. Adachi Y, Kinoshita O, Hatano M, Shintani Y,
Naito N, Kimura M, Nawata K, Nitta D, Maki H,
Ueda K, Amiya E, Takimoto E, Komuro I, Ono M.
Successful bridge to recovery in fulminant
myocarditis using a biventricular assist device: acase report. J Med Case Rep. 2017;11(1):295.
11. Tsuji M, Amiya E, Hatano M, Komuro I. Dilated
cardiomyopathy complicated with visceralheterotaxy. Eur Heart J. 2018;39(1):73.
12. Numata G, Amiya E, Kojima T, Fujiu K, Hatano M,
Watanabe M, Komuro I. Cardiac Resynchronization Therapy in Patients with Ebstein's Anomaly.
Int Heart J. 2017;58(5):816-819.
13. Minatsuki S, Hatano M, Maki H, Ando J, Komuro
I. The Structure of a Chronic Total Occlusion and

Its Safe Treatment in a Patient with Chronic
Thromboembolic Pulmonary Hypertension. Int
Heart J. 2017;58(5):824-827.
14. Kato NP, Okada I, Kagami Y, Endo M, Hatano M,
Ono M, Jaarsma T, Kinugawa K. Quality of life offamily caregivers of patients with a left ventricularassist device in Japan. J Cardiol. 2018;71(1):81-87.
15. Kimura M, Nawata K, Kinoshita O, Yamauchi H,
Hoshino Y, Hatano M, Amiya E, Kashiwa K, Endo
M, Kagami Y, Nemoto M, Ono M. Readmissions
after continuous flow left ventricular assist device
implantation. J Artif Organs. 2017;20(4):311-317.
16. Tamura Y, Kumamaru H, Satoh T, Miyata H,
Ogawa A, Tanabe N, Hatano M, Yao A, Abe K,
Tsujino I, Fukuda K, Kimura H, Kuwana M,
Matsubara H, Tatsumi K; Japan PH Registry(JAPHR) Network. Effectiveness and Outcome of
Pulmonary Arterial Hypertension-Specific Therapy in Japanese Patients With Pulmonary Arterial
Hypertension. Circ J. 2017 Dec;82(1):275-282.
17. Kiriyama H, Amiya E, Hatano M, Hosoya Y, Maki
H, Nitta D, Saito A, Shiraishi Y, Minatsuki S, SatoT, Murakami H, Uehara M, Manaka K, Makita N,
Watanabe M, Komuro I. Rapid Improvement of
thyroid storm-related hemodynamic collapse by
aggressive anti-thyroid therapy including steroid
pulse: A case report. Medicine (Baltimore). 2017.
18. Hara H, Takeda N, Morita H, Hatano M, Amiya E,
Maki H, Minatsuki S, Taki M, Shiraishi Y,
Fujiwara T, Maemura S, Komuro I. Three novel
BMPR2 mutations associated with advanced
pulmonary arterial hypertension. Hum Genome Var.
2017.
19. Tanabe N, Ikeda S, Tahara N, Fukuda K, Hatano M,
Ito H, Nakayama T, Anzai T, Hashimoto A, Inoue
T, Kajinami K, Kihara Y, Kinoshita H, Kuwahara
K, Murohara T, Okazaki O, Sakai S, Satoh T,
Takeda Y, Takeishi Y, Taniguchi M, Watanabe H,
Yamamoto T, Yamauchi-Takihara K, Yoshioka K,
Sasayama S. Efficacy and Safety of an Orally
Administered Selective Prostacyclin Receptor
Agonist, Selexipag, in Japanese Patients With
Pulmonary Arterial Hypertension. Circ J. 2017 (InPress)
20. Yamaguchi J, Tanaka T, Saito H, Nomura S,
Aburatani H, Waki H, Kadowaki T, Nangaku M.
Echinomycin inhibits adipogenesis in 3T3-L1 cells

415

in a HIF-independent manner. Sci Rep. 7: 6516.
2017.
21. Higo T, Naito AT, Sumida T, Shibamoto M, Okada
K, Nomura S, Nakagawa A, Yamaguchi T, Sakai T,
Hashimoto A, Kuramoto Y, Ito M, Hikoso S,
Akazawa H, Lee JK, Shiojima I, McKinnon PJ,
Sakata Y, Komuro I. DNA single-strand breakinduced DNA damage response causes heart failure.
Nat Commun. 8: 15104.
22. Kamo T, Akazawa H, Suda W, Saga-Kamo A,
Shimizu Y, Yagi H, Liu Q, Nomura S, Naito AT,
Takeda N, Harada M, Toko H, Kumagai H, Ikeda
Y, Takimoto E, Suzuki JI, Honda K, Morita H,
Hattori M, Komuro I. Dysbiosis and compositional
alterations with aging in the gut microbiota ofpatients with heart failure. PLoS One. 2017.

Social Cooperation Program417

Department of Lipidomics
Professor
Takao Shimizu, M.D., Ph.D.
Yoshiya Oda, Ph.D.

Associate Professor
Fuyuki Tokumasu, Ph.D.

Assistant Professor
Suzumi Tokuoka, Ph.D.

Homepage

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

Introduction and Organization

Research activities

The Department of Lipidomics was established in
April 2011, funded by Shimadzu Corp. and Ono
Pharmaceutical Co., Ltd. The objective of the laboratory is to establish and improve mass spectrometrybased lipidomics methodologies, and its application tobiomedical studies including basic lipid biology as
well as clinical research.
The laboratory was started with three staff scientists,
Takao Shimizu (Professor), Yoshihiro Kita (Associate
Professor. He moved to Life Science Core Facility in
Dec. 2013), and Suzumi Tokuoka (Assistant Professor). In April, 2014, Fuyuki Tokumasu joined as an
Associate Professor and in May 2018, Yoshiya Oda
joined as a professor. In 2014, we had another assistant professor, two guest researchers and two technicalassistants.

Our research interests cover following topics.

Teaching activities
The department staffs gave several lectures forundergraduate and graduate students. For undergraduate students, Drs. Shimizu and Kita delivered
several lectures on biochemistry. Dr. Kita gave
lectures on “Proteome and metabolome” for master’s
students and “Principles and Applications of Mass
Spectrometry” for doctoral students.

Multiplex quantitation strategy for lipid mediators
Lipid mediators, including prostaglandins, leukotrienes, platelet-activating factor, and many otherbioactive lipid metabolites are attracting great
attention as disease-related or physiologically important molecules. Comprehensive analysis of known
lipid mediators is a useful, unbiased method in diseasemechanism studies, and the lipid mediator profile is a
useful parameter that characterizes disease status aswell. We have developed an original multiplex
quantification method for trace amounts of lipid
mediators using liquid chromatography-tandem mass
spectrometry (LC-MS/MS). We are developing moresensitive and rapid methods that cover more lipid
mediators, which meet the demands on various
large-scale studies and high-throughput screening
approaches.
Lipid biomarker discovery
Lipid biomarker discovery by liquid chromatographymass spectrometry-based method requires a high-level
integration of chromatography and mass spectrometry,
which ensures lipid separation, semi-quantitative detection, and identification. We are collaborating withindustries to overcome known difficulties in lipid
chromatography, develop differential analyses and418feature-extraction methods, and establish an intelligent analytical system linked with lipid database.
Methods for clinical samples
Clinical samples such as blood, urine, feces, andtissue biopsies vary greatly as compared with
controlled animal studies. Furthermore, sampling andstorage conditions are not always optimized for lipid
analysis. We are developing techniques for handlingclinical samples for a practical lipidomics analysis.
Metabolic flux analysis of lipids
A simple lipidomics analysis provides large datasetsthat describe the amount-based profile of lipidome.
However, such a ‘snapshot’ analysis is not sufficientto understand the dynamics of lipid metabolic pathway,
because changes in metabolic flux is not always
reflected to static amount of metabolites. To overcome
this situation, we are developing a flux-oriented
lipidomics analysis using stable-isotope tracers.
Lipid biomarker/lipid mediator discovery using
animal models
Appling the latest lipidomics technologies to theanalysis of specimens from the animal models forvarious diseases including metabolic disease, we aretrying to discover novel lipid biomarkers. We also
analyze various gene-deficient mice and transgenic
mice to seek important lipid markers, lipid mediators,
and lipid profiles.
Discovery of novel lipid mediator metabolizing
pathways
Although major biosynthetic and catabolic
pathways for classical lipid mediators have been well
documented so far, there are still possibilities for yet
unidentified lipid mediator metabolizing pathways invivo. We have obtained preliminary data for novel
lipid mediator-producing pathway using genedeficient mice. Using the latest lipidomics techniques
to the cell cultures and animal models, we will
elucidate a novel lipid mediator related pathway andits biological significance.
Analyses of lipid profile and energy recycling
mechanism in Plasmodium falciparum (humanmalaria parasite)
Human malaria impacts on human healthworld-wide, resulting in close to430,000 victims eachyear. However, developments of anti-malarial drug
have been hampered by quick emergence of drug
resistant parasites. To better understand malaria
parasite biology and drug resistance mechanisms, westudy molecular pathways of lipid metabolism inparasite and biophysical properties of intracellular
membranes that are responsible for malaria protein
delivery to the host erythrocyte membrane. Since
parasites grow inside human erythrocytes, clean
separation of parasites from the host cell and precise
biochemical analyses are often difficult tasks. In ourlaboratory, we combine lipid profiling techniques, ahigh-resolution
fluorescencemicroscopy,
andadvanced biophysical analyses to achieve our research
objectives.

References
1. Tabe S, Hikiji H, Ariyoshi W, Hashidate-Yoshida T,
Shindou H, Shimizu T, Okinaga T, Seta Y, Tominaga
K, Nishihara T. Lysophosphatidylcholine acyltransferase 4 is involved in chondrogenic differentiation of ATDC5 cells. Sci Rep, 7, 16701(2017)
2. Kimura H, Suzuki M, Konno S, Shindou H, Shimizu
T, Nagase T, Miyazaki T, Nishimura M.
Orchestrating role of apoptosis inhibitor ofmacrophage in the resolution of acute lung injury. J
Immunol, 199, 3870-3882 (2017)
3. Iizuka-Hishikawa Y, Hishikawa D, Sasaki J, Takubo
K, Goto M, Nagata K, Nakanishi H, Shindou H,
Okamura T, Ito C, Toshimori K, Sasaki T, Shimizu T.
Lysophosphatidic acid acyltransferase 3 tunes themembrane status of germ cells by incorporating
docosahexaenoic acid during spermatogenesis. J
Biol Chem, 292, 12065-12076 (2017)
4. Shindou H, Koso H, Sasaki J, Nakanishi H, Sagara
H, Nakagawa MK, Takahashi Y, Hishikawa D,
Iizuka-Hishikawa Y, Tokumasu F, Noguchi H,
Watanabe S, Sasaki T, Shimizu T. Docosahexaenoic
acid preserves visual function by maintaining
correct disc morphology in retinal photoreceptor
cells. J Biol Chem, 292, 12054-12064 (2017)
5. Takeda T, Komiya Y, Koga T, Ishida T, Ishii Y,
Kikuta Y, Nakaya M, Kurose H, Yokomizo T,
Shimizu T, Uchi H, Furue M, Yamada H. Dioxininduced increase in leukotriene B4 biosynthesis
through the aryl hydrocarbon receptor and its

419

relevance to hepatotoxicity owing to neutrophil
infiltration. J Biol Chem, 292. 10586-10599 (2017)
6. Shindou H, Shiraishi S, Tokuoka MS, Takahashi Y,
Harayama T, Abe T, Bando K, Miyano K, Kita Y,
Uezono Y, Shimizu T. Relief from neuropathic painby blocking of platelet-activating factor-pain loop.
FASEB J, 31, 2973-2980 (2017)
7. Shimura M, Shindou H, Szyrwiel L, Tokuoka SM,
Hamano F, Matsuyama S, Okamoto M, Matsunaga
A, Kita Y, Ishizaka Y., Yamauchi K, Kohmura Y,
Lobinski R, Shimizu I, Shimizu T. Imaging of intracellular fatty acids by scanning X-ray fluorescencemicroscopy. FASEB J. 30, 4149-4158 (2016) Epub.
8. Kita Y, Yoshida K, Tokuoka MS, Hamano F,
Yamazaki M, Sakimura K, Kano M, Shimizu T.
Fever is mediated by conversion of endocannabinoid 2-arachidonoylglycerol to prostaglandin E2.
PLoS ONE, 10, e0133663 (2015)
9. Harayama T, Shindou H, Kita Y, Otsubo E, Ikeda
K, Chiba S, Weaver T, Shimizu T. Establishment
of LC-MS method for the analysis ofpalmitoylated surfactant proteins. J. Lipid Res., 56,
1370-1379 (2015)
10. Yamada M, Kita Y, Kohira T, Yoshida K, Hamano
F, Tokuoka SM, Shimizu T. A comprehensive
quantification method for eicosanoids and related
compounds by using liquid chromatography/mass
spectrometry with high speed continuous ionization polarity switching. J. Chrom. B, 995, 74-84(2015)
11. Hashidate-Yoshida T, Harayama T, Hishikawa D,
Morimoto R, Hamano F, Tokuoka SM, Eto M,
Tamura-Nakano M, Yanobu-Takanashi R,
Mukumoto Y, Kiyonari H, Okamura T, Kita Y,
Shindou H, Shimizu T. Fatty acyl-chain remodeling by LPCAT3 enriches arachidonate inphospholipid membranes and regulates triglyceride transport. eLife, 4, e06328 (2015)12. Hayakawa EH, Tokumasu F, Usukura J, Matsuoka
H, Tsuboi T, Wellems TE. Imaging of thesubsurface structures of "unroofed" plasmodium
falciparum-infected erythrocytes. Exp. Parasitol.,
153, 174-179 (2015)
13. Asahara M, Ito N, Yokomizo T, Nakamura M,
Shimizu T, Yamada Y. The absence of the leukotriene B4 receptor BLT1 attenuates peripheral
inflammation and spinal nociceptive processing

following intraplantar formalin injury. MolecularPain, 11.11 (2015)
14. Chagas AC, McPhie P, San H, Narum D, Reiter K,
Tokumasu F, Brayner FA, Alves LC, Ribeiro JM,
Calvo E. Simplagrin, a platelet aggregation
inhibitor from Simulium nigrimanum salivary
glands specifically binds to the Von Willebrandfactor receptor in collagen and inhibits carotid
thrombus formation in vivo. PLoS Negl. Trop.
Dis., 8, e2947 (2014)
15. Tokumasu F, Crivat G, Ackerman H, Hwang J,
Wellems TE. Inward cholesterol gradient of themembrane system in P. falciparum -infected
erythrocytes involves a dilution effect fromparasite-produced lipids. Biol. Open, 3, 529-541(2014)
16. Yoshioka W, Kawaguchi T, Fujisawa N, AidaYasuoka K, Shimizu T, Matsumura F, Tohyama C.
Predominant role of cytosolic phospholipase A2α
in dioxin-induced neonatal hydronephrosis inmice. Sci. Rep., 4, 4042 (2014)
17. Tarui M, Shindou H, Kumagai K, Morimoto R,
Harayama T, Hashidate T, Kojima H, Okabe T,
Nagano T, Nagase T, Shimizu T. Selective
inhibitors of a PAF biosynthetic enzyme lysophosphatidylcholine acyltransferase 2. J. LipidRes., 55, 1386-1396 (2014)18. Harayama T, Eto M, Shindou H, Kita Y, Otsubo E,
Hishikawa D, Ishii S, Sakimura K, Mishina M,
Shimizu T. Lysophospholipid acyltransferases
mediate phosphatidylcholine diversification toachieve the physical properties required in vivo.
Cell Metab., 20, 295-305 (2014)
19. Morimoto R, Shindou H, Tarui M, Shimizu T.
rapid production of platelet-activating factor is
induced by protein kinase Cα-mediated phosphorylation of lysophosphatidylcholine acyltransferase 2 protein. J. Biol. Chem., 289, 1556615576 (2014)
20. Liu M, Saeki K, Matsunobu T, Okuno T, Koga T,
Sugimoto Y, Yokoyama C, Nakamizo S,
Kabashima K, Narumiya S, Shimizu T, Yokomizo
T. 12-Hydroxyheptadecatrienoic acid promotes
epidermal wound healing by accelerating
keratinocyte migration via BLT2 receptor. J. Exp.
Med., 211, 1063-1078 (2014)

420

Voice Analysis of Pathophysiology
Project Associate Professor
Shinichi TOKUNO, M.D.,Ph.D.

Project Assistant Professor
Mitsuteru NAKAMURA, Ph.D.

Websitehttp://www.univ.tokyo/

Introduction and Organization

Teaching activities

Department of Voice Analysis of Pathophysiology
was established as a Social Cooperation Program on
September 2014, funded by Mazda Co., Ltd. and MKI(Mitsui Knowledge Industry) Co., Ltd. Professor
Yahagi, Emergency and Critical Care Medicine,
assisted us at that time. From September 2017, We
funded by Mazda Co., Ltd. and PST Inc. Professor
Yamada, Anesthesiology, assisted us at that time.
Purpose of our department is “to establish Verbal
Analysis of Pathophysiology as academic In order tobuild a safe and secure society in which those whoneed emergency medical care can reach timely andappropriate emergency medical care. That is followed
to build a system to support an approach to emergency
medical care not only after onset of the disease but
also before onset of the disease in daily life”.
In general, the physician discerns a qualitativechange in the patient's voice and inferred his/her
medical condition. Verbal Analysis of Pathophysiology Technology is to visualize the condition of
the patients from his /her voice, to assist in the
diagnosis, treatment and prevention. Verbal Analysis
of Pathophysiology academically organized thistechnology, and visualizes the disease by using thebiometric information of the voice which has not been
so far utilized
Faculties were Shinichi TOKUNO, M.D.,Ph.D.,
Project Associate Professor, Mitsuteru NAKAMURA,
Ph.D., Project Assistant Professor and one project
researchers. Additionally, two guest researchers willattend our department.

Shunji MITSUYOSHI, Project Lecturer was
performing a lecture about overview of the verbal
analysis of pathophysiology technology (PST:
Psychoanalysis System Technology) and the voice
emotion recognition technology (ST: Sensibility
Technology) underlying PST in the department ofengineering.

Research activities
It includes voluntary component such as language
and involuntary component which is mainly derived
from the autonomic nervous in voice. Voice emotion
recognition technology which recognizes an emotionof the speaker by assessing patterning the involuntarycomponent has already been established. Our research
forces on the assessment of the medical validity of theverbal analysis of pathophysiology technology (PST:
Psychoanalysis System Technology) which measure
the health of mind (depressive or manic) from thevoice, and the research for the society implementationof this technology. Additionally, we will further
develop this technology, and try to applicate it to theother diseases.
 Research for medical verification and social
implementation of depression evaluation by voice
1) Voice comparison of healthy subjects and patients
Currently, by analyzing the voice for long term
about two weeks, it was possible to substantially
identify the voice of patients and healthy subjects.
In the future, to increase the accuracy, we will
increase the number of cases.

421

2)

3)

4)

5)



1)

2)



A study on the monitoring of health status byvoice using a smartphone
As a social implementation research, we areconducting prospective research on long-term use
by volunteers.
Use in industrial hygiene field of stress check byvoice
As research for social implementation, we areconducting a study to use our technology in thecontext of industrial hygiene.
Verification in other languages
In order to confirm the usefulness of languages
other than Japanese, we are conducting a joint
research of the speech database of the foreign
languages and other countries.
The detailed study by multicenter study
Because of the robustness evaluation oftechnology, we are conducting joint research inthe multi-center.
Application of the verbal analysis of pathophysiology technology to other than the stressdepression
We perform the joint research with Mazda Co.,
Ltd., which our investment company.
sleep apnea syndrome
By the analysis of voice in the awakening andsnoring in falling asleep of the patients who have
sleep apnea syndrome, we have done research on
the measurement of the quality of sleep.
Application to other diseases
We are currently conducting research on
psychiatric disorders (major depression, bipolar
disorder), neurological disorders (Parkinson's disease), dementia (including Alzheimer's disease),oral surgery diseases (tongue adhesions) and soon.
A study for the effects of driving a car on thehealth of maind
We perform the joint research with Mazda Co.,
Ltd., which our investment company.

References
1.

Tokuno S. Pathophysiological Voice Analysis for
Diagnosis and Monitoring of Depression. In:
Yong-Ku Kim, editors. Understanding Depression. Volume 2. Clinical Manifestations, Diagno-

2.

3.

4.

5.

6.

7.

sis and Treatment. Singapore: Springer; 2018. p.
83-95.
Shinohara S, Omiya Y, Hagiwara N, et al. Case
Studies of Utilization of the Mind Monitoring
System (MIMOSYS) Using Voice and Its Future
Prospects. ESMSJ (Econophysics, Sociophysics& other Multidisciplinary Sciences Journal).
2017;7(1):7-12.
Higuchi M, Yamamoto I, Omiya Y, et al.
Mitsuyoshi S, Tokuno S. Measurement of Stress
Level to Prevent Post-Traumatic Stress Disorder
Developed by Identifying Dead Bodies. ESMSJ(Econophysics, Sociophysics & other Multidisciplinary Sciences Journal). 2017;7(1):13-18.
Hagiwara N, Omiya Y, Shinohara S, et al.
Difference in Voice Analysis Result by Pre andPost Processing of Telephone Line. Conf Proc
IEEE Eng Med Biol Soc. 2017;Jul:242-245.
Shinohara S, Omiya Y, Nakamura M, et al.
Multilingual evaluation of voice disability index
using pitch rate. Advances in Science Technology
and Engineering Systems Journal. 2017;2(3):765772.
Hagiwara N, Omiya Y, Shinohara S, et al.
Validity of Mind Monitoring System as a Mental
Health Indicator using Voice. Advances inScience, Technology and Engineering Systems
Journal. 2017;2(3):338-344.
Mitsuyoshi S, Nakamura M, Omiya Y, et al.
Mental status assessment of disaster relief
personnel by vocal affect display based on voice
emotion recognition. Disaster and Military
Medicine, 2017;3(1):4.

422

Department ofAdvanced Nursing Technology
Project Associate Professor
Ryoko Murayama, Ph.D., R.N.M.

Project Assistant Professor
Mari Abe, MHS, R.N.

Visiting Researcher
Hidenori Tanabe, MS.

Homepage http://ant.m.u-tokyo.ac.jp/index.html
Introduction and Organization
The Department of Advanced Nursing Technology
was established in December 2012 with the aim ofdeveloping new academic fields to create advanced
nursing technology based on clinical evidence. Our
primary belief is that “Never let patients endure
suffering in health care.” thus we hope that ouractivities will directly assist patients to live longer andhealthier lives.
To date, significant difficulties in creating advanced
nursing technology have resulted in a gap between
academic research and needs of the clinical setting.
Thus, advanced nursing technology strategies have notbeen applied in hospitals due to the unsuitability ofsuch scientific processes to this clinical setting,despite being beneficial to academic nursing
researchers at universities. In contrast, new nursing
technologies are often developed because of nurses’
experiences in clinical settings but have certain
limitations such as unavailability of scientificprocesses. Furthermore, systems to promote andsupport nurses who wish to undertake research in theclinical setting are insufficient.
The Department of Advanced Nursing Technology
was established at the University of Tokyo Hospital(Tokyo, Japan), with the support of Terumo Co.,Tokyo, Japan, as a social cooperation program. The
United Cooperation Program at the University ofTokyo, established to solve the abovementioned
difficulties and further the development of nursing
technology, comprises the Department of Gerontological Nursing/Wound Care Management, Departmentof Nursing, and Department of Diabetes andMetabolic Diseases. We aim to develop a newresearch model through collaborative research with
the Departments of Nursing and Medical Examination
at the University of Tokyo Hospital 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. Our
collaborative research has been promoted withadditional investment from the Paramount Bed
Corporation since December 2015.
The team includes the following members fromvarious departments at the University of Tokyo:
Ryoko Murayama (Project Associate Professor) andMari Abe (Project Assistant Professor), as well as
Hidenori Tanabe (Visiting Researcher; from Terumo
Co.).
Furthermore, the Global Nursing Research Center(GNRC), Graduate School of Medicine, the Universityof Tokyo, has been established in April 2017. We werein charge of the department of Clinical Nursing
Technology, Division of Care Innovation of GNRC,
and contributed to promote research into an innovative
nursing science and to create an interdisciplinary423

research and educational environment that fosters
young leaders in nursing research.

Teaching activities
We have guided Master’s and PhD course students
from the Department of Gerontological Nursing/
Wound Care management on matters concerning
research planning and practical work. Further, wehave been involved in providing lectures on topics,
such as Gerontological Nursing and Wound Care
Nursing, for undergraduates, master course students,
and PhD course students within the Department ofGerontological Nursing/Wound Care management.
The primary doctorate theme of 2017 was“Interventional study by bundle care to reducemechanical irritation for prevention of peripheral
intravenous catheter failure”.
We were in charge of lectures about nursing
translational research at the seminar hosted by GNRC
for post-doctoral fellows and other researchers.
(Introduction seminar to Nursing Science andEngineering)Research activities
1. Activity policy
We will develop a new nursing research scheme
aimed at identifying clinical needs relating to ourprimary belief, “never let patients endure suffering in
health care.” Using multidisciplinary studies andresearch, we will seek solutions to clinical issues innursing. Regarding our scientific approach, we willconduct epidemiologic surveys and genetic research,followed by evaluation of the technologies/devices
developed in collaboration with companies,
endeavoring to provide epoch-making technologies
that meet clinical needs utilizing the Nursing
Translational Research system.
Several research projects are also ongoing in our
department including development of nursing technology for early detection of extravasation, clarificationof infiltration, mechanisms, development of a new
intravenous catheter to prevent catheter failures, and a
proposal or a new program on infusion therapy
management. These projects are being conducted incollaboration with nurses at the University of Tokyo
Hospital.

We provide nurses with information regarding the
career ladder system within the Department of
Nursing at the University of Tokyo Hospital.
Evaluation of thermo-film for early detection of
extravasation is a component of this system.
We offer consultations on research matters andprovide guidance on article writing to promote nursing
research in the clinical setting. A study meeting isscheduled with the graduate school of the Universityof Tokyo to educate nurses regarding research.
2. Research fields and themes in 2017
 Understanding of the mechanisms that lead toperipheral intravenous catheter failures (PIV-CF).
 Development of a new intravenous catheter toprevent PIV-CF.
 Development of thermo-film for early detection of
extravasation.
 Development of a training program for technicalimprovement of peripheral venous catheter
placement using ultrasonography.
In addition, we have conducted research on pressure
ulcers of wheelchair athletes as a research topic in thespecialized Department of Gerontological Nursing/
Wound Care management.
We have received the following award for our
research: Best Research Award from 26th Conferenceof Japanese Society of Wound, Ostomy, andContinence Management (June 2017); “Characteristics
of subcutaneous tissue of peripheral injection puncturesite in paclitaxel / carboplatin therapy.”

References
1.

2.

Sakurai S, Hanafusa N, Kato H, Iizaka S,
Murayama R, Nangaku M. Questionnaire Survey
on Nutritional Supplement Therapy and Exercise
Training at Hemodialysis Facilities in Japan,
Renal Replacement Therapy. 2017; 3: 60,
https://doi.org/10.1186/s41100-017-0137-4
Matsui Y, Murayama R, Tanabe H, Oe M, Motoo
Y, Wagatsuma T, Michibuchi M, Kinoshita S,
Sakai K, Konya C, Sugama J, Sanada H.
Evaluation of the Predictive Validity ofThermography in Identifying Extravasation With
Intravenous Chemotherapy Infusions. Journal of

424

3.

4.

5.

6.

7.

Infusion Nursing. 2017; 40(6): 367-374.
Abe M, Oe M, Murayama R, Takahashi M, Zushi
Y, Tanabe H, Takamoto I, Suzuki R, Yamauchi T,
Kadowaki T, Komiyama C, Sanada H. Development of an Automatic Puncturing and Sampling
System for a Self-Monitoring Blood Glucose
Device. Diabetes Technology & Therapeutics.
2017; 19(11): 651-659.
Takahashi T, Murayama R, Oe M, Nakagami G,
Tanabe H, Yabunaka K, Arai R, Komiyama C,
Uchida M, Sanada H. Is thrombus with
subcutaneous edema detected by ultrasonography
related to short peripheral catheter failure?
Journal of Infusion Nursing. 2017; 40(5): 313322.
Murayama R, Uchida M, Oe M, Takahashi T,
Oya M, Komiyama C, Sanada H. Removal of
peripheral intravenous catheters due to catheter
failures among adult patients. Journal of Infusion
Nursing. 2017; 40(4): 224-231.
Oya M, Murayama R, Oe M, Yabunaka K,
Tanabe H, Takahashi T, Matsui Y, Otomo E,
Komiyama C, Sanada H. Continuous thermographic observation may predict extravasation inchemotherapy-treated patients. European Journalof Oncology Nursing. 2017; 28: 56-61.
Shiraishi M, Haruna M, Matsuzaki M, Murayama
R, Sasaki S. Availability of two self-administered
diet history questionnaires for pregnant Japanesewomen: A validation study using 24-hour urinary
markers, Journal of Epidemiology. 2017; 27(4):172-179.

425

Department of Health Services
Research
Project Associate Professor
Taisuke Jo, M.D.,Ph.D.

Project Assistant Professor
Nobuaki Michihata, M.D., MPH.

Homepage http://webpark1902.sakura.ne.jp/wp/
Introduction and Organization
The Department of Health Services research (HSR),
a Social Cooperation Program, was founded byProfessor Hideo Yasunaga, Department of Clinical
Epidemiology & Health Economics with the supportof Professor Takahide Nagase, Department ofRespiratory Medicine in April 2016. The program wasfunded by Tsumura & Co., Tokyo, Japan.
The objective of the Department of HSR was toconvey and develop HSR, which encompasses clinicalmedicine, clinical epidemiology and health economics,
to pursue maintenance of health services particularlyin the aging society in Japan. Education and trainingof personnel to cultivate human resources such as
researchers and analysts in HSR is another importantmission of this program.
The founding staffs were Taisuke Jo (Project
Associate Professor), Nobuaki Michihata (Project
Assistant Professor) and Yusuke Sasabuchi (Project
Assistant Professor). Staffs in the year 2017 were
Taisuke Jo and Nobuaki MIchihata.

Teaching activities
All the members of HSR participated in the lecturesof Clinical Epidemiology, a curriculum of School of
Public Health (SPH) in The University of Tokyo. The
members also contributed to the education andtraining of individual students of SPH as well as
students of Graduate School of Medicine, The
University of Tokyo.

Taisuke Jo (Project Associate Professor)
participated in the series of clinical lectures in
Respiratory Medicine for students of Faculty of
Medicine, The University of Tokyo.

Research activities
Health Services Research covers a broadcross-disciplinary field involving studies of structures,processes and outcomes assessment in clinicalepidemiology and health services, studies evaluating
quality of health care and analysis of heath economics,
finance and allocation of medical resources. Utilizing
large databases, the members of HSR were working toaddress the following issue.
1) Clinical and epidemiological research questions related to various disease, including respiratory disease.
2) Outcomes and cost effectiveness in both western
medicine and eastern medicine in Japan.
3) Impact of super aging society on population
dynamics and demand of health services.
4) Efficient distribution of medical staffs, medical
institutions and armamentarium.
The followings are the examples of studies
conducted in 2017.
1) Development of a nomogram for predicting inhospital mortality of patients with exacerbation ofchronic obstructive pulmonary disease.
Patients with chronic obstructive pulmonary disease(COPD) often experience exacerbations of theirdisease, sometimes requiring hospital admission and426

being associated with increased mortality. Althoughprevious studies have reported mortality fromexacerbations of COPD, there is limited information
about prediction of individual in-hospital mortality.
We therefore aimed to use data from a nationwide
inpatient database in Japan to generate a nomogramfor predicting in-hospital mortality from patients'characteristics on admission.
We retrospectively collected data on patients with
COPD who had been admitted for exacerbations andbeen discharged between July 1, 2010 and March 31,
2013. We performed multivariable logistic regression
analysis to examine factors associated with in-hospitalmortality and thereafter used these factors to develop
a nomogram for predicting in-hospital prognosis.
The study comprised 3,064 eligible patients.
In-hospital death occurred in 209 patients (6.8%).
Higher mortality was associated with older age, being
male, lower body mass index, disturbance of
consciousness, severe dyspnea, history of mechanicalventilation, pneumonia, and having no asthma on
admission. We developed a nomogram based on thesevariables to predict in-hospital mortality. The
concordance index of the nomogram was 0.775.
Internal validation was performed by a bootstrap
method with 50 resamples, and calibration plots were
found to be well fitted to predict in-hospital mortality.
We developed a nomogram for predicting
in-hospital mortality of exacerbations of COPD. This
nomogram could help clinicians to predict risk of
in-hospital mortality in individual patients with COPD
exacerbation.
2) Prognostic nomogram for inpatients with asthma
exacerbation
Asthma exacerbation may require a visit to theemergency room as well as hospitalization and canoccasionally be fatal. However, there is limited
information about the prognostic factors for asthma
exacerbation requiring hospitalization, and nomethods are available to predict an inpatient's
prognosis. We investigated the clinical features andfactors affecting in-hospital mortality of patients withasthma exacerbation and generated a nomogram topredict in-hospital death using a national inpatient
database in Japan.
We retrospectively collected data concerning
hospitalization of adult patients with asthma

exacerbation between July 2010 and March 2013using the Japanese Diagnosis Procedure Combination
database. We recorded patient characteristics andperformed Cox proportional hazards regression
analysis to assess the factors associated with all-cause
in-hospital mortality. Then, we constructed anomogram to predict in-hospital death.
A total of 19,684 patients with asthma exacerbation
were identified; their mean age was 58.8 years(standard deviation, 19.7 years) and median length of
hospital stay was 8 days (interquartile range, 5-12days). Among study patients, 118 died in the hospital(0.6%). Factors associated with higher in-hospitalmortality included older age, male sex, reduced levelof consciousness, pneumonia, and heart failure. A
nomogram was generated to predict the in-hospital
death based on the existence of seven variables atadmission. The nomogram allowed us to estimate theprobability of in-hospital death, and the calibration
plot based on these results was well fitted to predict
the in-hospital prognosis.
Our nomogram allows physicians to predict
individual risk of in-hospital death in patients withasthma exacerbation.
3) Adjuvant chemotherapy versus chemoradiotherapy
for small cell lung cancer with lymph node metastasis:a retrospective observational study with use of anational database in JapanThe optimal postoperative treatment strategy forsmall cell lung cancer (SCLC) remains unclear,especially in patients with lymph node metastasis. We
aimed to compare the outcomes of patients with SCLC
and lymph node metastasis treated with postoperative
adjuvant chemotherapy or chemoradiotherapy.
We retrospectively collected data on patients withpostoperative SCLC diagnosed with N1 and N2 lymph
node metastasis from the Diagnosis Procedure
Combination database in Japan, between July 2010
and March 2015. We extracted data on patient age, sex,
comorbidities, and TNM classification at lungsurgery; operative procedures, chemotherapy drugs,
and radiotherapy during hospitalization; and discharge
status. Recurrence-free survival was compared
between the chemotherapy and chemoradiotherapy
groups using multivariable Cox regression analysis.
Median recurrence-free survival was 1146 days
(95% confidence interval [CI], 885-1407) in the427

chemotherapy group (n = 489) and 873 days (95% CI,
464-1282) in the chemoradiotherapy group (n = 75).
There was no significant difference between theseafter adjusting for patient backgrounds (hazard ratio,
1.29; 95% CI, 0.91-1.84).
There was no significant difference inrecurrence-free survival between patients with SCLC
and N1-2 lymph node metastasis treated withpostoperative adjuvant chemotherapy and chemoradiotherapy. Further randomized clinical trials areneeded to address this issue.
The members of HSR are further mounting an effort
to accomplish the task in cooperation with the Department of Clinical Epidemiology & Health Economics
and the Department of Respiratory Medicine.

References
1. Okubo Y, Michihata N, Uda K, Morisaki N,
Miyairi I, Matsui H, Fushimi K, Yasunaga H.
Dose-response relationship between weight status
and clinical outcomes in pediatric influenzarelated respiratory infections. Pediatr Pulmonol.
2018;53(2):218-23.
2. Okubo Y, Michihata N, Morisaki N, Uda K,
Miyairi I, Ogawa Y, Matsui H, Fushimi K,
Yasunaga H. Recent trends in practice patterns
and impact of corticosteroid use on pediatricMycoplasma pneumoniae-related respiratory
infections. Respir Investig. 2018;56(2):158-65.
3. Okubo Y, Michihata N, Morisaki N, Kinoshita N,
Miyairi I, Urayama KY, Yasunaga H. Recent
patterns in antibiotic use for children with group A
streptococcal infections in Japan. J Glob
Antimicrob Resist. 2018;13:55-9.
4. Okubo Y, Michihata N, Morisaki N, Hangai M,
Matsui H, Fushimi K, Yasunaga H. Recent trends
in practice patterns and comparisons between
immunoglobulin and corticosteroid in pediatricimmune thrombocytopenia. Int J Hematol. 2018;
107(1):75-82.
5. Koizumi C, Michihata N, Matsui H, Fushimi K,
Yasunaga H. In-Hospital Mortality for Hepatic
Portal Venous Gas: Analysis of 1590 Patients
Using a Japanese National Inpatient Database.
World J Surg. 2018;42(3):816-22.
6. Hiyama N, Sasabuchi Y, Jo T, Hirata T, Osuga Y,

Nakajima J, Yasunaga H. The three peaks in age
distribution of females with pneumothorax: anationwide database study in Japan. Eur J
Cardiothorac Surg. 2018.
7. Urushiyama H, Jo T, Yasunaga H, Yamauchi Y,
Matsui H, Hasegawa W, Takeshima H, Hiraishi Y,
Mitani A, Fushimi K, Nagase T. Adjuvant chemotherapy versus chemoradiotherapy for small celllung cancer with lymph node metastasis: aretrospective observational study with use of anational database in Japan. BMC Cancer. 2017;17(1):613.
8. Sakamoto Y, Yamauchi Y, Yasunaga H, Takeshima
H, Hasegawa W, Jo T, Sasabuchi Y, Matsui H,
Fushimi K, Nagase T. Development of anomogram for predicting in-hospital mortality ofpatients with exacerbation of chronic obstructive
pulmonary disease. Int J Chron Obstruct Pulmon
Dis. 2017;12:1605-11.
9. Ono S, Ono Y, Michihata N, Sasabuchi Y,
Yasunaga H. Effect of Pokemon GO on incidenceof fatal traffic injuries: a population-based
quasi-experimental study using the national trafficcollisions database in Japan. Inj Prev. 2017.
10. Okubo Y, Michihata N, Yoshida K, Morisaki N,
Matsui H, Fushimi K, Yasunaga H. Impact ofpediatric obesity on acute asthma exacerbation in
Japan. Pediatr Allergy Immunol. 2017;28(8):763-7.
11. Matsui H, Jo T, Fushimi K, Yasunaga H.
Outcomes after early and delayed rehabilitationfor exacerbation of chronic obstructive pulmonary
disease: a nationwide retrospective cohort study inJapan. Respir Res. 2017;18(1):68.
12. Jo T, Yasunaga H, Sasabuchi Y, Michihata N,
Morita K, Yamauchi Y, Hasegawa W, Takeshima
H, Sakamoto Y, Matsui H, Fushimi K, Nagase T.
Association between dementia and discharge
status in patients hospitalized with pneumonia.
BMC Pulm Med. 2017;17(1):128.
13. Hasegawa W, Yamauchi Y, Yasunaga H,
Takeshima H, Sakamoto Y, Jo T, Sasabuchi Y,
Matsui H, Fushimi K, Nagase T. Prognostic
nomogram for inpatients with asthma exacerbation. BMC Pulm Med. 2017;17(1):108.2016;
58(11):1171-5.

428

Department of Skincare Science
Project Associate Professor
Takeo Minematsu, Ph.D.

Project Lecturer
Nao Tamai, Ph.D., R.N.

Homepage

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

Introduction and Organization

Research activities

The Department of Skincare Science was establishedin the Graduate School of Medicine with funding from
Saraya Co., Ltd. on February 1st, 2017. We try todevelop new nursing technologies to evaluate andimprove the physiological conditions of vulnerable
skin due to aging and diseases.
The department is currently headed by one Project
Associate Professor and assisted by one ProjectLecturer.

1. Activity policy
The skin is a unique organ which we can directly see
and touch. Because several sensory systems are
distributed in the skin, skin disorders have unique
physical and mental influences. Healthy skin is,therefore, a foundation of a healthy life. The
Department of Skincare Science was founded toestablish skincare for people with vulnerable skin due
to aging and dermopathy.
Our project associate professor was also in chargeof the Department of Biological Nursing, Division ofCare Innovation, Global Nursing Research Center, andworked to establish and spread methodologies to study
the biological properties of nursing problems.
We delivered lectures about analytical thinking
processes and physiological/molecular biology
techniques for many nursing researchers and clinicalnurses in the bioengineering nursing research seminarorganized by Global Nursing Research Center on July
2017. We furthermore organized an advanced
hands-on seminar of bioengineering nursing researchmethodologies on February 2018.

Teaching activities
In FY 2017, we provided the following lectures forundergraduates, master course students, or Ph.D.
course students:a) Introduction of Nursing Science (A in 1st/2nd yr)b) Gerontological Nursing in Gerontological Nursing(A2 in 3rd yr/ S1 in 4th yr)c) Clinical Practice (S2 in 4th yr)d) Gerontological Nursing I (S1)e) Wound Care Management I (S2)
We advised graduate course students belonging to
the Department of Gerontological Nursing/Wound
Care Management on matters concerning researchplanning and practice work.
The following were master’s research themes in2017:“Prediction of healing in Category I pressure ulcers byskin blotting with a lymphangiogenesis marker,
vascular endothelial growth factor C: A pilot study.”

2. Research themes in 2017
Since February 2017, we have worked with Saraya
Co., Ltd., to develop new nursing technologies using
wound blotting, with a goal of incorporating woundblotting into practical use in 2018. In furtherance of
this effort, we have also contributed to the 2020 Tokyo
Paralympic Games through pressure ulcer care forwheelchair athletes.

429

 Development of non-invasive skin assessment
methods using skin blotting
Evaluation of skin barrier functions
Detection of tinea pedis
Detection of dehydration
 Development and practical realization of woundassessment methods using wound blotting
Prediction of pressure ulcer healing
Detection of wound biofilm
 Scalp care science
Early detection and prevention of male patternalopecia
Changes of physiology on the scalp duringchemotherapy
Effects of medical wigs during chemotherapy
 Pressure ulcer care in wheelchair athletesSurvey of pressure ulcers
 Skin regenerative medicine
Survey of pressure ulcers
 Development of scaffold materials to regenerate
ultrastructure of epidermis
Regarding international activities, our department
has been promoting collaborative research about
improving the prediction and prevention of skin tears
with researchers in Curtin University (Australia).
In addition, our research was recognized in the formof several awards, as follows: Article award from Japanese Society of Wound,
Ostomy, and Continence Management in 2017.
Hori N, Tamai N, Noguchi H, Nakagami G,
Sugama J, Mori T, Sanada H．Development andassessment of air mattress with independent air cellpressure control responsive to interface pressure
distribution. Journal of Japanese Society of Wound,
Ostomy, and Continence Management. 2016;20(3):300-9.
 Best Presentation Award．21st East Asian Forum of
Nursing Scholars & 11th International Nursing
Conferences
Sari WD, Minematsu T, Yoshida M, Sanada H．
Skin blotting as a measure of albumin and nerve
growth factor β can predict presence pruritus
among elderly population. Seoul (Korea), 2018/1/
11-12.

References
1. Uehata Y, Yoshida M, Yabunaka K, Minematsu T,
Tamai N, Sugama J, Sanada H. Relationship ofskin hardness of the temporal region to nutritional
status. Journal of Nursing Science andEngineering. 2017;4(1):49-57.
2. Nakagami G, Schultz G, Gibson DJ, Phillips P,
Kitamura A, Minematsu T, Miyagaki T, Hayashi A,
Sasaki S, Sugama J, Sanada H. Biofilm detection
by wound blotting can predict slough development in pressure ulcers: a retrospective observational study. Wound Repair and Regeneration.
2017;25(1):131-8.
3. Tamai N, Minematsu T, Tsunokuni S, Aso K,
Higashimura S, Nakagami G, Sanada H. Detectionof albumin using skin blotting as a measure ofskin barrier function. Journal of Nursing Scienceand Engineering. 2017;4(2):116-20.
4. Nozawa K, Tamai N, Minemtsu T, Kitamura A,
Saegusa M, Amaike K, Sanada H. Situation of
occurrence and morphological characteristics ofpressure ulcers among inpatients with mental
illness. Journal of Japanese Society of Wound,
Ostomy, and Continence Management. 2017;21(1):10-24.
5. Minematsu T, Nakagami G, Mugita Y, Tamai N,
Sanada H. Development of a distribution analysis
method for metalloproteinase activity by
combining wound blotting and zymography
techniques ： A pilot study in mice. Journal of
Nursing Science and Engineering. 2018;5(1):58-64.
6. Takahashi T, Murayama R, Tanabe H, Tamai N,
Yabunaka K, Sanada H. Observational study at thetime of peripheral venous catheter placement
using the ultrasonography and qualitativesketching method. Journal of Nursing Science andEngineering. 2018;5(1):2-11.

430

Department of
Imaging nursing Science
Project Associate Professor
Koichi Yabunaka, Ph,D

Project Lecturer
Mikako Yoshida, Ph.D

Project Assistant Professor
Masaru Matsumoto, Ph.D.

Collaborative Researcher
Mayumi Handa, Mikihiko Karube

Homepage

http://www.imagingnursing.m.u-tokyo.ac.jp/index.html

Organization history and overview
The Imaging Nursing department was founded aspart of the Corporate Sponsored Research Programs
offered by the Graduate School of Medicine, The
University of Tokyo in April 2017 aiming to realize “asafe, secure and comfortable life for patients receivingcare”. The department seeks to conduct translational
research through surveys on the actual nursing carecondition that are based on imaging technology,
proposing nursing techniques, and the evaluation, withthe goal of developing care systems and applying it toclinical settings.
Specific plans include developing (1)an ultrasoundtechnology support system for nursing care; (2)aremote support system using imaging technology toassist medical care, and (3)development of innovativetechnologies using new imaging techniques innursing.
This Corporate Sponsored Research Program
established with cooperation of Fujifilm and with the
Department of Gerontological Nursing / Wound CareManagement as partner departments aiming to findsolutions to these challenges and to further the
progress in nursing technologies. It aspires to establish
imaging nursing technologies in clinical nursing

settings in Japan, a forerunner in shifting towards a
globally unprecedented super-aging society and to be
the first transmitters of new discoveries to the world.
Department members are Specially Appointed
Associate Professor Koichi Yabunaka, Specially
Appointed Lecturer Mikako Yoshida, Specially
Appointed Assistant Professor Masaru Matsumoto,and Joint Researchers Mayumi Handa and Mikihiko
Karube (Fujifilm). Associate Professor concurrently
served as a visualized nursing field of division of careinnovation in Medical Graduate School of Global
Nursing Research Center and is striving to establish
and disseminate imaging nursing skills in nursing
research.

Education
We instructed and cooperated with graduate
students of the Department of Gerontological Nursing/ Wound Care Management about their research plans
through seminars and practical training.
We taught some of the undergraduate and graduate
lectures with Department of Gerontological Nursing /Wound Care Management （Master’s course in Wound
Care Nursing I, practical training in Health Sciences）.
The master’s thesis in the academic year 2017 is as431

follows: (1 title)“ Fecal distribution changes using colorectal
ultrasonography in elderly patients with physical andcognitive impairment at long-term care facilities: A
longitudinal observational study.”
As external lectures and workshops to increaseawareness, we have held lectures on skin andelimination care at levels equivalent to curricula for
Certified Nurses in Wound, Ostomy and Continence
Nursing at the Fukuoka Nursing Association, Nurse
Training Center of the Kyoto Tachibana University
and Shizuoka Cancer Center. We have also held
lectures of levels equivalent to curricula for Certified
Nurses in the Nursing Training School of the JapaneseNursing Association. We also offered a lecture as partof the University of Nottingham summer program.
At the seminar on nursing science and engineeringsponsored by the Global Nursing Research Center, we
lectured imaging nursing skills to many nursing
researchers and clinical nurses. In addition, we gavehands-on training on ultrasound technology useful for
nursing to those who want hands-on seminar among
participants in this introductory seminar.

Research
This course seeks to develop nursing assessment skills
using ultrasonography techniques and promoteresearch in imaging nursing that directly contributes toclinical settings. To this end, we are developing a
versatile portable ultrasound device that is ultralightweight, produces high image quality and operates onwide range of frequencies. Furthermore, a nursing
assessment coaching software is developed by imaging analysis to support assessment by nurses that does
not require special techniques.
Specifically, we have conducted research anddevelopment on the following topics in our Japan
Agency for Medical Research and Developmentfunded study titled, “Constructing a multidisciplinary
system implementing advanced nursing techniques tosupport eating and defecating in patients receiving
home and facility care.”1) Development and assessment of home/long-termcare facility multidisciplinary system to support
eating and swallowing2) Development and assessment of home/long-termcare facility multidisciplinary system to support
bowel elimination
In addition, we have developed software to support
autonomy in urinary elimination using ultrasounddevices and also have assessed deep tissue injury(unstageable bedsores) with ultrasound devices.
Furthermore, we have organized ultrasound seminars
for nurses with the cooperation of the graduate school
to provide the knowledge and techniques required for
conducting a research.
Of these research activities, we have received awards
on the following subjects.
・Honorable mention award at the 5th Annual Meetingof Nursing Science and Engineering（October 2017）;“Sleep evaluations for 24h and monitoring of vital
signs in a bedridden elderly patient with disorder ofconsciousness”
・Honorable mention award at the 5th Annual Meetingof Nursing Science and Engineering（October 2017）;“New quantitative indicators of evaluating the skincare regimen for older adults with dry skin by using
the digital image analysis”
・ Best Research Award from 26th Conference ofJapanese Society of Wound, Ostomy, and ContinenceManagement (June 2017); “Characteristics ofsubcutaneous tissue of peripheral injection puncturesite in paclitaxel / carboplatin therapy.”

References
1. Yabunaka K, Matsumoto M, Yoshida M, Tanaka S,
Miura Y, Tsutaoka T, H, a M, Nakagami G,
Sugama J, Sanada H. Assessment of rectal feces
storage condition by a point-of-care pocket-size
ultrasound device for healthy adult subjects: apreliminary study. Drug Discoveries andTherapeutics. 12(1): 42-46,2018.
2. Miura Y, Nakagami G, Yabunaka K, Tohara H,
Noguchi H, Mori T, Sanada H. A Randomized
Controlled Trial to Investigate the Effectivenessof the Prevention of Aspiration Pneumonia Using
Recommendations for Swallowing Care Guided
by Ultrasound Examination. Healthcare. 6(1), 15,2018.
3. Komagata K, Yabunaka K, Nakagami G, Ikeda M,
Takehara K, Takemura Y, Sanada H. Confirming
the placement of nasogastric tubes by hand-

432

carried ultrasonography device. Journal of
Nursing Science and Engineering. 5 (1): 52-57,
2018.
4. Matsumoto M, Ogai K, Aoki M, Urai T,
Yokogawa M, Tawara M, Kobayashi M,
Minematsu T, Sanada H, Sugama J. Changes indermal structure and skin oxidative stress inoverweight and obese Japanese males after weight
loss: a longitudinal observation study. Skin
Research and Technology. 24(3):407-416, 2018.
5. Matsumoto M, Ogai K, Ohashi R, Tanaka K, Aoki
M, Kobayashi M, Sugama J. Influences ofdifferent methods of cleaning agent removal on
the effectiveness of skin dirt removal. Journal of
Nursing Science and Engineering. 5(1):22-30,
2018.
6. Ogai K, Matsumoto M, Dai M, Aoki M,
Kobayashi M, Maeba H, Uchide K, Sugama J.
Comparative study on high-frequency ultrasonography and histological structure of the skin:
Relationship between collagen/elastin content andechogenicity, Journal of Nursing Science andEngineering. 5(1):65-73, 2018.
7. Ogai K, Matsumoto M, Aoki M, Ota R,
Hashimoto K, Wada R, Kobayashi M, Sugama J.
Wash or wipe? A comparative study of skinphysiological changes between water washing andwiping after skin cleaning. Skin Res Technol.
23(4):519-524, 2017.
8. Takahashi T, Murayama R, Oe M, Nakagami G,
Tanabe H, Yabunaka K, Arai R, Komiyama C,
Uchida M, Sanada H. Is thrombus with
subcutaneous edema detected by ultrasonography
related to short peripheral catheter failure? aprospective observational study. J Infus Nurs.
40(5):313-322, 2017.
9. Iuchi T, Kobayashi M, Tsuchiya S, Ohno N, Dai
M, Matsumoto M, Ogai K, Sato A, Sawazaki T,
Miyati T, Tanaka S, Sugama J. Objective assessment of leg edema using ultrasonography with agel pad. PLoS One. 2017 Aug 9;12(8):e0182042.
10. Yatake H, Sawai Y, Nishi T, Nakano Y, Nishimae
A, Katsuda T, Yabunaka K, Takeda Y, Inaji H.
Accuracy assessment methods of tissue marker
clip placement after 11-gauge vacuum-assisted
stereotactic breast biopsy: comparison of
measurements using direct and conventional

methods. Breast Cancer. 24(4): 593-600, 2017.
11. Yoshida M, Igawa Y, Higashimura S, Suzuki M,
Niimi A, Sanada H. Translation and reliability andvalidity testing of a Japanese version of theIntermittent Self-Catheterization Questionnaire
among disposable and reusable catheter users.
Neurourol Urodyn. 36(5):1356-1362, 2017.
12. Uehata Y, Yoshida M, Yabunaka K, Minematsu T,
Sugama J, Sanada H. Relationship of skinhardness of the temporal region to nutritional
status. Journal of Nursing Science Engineering.
4(1): 49-57, 2017.

433

Department of Innovative
Dementia Prevention
Project Associate Professor
Tadafumi Hashimoto, Ph.D.

Project Assistant Professor
Ryoko Ihara, M.D., Ph.D.

Homepage

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

Department of Innovative Dementia Prevention was
launched on July 2017, through the financial supportof Kobayashi Pharmaceuticals, with assistance by the
Department of Neuropathology. Two faculty staffs,
Tadafumi Hashimoto as the Project Associate
Professor and Ryoko Ihara as the Project AssistantProfessor started the research projects, with Dr.
Daisuke Izawa of Kobayashi as a collaborative
researcher.
The aged society in Japan urges us to challenge thedementing disorders including Alzheimer’s disease(AD), although there has emerged no effective
therapeutic strategies against AD based on its
pathomechanism. Our laboratory will conduct basic
research on the molecular mechanism of dementia anddevelopment of clinical measures for evaluation ofefficacies of the therapeutic drugs in parallel, aiming
at identifying the novel targets for prevention andearly treatment of dementia and establish methods toprevent or delay the progression of dementia by drugs
and functional foods. We also will be actively
involved in the education and outreach activities ofbasic and clinical research on AD and dementia.

Education
In 2017, Department of Innovative Dementia
Prevention was involved in the education throughresearch activities of two doctor course graduate
students of the Graduate School of Medicine, one
master course graduate student of the School of

Pharmaceutical Sciences, as well as one medical
student belonging to the Medical Scientist Training
Program. In addition, one master course graduate
student of the Graduate School of Engineering
underwent research training as an activity of Graduate
Program for Leaders in Life Innovation (GPLLI). RI
has given a lecture on “clinical studies on AD” tostudents and residents belonging to the Program for
Clinical Researcher Training.

Research
Department of Innovative Dementia Prevention isconducting research in the following four directions,based on the amyloid hypothesis of AD, toward thegoal of developing strategies for prevention ofdementia and AD.
① Molecular mechanism of A dynamics in thebrain
Amyloid  peptide (A), a causative protein for AD,
is produced from Aprecursor protein (APP) throughtwo-step proteolysis by - and -secretases, and thensecreted into the extracellular space. Once released
outside the neurons, A is readily cleared by proteolytic degradation or transported outside the brains.
However, A that escaped from the clearance starts toaggregate and deposit forming amyloid fibrils. Thus,
the elucidation of the A dynamics in the brain, comprised of the elementary processes of “production”,“secretion”, “aggregation” and “deposition”, is vital tothe clarification of the pathogenic mechanism of AD434

as well as development of therapeutic and prevention
strategies against AD. However, to quantitatively
analyze each of the process, there is a compelling needfor accurate quantitation of A that is present at
picomolar levels in brains.
We have adopted the microdialysis technique using
dialysis membrane of ~1000 kDa cut-off that enables
the recovery of brain interstitial fluids andquantitation of the levels, rates of production andclearance of A in the hippocampus and other parts ofthe brains (Yamamoto K, et al., Cell Rep., 2015). In
combination with the in vivo seeding experiments
injecting aggregation seeds for A and evaluate thefollowing A deposition (Hori Y, et al., J. Biol. Chem.,2015), we have identified a >200 kDa high molecularweight A oligomer species in the soluble fractions ofbrains of APP transgenic mice (Hashimoto T, Soc for
Neuroscience meeting 2017). We will further identify
A species that are involved in the A dynamics in thebrain, including those specifically involved indeposition or toxicity of A.
② Elucidation of the role of apolipoprotein E (apoE)in the pathogenesis of AD, and development ofmethod of AD prevention targeting apoE
Apolipoprotein E (apoE) is produced by astrocytes
and comprises the major lipoprotein in the central
nervous system. Human APOE gene has three genetic
polymorphisms (2, 3, 4), resulting in the production of three protein isoforms (apoE2, apoE3, apoE4)
harboring different amino acids at two critical residues
at positions 112 and 158. The allele frequency of
ApoE4 allele is ~8-10% in normal population,
whereas it is elevated to >30-40% in AD. Thus,
ApoE4 is a strong genetic risk factor of AD, although
the mechanism whereby ApoE4 accelerates AD
pathophysiology has remained elusive, without any
effective therapeutic strategies targeting apoE.
We have created a series of bigenic mice bycrossing knock-in (KI) mice expressing human apoE2,
E3 or E4 with APP transgenic mice, and we are
currently trying to examine how each human isoform
of apoE influences on A dynamics in the brain. This
will lead us to the intervention into the effect of apoE
isoforms on Ab, toward the goal of AD prevention. In
2017, we have found a significant decrease in Adeposition in the brains of human apoE3 KI/APPtransgenic mice. We also found that the Ab levels in
the interstitial fluids of human apoE3 KI/APPtransgenic mice are similar to those in APP transgenic
mice by in vivo microdialysis method. We also haveestablished a method to monitor the interaction
between A and apoE using a bi-molecular complementation assay. We will use this unique assay system
to identify small molecule drugs that modulate theinteraction of apoE and A.
③ Establishment of a novel AD model using threedimensional culture system for the developmentof prevention methods targeting brain A
metabolism.
To overcome the lack of experimental paradigms
for the evaluation of aggregation and deposition invitro, we adopted 3-dimensional culture system using
Matrigel for the neuronal differentiation of human
ReNcell-VM neuronal precursor cells, to observe theprocess of A deposition and A-dependent neurotoxicity reminiscent to that in AD brains. We will use
this system for the development of anti-dementia
drugs targeting A production and deposition.
④ Clinical studies on the clinical and cognitive
measures in the early stages of AD.
We have set out to the systematic analysis of theclinical data on the natural course of the early stage fo
AD derived from Japanese Alzheimer’s Disease
Neuroimaging Initiative (J-ADNI), with a special
focus on the preclinical AD stage, where elderly
individuals are clinically and cognitively normal but
positive for amyloid biomarkers. We have found that
preclinical AD individuals lack learning effects in the
cognitive tests, e.g., MMSE and logical memory,
presumably representing subtle cognitive deficits. We
also aim at international harmonization and compareson of the evaluation of cognitive decline, using
US-ADNI database and other international datasets.

Publications
1. Mano T, Nagata K, Nonaka T, Tarutani A,
Imamura T, Hashimoto T, Bannai T, Koshi-Mano
K, Tsuchida T, Ohtomo R, Takahashi-Fujigasaki J,
Yamashita S, Ohyagi Y, Yamasaki R, Tsuji S,
Tamaoka A, Ikeuchi T, Saido TC, Iwatsubo T,435

Ushijima T, Murayama S, Hasegawa M, Iwata A.
Neuron-specific methylome analysis reveals
epigenetic regulation and tau-related dysfunctionof BRCA1 in Alzheimer’s disease. Proc Natl Acad
Sci U S A. 2017 Nov 7;114(45):E9645-E9654.
2. Arbel-Ornath M, Hudry E, Boivin JR, Hashimoto
T, Takeda S, Kuchibhotla, KV, Hou S, Lattarulo
CR, Belcher AM, Shakerdge M, Trujillo PB,
Muzikansky A, Betensky RA, Hyman BT, Bacskai,
BJ. Soluble oligomeric amyloid- induces
calcium dyshomeostasis that precedes synapse
loss in the living mouse brain. Mol Neurodegen.
2017 Mar 21;12(1):27.
3. Ihara R. Current clinical assessment scales andcognitive tests in global clinical studies on
Alzheimer’s disease. Brain Nerve. 2017 Jul;69(7):781-787.
4. Shimada H, Shoji M, Ikeuchi T, Suzuki K, Senda
M, Ishii K, Matsuda H, Iwata A, Ihara R,
Iwatsubo T, Mutoh K, Nakazawa E, Sekijima Y,
Mori E, Ikeda M, Ikeda M, Kawakatsu S,
Nakanishi A, Hashimoto M, Nunomura A,
Matsubara E, Fukui M, Shirato T, Hirai K,
Sakamoto M, Fujii H, Mori H. DIAN/DIAN-J/
DIAN-TU. Brain Nerve. 2017 Ful;69(7):701-709.

Social Cooperation Program(22nd Century Medical and Research Center)437

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 development of
a novel integration system in which pieces of patients’
healthcare information are virtually combined andstored 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 achieved bythese innovative systems.

Research activities
 DialBetics: A novel smartphone-based selfmanagement support system for type 2 diabetes
patients
Patients with diabetes are expected to have access tothe integral components of diabetes care. Selfmanagement is the core of diabetes treatment because
it ties the components of diabetes therapy together,enabling patients to assess and control the interplay ofnutrition, physical activity, emotional/physical stress,and medications that are critical with diabetes. There
had long been a need for an effective self-management
tool that could automate and standardize much of thecounseling process, facilitating self-monitoring ofblood glucose, blood pressure, body weight andlifestyle, and particularly diet and exercise. Accordingly, we developed just such a real-time, partiallyautomated interactive system to interpret patients’
data—biological information, exercise, and dietcontent calculated from a message sent by patients—
and respond with appropriate actionable findings,
helping the patients achieve diabetes self-management.
In addition, the safety and clinical effectiveness of thesystem had to be examined. A one-month, non-blinded,
non-randomized uncontrolled study was conducted; itdemonstrated that DialBetics was a feasible andeffective tool for type 2 diabetes patients who also
received insulin therapy. We conducted a 3-monthclinical trial for type 2 diabetes patients using
DialBetics in Pavia, Italy. The effectiveness of thissystem was also confirmed in Italy. In our latest study,
we conducted a questionnaire survey that adopts AI
technology as a function of DialBetics for diabetic
patients.
 GlucoNote: Self-management and recording
application for the type 2 diabetes and diabetes
spare group
We started a clinical study using smartphone
application with ResearchKit by Apple Inc. that iscalled "GlucoNote" for type 2 diabetes patients anddiabetes spare group. This application continuously
collects home vital data such as blood glucose level,
blood pressure, weight, active mass, and also lifestyledata ― dietary intake, exercise and sleep. Total 522
patients signed up for the study during one year. It was438

indicated that patients who continue to measurethemselves―self-management― resulting in weightdecrease.
 HearTily: Self-management and recording application for arrhythmia
To investigate the association between arrhythmia andlifestyle, we developed the smartphone application"Heartily" for arrhythmic self-management again using
Apple’s ResearchKit by Apple Inc. About 15,000
participants used Heartily after the application was
released, and a new arrhythmia people were detected in
1.9% of them.
 Multi-institutional joint prospective study onarrhythmia detection efficiency by wearable heart
rate monitor
Cardiogenic cerebral infarction has a poor prognosis inthat it leaves big sequelae, and its early detection isimportant. In order to investigate whether it is possible
to capture pulse irregularities simply and conveniently,
we planned research to monitor long-term heart rateusing a wearable heart rate monitor that is on themarket. We conducted clinical research for 100
workers who are at risk of developing cerebral
infarction if they have atrial fibrillation, such as highblood pressure, diabetes, cerebral infarction, heart
failure etc. New atrial fibrillation were confirmed in
two participants. It was suggested that atrial fibrillation
can be detected by long-term electrocardiogram
monitoring.
 Inspection of the correlation of blood sugar leveland expiration acetone measurements
To diagnose ketoacidosis under diabetes mellitus
require measurement of blood test and urinalysis. We
studied the correlation of expiration acetone levels
using portable expiration acetone measuring systemand blood acetone levels. We conducted the clinical
trial with 120 diabetic patients, and also investigatedthe variation of error within same participants.
A patent has been applied for.
 Sur vey of medication, health care and intent to use
personal health record in ethical pharmacy users.
This survey was to clarify whether medication
management requires PHR and what kind of items theusers are required for management of PHR. We
surveyed 3,717 people and got responses from 2,307
people. Results were presented at the 37th joint
conference on medical informatics.

 DialBeticsLite for health guidance object persons
Health guidance is a support program for object
persons of metabolic syndrome to improve theirlifestyle. We conducted a clinical trial to study theeffect of DialBeticsLite and differences from type 2
diabetes patients using DialBetics for health guidance
object persons in four companies. Notably, we(University of Tokyo hospital) make DialBeticsLite fit
for practical use in a company.
Future directions
To fulfill our mission, we plan to generalize thefindings made in the several clinical studies, andpromote ongoing and growing telemedicine service
with the use of ICT in the future.

Publications in English(Original article)
1. Fujiu K, Shibata M, Nakayama Y, Ogata F,
Matsumoto S, Noshita K, Iwami S, Nakae S,
Komuro I, Nagai R, Manabe I, A heart-brain-kidney
network controls adaptation to cardiac stress throughtissue macrophage activation and cellular communication, Nature Medicine, 2017, doi:10.1038/nm.
4326
2. Matsuda J, Fujiu K, Roh S, Tajima M, Maki H,
Kojima T, Ushiku T, Nawata K, Takeda N, Watanabe
M, Akazawa H, Komuro I. Cardiac sarcoidosis
diagnosed by incidental lymph node biopsy. Int
Heart J. 2017;58:140-143
3. Numata G, Amiya E, Kojima T, Fujiu K, Hatano M,
Watanabe M, Komuro I. Cardiac resynchronization
therapy in patients with ebstein&apos;s anomaly: acase report. Int Heart J, 2017
4. Nakayama Y, Fujiu K., Can Anti-inflammatory
Therapy Prevent Atrial Fibrillation in Myocardial
Infarction Patients?, Int Heart J. 2018;59(1):3-5.
5. Matsubara T, Fujiu K, Correlation between nutriational state and prognosis of heart failure, with afocus on the immune system, Int Heart J. 2018, in
press

439

6.

7.

8.

9.

Kojima T; Fujiu K, Fukuma N, Matsunaga H,
Oshima T; Matsuda J; Matsubara T; Shimizu Y;
Oguri G; Hasumi E; Morita H; Komuro I,
Periprocedural Complications in Patients Undergoing Catheter Ablation of Atrial Fibrillation
without Discontinuation of a Vitamin K Antagonist
and DOACs, Circ J, 2018, in press
Makimoto H, Shimizu K, Fujiu K, Lin T, Oshima T,
Amiya E, Yamagata K, Kojima T, Daimon M,
Nagatomo R, Waki K, Meyer C, Komuro I, Effect ofSympatholytic Therapy on Circadian Cardiac
Autonomic Activity in Non-diabetic Chronic Kidney
Disease, Int Heart J, in press
Iwazaki K, Kojima T, Murasawa T, Yokota J,
Tanimoto H, Hasumi E, Cho K, Fujiu K, Komuro I,
A case of a cardiac resynchronization therapydefibrillator exhibiting a lower and alternately
variable basic rate, Int Heart J, in press
Yonenaga A, Hasumi E, Fujiu K, Ushiku A, Hosoya
Y, Hatano M, Ando J, Morita H, Watanabe M,
Komuro I, Prognostic improvement of acute necrotizing eosinophilic myocarditis (ANEM) through arapid pathological diagnosis and appropriate therapy,
Int Heart J, in press.

440

Department of Healthcare Quality
Assessment
Project Professor
Hiroaki Miyata, Ph.D.

Project Associate Professor
Kan Nawata, M.D., Ph.D.

Project Lecturer
Hiraku Kumamaru, M.D., Sc.D.

Project Assistant Professor
Naoaki Ichihara, M.D., Ph.D., M.P.H.

Researcher
Hiroyuki Yamamoto, M.D., Ph.D., M.P.H.,
Eriko Fukuchi, M.S.,
Shun Kosaka, M.D., Ph.D.
Hiroki Nogawa, M.D., Ph.D.,
Hideki Endo, M.D.,

Clerical Staff
Chieko Fujimura

Clerical Staff (Secretary)
Takayo Nakamura

Homepage

http://hqa.umin.jp/

Introduction and Organization
The Department of Healthcare Quality Assessment(HQA) was established in 2006 and has been engaging
in research on healthcare quality improvement incollaboration with the Department of Cardiothoracic
Surgery in University of Tokyo.
The objective of providing healthcare is to provide
high quality healthcare services to all patients.
Institute of Medicine states that health care reform
should focus on improving the patients’ health as wellas health care values that they think are important.

In the 21st century, this viewpoint, together withinsight from health economics, has been the firstpriority in the field of medicine and healthcare.
“Quality improvement initiative,” therefore, needs toadjust the healthcare systems to accommodate thefee-for-service perspectives while improving theclinical environment for both patients and providers.

Research activities
Department of Healthcare Quality Assessment (HQA)
has been actively collaborating with healthcare

441

professionals and various clinical committees as theyplay key roles in the quality improvement initiatives
in the field. In such positive environment driven by
the patient-centered philosophy, the patients receive
more satisfying care, physicians are rewarded for their
excellence, and healthcare costs are sustained. To
accomplish this goal, there are 3 principles thatnavigate us through the journey: (a) the topmost value
should always be on that of patients, (b) all medical
practices should be organized around medical
conditions as well as the care cycles of the patients,and (c) the results---risk-adjusted outcomes andmedical costs spent---must be scientifically measured
and evaluated.
In April 2010, the Japan Society of Surgery and 10
related surgical societies founded the National
Clinical Database (NCD), which is an all-Japanendeavor that aims to build a large-scale,comprehensive clinical registry that utilize the “bigdata” to improve the quality of surgery as well as
surgical sciences in Japan. HQA has been playing
important academic roles in the project since its birth.
The actual data entry started from January 1st, 2011,
and since then NCD has been collecting approximately 95% of all surgical operations across Japan in
the collaboration with the clinical societies. NCD is
also connected with the participating societies’ boardof certification systems, which makes it unique among
other large-scale clinical registries in the world. Today
more than 5,200 hospitals and clinics are participatingin NCD with the accumulated data of 6.5 million cases(approximately 1.2 million each year).
HQA has developed risk models for different groupsof surgical procedures that help us implement several
practical tools aimed for medical professionals in the
joint research activity with Japan Cardiovascular
Surgery Database (JCVSD). One of those tools is
JapanSCORE, which allows a user to calculate apatient’s post-operative risk of mortality andmorbidities.
Another tool called RiskCalculator
returns a medical professional the calculated risk ofmortality and morbidity in a real-time manner afters/he inputs a minimum number of pre-operative risk
information. Both tools can be used in medical teammeetings as well as in sessions with patients to reachbetter informed consent. Just like JCVSD’s
JapanSCORE and RiskCalculator, feedback tools

based on the NCD data have been provided todifferent subspecialty areas. All of these activities
help Japan’s healthcare quality initiatives in various
places, and HQA is proud of being part of it.
HQA also has conducted evidence-based policy
analysis to help federal and local government todevelop better healthcare policy-making. It is anacademic activity that contributes in a different angle
to the endeavor of healthcare quality improvement
than those with healthcare professionals in the field,
described above. In 2012, HQA started participating
in a series of research to evaluate the validity ofJapan’s cancer control policy framework using various
stakeholders’ perspectives. Interview as well as
questionnaire studies were conducted in accordancewith the Basic Plan for Implementing Cancer Control
administered by the Japanese Government.
Clinical databases like NCD are the core componentsof quality improvement initiative in many health careservices such as in the field of thoracic surgery.
HQA supports NCD’s systematic data collection, data
management, practical analyses, and the developmentof useful feedback systems. Recently, non-surgicalfields such as clinical oncology are also joining NCD
and this trend becomes stronger. Our benchmarking
projects backed up by NCD’s big data will keep
driving the quality improvement activities in many
healthcare fields.
Increasing numbers of clinical research output has
been coming out of the detailed analyses on NCD datain the collaboration of each specialty field. Besideprofessional societies, pharmaceutical companies aswell as medical device firms are now start operating
their post-marketing surveillance databases in relation
with NCD. Working in between NCD, the firms,
PMDA (Pharmaceuticals and Medical Devices
Agency), and the related medical societies, HQA helps
the project moving forward by giving academic
support. Furthermore, HQA has been involved withinternational research collaboration such as American
College of Surgeon’s NSQIP and Asian Cardiac
Database while contributing to the quality
improvement activities in different regions of theworld.

442

References
1. Takahashi A, Kumamaru H, Tomotaki A,
Matsumura G, Fukuchi E, Hirata Y, Murakami A,
Hashimoto H, Ono M, Miyata H. Verification of
Data Accuracy in Japan Congenital Cardiovascular Surgery Database Including Its
Postprocedural Complication Reports. World J
Pediatr Congenit Heart Surg. 9(2):150-156 2018
Mar
2. Miyata H, Mori M, Kokudo N, Gotoh M, Konno
H, Wakabayashi G, Matsubara H, Watanabe T,
Ono M, Hashimoto H, Yamamoto H, Kumamaru
H, Kohsaka S, Iwanaka T. Association between
institutional procedural preference and in-hospitaloutcomes in laparoscopic surgeries; Insights froma retrospective cohort analysis of a nationwide
surgical database in Japan. PLoS One. 13(3) 2018
Mar 5
3. Kodera Y, Yoshida K, Kumamaru H, Kakeji Y,
Hiki N, Etoh T, Honda M, Miyata H, Yamashita Y,
Seto Y, Kitano S, Konno H. Introducing laparoscopic total gastrectomy for gastric cancer ingeneral practice: a retrospective cohort study
based on a nationwide registry database in Japan.
Gastric Cancer. [Epub ahead of print]2018 Feb 9.
4. Numasawa Y, Ueda I, Sawano M, Kuno T,
Kodaira M, Noma S, Suzuki M, Miyata H,
Fukuda K, Kohsaka S. Relation of Baseline
Hemoglobin Level to In-Hospital Outcomes inPatients Who Undergo Percutaneous Coronary
Intervention (from a Japanese Multicenter
Registry). Am J Cardiol. 121(6)695-702 2018 Mar
15.
5. Saito A, Hirahara N, Motomura N, Miyata H,
Takamoto S. Correction to: Current status ofcardiovascular surgery in Japan, 2013 and 2014: A
report based on the Japan Cardiovascular Surgery
database 3. Coronary artery bypass surgery. Gen
Thorac Cardiovasc Surg. 66(3):182-183. 2018
Mar
6. Miyairi T, Miyata H, Chiba K, Nishimaki H,
Ogawa Y, Motomura N, Takamoto S; Japan Adult
Cardiovascular Database Organization. Influenceof Timing After Thoracic Endovascular Aortic
Repair for Acute Type B Aortic Dissection. Ann
Thorac Surg. [Epub ahead of print]2017 Dec 23.

7. Etoh T, Honda M, Kumamaru H, Miyata H,
Yoshida K, Kodera Y, Kakeji Y, Inomata M,
Konno H, Seto Y, Kitano S, Hiki N. Morbidity
and mortality from a propensity score-matched,prospective cohort study of laparoscopic versus
open total gastrectomy for gastric cancer: datafrom a nationwide web-based database. Surg
Endosc.[Epub ahead of print]2017 Dec 7
8. Nakano K, Hirahara N, Motomura N, Miyata H,
Takamoto S. Current status of cardiovascularsurgery in Japan, 2013 and 2014: A report basedon the Japan Cardiovascular Surgery Database. 4.
Valvular heart surgery. Gen Thorac Cardiovasc
Surg. 66(1):13-18, 2018 Jan[Epub 2017 Nov 13.]
9. Saito A, Hirahara N, Motomura N, Miyata H,
Takamoto S. Current status of cardiovascularsurgery in Japan, 2013 and 2014: A report basedon the Japan Cardiovascular Surgery Database 3.
Coronary artery bypass surgery. Gen Thorac
Cardiovasc Surg. 66(1):8-12, 2018 Jan; [Epub2017 Nov 13.]
10. Hirata Y, Hirahara N, Murakami A, Motomura N,
Miyata H, Takamoto S. Current status ofcardiovascular surgery in Japan 2013 and 2014: A
report based on the Japan Cardiovascular Surgery
Database. 2: Congenital heart surgery. Gen Thorac
Cardiovasc Surg. 66(1):4-7. 2018 Jan; [Epub 2017
Nov 13.]
11. Takamoto S, Motomura N, Miyata H, Tsukihara H.
Current status of cardiovascular surgery in Japan,
2013 and 2014: A report based on the Japan
Cardiovascular Surgery Database (JCVSD). 1:
Mission and history of JCVSD. Gen Thorac
Cardiovasc Surg. 66(1):1-3 2018 Jan; [Epub 2017
Nov 13.]
12. Kikuchi H, Miyata H, Konno H, Kamiya K,
Tomotaki A, Gotoh M, Wakabayashi G, Mori M.
Development and external validation ofpreoperative risk models for operative morbidities
after total gastrectomy using a Japanese webbased nationwide registry. Gastric Cancer. 20(6):987-997. 2017 Nov.
13. Inohara T, Kohsaka S, Miyata H, Sawano M,
Ueda I, Maekawa Y, Fukuda K, Jones PG, Cohen
DJ, Zhao Z, Spertus JA, Smolderen KG.
Prognostic Impact of Subsequent Acute Coronary
Syndrome and Unplanned Revascularization on

443Long-Term Mortality After an Index PercutaneousCoronary Intervention: A Report From a JapaneseMulticenter Registry. J Am Heart Assoc. 6(11).
2017 Oct 27.
14. Nomura S, Sakamoto H, Glenn S, Tsugawa Y, Abe
SK, Rahman MM, Brown JC, Ezoe S, Fitzmaurice
C, Inokuchi T, Kassebaum NJ, Kawakami N, Kita
Y, Kondo N, Lim SS, Maruyama S, Miyata H,
Mooney MD, Naghavi M, Onoda T, Ota E, Otake
Y, et al.Population health and regional variationsof disease burden in Japan, 1990-2015: asystematic subnational analysis for the Global
Burden of Disease Study 2015. Lancet. 390(10101):1521-1538. 2017 Sep 23.
15. Hirata Y, Miyata H, Hirahara N, Murakami A,
Kado H, Sakamoto K, Sano S, Takamoto S.
Long-Term Results of Bilateral Pulmonary Artery
Banding Versus Primary Norwood Procedure.
Pediatr Cardiol. 39(1):111-119 2018 Jan. [Epub2017 Sep 21]
16. Kodashima S, Tanaka K, Matsuda K, Fujishiro M,
Saito Y, Ohtsuka K, Oda I, Katada C, Kato M,
Kida M, Kobayashi K, Hoteya S, Horimatsu T,
Matsuda T, Muto M, Yamamoto H, Ryozawa S,
Iwakiri R, Kutsumi H, Miyata H, Kato M,
Haruma K, et al. First progress report on the Japan
Endoscopy Database project. Dig Endosc. 30(1):20-28 2018 Jan
17. Hiki N, Honda M, Etoh T, Yoshida K, Kodera Y,
Kakeji Y, Kumamaru H, Miyata H, Yamashita Y,
Inomata M, Konno H, Seto Y, Kitano S. Higher
incidence of pancreatic fistula in laparoscopic
gastrectomy. Real-world evidence from a nationwide prospective cohort study. Gastric Cancer.
21(1):162-170.2018 Jan,
18. Shimizu H, Hirahara N, Motomura N, Miyata H,
Takamoto S. Current status of cardiovascularsurgery in Japan, 2013 and 2014: a report basedon the Japan Cardiovascular Surgery Database 5.
Thoracic aortic surgery. Gen Thorac Cardiovasc
Surg. 65(12):671-678 2017 Dec [Epub 2017 Sep
5.]
19. Kawamoto S, Miyata H, Motomura N, Tanemoto
K, Takamoto S, Saiki Y. Surgical Outcomes of
Isolated Coronary Artery Bypass Grafting for
Acute Coronary Syndrome- Based on the Japan
Adult Cardiovascular Surgery Database. Circ J.

82(1):123-130. 2017 Dec 25 [Epub 2017 Sep 1.]
20. Tamura Y, Kumamaru H, Satoh T, Miyata H,
Ogawa A, Tanabe N, Hatano M, Yao A, Abe K,
Tsujino I, Fukuda K, Kimura H, Kuwana M,
Matsubara H, Tatsumi K; Japan PH Registry(JAPHR) Network. Effectiveness and Outcome of
Pulmonary
Arterial
Hypertension-Specific
Therapy in Japanese Patients With Pulmonary
Arterial Hypertension. Circ J. 82(1):275-282.
2017 Dec 25, [Epub 2017 Jul 26.]
21. Endo S, Ikeda N, Kondo T, Nakajima J, Kondo H,
Yokoi K, Chida M, Sato M, Toyooka S, Yoshida K,
Okada Y, Sato Y, Okada M, Okumura M, Chihara
K, Fukuchi E, Miyata H. Model of lung cancer
surgery risk derived from a Japanese nationwide
web-based database of 78 594 patients during
2014-2015. Eur J Cardiothorac Surg. 52(6):11821189. 2017 Dec 1;
22. Kimura M, Nawata K, Kinoshita O, Yamauchi H,
Hoshino Y, Hatano M, Amiya E, Kashiwa K,
Endo M, Kagami Y, Nemoto M, Ono M.
Readmissions after continuous flow left
ventricular assist device implantation. J Artif
Organs. 20(4):311-317. 2017 Dec.
23. Kohsaka S, Murata T, Izumi N, Katada J, Wang F,
Terayama Y. Bleeding risk of apixaban,
dabigatran, and low-dose rivaroxaban comparedwith warfarin in Japanese patients with nonvalvular atrial fibrillation: a propensity matchedanalysis of administrative claims data. Curr Med
Res Opin. 33(11):1955-1963. 2017 Nov.
24. Adachi Y, Kinoshita O, Hatano M, Shintani Y,
Naito N, Kimura M, Nawata K, Nitta D, Maki H,
Ueda K, Amiya E, Takimoto E, Komuro I, Ono M.
Successful bridge to recovery in fulminant
myocarditis using a biventricular assist device: acase report. J Med Case Rep. 11(1):295. 2017 Oct
24.
25. Nakatani T, Sase K, Oshiyama H, Akiyama M,
Horie M, Nawata K, Nishinaka T, Tanoue Y, Toda
K, Tozawa M, Yamazaki S, Yanase M, Ohtsu H,
Ishida M, Hiramatsu A, Ishii K, Kitamura S;
J-MACS investigators. Japanese registry for
Mechanically Assisted Circulatory Support: First
report. J Heart Lung Transplant. 36(10):10871096. 2017 Oct.
26. Kumamaru KK, Sano Y, Kumamaru H, Hori M,

444

Takamura T, Irie R, Suzuki M, Hagiwara A,
Kamagata K, Nakanishi A, Aoki S. Radiologist
involvement is associated with reduced use of
MRI in the acute period of low back pain in a
non-elderly population. Eur Radiol. 2017 Oct 23.
[Epub ahead of print]
27. Nakachi T, Kohsaka S, Yamane M, Muramatsu T,
Okamura A, Kashima Y, Matsuno S, Sakurada M,
Kijima M, Tanabe M, Habara M. Impact ofHemodialysis on Procedural Outcomes of
Percutaneous Coronary Intervention for Chronic
Total Occlusion: Insights From the JapaneseMulticenter Registry. J Am Heart Assoc. 6(10).
pii: e006431. 2017 Oct 11.
28. Matsushita K, Harada K, Miyazaki T, Miyamoto T,
Kohsaka S, Iida K, Tanimoto S, Yagawa M,
Shiraishi Y, Yoshino H, Yamamoto T, Nagao K,
Takayama M. Effect of Heart Failure Secondary
to Ischemic Cardiomyopathy on Body Weight andBlood Pressure. Am J Cardiol. 120(9):1589-1594.
2017 Nov 1
29. Hoashi T, Hirahara N, Murakami A, Hirata Y,
Ichikawa H, Kobayashi J, Takamoto S. Current
Surgical Outcomes of Congenital Heart Surgery
for Patients With Down Syndrome in Japan. Circ J.
82(2):403-408. 2018 Jan 25.
30. Saito Y, Yamamoto H, Nakajima H, Takahashi O,
Komatsu Y. Incidence of and risk factors for
newly diagnosed hyperkalemia after hospitaldischarge in non-dialysis-dependent CKD patientstreated with RAS inhibitors. PLoS One. 12(9):e0184402. 2017 Sep 6.
31. Shimura T, Yamamoto M, Kano S, Kagase A,
Kodama A, Koyama Y, Otsuka T, Kohsaka S,
Tada N, Yamanaka F, Naganuma T, Araki M,
Shirai S, Mizutani K, Tabata M, Ueno H, Takagi
K, Higashimori A, Watanabe Y, Hayashida K.
Impact of frailty markers on outcomes after
transcatheter aortic valve replacement: insightsfrom a Japanese multicenter registry. Ann
Cardiothorac Surg. 6(5):532-537. 2017 Sep.
32. Inohara T, Kimura T, Ueda I, Ikemura N,
Tanimoto K, Nishiyama N, Aizawa Y, Nishiyama
T, Katsumata Y, Fukuda K, Takatsuki S, Kohsaka
S. Effect of Compliance to Updated AHA/ACC
Performance and Quality Measures Among
Patients With Atrial Fibrillation on Outcome(from Japanese Multicenter Registry). Am J
Cardiol. 120(4):595-600. 2017 Aug 15.
33. Sawano M, Kohsaka S, Abe T, Inohara T,
Maekawa Y, Ueda I, Sueyoshi K, Suzuki M,
Noma S, Numasawa Y, Miyata H, Fukuda K,
Smolderen KG, Spertus JA. Patterns of statin
non-prescription in patients with establishedcoronary artery disease: A report from acontemporary multicenter Japanese PCI registry.
PLoS One. 12(8) 2017 Aug 17.
34. Ono T, Kohsaka S, Takatsuki S, Fukuda K, Suzuki
M. Inconsistent Dosing of Non-Vitamin K Oral
Anticoagulants: Differences Between the UnitedStates and Japan. J Am Coll Cardiol. 70(1):118.
2017 Jul 4.
35. Takeuchi H, Miyata H, Ozawa S, Udagawa H,
Osugi H, Matsubara H, Konno H, Seto Y,
Kitagawa Y. Comparison of Short-Term Outcomes
Between Open and Minimally Invasive
Esophagectomy for Esophageal Cancer Using a
Nationwide Database in Japan. Ann Surg Oncol.
24(7):1821-1827. 2017 Jul.
36. Ueki C, Miyata H, Motomura N, Sakaguchi G,
Akimoto T, Takamoto S. Previous PercutaneousCoronary Intervention Does Not Increase Adverse
Events After Coronary Artery Bypass Surgery.
Ann Thorac Surg. 104(1):56-61. 2017 Jul.
37. Watanabe T, Miyata H, Konno H, Kawai K,
Ishihara S, Sunami E, Hirahara N, Wakabayashi G,
Gotoh M, Mori M. Prediction model forcomplications after low anterior resection basedon data from 33,411 Japanese patients included in
the National Clinical Database. Surgery. 161(6):1597-1608. 2017 Jun.
38. Oshima T, Hara H, Takeda N, Hasumi E, Kuroda
Y, Taniguchi G, Inuzuka R, Nawata K, Morita H,
Komuro I. A novel mutation of NFIX causes
Sotos-like syndrome (Malan syndrome) complicated with thoracic aortic aneurysm and dissection.
Hum Genome Var. 4:17022. 2017 Jun 1.
39. Ikemura N, Sawano M, Shiraishi Y, Ueda I,
Miyata H, Numasawa Y, Noma S, Suzuki M,
Momiyama Y, Inohara T, Hayashida K, Yuasa S,
Maekawa Y, Fukuda K, Kohsaka S. Barriers
Associated With Door-to-Balloon Delay inContemporary Japanese Practice. Circ J. 81(6):815-822. 2017 May 25.

445

40. Takai H, Miyata H, Motomura N, Sasaki K,
Kunihara T, Takamoto S. Comparison of earlyoutcomes of surgical ablation procedures for atrial
fibrillation concomitant to non-mitral cardiac
surgery: a Japan Adult Cardiovascular Surgery
Database study. Gen Thorac Cardiovasc Surg.
2017 May 23. [Epub ahead of print]
41. Inohara T, Kohsaka S, Yamaji K, Amano T, Fujii
K, Oda H, Uemura S, Kadota K, Miyata H,
Nakamura M; J-PCI Registry Investigators.
Impact of Institutional and Operator Volume on
Short-Term Outcomes of Percutaneous Coronary
Intervention: A Report From the Japanese
Nationwide Registry. JACC Cardiovasc Interv.
10(9):918-927. 2017 May 8.
42. Aoki S, Miyata H, Konno H, Gotoh M, Motoi F,
Kumamaru H, Wakabayashi G, Kakeji Y, Mori M,
Seto Y, Unno M. Risk factors of serious
postoperative complications after pancreaticoduodenectomy and risk calculators for predicting
postoperative complications: a nationwide studyof 17,564 patients in Japan. J Hepatobiliary
Pancreat Sci. 24(5):243-251. 2017 May.
43. Numasawa Y, Sawano M, Miyata H, Ueda I,
Noma S, Suzuki M, Kuno T, Kodaira M,
Maekawa Y, Fukuda K, Kohsaka S. Outcomes
After Percutaneous Coronary Intervention of
Acute Coronary Syndrome Complicated With
Cardiopulmonary Arrest (from a Japanese Multicenter Registry). Am J Cardiol. 119(8):1173-1178.
2017 Apr 15.
44. Miyahara S, Miyata H, Motomura N, Takamoto S,
Okita Y; Japan Cardiovascular Surgery Database
Organization. Clinical significance of chronic
obstructive pulmonary disease in patients
undergoing elective total arch replacement:
analysis based on the Japan Adult Cardiovascular
Surgery Database. Eur J Cardiothorac Surg. 51(4):761-766. 2017 Apr 1.

University Hospital
Clinical Divisions

University Hospital
Central Clinical Facilities

448

Department of Clinical Laboratory
Professor
Yutaka Yatomi, M.D.

Associate Professor
Hitoshi Ikeda, M.D.

Lecturer
Masao Daimon, M.D., Makoto Kurano, M.D.
Daiya Takai, M.D., Masato Yumoto, M.D.,

Associate
Tomoko Nakao, M.D., Masako Nishikawa, M.D
Masaya Sato, M.D., Atsushi Yasumoto, M.D.

Chief Technologist
Shinji Sone, M.T.

Homepage

http://lab-tky.umin.jp/

Introduction and Organization
Department of Clinical Laboratory consists of thefollowing sections, and the 3rd - generation
Laboratory Automation System is in full operation,and ordering of laboratory tests, the flow of samples,
operation of laboratory analyzers, quality control ofanalysis, and data reporting are all controlled by the
Laboratory Automation computer system.
Thissystem has greatly improved the quality, safety, andefficiency of the laboratory and contributed to bothpatients and doctors by providing rapid and highquality laboratory testing.
The 1st Section
This section deals mainly with the maintenance oflaboratory system and blood and urine sampling. In
2017, 236,135 outpatient blood sampling were
performed in this section. Furthermore, 235,907 urine
samples were examined.
The 2nd Section
This section deals with clinical biochemistry andimmuno-serology tests. In 2017, over 5,404,261

serum enzyme tests (such as AST and ALT), and570,582 immunological tests were performed.
The 3rd Section
This section deals with laboratory hematology and
DM-related tests, gene analysis tests and urinalysis.
In 2017, 1,216,930 samples were examined for complete blood cell counts, cell surface marker analysis,
prothrombin time, fibrinogen, glucose, and HbA1C
tests.
The 4th Section
This section deals with physiological tests,
including circulatory, pulmonary, and neuromuscularfunction ones.
In 2017, 45,506 ECG, 25,494
pulmonary function tests, 11,067 echocardiography
tests, 17,638 abdominal echography tests, and 9,762
EEG were performed.

Teaching activities
Lectures are given to the fourth, fifth and sixth grade
medical students on clinical tests including
hematology, chemistry, endocrinology, immunology,

449

bacteriology, cardiology, and pulmonary function.
The reversed CPC program is presented to the sixth
grade students. Clinical clerkship is provided for thesixth year medical students, in small groups of 6-7
students for one-week duration. In this course,
students learn clinical and practical knowledge andtechniques on various laboratory tests. Students
from professional schools also study laboratory
medicine under the guidance of members in ClinicalLaboratory Center.

Research activities
The main goal of our research projects is thedevelopment of new and useful laboratory tests, andelucidation of pathophysiology of diseases throughlaboratory tests. The areas included are: i) (Patho)
physiological roles of lysophospholipid mediators andits application into laboratory medicine, ii) platelet
biology, iii) novel biomarker in liver diseases, iv) AI
and data mining in laboratory medicine, v) genetic
testing, vi) oxidized albumin as a redox marker, vii)
analysis of cardiac functions using ultrasound, viii)
elucidation of abnormality in epigenetics in cancer
and its clinical application, and x) analysis of brain
functionusing
magnetoencephalographyandnear-infrared spectroscopy.

References
Original article:
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Saigusa, D., Nagamatsu, T., Hirota, Y., Fujii, T.,
Tsuchiya, S., Taketomi, Y., Sugimoto, Y.,
Murakami, M., Arita, M., Kurano, M., Ikeda, H.,
Yatomi, Y., Chun, J., and Aoki, J. Autotaxinlysophosphatidic acid-LPA3 signaling at theembryo-epithelial boundary controls decidualizetion pathways. EMBO J. 36: 2146-2160, 2017.
2. Baba, H., Kurano, M., Nishida, T., Hatta, H.,
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Detection of Dysmorphic Red Blood Cells andRenal Tubular Epithelial Cells with a Modified
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4. Daikoku, T. and Yumoto, M. Single, but not dual,
attention facilitates statistical learning of two
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Statistical learning of an auditory sequence andreorganization of acquired knowledge: A timecourse of word segmentation and ordering.
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Sasano, T., Sumi, Y., Koike, K. Yatomi, Y., andIkeda, H. Ultrasound evaluation of liver stiffness:accuracy of ultrasound imaging for the predictionof liver cirrhosis as evaluated using a liver
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8. Hassan, A., Dohi, T., Miyauchi, K., Ogita, M.,
Kurano, M., Ohkawa, R., Nakamura, K., Tamura,
H., Isoda, K., Okazaki, S., Yatomi, Y., and Daida,
H. Prognostic impact of homocysteine levels andhomocysteine thiolactonase activity on long-termclinical outcomes in patients undergoing percutaneous coronary intervention. J. Cardiol. 69:
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9. Jiang, Y., Lei, C., Yasumoto, A., Kobayashi, H.,
Aisaka, Y., Ito, T., Guo, B., Nitta, N., Kutsuna, N.,
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K. Label-free detection of aggregated platelets inblood by machine-learning-aided optofluidic
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10. Kawata, T., Daimon, M., Kimura, K., Nakao, T.,
Lee, S.L., Hirokawa, M., Kato, T.S., Watanabe,M., Yatomi, Y., and Komuro, I. Echocardiographic assessment of right ventricular function inroutine practice: Which parameters are useful topredict one-year outcome in advanced heart
failure patients with dilated cardiomyopathy? J.
Cardiol. 70: 316-322, 2017.

450

11. Kawata, T., Daimon, M., Lee, S.L., Kimura, K.,
Sawada, N., Chiang, S.J., Mahara, K., Okubo, T.,
Nakao, T., Hirokawa, M., Xu, B., Kato, T.S.,
Watanabe, M., Yatomi, Y., and Komuro, I.
Reconsideration of Inferior Vena Cava Parameters
for Estimating Right Atrial Pressure in an East
Asian Population - Comparative Simultaneous
Ultrasound-Catheterization Study. Circ J. 81:
346-352, 2017.
12. Komeno, Y., Uchida, N., Sato, Y., Uryu, H.,
Iwata, Y., Masuda, A., Iihara, K., Yatomi, Y.,
Taniguchi, S., and Ryu, T. Bosutinib as the
fourth-line therapy for a patient with T315Ipositive lymphoid blastic phase chronic myeloid
leukemia. Oncology Letters 13: 4285-4289, 2017.
13. Kurano, M., Nishikawa, M., Kuma, H., Jona, M.,
and Yatomi, Y. Involvement of Band3 in theefflux of sphingosine 1-phosphate from erythrocytes. PLoS One 12: e0177543, 2017.
14. Kurano, M., Hara, M., Ikeda, H., Tsukamoto, K.,
and Yatomi, Y. Involvement of Cholesteryl Ester
Transfer Protein in the Shift of Sphingosine
1-Phosphate Among Lipoproteins and in the
Modulation of its Functions. Arterioscler.
Thromb. Vasc. Biol. 37: 506-514, 2017.
15. Kurano, M., Kano, K., Dohi, T., Matsumoto, H.,
Igarashi, K., Nishikawa, M., Ohkawa, R., Ikeda,
H., Miyauchi, K., Daida, H., Aoki, J., and Yatomi,
Y. Different Origins of Lysophospholipid
Mediators between Coronary and Peripheral
Arteries in Acute Coronary Syndrome. J. Lipid
Res. 58: 433-442, 2017.
16. Maeda, S., Nakamura, T., Harada, H., Tachibana,Y., Aritake, K., Shimosawa, T., Yatomi, Y., and
Murata, T. Prostaglandin D2 metabolite in urine is
an index of food allergy. Sci. Rep. 7: 17687,
2017.
17. Masudo, R., Yasukawa, K., Nojiri, T., Yoshikawa,N., Shimosaka, H., Sone, S., Oike, Y., Ugawa, A.,
Yamazaki, T., Shimokado, K., Yatomi, Y., andIkeda, H. Evaluation of human nonmercaptalbumin as a marker for oxidative stress andits association with various parameters in blood. J.
Clin. Biochem. Nutr. 61: 79-84, 2017.
18. Matsuda, K., Taoka, K., Jona, M., Masuda, A.,
Arai, S., Nakamura, F., Yatomi, Y., andKurokawa, M. Clinical features of hematologicaldisorders with increased large granularlymphocytes (LGLs): a retrospective study. Ann.
Hematol. 96: 2113-2115, 2017.
19. Mori, E., Kurano, M., Tobita, A., Shimosaka, H.,
and Yatomi, Y. Existence of a squamous cell
carcinoma antigen-immunoglobulin complex
causes a deviation between squamous cell
carcinoma antigen concentrations determinedusing two different immunoassays: first report ofsquamous cell carcinoma antigen coupling withimmunoglobulin A. Ann. Clin. Biochem. 54: 655663, 2017.
20. Sakatani, T., Maemura, K., Hiyama, N., Amano,Y., Watanabe, K., Kage, H., Fukayama, M.,
Nakajima, J., Yatomi, Y., Nagase, T., and Takai,
D. High expression of IRE1 in lung adenocarcinoma is associated with a lower rate ofrecurrence. Jpn. J. Clin. Oncol. 47: 543-550,
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21. Sato, M., Tateishi, R., Yasunaga, H., Horiguchi,
H., Matsui, H., Yoshida, H., Fushimi, K., andKoike K. The ADOPT-LC score: a novel
predictive index of in-hospital mortality ofcirrhotic patients following surgical procedures,
based on a national survey. Hepatol. Res. 47:
E35-E43, 2017.
22. Sato, M., Tateishi, R., Yasunaga, H., Matsui, H.,
Fushimi, K., Ikeda, H., Yatomi, Y., and Koike, K.
Association between hospital volume andin-hospital mortality following radiofrequency
ablation for hepatocellular carcinoma. BJS Open
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23. Sato, M., Tateishi, R., Yasunaga, H., Matsui, H.,
Horiguchi, H., Fushimi, K., and Koike K.
Mortality and hemorrhagic complications
associated with radiofrequency ablation fortreatment of hepatocellular carcinoma in patientson hemodialysis for end-stage renal disease: anationwide survey. J. Gastroenterol. Hepatol. 32:
1873-1878, 2017.
24. Takahashi, C., Kurano, M., Nishikawa, M., Kano,K., Dohi, T,. Miyauchi, K., Daida, H., Shimizu, T.,
Aoki, J., and Yatomi, Y. Vehicle-dependent
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25. Yamaguchi, H., Satoh, Y., Ishigami, H., Kurihara,
M., Yatomi, Y., and Kitayama, J.Peritoneal
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26. Yasumoto, A., Ishiura, R., Narushima, M., andYatomi, Y. Successful treatment with dabigatran f
xr consumptive coagulopathy associated withextensive vascular malformations. Blood Coagul
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27. Yasumoto, A., Tokuoka, S.M., Kita, Y., Shimizu,T., and Yatomi, Y. Multiplex quantitative analysis
of eicosanoid mediators in human plasma andserum: Possible introduction into clinical testing.
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Targeting gene expression to specific cells ofkidney tubules in vivo, using adenoviral promoter
fragments. PLoS One. 12: e0168638, 2017.

452

Surgical Center
Director (Professor)
Hiroshi Yasuhara M.D., Ph.D.

Associate Professor
Kazuhiro Fukatsu. M.D., Ph.D.

Lecturer
Ryoji Fukushima, M.D., Ph.D.

Associate
Saito Yuhei, M.S.
Satoshi Murakoshi, M.D., Ph.D.

Homepage

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

Introduction and Organization
Uniform management of operating rooms (OR) firstbegan at the University of Tokyo Hospital in July
1955. The office, so called the surgical center, waslocated in the Old Central Building until December
1987. The center moved to the new Central Clinical
Service Building 1 in January 1988, when the surgicalcenter had 14 ORs including one bio-clean room. The
administrative staff included 4 doctors, 75 nurses, 6technical officials, 5 part-time employees. The surgical center became to provide managerial services of
the OR to 18 surgical departments after moving into
the new office building. The total number ofoperations remained to be below 6,300 a year between
1999 and 2000 because of the limitation of number of
ORs and nurses.
In July 2001, the branch hospital in Mejiro area wasmerged with the University of Tokyo Hospital in
Hongo area, which opened a new Ward B Building in
October 2001. After the merger, the number ofelective operations markedly increased and becameover 7,300. The two additional ORs began to be usedtentatively to accommodate an enormous increase in
the number of elective operations. The one OR was set
up on the ICU/CCU/HCU floor in the new Ward A
Building and the other was in the Outpatient Clinic

Building. The outpatient OR orthopedic outpatientswas diverted for the general OR, which was used forthe short-stay and day surgery. In April 2014, one OR
was renovated into a hybrid OR which is equippedwith advanced interventional imaging system for thepatients undergoing interventional surgical treatment.
Until September 2001, the elective operations had
been performed in 9.5 ORs/day on average. After
October 2001, 12 ORs/day began to be used. In 2006,
the Central Clinical Service Building 2, which had 11
ORs, was completed to solve the shortage of thenumber of ORs. As a result, the total number of ORs
became 23, and then the number of operations has
tremendously increased. More recently, “On call PM
block time” has been introduced to improve OR
utilization.
A total of 8,485, 9,550, 9921, 9,944, 10,394, 10,170,
10,752, 11,235, 11,150, 10,960, 11,161 and 11,014
operations were performed in 2006, 2007, 2008, 20092010, 2011, 2012, 2013, 2014, 2015, 2016 and 2107
fiscal year, respectively. The number of operations in2016 fiscal year counts for approximately 1.8 times
comparing to that in 2001.
These days more and more patients undergo theoperation, using surgical endoscope, such as
laparoscopy/thoracoscopy -assisted operation. There is453

also an apparent increase in the number of patients
who are at high risk with critical morbidity or carrierof the particular types of pathogenic bacteria, such as
tuberculosis, MRSA, pseudomonas aeruginosa, HBV,HCV and HIV.

Scope of Activities of Surgical Center
The surgical center covers broad area of clinicalactivities ranging from the operation schedule to theeducation of the medical students and healthcare
workers, and research on healthcare practices.

Operation Schedule
All operations of in-patients are performed in 23
ORs at the surgical center. Computer system has beenutilized in order to handle the information on
operation. In May 1999, the on-line system wasintroduced to order the elective and urgent/emergent
operations through the computer terminal in the wards.
The input of postoperative patient information started
from March in 2000.
The present status of the operation process began to
be seen through the computer monitor from May in1997. This system also enabled the medical staff toknow the availability of the ORs of the next day. From
November in 2000, the medical staff can see theoperation schedule through the hospital computer
network. The photographs of surgical sites, resectedorgans and live video image began to be delivered tothe clinical departments from February in 1997.
The SPD system and the progressive patient caresystem started in the Ward A Building and Central
Clinical Service Building 2 in order to improve theworkflow of hospital in October 2001. In the surgicalcenter, this SPD system has been available since
September in 2002.
Recently, the number of complicated and long
surgical procedures using advanced technology has
dramatically increased. In addition, more and morepatients tend to undergo surgery using artificial
implant, joint prosthesis or intraocular lenses. Thoseoperations include organ transplantation, microvascular surgery, cardiovascular surgery, minimallyinvasive surgery and navigation-guided orthopedic/
neurosurgical surgery and stent grafting for theabdominal or thoracic aortic aneurysms. Organtransplantation and intraoperative three-dimensional
echo-guided surgery are also frequently performed.
Minimally invasive surgery is another recent trend of
the operation. Those include MIDCAB operations for
CABG and endovascular treatment for heart
anomalies such as ASD and VSD. More recently, therobotic surgery has started at the surgical center.
Healthcare-Associated infections (HAIs) are criticalissues in the surgical center. It is mandatory to educate
how to prevent HAIs and occupational infections. As
the number of operation associated with emergenceand re-emergence infectious diseases such as HIV andtuberculosis has increased, all health care staff in thesurgical center are required to adhere to the principles
of standard precautions and transmission-based
precautions.

Teaching Activities
The following lectures or seminar are given to theundergraduates and postgraduates medical students:
aseptic techniques, sterilization/disinfection methods,
prevention of perioperative infections, humoral andcellular responses to trauma and shock, training ofscrubbing and gown techniques. The curriculum is
updated each year. Introductory course for disinfection,sterilization and preservation of surgical instruments
and medical devices was added in the training courses
in 1998, which gained more interest and popularity
among many students.
In the surgical center, the innovative surgicalinstruments and medical devices are recently
introduced to perform highly advanced operations
such as in the navigation surgery, transplantation
surgery, cardiovascular surgery and robotic surgery.
As a result, the education related to the assist for thosesurgical procedure has become most important
activities in the surgical center. The lectures ofadvanced technologies are in the curriculum for thesurgeons, the nursing staff and clinical engineers sothat they can understand how to use them in a proper
way.
Lectures for the nursing staff consist of a freshmancourse and an advanced course. The freshman course
is a basic training course for a scrub nurse or acirculating nurse. It consists of lectures of aseptic
techniques, de-contamination/sterilization methods,

454

prevention of perioperative infections, and on-sitetraining of scrubbing and gown techniques as wall as
aseptic preparation of surgical instruments in the OR.
An advanced course is prepared to the experienced
nurses as well. The purpose of this course is toupgrade their perioperative nursing skills so that they
can demonstrate full nursing skills even in thecomplicated and long operations such as transplantation surgery, open-heart surgery, neurosurgery
and robotic surgery.
There is also a training course to clinical engineers
and students of biomedical engineers. This training
course consists of introduction on the medical devices
and electronic instruments, precautions of accidental
troubles in handling surgical instruments/medical
devices, development of new surgical instruments/
medical devices, cardiopulmonary bypass techniques
and illumination techniques in the operating fields.
The contents of this course are summarized in the
manual for the nursing staff and contribute to decrease
the frequency of incident associated with surgicalinstruments and medical devices.
The on-job training are given to the non-nursing
staff including technical officials and temporary
employees and performed when they start their careers
in the surgical center. They are given lectures on
aseptic techniques, sterilization/disinfection methods,
prevention of perioperative infections, and maintenance of reusable surgical instruments such as forceps,
scissors and clamps. These subjects are summarized
and stated in the manual. Lectures are also given to
the senior technical officers and temporary employees
to promote their technical knowledge and skills.

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 management of equipment of endoscopyassisted surgery8) Centralization of the live video images of thesurgical field
9) Management of surgical devices using UID
10) Perioperative infection control and prevention
related to the sterilization
11) Maintenance of the surgical environment in theOR12) Maintenance and management of the surgicalequipment
13) Perioperative nutritional management of thesurgical patients
14) Others

References（2017）
1. Ri M, Fukatsu K, Miyakuni T, Yanagawa M,
Murakoshi S, Yasuhara H, Seto Y. Influences of
Vagotomy on Gut Ischemia-Reperfusion Injury inMice. Shock. 2017 May;47(5):646-652.
2. Saito Y, Yasuhara H, Murakoshi S, Komatsu T,
Fukatsu K, Uetera Y. Challenging residual
contamination of instruments for robotic surgery
in Japan. Infect Control Hosp Epidemiol 2017
Feb;38(2):143-146
3. Saito Y, Yasuhara H, Murakoshi S, Komatsu T,
Fukatsu K, Uetera Y. Priority of Patient Safety
Associated With Robotic Surgical InstrumentsResponse to Landenberg et al. Infect Control
Hosp Epidemiol. 2017 Jul;38(7):879-880.
4. Saito Y, Yasuhara H, Murakoshi S, Komatsu T,
Fukatsu K, Uetera Y. Concerns associated withcleaning robotic surgical instruments -Response to
Wallace et al. Infect Control Hosp Epidemiol.
2017 Aug;38(8):1014-5.

455

Department of Clinical Radiology
Professor (department manager)
Abe Osamu, M.D., Ph.D.

Lecturer (vice manager)
Jiro Sato, M.D.

Assistant Professor
Masaki Katsura, M.D., Ph.D.

Homepage

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

Introduction and Organization
In the Department of Clinical Radiology, clinicalservices on Diagnostic Radiology (imaging andintervention), Radiation Oncology (radiotherapy),
Nuclear Medicine and the Radiation Safety Control
System are provided in cooperation with radiology
technologists and nurses. Present constituent members
are as follows: three medical doctors, 75 radiological
technicians and 1 technical official of the radiation
control. The staff members of the Department ofRadiology (teachers, the graduate school students,
medical staffs, and the clinical trainees) join this. In
addition, the doctors of other departments and thenurses cooperate and are also engaged in the clinicalradiology activities.
Department of Clinical Radiology is actively
participating in the following projects. 1) PACS: We
have recently developed a radiology information
system (RIS) networking with hospital information
system (HIS) and PACS (picture archiving andcommunicating system). The PACS of the whole
hospital (the film-less imaging system) wasestablished in 2003. The new reporting system wasinstalled in 2002. 2) Radiation Safety Control:
Stimulated by the need for evaluating the individualaccumulated exposure dose by medical radiation, we
have started a working group to solve this problem.
We aim to provide the accumulated exposure dose
data on RIS. 3) Image Computing & Analysis
Laboratory: The clinical section of this project islocated at the reading room in the Diagnostic
Radiology Section. The main services are processingof volume image data into clinical 3D-images andanalysis of imaging data. 4) Researches on new
radiology techniques: Ongoing collaborative researches are as follows: image-guided radiation
therapy, clinical PET, multi-detector row CT, 3-Tesla
MRI, flat panel detector.

Clinical activities
1) Diagnostic Radiology:
The section of diagnostic radiology is responsible
for all the clinical examinations of CT, MRI, andangiography and vascular interventional procedures
except for cardiac and peripheral arterial studies. Allof these examinations are performed under therequests of clinicians. Over one hundred and fifty CT
examinations are performed using six MDCT scanners
each day. Interventional procedure such as percutaneous biopsy and abscess drainage are also doneby CT guidance. About seventy MR examinations aredone using two of 1.5-Tesla and four of 3-Teslascanners every day. Diagnostic and interventional
procedures are performed using six angiographic
units.
2) Nuclear medicine:
The section of nuclear medicine is responsible forall the radionuclide imaging examinations including
conventional scintigraphy such as bone, kidney,456

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.

457

Department of Pharmacy
Professor
Hiroshi Suzuki, Ph.D.

Lecturer
Tappei Takada, Ph.D.,

Masashi Honma, Ph.D.

Research Associate
Takahiro Amemiya, Ph.D.,

Yuki Ikebuchi, Ph.D.,

Yoshiyuki Ohno, Ph.D.,

Yoshiaki Kariya, Ph.D.,

Tomoko Mayuzumi,

Yoshihide Yamanashi, Ph.D.

Homepage

http://plaza.umin.ac.jp/~todaiyak/

Introduction and Organization
We have 9 faculty members, 72 pharmacy staffs,
and 8 graduate students and 5 undergraduate students
from the faculty of pharmaceutical sciences (as ofJanuary 1st, 2018).

Clinical activities
Department of Pharmacy consists of the following
six sections:1) Drug information and research section
This section offers drug information for questions
from medical persons, executes and supports the
medicine management to inpatients. In addition,
the section prepares materials for pharmaceuticalaffair committee, where each medicine isdiscussed whether it should be adopted or deleted.
Preparation of several periodicals regarding drug
information for clinicians is also included.
2) The dispensing section
After inspecting all prescriptions for contraindications or improper use, medications are
dispensed. Drug information is given to outpatientsfrom this section, using a private room ifnecessary. The computerized order system islinked with automatic packaging machines fororal medicines, automatic dispensing system andbarcode label printer for injection drugs.

3) Pharmaceutical section
This section sterilizes formulations of a pharmaceutical such as injection medicines, instillation
medicines and decontaminating chemicals. They
prepare capsule medicines, ointment medicines,
suppositories, central vein nutrition (IVH) for
inpatients and in-home care patients. After strict
inspection of prescriptions, they also dispenseanti-malignant tumor medicine (database isconstructed based on the submitted protocols andpatients’ information). In order to support
advanced medical care, they develop and check
formulations (characterization of the uniformity,
stability and so on) of the medicine which is quite
necessary for certain patients, but is not marketed.
4) Drug matters and drug management section
Drug matter section manages the adoption of
medical supplies (in-hospital and out-hospital),
periodically reconsiders the adopted medicines,
and also manages the accountings of all the
medicines and other materials used in our
department. This section also takes statistics ofevery information of drug affairs. Drug management section takes care of supplying and safekeeping of all the in-hospital medicines (2,508
items), out-patient medicines, anesthetics, muscle
relaxation drugs, psychotropic drugs, poison
medicines.

4585) Narcotic section
Under the supervision of authorized manager fornarcotics (the director of the department ofpharmacy), narcotics are properly managed,
recorded, reported, inspected and directed.
Narcotics are properly arranged and managed at
the dispensing section and each medical caresection.
6) Ward section
They contribute to the team medical care byproviding specialized drug information andsharing them with all the staffs involved in thetreatment as follows;① Supporting the proper use of medication bypharmacists stationed at ICU sections.
② Arrangement and mixing of injections forpatients at the staff station of Hematology andOncology.
③ Investigation of carrying medicines and theadverse effect histories, allergy histories etc. at
the time of hospitalization. Participation for
conferences. Procurement and appraisal ofpatients’ basic information about the disease,compilation of the medicine history. Monitoringof medication guidance and the adverse effectfor patients, and compilation of guidance record.
Offering the doctor with drug information,prescription design support and detailed
contents of medication guidance to each patient.
④ Investigation and management of ward stock
medicine.
⑤ Nutrient support of the patients as a member of
NST.
⑥ Management of proper use of narcotics as amember of palliative care team.
⑦ Management of proper use of antibiotics,
rounds of a hospital ward, and training of thestaffs as a member of ICT.
Statistical Data (fiscal year 2017)
Number of items on in-hospital formulary: 2,508
Number of prescriptions (ps.) filled or preparation(pp.) (annual)out-patients:
405,355 ps.
(outside :341,090 ps.)(inside :64,265 ps.)out-patient chemotherapy:
13,315 ps.

in-patients :232,080 ps.
injection drugs:
178,297 ps.
IVH:
2,432 pp.
chemotherapy:
10,013 pp.
TDM consultations (annual) :16,312 pp.
Numbers of hospital pharmaceutical cares (annual):
17,997 pp.

Education
The department of pharmacy takes various
responsibilities of education with regard to clinicalpharmacy, pharmacology, and pharmacokinetics forstudents and graduate students in the faculty of
medicine, in the faculty of pharmacy, and in theschool of integrated health sciences. We also have ourown half a year post-graduate training course
optimized for new pharmacists.
For students in the faculty of medicine, we are in
charge of "Pathogenetic and Pathology" as an optionalcourse lecture. We are providing a 3-days practicecourse as a part of compulsory clinical practice for theM3 or M4 students and teach clinical pharmaceutics
and practical knowledge of prescription and risk
management to them. For the students in the healthsciences and nursing, we are in charge of clinicalpharmacokinetics lectures as a part of a compulsory
subject, "Pharmacology and Toxicology".
For students in the faculty of pharmacy, we are in
charge of lectures for the undergraduate students:"Clinical Pharmacy" (compulsory subject). They are
educated for the clinical pharmacology andpharmacokinetics. For the graduate students, we are in
charge of “Special Lecture Basic Pharmaceutical
Science IV”, “Special Lecture Clinical Science”,“Advanced Course of Medical Pharmacy" as acooperator of the Clinical Pharmacokinetics. Recent
trends of the medical pharmacy as well as the practicaldevelopments and future visions of the department ofpharmacy are presented in this lecture. In addition tothem, we accept undergraduate and graduate students
from the faculty of pharmaceutical sciences andfaculty of medicine. They are doing various research
activities.
Six year course education system has been launchedin the field of pharmaceutical sciences since 2006. In
this system, the clinical training by pharmacists at the459

hospital is one of the most important curriculums. In
2017, we accepted clinical training students from The
University of Tokyo, Tokyo University of Pharmacy
and Life Sciences, Showa Pharmaceutical University,
Hoshi University, and Musashino University andeducated them for 2.5 months. In addition, we have
had an original one-year post-graduate training course
for pharmacists since long time before starting the
6-year course education system. They learned various
practical knowledge and techniques necessary for
hospital pharmacists. Such education style is still
continuing by shortening the period to half a year. In
2017, 13 pharmacists finished this course.
In addition, we are promoting life-long education ofpharmacists in the local area by holding regular
technical workshops and seminars.

based on those integrated understanding.
3. Establishment of the way to quantitative understanding and prediction of pharmacological-effectand adverse-effect of drugs directed against
particular molecular target. Finally, these outputs
would be feedbacked to early drug development
stages.
4. Elucidation of the molecular mechanism related tothe adverse effect of drugs using large-scale“-omics” analysis. Finally, the quantitative information would be applied to develop strategies toprevent / treat the adverse effect.
5. Absolute quantification of factors determining thepharmacokinetic profiles of drugs and its application to clinical pharmacokinetics and pharmacology field.

Research

Publications

It is evident that the molecular function ofparticular element cannot always be assigned to only
one function at whole body level, because one to one
simple correspondence is not common in our body. It
is also true that the understanding of the relationshipbetween drug and its ultimate target is not sufficient topredict the pharmacological/toxicological effects. We
need to understand not only the detailed molecularmachinery of drug target, but also its environment
surrounding the target (ex. other associated proteins,
signaling molecules, etc.), where and when it works,
and finally how it behaves as functional unit in our
body. This is a basic idea trying to understand “livingbody” as “system”. By further promoting this idea to“system pharmacology”, we will be able to identify amolecular target which is related to the pharmacological/toxicological output in clinical situation or evenat early drug development stage. Based on suchconcept, following projects are now ongoing:(1) Ando H, Hatakeyama H, Sato H, Hisaka A, Suzuki
H. Determinants of intestinal availability for
P-glycoprotein substrate drugs estimated byextensive simulation with mathematical absorption
models. J Pharm Sci. 2017;106:2771-79.
(2) Hashimoto H, Saito M, Kanda N, Yamamoto T,
Mieno M, Hatakeyama S. Dose-dependent effect of
daptomycin on the artificial prolongation ofprothrombin time in coagulation abnormalities: In
vitro verification. BMC Pharmacol Toxicol. 2017;18:74.
(3) Higashino T, Takada T, Nakaoka H, Toyoda Y,
Stiburkova B, Miyata H, Ikebuchi Y, Nakashima H,
Shimizu S, Kawaguchi M, Sakiyama M, Nakayama
A, Akashi A, Tanahashi Y, Kawamura Y, Nakamura
T, Wakai K, Okada R, Yamamoto K, Hosomichi K,
Hosoya T, Ichida K, Ooyama H, Suzuki H, Inoue I,
Merriman TR, Shinomiya N, Matsuo H. Multiple
common and rare variants of ABCG2 cause gout.
RMD Open. 2017;3:e000464.
(4) Kusunoki T, Nakagawa H, Tsukamoto M, Toyoda Y,
Kamiya K, Okada H, Hara S, Hatakeyama K,
Furukawa M, Ikeda K. Earwax phenotype related toa risk factor of middle ear cholesteatoma. M J Otol.
2017;1:003.
(5) Nakayama A, Nakaoka H, Yamamoto K, Sakiyama
M, Shaukat A, Toyoda Y, Okada Y, Kamatani Y,
Nakamura T, Takada T, Inoue K, Yasujima T, Yuasa

1. Elucidation of the molecular mechanism which
controls in vivo disposition of lipids / bile acids /uric acid, and establishment of new therapy forlife-style related diseases based on those
integrated understanding.
2. Elucidation of the dynamic regulatory mechanismof bone resorption / bone formation, and establishment of new therapy for bone metabolic disease460

H, Shirahama Y, Nakashima H, Shimizu S,
Higashino T, Kawamura Y, Ogata H, Kawaguchi M,
Ohkawa Y, Danjoh I, Tokumasu A, Ooyama K, Ito T,
Kondo T, Wakai K, Stiburkova B, Pavelka K, Stamp
LK, Dalbeth N, Eurogout C, Sakurai Y, Suzuki H,
Hosoyamada M, Fujimori S, Yokoo T, Hosoya T,
Inoue I, Takahashi A, Kubo M, Ooyama H, Shimizu
T, Ichida K, Shinomiya N, Merriman TR, Matsuo H,
Eurogout C. GWAS of clinically defined gout andsubtypes identifies multiple susceptibility loci that
include urate transporter genes. Ann Rheum Dis.
2017;76:869-77.
(6) Ogawa M, Yamanashi Y, Takada T, Abe K,
Kobayashi S. Effect of luteolin on the expression ofintestinal cholesterol transporters. Journal of
Functional Foods. 2017;36:274-79.
(7) Oriyama T, Yamamoto T, Yanagihara Y, Nara K,
Abe T, Nakajima K, Aoyama T, Suzuki H.
Evaluation of the permeation of antineoplastic
agents through medical gloves of varying materials
and thickness and with varying surface treatments. J
Pharm Health Care Sci. 2017;3:13.
(8) Saito M, Hatakeyama S, Hashimoto H, Suzuki T,
Jubishi D, Kaneko M, Kume Y, Yamamoto T,
Suzuki H, Yotsuyanagi H. Dose-dependent artificial
prolongation of prothrombin time by interaction
between daptomycin and test reagents in patients
receiving warfarin: A prospective in vivo clinicalstudy. Ann Clin Microbiol Antimicrob. 2017;16:27.
(9) Toyoda Y, Kashikura K, Soga T, Tagawa YI.
Metabolomics of an in vitro liver model containing
primary hepatocytes assembling around an endothelial cell network: Comparative study on themetabolic stability and the effect of acetaminophen
treatment. J Toxicol Sci. 2017;42:445-54.
(10) Toyoda Y, Takada T, Gomi T, Nakagawa H,
Ishikawa T, Suzuki H. Clinical and molecularevidence of ABCC11 protein expression in axillary
apocrine glands of patients with axillary osmidrosis.
Int J Mol Sci. 2017;18.
(11) Toyoda Y, Takada T, Suzuki H. Spontaneous
production of glutathione-conjugated forms of 1,2dichloropropane: Comparative study on metabolic
activation processes of dihaloalkanes associatedwith occupational cholangiocarcinoma. Oxid Med
Cell Longev. 2017;2017:9736836.
(12) Yamamoto H, Takada T, Yamanashi Y, Ogura M,

Masuo Y, Harada-Shiba M, Suzuki H. VLDL/LDL
acts as a drug carrier and regulates the transport andmetabolism of drugs in the body. Sci Rep. 2017;7:633.
(13) Yamamoto T, Furihata K, Hisaka A, Moritoyo T,
Ogoe K, Kusayama S, Motohashi K, Mori A,
Iwatsubo T, Suzuki H. Notable drug-druginteraction between etizolam and itraconazole inpoor metabolizers of cytochrome P450 2C19. J
Clin Pharmacol. 2017;57:1491-99.
(14) Yamanashi Y, Takada T, Kurauchi R, Tanaka Y,
Komine T, Suzuki H. Transporters for the intestinal
absorption of cholesterol, vitamin E, and vitamin K.
J Atheroscler Thromb. 2017;24:347-59.

461

Rehabilitation Center
Professor
Nobuhiko Haga, M.D.

Lecturer

Yusuke Shinoda, M.D.

Research Associate
Yasuo Nakahara, M.D., Yasuaki Karasawa, M.D., Motomu Suga, M.D.,
Sayaka Fujiwara, M.D.

Homepage

http://todaireh.umin.ne.jp

Introduction and Organization
The physical therapy service started in 1963 at the
University of Tokyo Hospital, and then expanded toinclude occupational therapy and social work section.
In 1966 this service was converted to the central
rehabilitation service department as a part of theCentral Diagnostic and Therapeutic Service Department. The Central Rehabilitation Service became an
independent unit in 1970. After the reorganization of
the University of Tokyo Hospital according to majororganic classification in 1998, outpatient clinic asrehabilitation medicine was installed. The formal titleof our unit was changed from the Physical Therapy
Department to the Rehabilitation Department by thebudget measures in the fiscal year 2001, and we
integrated the related personnel categories, which
belonged to the orthopedic surgery department and thephysical medicine department.
At present our department consists of four sections.
Rehabilitation physicians’ section includes fivefull-time doctors and two other part-time doctors.
They work chiefly for clinical practice in medical
rehabilitation service, but also have to engage inteaching activities for medical students. Nineteen
physical therapists are working in the physical therapy
section. In the occupational therapy section, six
occupational therapists work for the generalrehabilitation service and the other four therapists
work for the psychiatric rehabilitation. Four acupunc-

ture therapists perform acupuncture and moxbustion.
In the Day-care Unit, clinical psychologists and nurses
also work. In 2006, speech therapists who had
belonged to other departments in the University ofTokyo Hospital were included in our department.
From 2009, a speech therapist added to ourdepartment, and now three therapists perform therapy
for patients with aphasia, dysarthria, and dysphagia.

Clinical activities
The professor serves as a director of Rehabilitation
Center, the University of Tokyo Hospital. The Rehabilitation Center and the Department of Rehabilitation
Medicine are united and engage in clinical practice.
We have at present no charged ward, and treat about
4,000 new referrals annually from almost all the
departments of the university hospital. We always takecharge of 250-300 patients corresponding about
25-30% of the whole number of inpatients. We also
see 30 people per day at the outpatient rehabilitation
setting. The numerical ratio of outpatient is being
reduced in order to give priority to the clinical service
corresponding to needs expansion of service toinpatients.

Teaching activities
We have provided several clinical curriculums on
rehabilitation medicine for 4th, 5th, and 6th year

462

medical students since 1973. The systematic lecture
series for 4th year medical students (M2) include thesubjects on rehabilitation for disorders such ascerebrovascular disturbances, respiratory disorders,
neuromuscular diseases, bone and joint diseases, andpediatric disorders as well as on outline of rehabilitation, and amputation/prostheses. We have provided aclinical practice in small group, so-called clinicalclerkship for 5th year students from Wednesday to
Friday every week. They experience a few patientsand learn how to take a patients’ history, physicalfindings, functional evaluation, and how to plan
rehabilitation programs. We have introduced a few ofelective students for elective clinical clerkship to ourcollaborating hospitals with specialized rehabilitationward.
In addition, we have provided the training ofstudents including physical therapy, occupational
therapy, and speech therapy. Twenty students or morecome and stay at the university hospital annually as along-term clerkship from several PT/OT/ST training
schools.

References
1.

2.

3.

4.

Research activities
Our research activities are growing up. In 2006, theRehabilitation Center moved to the new building and a
research laboratory was provided for the first time. As
the motion analysis system was partially renewed, weare planning our researches mainly in the field ofmusculoskeletal disabilities. In addition, we areplanning collaborating researches with other departments in our hospital, other faculties in our university,and institutions outside the University of Tokyo. The
ongoing and scheduled projects are as follows.
1) 3D Motion analysis of patients with musculoskeletal disorders
2) Study on the relationship between sensory deficit
and motor control
3) Rehabilitation and long-term outcome in patientswith skeletal dysplasias
4) Pathology and treatment for patients withcongenital limb deficiencies
5) Analysis of rehabilitation outcome using DPC
data

5.

6.

7.

Di Rocco M, Baujat G, Bertamino M, Brown M,
De Cunto CL, Delai PLR, Eekhoff EMW, Haga N,
Hsiao E, Keen R, Morhart R, Pignolo RJ, Kaplan
FS. International physician survey on management of FOP: a modified Delphi study. Orphanet
J Rare Dis. 12(1): 110, 2017Endoh S, Yamana H, Nakahara Y, Matsui H,
Fushimi K, Yasunaga H, Haga N: Risk factors forin-hospital mortality and reamputation following
lower limb amputation. Progress in Rehabilitation Medicine 2: 20170015, 2017
Hiraoka T, Palmer JB, Brodsky MB, Yoda M,
Inokuchi H, Tsubahara A: Food transit duration isassociated with the number of stage II transport
cycles when eating solid food. Arch Oral Biol:81; 186-191, 2017
Ishikawa Y, An Q, Nakagawa J, Oka H, Yasui T,
Tojima M, Inokuchi H, Haga N, Yamakawa H,
Tamura Y, Yamashita A, Asama H: Gait analysis
of patients with knee osteoarthritis by using
elevation angle: Confirmation of the planar law
and analysis of angular difference in the approximate plane. Advanced Robotics 31: 68-79, 2017
Kaneoka A, Pisegna JM, Saito H, Lo M, Felling
K, Haga N, LaValley MP, Langmore SE: A
systematic review and meta-analysis ofpneumonia associated with thin liquid versus
thickened liquid intake in patients who aspirate.
Clin Rehabil 31(8): 1116-1125, 2017
Kaneoka A, Pisegna JM, Inokuchi H, Ueha R,
Goto T, Stepp C, Nito T, LaValley MP, Haga N,
Langmore SE: Relationship between laryngeal
sensory deficits, aspiration and pneumonia inpatients with dysphagia. Dysphagia, Epub aheadof print, 2017
Kojima T, Ishikawa H, Tanaka S, Haga N,
Nishida K、Yukioka M, Hashimoto J, Miyahara H,
Niki Y, Kimura T, Oda H, Asai S, Funahashi K,
Kojima M, Ishiguro N: Characteristics offunctional impairment in patients with longstanding rheumatoid arthritis based on range of
motion of joints: Baseline data from a multicenterprospective observational cohort study toevaluate the effectiveness of joint surgery in the

463

8.

9.

10.

11.

12.

13.

14.

15.

treat-to-target era. Mod Rheumatol, Epub aheadof print, 2017
Kojima T, Ishikawa H, Tanaka S, Haga N,
Nishida K, Yukioka M, Hashimoto J, Miyahara H,
Niki Y, Kimura T, Oda H, Asai S, Funahashi K,
Kojima M, Ishiguro N: Validation and reliabilityof the Timed Up and Go test for measuring
objective functional impairment in patients withlong-standing rheumatoid arthritis: a crosssectional study. Int J Rheum Dis, Epub ahead ofprint, 2017
Mano H, Fujiwara S, Haga N: Adaptive
behaviour and motor skills in children with upper
limb deficiency. Prosthet Orthot Int, Epub aheadof print, 2017
Nakahara Y, Kitoh H, Nakashima Y, Toguchida J,
Haga N: The longitudinal study of activities ofdaily living and quality of life in Japanesepatients with fibrodysplasia ossificans progressiva. Disabil Rehabil, Epub ahead of print, 2017
Pisegna JM, Kaneoka A, Leonard R, Langmore
SE: Rethinking residue: Determining theperceptual continuum of residue on FEES toenable better measurement. Dysphagia, Epubahead of print, 2017
Sawada R, Shinoda Y, Niimi A, Nakagawa T,
Ikegami M, Kobayashi H, Homma Y, Haga N,
Tanaka S: Multiple acrometastases in a patientwith renal pelvic urothelial cancer. Case Rep
Urol, Epub ahead of print, 2017
Togo H, Rokicki J, Yoshinaga K, Hisatsune T,
Matsuda H, Haga N, Hanakawa T: Effects offield-map distortion correction on resting statefunctional connectivity MRI. Front Neurosci, 11:656, eCollection 2017
Tsuda Y, Nakagawa T, Shinoda Y, Kanatani A,
Kawai T, Taguchi S, Yamada Y, Sawada R, Kume
H, Homma Y, Tanaka S, Kawano H: Skeletalrelated events and prognosis in urothelial cancer
patients with bone metastasis. Int J Clin Oncol
22(3): 548-553, 2017
Uehara K, Ogura K, Akiyama T, Shinoda Y,
Iwata S, Kobayashi E, Tanzawa Y, Yonemoto T,
Kawano H, Kawai A: Reliability and validity ofthe musculoskeletal tumor society scoring system
for the upper extremity in Japanese patients. Clin
Orthop Relat Res 475(9): 2253-2259, 2017

464

Central Supply Service
Associate Professor
Kazuhiko Fukatsu, M.D., Ph.D.

Assistant Professor
Satoshi Murakoshi, M.D, Ph.D.

Homepage

http://www.cc.h.u-tokyo.ac.jp/mulins/zairyobu/

Introduction
Central supply service is an integrated place inthe hospital for cleaning and sterilization ofpreviously used devices. All re-usable devices aretransported to our division via automated guided
vehicle system from surgical center, ward andoutpatient clinics. The used instruments are cleaned
using standard precautionary procedures, disinfected,
reassembled, packaged, and sterilized. The sterilized
instruments are then placed at designated sites for use.
One associate professor and one assistantprofessor, one nurse, 8 staff members, and 26
members from external staff sources are the main
members of this division.

Facilities
The following facilities are located in an area of
1,077 square meters :Cleaning equipment : 7 washer disinfectors (WDs), 1
vacuum-ultrasonic cleaning unit.
Drying equipment : 5 system drying units.
Sterilizing equipment : 6 autoclaves, 2 ethylene oxide
gas sterilizers, 1 hydrogen peroxide plasma sterilizer,
1 hydrogen peroxide sterilizer, 1 low temperature
steam formaldehyde sterilizer.

Activities
Used devices are cleaned with automated washer
disinfectors and/or manual washing, then packaged
carefully into container sets or paper bags. The
packaged materials are sterilized with autoclaves,

ethylene oxide gas sterilizer or hydrogen peroxide
plasma sterilizer according to their characteristics. The
cleaning procedure is checked with test device. All
sterilization process is recorded and ensured bychemical indicators and biological indicators.
The number of devices handled in the central
supply service is dramatically increasing withincreased number of operations in the surgical centers(number of containers: 29419 for surgical center in2017).
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 5949 in 2017.

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. Saito Y, Yasuhara H, Murakoshi S, Komatsu T,
Fukatsu K, Uetera Y. Concerns Associated With
Cleaning Robotic Surgical Instruments-Response
to Wallace. Infect Control Hosp Epidemiol. 2017
Aug; 38(8):1014-1015.

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2. Shimizu N, Hatao F, Fukatsu K, Aikou S,
Yamagata Y, Mori K, Yamashita H, Nomura S,
Seto Y. Results of a nationwide questionnairebased survey on nutrition management following
gastric cancer resection in Japan. Surg Today.
2017 Dec;47(12):1460-1468.
3. Saito Y, Yasuhara H, Murakoshi S, Komatsu T,
Fukatsu K, Uetera Y. Priority of Patient Safety
Associated With Robotic Surgical InstrumentsResponse to Landenberg et al. Infect Control
Hosp Epidemiol. 2017 Jul;38(7):879-880.
4. Hatao F, Chen KY, Wu JM, Wang MY, Aikou S,
Onoyama H, Shimizu N, Fukatsu K, Seto Y, LinMT.
Randomized controlled clinical trial
assessing the effects of oral nutritional
supplements in postoperative gastric cancer
patients. Langenbecks Arch Surg. 2017 Mar;402(2):203-211.
5. Ri M, Fukatsu K, Miyakuni T, Yanagawa M,
Murakoshi S, Yasuhara H, Seto Y. Influences of
Vagotomy on Gut Ischemia-Reperfusion Injury inMice. Shock. 2017 May;47(5):646-652.
6. Saito Y, Yasuhara H, Murakoshi S, Komatsu T,
Fukatsu K, Uetera Y. Challenging Residual
Contamination of Instruments for Robotic Surgery
in Japan. Infect Control Hosp Epidemiol. 2017
Feb;38(2):143-146.

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Division of Diagnostic Pathology
Director (Associate Professor)
Tetsuo Ushiku, M.D., Ph.D.*

Deputy Director (Associate Professor)
Takeshi Sasaki, M.D., Ph.D. (Chief, Telepathology & Remote Diagnosis Promotion Center)

Professor
Masashi Fukayama, M.D., Ph.D.*

Associate Professor
Teppei Morikawa, M.D., Ph.D.*

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

Associate
Yukako Shintani-Domoto, M.D., Ph.D. (Hospital Lecturer),
Hiroyuki Abe, M.D., Ph.D. (Hospital Lecturer),
Zen-ichi Tanei, M.D., Ph.D.,

Atsushi Tanaka, M.D., Ph.D.

Munetoshi Hinata, M.D., Ph.D. *,Ryu Miyagawa, Ph.D.* (Research, Investigation of Health Hazard by Radiation)
Naoko Yamauchi, M.D., Ph.D. *,Mariko Tanaka, M.D., Ph.D. *Clinical Fellow
Kayoko Ichimura, M.D., Ph.D.,

Senior Resident
Atushi Kondo, M.D.,

Homepage

Shohei Murata, 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.
We set up Telepathology & Remote Diagnosis
Promotion Center (TRDP Center), and started Out-patient Clinic of Pathology. Chief of TRDP Center, Dr.
Sasaki explained the detail of cancer pathology to thepatients with breast cancer.
To promote the genomic medicine in clinicalpractice, we set up Center for Genome Pathology
Standardization (assisted by Japan Agency for
Medical Research and Development) (http://genome-467

project.jp/). The mission of the Center is to investigate
basic technologies for tissue banking, and to holdseminars for doctors and technicians (Drs. Sasaski,Morikawa, Kunita). Clinical Genome Conference
started in the University of Tokyo Hospital for theapplication of cancer clinical sequencing to medical
practice (Drs. T and A Ushiku) as a research project ofgenome medicine (Project organizer: Prof. HiroyukiMano). At the end of the fiscal year, the University ofTokyo Hospital is selected as a core cancer hospitalfor cancer genomics. Clinical sequence will beincorporated into actual medical practice as advanced
medical care from the next fiscal year.
We registered 1000 cases of whole slide images(WSI) in the research project of Japanese Society of
Pathology “Database of Pathology-WSI for Development of Artificial Intelligence (AI) Technique andAI-based Support System for Pathology Diagnosis” in2017. We also examined the problems in image
registration in the hospital with the Departments ofRadiology and Neurosurgery.

Clinical activities (diagnostic
pathology and autopsy)
The annual statistics of the pathologic practice in 2016
fiscal year consisted of 16,719 cases of histologicalexamination, 16,301 cases of cytology, 924 of frozen
histology, 408 of intra-operative cytology, 47 cases of
autopsy (16.7% of the autopsy rate), and 1 autopsy
case from an outside hospital.
The following surgical pathology conferences are
regularly held with each clinical division for the casesof various tumors of organs; thoracic organs (Drs.
Shinozaki-Ushiku, Hinata in charge), liver andpancreato-biliary tract (Drs. Yamauchi Tanaka), liver
metastasis (Dr. Abe), male genitourinary (Dr.
Morikawa) and female genital tracts (Drs. Ikemura,
Shintani-Domoto), breast (Drs. Ikemura, Sasaki), andbone and soft tissues (Drs. Ushiku, A Tanaka). Biopsy
conferences are also held in the cases of kidney (Drs.
Shintani-Domoto, Hinata), and skin (Dr. M Tanaka).
Our aim in the pathologic practices is to provide
the correct diagnosis as soon as possible. We are
addressing ‘one-day pathology’ using a rapidhistoprocessing machinery. We also perform double
check for reviewing the reports and slides for all casesof histological examination to prevent a potential
misdiagnosis.
Virtual slide scanners have been installed, whichenabled us to deposit the biopsy specimens as digital
information. We are setting out a future providing
system of pathologic images for clinical divisions.
We hold autopsy case conferences on every
Monday. Hospital clinico-pathological conferences(CPC)is also held every month as mentioned above,and two cases are discussed in each CPC. The
contents are provided as CPC Digest by the hospitalinternet.

Teaching activities
The lectures and exercise course of systemic
pathology are for the 2nd grade–students. ClinicalClerkship (CC) courses of autopsy and surgicalpathology are for the 4th grade students. Four students
of 3rd grade took the elective clinical clerkship course.
We instructed all clinical residents (junior course)
to submit a report of CPC case as an obligatory
requirement of their medical training for each of them.
We have made out the digest version of CPC slides
open in the hospital (Drs. Shintani and Hayashi), andalso started e-learning program for interns to solve theproblems in CPC by themselves, thereby facilitating
their understanding (Dr. Ikemura).
The Division of Diagnostic Pathology received
nine junior residents (total 34 months) in 2017 fortheir second-year program. Two residents participatedin the specialty training program under new system ofJapanese Board of Medical Specialties.

Research activities
Dr. Sasaki is in charge of the research to evaluate
feasibility of telepathology for daily practice ofdiagnostic pathology (ref.32 in Department of
Pathology and Diagnostic Pathology). We conduct
research of developing artificial intelligence(AI)-system, such as “Development of a support toolof pathology diagnosis such as rare cancers,
intraoperative report and double check using artificial
intelligence (Dr. Sasaki)”, and cooperate the project
by “Efficiency improvement and diagnostic support ofpathological diagnosis by automatic classification ofrenal biopsy pathology images using Deep Learning

468

Technology (Prof. Kazuhiko Ohe)”
We continue the study to investigate the usefulness of post mortem CT images for hospital autopsy(Drs. Shintani and Abe). We obtain postmortem
images with a CT apparatus in the autopsy-assisting
CT room, and compare the results with those of
autopsy in order to understand the patients’ pathophysiology (ref.25, 31 in Department of Pathology
and Diagnostic Pathology).
We continue the pathological studies ofneoplastic diseases on the basis of surgical pathology
conferences (see the pages of Department of
Pathology and Diagnostic Pathology). We also
cooperate for the projects developing PET and in vivo
imaging of cancers of Departments of Upper GI tract
Surgery and Hepato-biliary & Pancreas Surgery(ref.10 in Department of Pathology and Diagnostic
Pathology).
Dr. Miyagawa was a Research Associate ofDivision of Diagnostic Pathology, primarily engaged
in Investigation of Health Hazard by Radiation.

References (Case Reports Only)
See the corresponding section of Department of
Pathology and Diagnostic Pathology(1) Anzai H, Nozawa H, Tanaka J, Yasuda K, Otani
K, Nishikawa T, Tanaka T, Kiyomatsu T, Hata K,
Kawai K, Ushiku T, Ishihara S, Takano T,
Fukayama M, Watanabe T. Giant leiomyosarcoma of the rectum with lymph node metastasis: A case report and review of the literature.
Int J Surg Case Rep. 2017, 34, 27-31.
(2) Arakawa S, Kage H, Chino H, Hinata M, Hayashi
A, Toya T, Noguchi S, Ushiku T, Yamauchi Y,
Kurokawa M, Fukayama M, Nagase T. Reversionof serum VZV-IgG antibody preceding disseminated visceral varicella zoster after hematopoietic
stem cell transplantation. Ann Hematol. 2017,
96(3), 529-30.
(3) Hana T, Tanaka S, Nakatomi H, Shojima M,
Fukumoto S, Ikemura M, Saito N. Definitive
surgical treatment of osteomalacia induced byskull base tumor and determination of thehalf-life of serum fibroblast growth factor 23.
Endocr. J. 2017, 64(10), 1033-1039.

(4) Inui M, Nitadori JI, Tajima S, Yoshioka T,
Hiyama N, Watadani T, Shinozaki-Ushiku A,
Nagayama K, Anraku M, Sato M, Fukayama M,
Nakajima J. Mediastinal seminoma associatedwith multilocular thymic cyst. Surg Case Rep.
2017, 3(1), 7.
(5) Kaneko M, Kawai K, Murono K, Nishikawa T,
Sasaki K, Otani K, Yasuda K, Tanaka T,
Kiyomatsu T, Hata K, Nozawa H, Ishihara S,
Hayashi A, Shinozaki-Ushiku A, Fukayama M,
Watanabe T. Giant gastrointestinal stromal tumorof the vermiform appendix: A case report. Mol
Clin Oncol. 2017, 7(3), 399-403.
(6) Kitahara H, Nawata K, Kinoshita O, Itoda Y,
Shintani Y, Fukayama M, Ono M. Implantationof a Left Ventricular Assist Device for Danon
Cardiomyopathy. Ann Thorac Surg. 2017, 103(1),e39-e41(7) Maki H, Aoki T, Ishizawa T, Tanaka M, Sakatani
T, Beck Y, Hasegawa K, Sakamoto Y, Kokudo N.
Intraductal papillary neoplasm originating froman anomalous bile duct. Clin J Gastroenterol.
2017, 10(2), 174-8.
(8) Matsuki R, Okuda K, Mitani A, Yamauchi Y,
Tanaka G, Kume H, Homma Y, Hinata M,
Hayashi A, Shibahara J, Fukayama M, Nagase T.
A case of delayed exacerbation of interstitial lungdisease after discontinuation of temsirolimus.
Respir Med Case Rep. 2017, 22, 158-63.
(9) Mizuno H, Koya J, Fujioka Y, Ibaraki T,
Nakamura F, Hayashi A, Shinozaki-Ushiku A,
Akamatsu N, Hasegawa K, Kokudo N, Fukuyama
M, Kurokawa M. Extranodal NK/T cell
lymphoma in a living donor liver transplant
recipient. Ann Hematol. 2017, 96(6), 1051-2.
(10) Murono K, Ishihara S, Kawai K, Kaneko M,
Sasaki K, Yasuda K, Otani K, Nishikawa T,
Tanaka T, Kiyomatsu T, Hata K, Nozawa H,
Hayashi A, Ushiku T, Fukayama M, Watanabe T.
Non-occlusive mesenteric ischemia localized in
the transverse colon: a case report. Surg Case Rep.
2017, 3(1), 23.
(11) Sasaki K, Ishihara S, Hata K, Kiyomatsu T,
Nozawa H, Kawai K, Tanaka T, Nishikawa T,
Otani K, Yasuda K, Kaneko M, Murono K, Abe
H, Morikawa T, Watanabe T. Radiation-

469

associated colon cancer: A case report. Mol Clin
Oncol 2017, 6(6), 817-820.
(12) Shintani-Domoto Y, Shinozaki-Ushiku A, Okuma
H, Kurokawa M, Fukayama M. Laminar crystal
deposition in large vessels in a patient withcrystalglobulinemia. Pathol Int. 2017, 67(5), 26972.
(13) Shiratori H, Nishikawa T, Shintani Y, Murono K,
Sasaki K, Yasuda K, Otani K, Tanaka T,
Kiyomatsu T, Hata K, Kawai K, Nozawa H,
Ishihara S, Fukayama M, Watanabe T.
Perforation of jejunal diverticulum with ectopic
pancreas. Clin J Gastroenterol. 2017, 10(2),137-141.
(14) Sonoda H, Kawai K, Yamaguchi H, Murono K,
Kaneko M, Nishikawa T, Otani K, Sasaki K,
Yasuda K, Tanaka T, Kiyomatsu T, Hata K,
Nozawa H, Ishihara S, Aikou S, Yamashita H,
Ushiku T, Seto Y, Fukayama M, Watanabe T.
Lymphogenous metastasis to the transverse colonthat originated from signet-ring cell gastriccancer: A case report and review of the literature.
Clin Res Hepatol Gastroenterol. 2017, 41(6),e81-6.
(15) Takumida H, Yakabe M, Mori H, Shibasaki K,
Umeda-Kameyama Y, Urano T, Mano T, Hayashi
A, Ikemura M, Ogawa S, Akishita M. Case of a78-year-old woman with a neuronal intranuclear
inclusion disease. Geriatr Gerontol Int, 2017,17(12), 2623-5.
(16) Terada Y, Sato M, Abe H, Kuwano H, Nagayama
K, Nitadori JI, Anraku M, Nakajima J. Squamouscell carcinoma of the lung showing a groundglass nodule on high-resolution computed
tomography associated with pneumoconiosis: acase report. Surg Case Rep. 2017, 3(1), 107.
(17) Tsukui D, Kanda H, Shinozaki-Ushiku A,
Tateishi S, Takeshima Y, Nagafuchi Y, Sasaki O,
Iwasaki Y, Harada H, Shibuya M, Sumitomo S,
Shoda H, Kubo K, Fujio K, Nakamura F,
Kurokawa M, Fukayama M, Yamamoto K.
Polymorphic lymphoproliferative disorders inpatients with rheumatoid arthritis are associatedwith a better clinical outcome. Mod Rheumatol.
2017, 23, 1-5.

470

Department of Corneal
Transplantation
Associate Professor
Tomohiko Usui, M.D., Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/kakumaku.html

Introduction and Organization
The department of corneal transplantation wasestablished in 1976 as one of clinical sections in the
University of Tokyo Hospital. The purpose of theestablishment of this section is to carry out andpromote corneal transplantation and to perform
clinical and basic research in the corneal diseases andcorneal transplantation. The section is composed of adirector (Associate Professor Tomohiko Usui).

Clinical activities
The clinical activities of this section include corneal
transplantation and outpatient clinics for various
corneal diseases as a consulting corneal service. The
director is responsible not only for corneal transplantation but also for general ophthalmologicalpractice as a senior staff member of Department ofOphthalmology, University of Tokyo. The corneal
service for special cases are held every Monday (PM),Wednesday (AM), Thursday (AM), and Friday (AM).
Contact lens clinic for keratoconus and postkeratoplasty eyes and keratoconus clinic for providing
corneal crosslinking surgery, which is a brand-new
treatment to halt keratoconus progression, were heldin the afternoon of Wednesday. At the corneal service,
we determine indication for corneal transplantationand follow up patients after the surgery. Total 72
corneal surgeries including keratoplasty were
performed in 2016. In addition to the full-thickness
corneal transplantation (penetrating keratoplasty), we
have successfully performed corneal endothelial transplantation for patients with bullous keratopathy, themost common disease of corneal transplantation.
Generally, corneal transplantation is performed as
emergency operation, because we need to transplant
corneas as soon as possible.
The other important activities of the section include
mediation of donor eyes to other university hospitals
and medical institutes that need donor eyes for corneal
transplantation with cooperation of Eyebank. We arealso performing corneal transplantation using corneas
from American Eyebank as needed.
Followings are our main clinical themes to be
pursued to improve the safety and prognosis ofcorneal transplantation.
1) Positive proof that donors were free of such
infectious diseases as viral hepatitis, syphilis,
AIDS and acute T-cell leukemia to prevent
transmission to recipient patients through grafting.
2) Postoperative clinical outcomes are evaluated inregenerative medicine for ocular surface
reconstruction, such as cultured corneal limbal,
oral mucosal and conjunctival epithelial sheettransplantation on the amniotic membrane, fullthickness corneal transplantation, lamellar keratopasty, and endothelial keratoplasty.
3) Critical factors to affect clinical outcomes are
statistically investigated in various kinds 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 for471

young ophthalmologists on ophthalmological examinations at the outpatient clinic.

Research activities
We are conducting clinical research of postoperative results of DSAEK, clinical results of corneal
crosslinking, and clinical research of corneal biometryby using anterior segment OCT.
In addition, we are investigating the delivery of
nucleic acid based drug in corneal neovascularizationor corneal dystrophy, gene editing for corneal
dystrophy, the expression and function of novel mucin,
drug delivery system with soft contact lenses, corneal
graft rejection and statistical analysis of long term
results in corneal transplantation.

References
1: Taketani Y, Kitamoto K, Sakisaka T, Kimakura M,
Toyono T, Yamagami S, Amano S, Kuroda M,
Moore T, Usui T, Ouchi Y. Repair of the TGFBI
gene in human corneal keratocytes derived from a
granular corneal dystrophy patient via CRISPR/
Cas9-induced homology-directed repair. Sci Rep.
2017 Dec 1;7(1):16713.
2: Aixinjueluo W, Usui T, Miyai T, Toyono T,
Sakisaka T, Yamagami S. Accelerated transepithelial corneal cross-linking for progressive
keratoconus: a prospective study of 12 months. Br
J Ophthalmol. 2017 Sep;101(9):1244-1249.
3: Kim EC, Toyono T, Berlinicke CA, Zack DJ,
Jurkunas U, Usui T, Jun AS. Screening andCharacterization of Drugs That Protect Corneal
Endothelial Cells Against Unfolded Protein
Response
andOxidative
Stress.
InvestOphthalmol Vis Sci. 2017 Feb 1;58(2):892-900.
4: Benischke AS, Vasanth S, Miyai T, Katikireddy
KR, White T, Chen Y, Halilovic A, Price M, Price
F Jr, Liton PB, Jurkunas UV. Activation of
mitophagy leads to decline in Mfn2 and loss of
mitochondrial mass in Fuchs endothelial corneal
dystrophy. Sci Rep. 2017 Jul 27;7(1):6656.

472

Department of Cell Therapy andTransplantation Medicine
Professor
Mineo Kurokawa, M.D., Ph.D. (Hematology-Oncology)

Lecturer
Mitsuteru Hiwatari, M.D., Ph.D. (Pediatrics/Hematology-Oncology)

Assistant Professor
Kazuhiro Toyama, M.D., Ph.D. (Hematology-Oncology)
Hiroaki Maki, M.D., Ph.D. (Hematology-Oncology)

Homepage

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

Introduction and Organization
The Department of Cell Therapy and Transplantation Medicine was institutionally established in
1995, and was formally organized in 1996. At present,
the staff consists of the above-mentioned medical
doctors. Clinical facilities include 8 single-patient
rooms with high- efficiency particulate air filtrationand other high standards. Patients who are eligible forthe treatment with high-grade infectious prophylaxis
are admitted to the facilities.

Clinical activities
Approximately 100 patients have undergone
hematopoietic stem cell transplantation (HSCT) in our
department since 1995. Allogeneic bone marrowtransplantation from donors Japan Marrow Donor
Program (JMDP) as well as international bone marrowdonor programs, HSCT from HLA-mismatcheddonors, and donor lymphocyte infusion are available.
In 2017, 17 patients (including 2 children) received
autologous HSCT and 26 patients (including 8
children) allogeneic HSCT. We cooperate with themembers of Department of Hematology and Oncology,
Hematology/Oncology group in the Department ofPediatrics, and Department of Transfusion Medicine.

Allogeneic hematopoietic stem cell transplantation:
Bone marrow cells are operatively harvested andinfused without preservation. For peripheral blood
stem cell transplantation, leukapheresis is performed
with the use of an automated continuous flow blood
cell separator, and harvested cells are preserved at-196°C in cooperation with Department of Transfusion Medicine. Recently, transplantation after preconditioning of reduced intensity (RIST for reducedintensity HSCT or NST for non- myeloablative
HSCT) is commonly performed for the elderly andpatients with organ dysfunction. The development of
this strategy is expanding the eligibility of transplant
recipients. Allogeneic HSCT for the elderly is
performed under the admission of ethical committeeof the Faculty of Medicine.
High-dose chemotherapy with or without autologous stem cell support: High-dose chemotherapy isadministered according to the malignant disease. For
the autologous stem cell support, peripheral blood
stem cell is usually selected as a source of stem cells.
Similar procedures used in the allogeneic stem cell
harvest are performed for leukapheresis and preservation of autologous stem cell.

473

Clinical conference for hematopoietic stem celltransplantation: The conference is held monthly. The
members of Department of Hematology and Oncology,
Hematology/Oncology group in Department ofPediatrics, and Department of Transfusion Medicine
join the conference and discuss on HSCT recipients.

Teaching activities
Together with the members of Department of
Hematology and Oncology and Hematology/Oncology
group in the Department of Pediatrics, lecture courses
on etiology, pathogenesis, clinical and laboratory
features, differential diagnosis, therapy and prognosis
for all hematological diseases are provided to thesecond grade medical students. Clinical clerkshipcourses are given to the third grade medical students,
who join the patient care teams consisting of juniorand senior medical doctors and learn medical practices
and patient management, through playing a role as a
junior member of the team, as well as throughdiscussions and presentations.

Research activities
The major research projects are focused on clinicalstudies such as development of improved/new
methods for hematopoietic stem cell transplantation,
immunotherapy for hematopoietic malignancies, andbasic studies on hematopoietic stem cells, leukemogenesis and regenerative medicine using hematopoietic cells. In the area of pediatric oncology, we
continue the studies on molecular mechanisms ofpediatric malignancies such as neuroblastoma,
rhabdomyosarcoma, and infant leukemia.

References
1. Hiwatari M, Seki M, Akahoshi S, Yoshida K,
Miyano S, Shiraishi Y, Tanaka H, Chiba K,
Ogawa S, Takita J. Molecular studies reveal
MLL-MLLT10/AF10 and ARID5B-MLL genefusions displaced in a case of infantile acutelymphoblastic leukemia with complex karyotype.
Oncol Lett. 2017; 14:2295-2299.
2. Yanada M, Yano S, Kanamori H, Gotoh M, Emi
N, Watakabe K, Kurokawa M, Nishikawa A, Mori
T, Tomita N, Murata M, Hashimoto H, Henzan H,

Kanda Y, Sawa M, Kohno A, Atsuta Y, Ichinohe
T, Takami A. Autologous hematopoietic celltransplantation for acute promyelocytic leukemia
in second complete remission: outcomes before
and after the introduction of arsenic trioxide. Leuk
Lymphoma. 2017; 58:1061-1067.
3. Arai Y, Kondo T, Shigematsu A, Tanaka J,
Ohashi K, Fukuda T, Hidaka M, Kobayashi N,
Iwato K, Sakura T, Onizuka M, Ozawa Y, Eto T,
Kurokawa M, Kahata K, Uchida N, Atsuta Y,
Mizuta S, Kako S. Improved prognosis withadditional medium-dose VP16 to CY/TBI inallogeneic transplantation for high risk ALL in
adults. Am J Hematol. 2018; 93:47-57.
4. Uryu K, Nishimura R, Kataoka K, Sato Y,
Nakazawa A, Suzuki H, Yoshida K, Seki M,
Hiwatari M, Isobe T, Shiraishi Y, Chiba K,
Tanaka H, Miyano S, Koh K, Hanada R, Oka A,
Hayashi Y, Ohira M, Kamijo T, Nagase H,
Takimoto T, Tajiri T, Nakagawara A, Ogawa S,
Takita J. Identification of the genetic and clinicalcharacteristics of neuroblastomas using genomewide analysis. Oncotarget. 2017; 8:107513107529.
5. Watanabe K, Kato M, Ishimaru T, Hiwatari M,
Suzuki T, Minosaki Y, Takita J, Fujishiro J, Oka
A. Perioperative management of severe congenital
protein C deficiency. Blood Coagul Fibrinolysis.
2017; 28:646-649.

474

Department of Endoscopy andEndoscopic Surgery
Associate Professor
Mitsuhiro Fujishiro, M.D., Ph.D.

Associate
Shuntaro Yoshida, M.D., Ph.D.

Homepage

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

Introduction and Organization
Department of Endoscopy and Endoscopic Surgery
were established in April 1997. Although the present
regular staffs of our department are only two doctors,
about 80 doctors from other departments including thedepartment of internal medicine, surgery, gynecology
and otorhinolaryngology, participate the endoscopic
procedures.

Clinical activities
Endoscopic procedures, including upper gastrointestinal endoscopy, colonoscopy, bronchoscopy,
otorhinolaryngological endoscopy and gynecologicalendoscopy, are performed from Monday to Friday.
Emergency endoscopy is performed in the nighttime
or holidays. The numbers of endoscopic procedures ineach field are increasing gradually year by year andthe total number during 2016 school year reached to
20,000. In the gastrointestinal tract, image enhanced
endoscopy for detail inspection and therapeutic endos-

copy, 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, radiotherapy department, surgery department or
intensive care units. All endoscopes in our hospital arecollected in our department after use and disinfected.

Teaching activities
We participate in under-graduate education as a part ofsystemic lectures and bed-side learning by thedepartment of gastroenterology, surgery and otherdepartments. As for post-graduate education, training
opportunities for endoscopy and endoscopic surgery
are given to resident or young doctors in a program ofeach department.

475

Table 1. Endoscopic examinations in the Department of Endoscopy and Endoscopic Surgery
EGD*
Colonoscopy
Bronchoscopy
EUS**Enteroscopy
Laryngoscopy
Colposcopy

2008
9822
4679
165
402
133
63
256

2009
10682
4996
226
518
181
75
307

2010
10556
5152
255
551
181
70
361

2011
10963
5208
197
630
282
108
378

2012
11376
5688
196
698
282
823
365

2013
11840
6000
169
763
375
128
404

2014
11740
6043
218
766
396
102
327

2015
11874
6394
228
882
310
105
295

2016
11944
6814
362
1084
86
125
417

2017
11490
5921
350
1023
304
114
430

Total

15520

16566

17256

17764

18688

19679

19592

20088

20832

19632

*Esophagogastroduodenoscopy, **Endoscopic ultrasonography

Research activities
Our researches cover a variety of endoscopic fields incooperation with other departments.

References(1) Fujishiro M, Yoshida S, Matsuda R, Narita A,
Yamashita H, Seto Y. Updated evidence on
endoscopic resection of early gastric cancer fromJapan. Gastric Cancer. 2017 Mar;20(Suppl 1):3944..
(2) Maeda M, Nakajima T, Oda I, Shimazu T,
Yamamichi N, Maekita T, Asada K, Yokoi C,
Ando T, Yoshida T, Nanjo S, Fujishiro M,
Gotoda T, Ichinose M, Ushijima T. High impact
of methylation accumulation on metachronous
gastric cancer: 5-year follow-up of a multicentre
prospective cohort study. Gut. 2017 Sep;66(9):1721-1723..
(3) Niimi K, Ishibashi R, Mitsui T, Aikou S,
Kodashima S, Yamashita H, Yamamichi N,
Hirata Y, Fujishiro M, Seto Y, Koike K.
Laparoscopic and endoscopic cooperative
surgery for gastrointestinal tumor. Ann Transl
Med. 2017 Apr;5(8):187.
(4) Sakaguchi Y, Tsuji Y, Fujishiro M, Kataoka Y,
Saito I, Shichijo S, Minatsuki C, AsadaHirayama I, Yamaguchi D, Niimi K, Ono S,
Kodashima S, Yamamichi N, Koike K.
Evaluation of endoscopic submucosal dissection
using a new endosurgical knife DN-D2718B: afirst clinical feasibility study. Endosc Int Open.
2017 Jul;5(7):E670-E674.

(5) Yamada A, Niikura R, Maki K, Nakamura M,
Watabe H, Fujishiro M, Oka S, Fujimori S,
Nakajima A, Ohmiya N, Matsumoto T, Tanaka S,
Koike K, Sakamoto C. Proton pump inhibitor
therapy did not increase the prevalence of smallbowel injury: A propensity-matched analysis.
PLoS One. 2017 Aug 3;12(8):e0182586.
(6) Yamaguchi D, Kodashima S, Fujishiro M, Ono S,
Niimi K, Mochizuki S, Tsuji Y, Asada-Hirayama
I, Sakaguchi Y, Shichijo S, Minatsuki C,
Yamamichi N, Koike K. Evaluation of imageenhanced endoscopic technology using advanced
diagnostic endoscopy for the detection of earlygastric cancer: a pilot study. Endosc Int Open2017; 05(09): E825-E833(7) Ono S, Myojo M, Harada H, Tsuji K, Murakami
D, Suehiro S, Doyama H, Ando J, Saito I,
Fujishiro M, Komuro I, Koike K. Is it possible toperform gastric endoscopic submucosal dissection without discontinuation of a single antiplatelet of thienopyridine derivatives? Endosc Int
Open 2017; 05: E943–E949.
(8) Niikura R, Hirata Y, Suzuki N, Yamada A,
Hayakawa Y, Suzuki H, Yamamoto S, Nakata R,
Komatsu J, Okamoto M, Kodaira M, Shinozaki T,
Fujishiro M, Watanabe T, Koike K. Colonoscopy
reduces colorectal cancer mortality: A multicenter, long-term, colonoscopy-based cohort
study. PLoS One. 2017 Sep 28;12(9):e0185294.
(9) Mizutani H, Ono S, Ohki D, Takeuchi C, Yakabi
S, Kataoka Y, Saito I, Sakaguchi Y, Minatsuki C,
Tsuji Y, Niimi K, Kodashima S, Yamamichi N,
Fujishiro M, Koike K. Recent Development of476Techniques and Devices in Colorectal Endoscopic Submucosal Dissection. Clin Endosc.
2017 Nov;50(6):562-568(10) Yamamoto S, Ikeda M, Fujimoto F, Okamoto K,
Wakabayashi Y, Sato T, Tatsuno K, Kaburaki T,
Yoshida S, Okugawa S, Koike K, Moriya K.
Bilateral Candida endophthalmitis accompanying
Candida lusitaniae bloodstream infection: A casereport. J Infect Chemother. 2018 Feb;24(2):147149.
(11) Toyoshima O, Tanikawa C, Yamamoto R,
Watanabe H, Yamashita H, Sakitani K, Yoshida S,
Kubo M, Matsuo K, Ito H, Koike K, Seto Y,
Matsuda K. Decrease in PSCA expression caused
by Helicobacter pylori infection may promote
progression to severe gastritis. Oncotarget. 2017
Dec 14;9(3):3936-3945.
(12) Ota Y, Yamada A, Kobayashi Y, Niikura R,
Shimpoh T, Narita A, Yoshida S, Suzuki N,
Watabe H, Hirata Y, Ishihara S, Sunami E,
Watanabe T, Koike K. Diagnostic capability ofcolon capsule endoscopy for advanced colorectal
cancer: A pilot study. Dig Endosc. 2017 Sep;
29(6):695-701.
(13) Takahara N, Isayama H, Nakai Y, Yoshida S,
Saito T, Mizuno S, Yagioka H, Kogure H,
Togawa O, Matsubara S, Ito Y, Yamamoto N,
Tada M, Koike K. A Novel Partially Covered
Self-Expandable Metallic Stent with Proximal
Flare in Patients with Malignant Gastric Outlet
Obstruction. Gut Liver. 2017 Jul 15;11(4):481488.
(14) Nakada A, Niikura R, Yamada A, Yoshida S,
Hirata Y, Koike K. The incidence of postcolonoscopy colorectal cancer: a retrospective
long-term cohort study using a colonoscopy
database. Int J Colorectal Dis. 2017 Jun;32(6):839-845.
(15) Toyoshima O, Hata K, Yoshida S, Arita M.
New-generation chromoendoscopy may increase
confidence in the DISCARD2 study. Gut. 2017
Oct 11. pii: gutjnl-2017-314999. doi: 10.1136/
gutjnl-2017-314999. [Epub ahead of print] No
abstract available.
(16) Nishioka Y, Shindoh J, Yoshioka R, Gonoi W,
Abe H, Okura N, Yoshida S, Sakamoto Y,
Hasegawa K, Fukayama M, Kokudo N. ClinicalImpact of Preoperative Chemotherapy on
Microscopic Cancer Spread Surrounding
Colorectal Liver Metastases.Ann Surg Oncol.
2017 Aug;24(8):2326-2333.
(17) Shimpoh T, Hirata Y, Ihara S, Suzuki N,
Kinoshita H, Hayakawa Y, Ota Y, Narita A,
Yoshida S, Yamada A, Koike K. Prevalence of
pks-positive Escherichia coli in Japanese patientswith or without colorectal cancer.Gut Pathog.
2017 Jun 12;9:35.
(18) Nishizawa T, Suzuki H, Fujimoto A, Kinoshita H,
Yoshida S, Isomura Y, Toyoshima A, Kanai T,
Yahagi N, Toyoshima O. Effects of patient age
and choice of antisecretory agent on success oferadication therapy for Helicobacter pylori
infection. J Clin Biochem Nutr. 2017 May;60(3):208-210(19) Toyoshima O, Yamaji Y, Yoshida S, Matsumoto
S, Yamashita H, Kanazawa T, Hata K. Endoscopic gastric atrophy is strongly associated withgastric cancer development after Helicobacter
pylori eradication.Surg Endosc. 2017 May;31(5):2140-2148.
(20) Nishizawa T, Suzuki H, Sakitani K, Yamashita H,
Yoshida S, Hata K, Kanazawa T, Fujiwara N,
Kanai T, Yahagi N, Toyoshima O. Family history
is an independent risk factor for the progressionof gastric atrophy among patients with
Helicobacter pylori infection.United European
Gastroenterol J. 2017 Feb;5(1):32-36.

477

Department of Hemodialysis andApheresis
Professor
Masaomi Nangaku, M.D.,Ph.D.

Lecturer
Akihiko Matsumoto, M.D., Ph.D.
Yoshifumi Hamasaki, M.D., Ph.D.

Introduction and Organization
Hemodialysis and related blood purification therapy
had been individually performed in their respective
departments. However, all the departments’ apparatus
and human resources were centralized to form the
Department of Hemodialysis and Center for
Hemodialysis in 2000 at the University Hospital. The
Center for Hemodialysis was further renovated andstarted operations in Fall of 2006. This new Center for
Hemodialysis is equipped with one pressure control
unit in addition to 12 hemodialysis machines under astate-of-the-art hemodialysis control system. Ourconcept of a hemodialysis controlling system is a hub
to transfer all digital and analog data from patients andto monitor machines, including blood purification
machines, to the host computer in our hospital,
centralizing all data and administering medical coding
and billing robustly. Blood purification machines in
the ICU are also connectable to this system, which
was developed collaboratively with Nihon Kohden
Corp. Blood purification machines are selected
uniformly to secure patients’ safety while avoiding
human error and increasing the overall educational
quality of staff members.

Clinical activities
1.
2.

Start of maintenance hemodialysis therapy forend-stage renal disease (ESRD).
Regular hemodialysis therapy for hospitalized

3.
4.

5.

6.
7.
8.
9.

ESRD patients. Please note that our center does
not accept holiday dialysis.
Emergency hemodialysis and hemodiafiltration
for ICU patients.
Plasma exchange for neurodegenerative diseases,
collagen diseases, TMA (TTP), and pre/post solidorgan transplant patients.
Double filtration plasmapheresis (DFPP) for
collagen diseases, dermatological disorders,
myasthenia gravis, waldenstrom macroglobulinemia.
LDL apheresis for familial hypercholesterolemia,
nephrotic syndrome, and PAD patients.
White blood cell elimination therapy for inflamematory bowel diseases such as ulcerative colitis.
Cell-free and concentrated ascites reinfusion
therapy (CART) for refractory ascites.
Induction and maintenance of peritoneal dialysis
for ESRD.

Teaching activities
1.

2.
3.
4.

A systematic review course for M2 students,
which covers clinical features, diagnosis, andevidence-based therapeutic strategies for acutekidney injury and acute renal failure.
Technical development course for medical
engineers and nurses.
Tutorial course for clinical fellows applying to
the speciality of blood purification therapy.
Exposure in hemodialysis & apheresis course to

478

5.

6.

second year residents on request.
Our state-of-the-art blood purification protocols
are summarized in Japanese handbook in 2010
[Apheresis Pocket Manual] and 2011 [CRRTPocket Manual]. English and Chinese version of“Apheresis Pocket Manual” is available for
global experts of Apheresis therapy.
Our department takes main part in Critical Care
Nephrology Course for educating young clinicalresearchers and fellows in collaboration with
Department of Critical Care Medicine.

Research activities
1.
2.
3.
4.

5.
6.
7.
8.
9.

Prognostic analysis for post-liver transplantpatients received plasma exchange therapy.
Identification of prognostic factors in AKI/CRRT
patients.
Genome wide association study for Nephrotic
syndrome and those functional analyses.
Associations between factors at the initiation ofrenal replacement therapy and prognosis in
ESRD patients.
Elucidation of basic mechanisms in cardio-renal
syndrome and intervention.
Pathophysiology of acute kidney injury and its
applicability for renal regenerative study.
AKI biomarkers and those clinical significance in
ICU/CCU.
Renal biomarker to determine clinicalactionability in CKD and type-2 DN.
The potentiality of urine biomarker tests fordeveloping country [JICA-JST: Science andTechnology Research Partnership for Sustainable
Development].

References
1.

2.

Matsuura R, Srisawat N, Claure-Del Granado R,
Doi K, Yoshida T, Nangaku M, Noiri E. Use of the
Renal Angina Index in Determining Acute Kidney
Injury. Kidney Int Rep. 3, 677-683 (2018)
Matsuura R, Komaru Y, Miyamoto Y, Yoshida T,
Yoshimoto K, Isshiki R, Mayumi K, Yamashita T,
Hamasaki Y, Nangaku M, Noiri E, Morimura N,
Doi K. Response to different furosemide doses
predicts AKI progression in ICU patients withelevated plasma NGAL levels. Ann Intensive

Care. 8, 8 (2018)
3. Komaru Y, Inokuchi R, Ueda Y, Nangaku M, Doi
K. Use of the anion gap and intermittent hemodialysis following continuous hemodiafiltration in
extremely high dose acute-on-chronic lithium
poisoning: A case report. Hemodial Int. 22, E15E18 (2018)
4. Iwagami M, Yasunaga H, Matsui H, Horiguchi H,
Fushimi K, Noiri E, Nangaku M, Doi K. Impact ofend-stage renal disease on hospital outcomesamong patients admitted to intensive care units: A
retrospective
matched-paircohortstudy.
Nephrology (Carlton). 22, 617-623 (2017)
5. Iwagami M, Yasunaga H, Noiri E, Horiguchi H,
Fushimi K, Matsubara T, Yahagi N, Nangaku M,
Doi K. Potential Survival Benefit of Polymyxin B
Hemoperfusion in Septic Shock Patients on
Continuous Renal Replacement Therapy: A
Propensity-Matched Analysis. Blood Purif. 42,
9-17 (2016)
6. Isshiki R, Asada T, Sato D, Sumida M, Hamasaki Y,
Inokuchi R, Matsubara T, Ishii T, Yahagi N,
Nangaku M, Noiri E, Doi K. Association of
Urinary
Neutrophil
Gelatinase-AssociatedLipocalin With Long-Term Renal Outcomes in
ICU Survivors: A Retrospective Observational
Cohort Study. Shock. 46, 44-51 (2016)
7. Mayumi K, Yamashita T, Hamasaki Y, Noiri E,
Nangaku M, Yahagi N, Doi K. IMPACT OF
CONTINUOUS
RENALREPLACEMENTTHERAPY INTENSITY ON SEPTIC ACUTEKIDNEY INJURY. Shock. 45, 133-138 (2016)
8. Hasegawa S, Kato H, Hamasaki Y, Koiwa T,
Nangaku M. Positron emission tomography in the
diagnosis of cyst infections. Kidney Int. 91, 759(2017)
9. Katagiri D, Hamasaki Y, Doi K, Negishi K, Sugaya
T, Nangaku M, Noiri E. Interstitial renal fibrosis
due to multiple cisplatin treatments is amelioratedbysemicarbazide-sensitiveamineoxidaseinhibition. Kidney Int. 89, 374-385 (2016)
10. Yamashita T, Noiri E, Hamasaki Y, Matsubara T,
Ishii T, Yahagi N, Nangaku M, Doi K.
Erythropoietin concentration in acute kidney injury
is associated with insulin-like growth factorbinding protein-1. Nephrology (Carlton). 21, 693699 (2016)

479

11. Iwagami M, Yasunaga H, Noiri E, Horiguchi H,
Fushimi K, Matsubara T, Yahagi N, Nangaku M,
Doi K. Current state of continuous renal replacement therapy for acute kidney injury in Japaneseintensive care units in 2011: analysis of a national
administrative database. Nephrol Dial Transplant.
30, 988-995 (2015)
12. Okamoto K, Honda K, Doi K, Ishizu T, Katagiri D,
Wada T, Tomita K, Ohtake T, Kaneko T, Kobayashi
S, Nangaku M, Tokunaga K, Noiri E. Glypican-5
Increases Susceptibility to Nephrotic Damage in
Diabetic Kidney. Am J Pathol. 185, 1889-1898(2015)
13. Sumida M, Doi K, Ogasawara E, Yamashita T,
Hamasaki Y, Kariya T, Takimoto E, Yahagi N,
Nangaku M, Noiri E. Regulation of Mitochondrial
Dynamics by Dynamin-Related Protein-1 in Acute
Cardiorenal Syndrome. J Am Soc Nephrol. 26,
2378-2387 (2015)14. Shimizu K, Doi K, Imamura T, Noiri E, Yahagi N,
Nangaku M, Kinugawa K. Ratio of urine and bloodurea nitrogen concentration predicts the responseof tolvaptan in congestive heart failure.
Nephrology(Carlton). 20, 405-412 (2015)
15. Iwagami M, Yasunaga H, Noiri E, Horiguchi H,
Fushimi K, Matsubara T, Yahagi N, Nangaku M,
Doi K. Choice of renal replacement therapy
modality in intensive care units: data from aJapanese Nationwide Administrative Claim Database. J Crit Care. 30, 381-385 (2015)16. Hanafusa N, Torato T, Katagiri D, Usui T,
Matsumoto A, Noiri E, Nangauku M. Deep veinpuncture under ultrasonographic guidance-an alternative approach for vascular access of apheresis
therapies. J Clin Apher. 30, 380-381 (2015)
17. Ito T, Hanafusa N, Iwase S, Noiri E, Nangaku M,
Nakagawa K, Miyagawa K. Effects of cell-free andconcentrated ascites reinfusion therapy (CART) on
symptom relief of malignancy-related ascites. Int J
Clin Oncol. 20, 623-628 (2015)

480

Department of Medical Community
Network and Discharge Planning
Professor
Kiyoto Kasai, M.D.,Ph.D. (concurrently)

Associate Professor
Masahiko Sumitani, M.D., Ph.D. (concurrently)

Lecturer
Koichiro Nagano, M.D., Ph.D.

Associate
Tsukasa Inajima, M.D, Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/organization/introduce/index.html

Introduction and Organization
In April 1997, plans for the Department of Medical
Social Service and Welfare were initiated by the
University of Tokyo Hospital with the aim ofsupporting inpatients upon discharge. The Department
was officially authorized in April 2000, the firstamong national universities. In April 2005, theDepartment began providing assistance to outpatientsreferred from other hospitals and was renamed theDepartment of Medical Community Network andDischarge Planning. The Department provides
assistance to outpatients referred from local medical
institutions, to inpatients being discharged to theirhomes, and to inpatients being transferred to local
medical institutions.

Clinical activities
Assistance to patients receiving 9 medica I treatment:
The Department provides assistance to outpatientsreferred from local medical institutions. Our staff
helps patients make appointments and follow procedures to receive medical treatment. The Department
assists new outpatients in arranging general consultations, helps outpatients schedule spedalized treatment,

and provides assistance to patients who have beenreferred to a specific physician.
Assistance to inpatients upon discharge: The
Department provides assistance to patients for whomtransfer to a local medical institution or discharge tohome if need arises.
Many of such patients are highly dependent on
medical care due to the severity of their condition. For
those receiving medical care at home, our department
staff arranges home visits by primary care doctors andnurses. For patients being transferred to local
institutions, our staff provides assistance both togeneral hospitals and hospice care units.
Home Care Support (Home Care Support clinic): Our
Home Care Support Clinic, which offers home care
support to our outpatients, has been running since
Janualy 2003. The clinic supports the implementationand coordination of home care services, and refers
outpatients requesting hospital admission to otherhospitals or facilities.
Consultation by Social Worker (Consultation on
Recuperation): Our consultation service provided bysocial workers has been running since 2012. Oursocial workers mainly consult enquiries regarding
patient recuperation.

481

Transferring out patients to local institutes: Aiming todefining the distinction of the medical role between
the University Hospital and local institutes andfacilitate transferring our outpatients to them, theproportion of such transferring patients to first-visit
patients keeps more than 80%.

Teaching activities
We educate undergraduate students of the Medical
Social Working and Welfare of other university.

Research activities
Our research field covers investigating appropriate
patient numbers for assistance to inpatients upondischarge in the University hospital; and investigating
how to assist working and job in patients with severe
illness.

482

Clinical Research Support Center
Professor, Director
Tsutomu Yamazaki, M.D., Ph.D.

Associate Professor, Vice Director
Chie Sakanaka, M.D., Ph.D.

Project Lecturer, Vice Director
Tetsuya Ueda, M.D., Ph.D.

Assistant Professor
Munenori Takata, M.D., Ph.D.
Yukari Uemura, Ph.D.

Project Assistant Professor
Akiko Kishi Svensson, M.D., Ph.D.
Takuya Kawahara, Ph.D.
Gaku Oguri, M.D., Ph.D.
Mihoko Shibuya, M.D., Ph.D.
Keiko Ueda, M.D., Ph.D.

Homepage http://www.h.u-tokyo.ac.jp/english/centers-services/central-clinicalfacilities/clinical-research-support-center/index.html
History and Organization
The Clinical Research Support Center was
established in 2010. It originated from Clinical Trial
Managing Center, which was established in 1998, andsubsequently the former Clinical Research Center,
which was established in 2001. It belongs to thecentral clinical division of the hospital and provides
supports not only for clinical trials but also forinvestigator-initiated (independent) clinical studies.
However, given the increasing diversity and volume
of clinical research conducted in the University ofTokyo Hospital, demand mounted for the structural
framework to provide support for multi-centercollaborative studies, research on new technology inevidence-based medicine and translational researchetc. In response to such diversified demands, theformer Clinical Research Center was reorganized in
April 2010 into the Clinical Research Support Center,enabling strengthened support and expeditious
promotion of clinical research.
The Center at the beginning consisted of Site
Coordinating Unit, roughly equivalent to the former
Clinical Research Center, and Central Coordinating
Unit, which provides coordinating functions forresearch such as multicenter trials.
Site Coordinating Unit is comprised of the[Institutional Review Board (IRB) Secretariat
Division] [Investigational Drug/Information Control
Division] and [Clinical Research Coordinator
Division], each charged with IRB secretarial affairs,
management of drugs used in the conduct of clinicalresearch and provide assistance with safety
information reporting, and clinical research483

coordination activities. In addition to the existing
Consultation Division, new divisions such as
Operation Division, Biostatistics Division, DataManagement Division, Monitoring Division and
Safety Information Division and Operation Division
have been added to the Central Coordinating Unit.
The Center was selected in 2011 as an MHLWfunded Center of Excellence for early stage andexploratory clinical trials of drugs for psychiatric andneurological diseases, enabling the Center to reinforce
the staff and to be equipped with Phase I Unit that canconduct Phase 1 first-in-human clinical trial. Thus, thethird unit, i.e., P1 Unit was established in May 2012
with 13 beds exclusively used for clinical studies,making it possible to provide seamless support to thecomplete clinical development process.
We revised rules and procedures in compliance withthe “Ethical Guidelines for Medical and HealthResearch Involving Human Subjects” that came into
effect in April 2015 and examined the realignment ofclinical research functions aimed at strengthening
governance functions of the University of Tokyo
Hospital.
In January 2015, we established Clinical Research
Governance Division and later Office of Clinical
Quality Assurance & Compliance was createdindependently of the Clinical Research Center
responsible for conducting quality assurance audits.
Also, with the aim to improve quality of clinicalresearch in clinical departments, we appointed 1-2 tostaff from each clinical department to serve asconcurrent clinical instructors, thereby strengthening
supervision and monitoring system in the departments.
In April 2016, we transferred ethical review processof specific clinical trials (involving invasion andintervention) to the Faculty of Medicine IRB to ensuretransparency of clinical research. IRB for evaluating
industry-sponsored and investigator-initiated clinical
trials was newly established in the hospital. With
respect to the secretarial and administrative duties,
center will continue to take responsibilities.
Moreover, a specific clinical research steeringcommittee was established under the hospital director
and external audit committee to seek external
evaluation. In addition, we integrated clinical research
management system by strengthening management ofconflicts of interest, created educational environment

for clinical research personnel, formed collaboration
with the Clinical Evaluation and Safety Division tostrengthen safety management system. As a result, theUniversity of Tokyo Hospital received accreditation asa core clinical research hospital under Medical Care
Act. Since then our hospital has been functioning as acore clinical research hospital in Japan.
Based on the enforcement of the Act on the Safety ofRegenerative Medicine, the Certified Special
Committee for Regenerative Medicine was establishedat the Central Administrative Office of the university.
And Clinical Research Support Center undertook
responsibilities for secretarial and administrative
duties.
We established 3 new divisions outside the unit,
Education and Training Division, Clinical Trial
Implementation Division and University Hospital
Network Promotion Division. Moreover, in order tostrengthen the functions involved widely by theClinical Research Support Center, we established
Education and Training Division, Research Implementation Division and University Hospital Network
Promotion Division outside the unit, last year. In thecurrent fiscal year, we further integrated safety
information functions of the Site Coordinating Unit
and the Central Coordinating Unit and set it as a new
Safety Information Management Division out the unit.
The division remaining in the Site Coordinating Unit
was named as the Investigational Drug Management
Division. Furthermore, Consultation Division wasmove outside the unit. Regulatory Strategy Division
was also established in the Central Coordinating Unit
in 2017.
In order to strengthen governance and functionality
within the center, Central Clinical Research Manager
and Advanced Medical Care Program Manager wereplaced to ensure that the clinical research are
implementation appropriately by collaborating with
the Department of Clinical Research Governance. We
are also preparing for the Clinical Trials Act to be
enforced in April 2018.
As of March 2017, the Center has 9 teaching staff(1 professor, 1 associate professor, 1 project lecturer,
2 assistant professors, 5 project assistant professors,
there are 23 full-time staff members assigned to theSite Coordinating Unit (9 pharmacists, 6 nurses,
3 laboratory technicians, 2 clinical psychologists,

484

1 project academic support staff and 2 clerical staffs.
The number of full-time staff assigned to the Central
Coordinating Unit is 21. (1 specially appointed staff,
6 pharmacists, 5 laboratory technicians, 4 project
academic support staff and 5 clerical staff members.
Safety Information Management Division has 3
pharmacists and 1 clerical staff. The P 1 Unit consistsof 23 staff members (13 nurses, 8 laboratory
technicians, 1 project academic support staff and 1
clerical staff).

Clinical Research Support
Activities
The duties of the Center range from serving as thesecretariat for the IRB to supporting the implementation and reporting of clinical trials.

<Site Coordinating Unit>
In 2004, the Site Coordinating Unit began providing
assistance for investigator-initiated clinical trials
evaluating therapeutic drugs and studies involving
unapproved drugs in addition to conventional clinical
trials (use of unapproved drugs in clinical research
was shifted to Research Ethics Committee of Graduate
School of Medicine and School of Medicine). In
2018, it was moved to Evaluation Committee on
Unapproved News Drugs. To further improve thequality of these research we decided to adopt
ICH-GCP guidance and complied with the following
guidelines, procedure manuals, styles and guidanceetc.
1) Guidelines for investigator-initiated study and useof unapproved drugs in clinical research.
(Guidelines for implementing specified clinical
trial, as of April 2016)2) Procedures for conducting investigator-initiatedclinical study and use of unapproved drugs inclinical research.
(Procedure manual for implementing specificclinical trial, as of April 2016)
3) Guidance for writing research protocol forvoluntary clinical research.
(Guidance for writing research protocol for
specific clinical trial, as of April 2016)
4) Guidance for writing informed consent forvoluntary clinical research.

(Guidance for writing informed consent for
specific clinical research, as of April 2016)5) Handling guidelines for financial burden on
patients participating in investigator-initiatedtrials and clinical research.
From 2009, we have been providing support for allinvasive and interventional clinical research.
For secure process of the applications of industrysponsored clinical trials to IRB, we hold preliminary
hearing system (named as “protocol presentation”)
before IRB. As a result, we could avoid
re-examination of research.
The items processed by the Center as the IRB
secretariat in fiscal 2017 included, as for industrysponsored trials for marketing approval, 35 new
protocol applications, 65 study extension applications,396 protocol amendment applications, 910 SAE/safety
information reports, 31 study closure or termination
reports. As for intervention studies, the Center
processed 23 new protocols, 171 applications for
protocol amendment, 61 SAE/safety information
reports, and75 reports for study closure or
termination.
Protocol presentations of industry-sponsored trials
prior to application to IRB totaled 17 applications.
Preliminary
consultation
andguidanceforinvestigator-initiated research application 26 and 58
applications, respectively.
Clinical Research Support Center managed
drug/device inventory for 99 clinical trials (drug 96,
devices 3) for regulatory approval, 4 post marketing
research, 42 investigator-initiated clinical research,and 7 cases of compassionate use, 4 tissue-engineered
medical products in fiscal 2017. The number ofprescriptions processed was 993 for research forapproval and post marketing research combined, 462
for investigator-initiated clinical research. We
managed trial drugs centrally for 2 multicenter
research shipped them for 34 times. We masked
investigational drugs for 4 double-blind placebo
controlled research studies.
Clinical research coordinators (CRC) of the Center
have been supporting all clinical trials for approvaland post marketing research since 2002. We started
supporting in part investigator-initiated research in2004. In 2005 we started providing CRC support toinvestigator-initiated research on a beneficiary-pays

485basis, and clinical pharmacology studies in healthy
volunteers in 2012. CRCs exclusively involved ininvestigator-initiated research, have been employed asneeded. CRC support for Advanced Medical Care
Program B which Tokyo University Hospital
participated as a head investigational site was initiatedin 2017. The number of research participants that
CRCs interacted with was 4466 in 2017. The numberof monitoring visits was 911 in 2017.
As part of patient awareness campaign, we continued
updating the Center homepage, prepared leaflets anddistributed them at outpatient receptions. The leaflets
contain information about research currently recruiting participants. CRCs provides consultation topatients or their families participating in clinical trials
or who are considering to enroll in a clinical trial inclose cooperation with the Patients Relations andClinical Ethics Center, Department of Medical Community Network and Office of Medical Accounting.
The number of consultation cases was 213 in 2017.

<Central Coordinating Unit>
Central Coordinating Unit, established in 2010, hasbeen implementing the system successively partly
supported by the MHLW-funded Early-Stage andExploratory Clinical Trial Project.
In order to comply with the "Ethical Guidelines for
Medical and Health Research Involving Human
Subjects enacted in 2014", we classified clinicalresearch according to guidelines, validation studies
and exploratory studies and started accepting all
assistance requests for validation studies at the central
coordinating unit, starting from May 2015. Moreover,since clinical departments were placed in charge ofmonitoring and data management of all exploratory
studies, and the center undertook responsibility forsupervision of the quality control (QC).
As of fiscal 2017, we have accepted 46 clinicalresearch projects for providing support (14investigator-initiated clinical trials (including 10
studies which the University of Tokyo Hospital
participated as a head institution and 6 Advanced
Medical Care B Programs). We also supported 9
clinical studies initiated by the other institutions(including 4 investigator-initiated clinical trials). Oneof the major achievements is the investigator-initiatedclinical trial of the pediatric ventricular assist device;

the trial was initiated in February 2012, applied forregulatory approval in November 2014, and approved
marketing in June 18, 2015.

< Safety Information Management Division >This division manages SAE (severe adverse event)reporting and supports various safety reporting inorder to ensure safety of the clinical studies.
<P1 Unit>
Since its establishment in May 2012, the Phase 1
Unit has undertaken various preparations to respond toearly phase clinical research, such as development of
SOP program, procedure manuals, establishment of
in-house collaboration system, on-the job training forstaff and the system for recruiting health volunteers.
P1 unit conducted its very first clinical study in
October
2012.
In
2017,
we
completed;investigator-initiated phase I study (single dose,
multiple doses) for autism spectrum disorder drug. We
are also conducting global phase I study for
Alzheimer’s disease drug, independent study in
Alzheimer’s disease patients, investigator-initiatedPhase I study for rare pulmonary disease drug,
Bioequivalence study for generic drug, and global
phase Ⅲ study in healthy senior volunteers for
Alzheimer’s disease drug since September 2016.
<University Hospital Clinical Trial Alliance>
University Hospital Clinical Trial Alliance (UHCT
Alliance) comprised of 6 national university hospitals(The University of Tokyo, Niigata University, Gunma
University, Tsukuba University, Tokyo Medical and
Dental University and Chiba University) located in thecentral part of Japan was established in February 2006.
In February 2007 Shinshu University and in February
2013 Yamanashi University joined the Alliance as the
7th and 8th member university, respectively. And in
February 2015 the University of Tokyo the Institute ofMedical Science joined the Alliance as the 8th
member university 9 hospitals.
From April 2014 on, as a second phase of the project,
we developed a system to strengthen cooperation inclinical research education and training and development of seeds. As part of the Alliance activities the
University of Tokyo developed a clinical researchsupport system UHCT ACReSS jointly with Fujitsu in486

2011, to support clinical researchers in the quality andproject management. UHCT ACReSS can easily becustomized by researchers. The system is being usedpractically by 241 projects as of March 2018.
Currently, we are expanding the use of it toresearchers other than Alliance members.
We have also developed curriculum called CREDITS(Continuous Systematic Education & Training
Curriculum for Clinical Researchers and Specialists)
jointly with the Education and Training Division in
2015. Currently, we are expanding the use outside thealliance members. Activities between the UHCT
Alliance and the University of Tokyo TR based
regional network started in 2015, as seeds development project of Alliance members.

<National University Hospital Clinical Research
Initiative>
In October 2012, we launched National University
Hospital Clinical Research Initiative (NUH-CRI). The
administrative affairs of the Initiative have been takenover by the Alliance Office (located within the
University of Tokyo) from the preparatory meeting inJuly 2012. The initiative considered to share education
curriculum as one of the common educational
programs of national university hospitals nationwide.
The curriculum was provided to each university
hospital by the National University Hospital Councilof Japan.
Feasibility assessment system was developed forinvestigator initiated clinical study in order to support
and promote clinical trials conducted at the National
University Hospitals. Contract templates were createdfor investigator initiated research and to be provided
to each university hospital by the National University
Hospital Council of Japan.
A booklet of unique efforts of each participating
university was published and reported on the website
home page.

Education/Training
The Center has been accepting medical students infinal year for training course in ‘Clinical Clerkship’since it become mandatory in 2013. In addition, we
accepted graduate students for 2 day training (enrolled
in Master’s and Doctoral courses) in the Faculty of

Medicine, Graduate School of Pharmaceutical
Sciences and the School of Engineering, who took
Medical Innovation Initiative course. Medical
Innovation Initiative is part of “Fostering Medical
Researcher of the Future” project adopted by MEXT
(Ministry of Education, Culture, Sports andTechnology). Also, we accepted students enrolled in
graduate school and Faculty of Pharmaceutical
Sciences, both from inside and outside universities. In
addition, resident physicians underwent one-monthtraining at the Center, as a part of the M.D. residencytraining program. Starting in 2017, we have beenoffering lecture program “Clinical Research” for M2
medical students.
Education and Training Division was established in2015 and has been providing education and training
for students and researchers. In particular, we havedeveloped curriculum called CREDITS (Continuous
Systematic Education & Training Curriculum for
Clinical Researchers and Specialists) jointly with the
University Hospital Clinical Trial Alliance or (UHCT
Alliance). Currently, 5400 participants are registered
for the program.
In 2015, we introduced clinical instructor system inwhich physicians from clinical departments
concurrently serve as a clinical instructor, centrally
manage information on clinical research conducted intheir own departments and hold regular training
sessions to disseminate information on education andtraining programs.
The University of Tokyo Hospital has conductedannual CRC training course for national, public andprivate university hospitals since 2010, commissionedby the Ministry of Education. In June 2017, 5-day
training was held under the auspices of the hospital, in
which 98 trainees (including 5 from the UTokyo) fromuniversity hospitals across the country participated.
In addition, we held a joint workshop series with 8
alliance universities in the Kanto Koshinetsu area, (6organized by the UTokyo) which consisted of 5
monitoring workshops, 5 clinical research lecture
series. Workshops were attended by 195, 79 (168, 24
participants from UTokyo) and 400 (156 from
UTokyo) respectively.
In 2017, Japan Agency for Medical Research andDevelopment (AMED) sponsored training workshop
for clinical research personnel (1 day, 2 sessions, held

487

at the University of Tokyo, 30 (4 from UTokyo) and30 (7 from UTokyo) participants in each session), The
University of Tokyo – National University ofSingapore joint international symposium on “Human
Resources Development” was also held in 2017(2-days, 75 participants).
Furthermore, in response to the shortage ofbiostatisticians, biostatistics and bioinformatics course
was established by AMED, at the university hospital.
Master’s course starting in FY2018 will also beestablished within the Graduate School of Interdisciplinary Information Studies. Clinical Research
Support Center has established system to conduct
practical training for course participants.
The Center holds annual “Clinical Research
Seminar” in March, nearly 300 people from academia
and companies participated last year.

3)

4)

Research Activities
In April 2007, clinical trial data management course(endowed course) was launched with the support of
the Center and the Biostatistics Department, Graduate
School of Medicine, conducting research and education on data management and biostatistics focused onpractical application to research.
As of fiscal 2017, the Center was involved in 30
presentations in scientific meetings, of which 26 wereas lead presenters, international conferences 3 (Takata,
Koide). The Japan Society of Clinical Pharmacology
and Therapeutics 6 (Watanabe, Yoshimoto, Haga,
Wada, Kageyama, Sujino), Conference on CRC andClinical Research 1 (Watanabe), Japan Society ofClinical Trials and Research 5 (Takata, Tanaka,
Uemura, Kawahara, Honma),
DIA Japan 1(Kageyama) , 16 publications and academic papers etc.
(English papers 12, Japanese papers 4).

5)

6)

Publications
1)

2)

Sugawara K, Yamashita H, Uemura Y, Mitsui T,
Yagi K, Nishida M, Aikou S, Mori K, Nomura S,
Seto Y. Numeric pathologic lymph node classification shows prognostic superiority to topographic pN classification in esophageal squamouscell carcinoma. Surgery. 162(4):846-856, 2017
Nakagawa T, Komemushi Y, Kawai T, Otsuka M,
Miyakawa J, Uemura Y, Kanatani A, Taguchi S,

7)

Naito A, Suzuki M, Nishimatsu H, Hirano Y,
Tanaka Y, Matsumoto A, Miyazaki H, Fujimura T,
Fukuhara F, Kume H, Igawa Y, Homma Y.
Efficacy of post-nephroureterectomy cisplatinbased adjuvant chemotherapy for locallyadvanced upper tract urothelial carcinoma: amulti-institutional retrospective study. World
Journal of Urology. 35(10): 1569-75, 2017
Miura M, Shirai S, Uemura Y, Jinnouchi H,
Morinaga T, Isotani A, Watanabe S, Hayashi M,
Kamioka N, Nagasawa A, Kakumoto K, Seo K,
Arai Y, Hanyu M, Ando K. Early safety andefficacy of transcatheter aortic valve implantation
for Asian nonagenarians (from KMH Registry).
International Heart Journal. 58(6): 900-7, 2017
Watanabe T, Kuranami M, Inoue K, Masuda N,
Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y,
Ohashi Y. Comparison of AC-taxane vs. AC-free
regimen and Paclitaxel vs. Docetaxel in NodePositive Breast Cancer Patients -Final Results of
the N-SAS BC (National Surgical Adjuvant Studyof Breast Cancer) 02 Trial, a Randomized
Comparative Phase 3 Study. Cancer. 123(5): 75968, 2017
Tsuruya K, Uemura Y, Hirakata H, Kitazono T,
Tsubakihara Y, Suzuki M, Ohashi Y. Association
between responsiveness to methoxy polyethylene
glycol-epoetin beta and renal survival in patientswith non-dialysis-dependent chronic kidney disease: a pooled analysis of individual patient-level
data from clinical trials. Nephrology. 22(10):769775, 2017
Tanaka S, Miyazaki T, Uemura Y, Miyakawa N,
Gorai I, Nakamura T, Fukunaga M, Ohashi Y,
Ohta H, Mori S, Hagino H, Hosoi T, Sugimoto T,
Itoi E, Orimo H, Shiraki M. Comparison of
concurrent treatment with vitamin K2 andrisedronate compared with treatment withrisedronate alone in patients with osteoporosis:
Japanese Osteoporosis Intervention Trial-03. J
Bone Miner Metab. 25(4): 385-95, 2017
Nakagawa T, Taguchi S, Uemura Y, Kanatani A,
Ikeda M, Matsumoto A, Yoshida K, Kawai T,
Nagata M, Komemushi Y, Suzuki M, Enomoto Y,
Nishimatsu H, Ishikawa A, Nagase Y, Kondo Y,
Tanaka Y, Okaneya T, Hirano Y, Minowada S,
Shinohara M, Miyazaki H, Fujimura T, Fukuhara

488

H, Kume H, Igawa Y, Homma Y. Nomogram for
Predicting Survival of Metastatic Urothelial
Carcinoma of the Bladder after Radical
Cystectomy. Urologic Oncology. 35(7): 457.e-15457, 2017
8) Takata M, Amiya E, Watanabe M, Hosoya Y,
Nakayama A, Fujiwara T, Taya M, Oguri G,
Hyodo K, Takayama N, Takano N, Mashiko T,
Uemura Y, Komuro I. An exploratory study on
the efficacy and safety of a BCAA preparation
used in combination with cardiac rehabilitation
for patients with chronic heart failure. BMC
Cardiovasc Disord. 27;17(1):205, 2017
9) Takata M, Amiya E, Watanabe M, Hosoya Y,
Nakayama A, Fujiwara T, Taya M, Oguri G,
Hyodo K, Takayama N, Takano N, Mashiko T,
Uemura Y, Komuro I. An exploratory study on
the efficacy and safety of a BCAA preparation
used in combination with cardiac rehabilitation
for patients with chronic heart failure. BMC
Cardiovascular Disorders. 27;17(1):205, 201710) Kishi A, Uchida I, Koide D, Imamura K. JapaneseInitiative for Education in Pharmaceutical
Medicine and Clinical Research Training. J Med
Dev Sci. 3(1);1-10, 201711) Shiroiwa T, Fukuda T, Shimozuma K, Mouri M,
Hagiwara Y, Kawahara T, Osumi S, Hozumi Y,
Sagara Y, Ohashi Y, Mukai H. Cost-effectivenessanalysis on the introduction of S-1 therapy tofirst-line metastatic breast cancer treatment:
results from the randomized phase III SELECT
BC trial. BMC Cancer. 17(1):773, 201712) Kawahara T, Fukuda M, Oba K, Sakamoto J,
Buyse M. Meta-analysis of randomized clinical
trials in the era of individual patient data sharing.
International Journal of Clinical Oncology. 23(3):403-409, 2017

489

University Hospital Medical
Information Network (UMIN)
CenterProfessor
Takahiro Kiuchi, M.D., Ph.D.

Associate Professor
Hirono Ishikawa, Ph.D.

Lecturer
Masafumi Okada, M.D., Ph.D.

Instructor
Mio Kato, Ph.D.
Tsuyoshi OkuharaHomepage

http://www.umin.ac.jp/

Introduction and Organization
The University hospital Medical Information Network(UMIN) (the original name was the University
Medical Information Network), was established in
1989. While general-use computer systems were
implemented at all national university hospitals
around the end of the Showa era (late 1980s), Dr.
Shigekoto Kaihara, chair and professor at the HospitalComputer Center, University of Tokyo Hospital, led aproject to connect these computer systems in a
network in order to share information for better
communication. Finally, the Ministry of Education,
Culture, Sports, Science and Technology approved abudget to initiate the UMIN Center. The UMIN Center
was founded within the Hospital Computer Center,
University of Tokyo Hospital, and was officiallyopened in March 1989.
Dr. Tsunetaro Sakurai
became an associate professor as the first full-time
UMIN staff. The following are the objectives of the
UMIN Center, as initially outlined in 1989 (No.6 wasadded later):

1. Provide up-to-date information for healthcare
professionals
2. Promote digitalized communication among
healthcare professionals
3. Support collaborative projects among university
hospitals
4. Support collaborative medical research
5. Standardize data format and support datacollection
6. Support medical education and clinical training
The original UMIN system utilized an N1 protocol,
which was developed in Japan and was the only
solution at the time to connect general-use computersof the five major computer vendors in Japan, although
it was poor in function, supporting only line-mode,character-based terminals.
In 1994, we launched a service through the Internet,
and it began to spread in those days. The number of
UMIN users gradually increased, mainly in the E-mailservice.
In 1996, Dr. Takahiro Kiuchi took up a new post while

490

Dr. Sakurai was promoted to professor at Hokkaido
University. Dr, Kiuchi updated the system to be
web-based. With the rapid spread of the Internet in
Japan, UMIN users dramatically increased.
The UMIN Center subsequently started to provide
three major information services: (1) the ELBIS(Electronic Library for Biomedical Sciences) as of1997, (2) the INDICE (Internet Data and Information
Center of Clinical Research) as of 2000, and (3) the
EPOC (Evaluation System of Postgraduate ClinicalTraining) as of 2004.
In April 2002, the UMIN Center became an
independent entity, with the adjusted name of
University Hospital Medical Information Network
Center, as per an internal arrangement at the
University of Tokyo Hospital. In 2003, a budget for
a new professor position was officially approved by
the Ministry of Education, Culture, Sports, Scienceand Technology. Then, Dr. Kiuchi was promoted to
become the first professor of the UMIN Center on
April 1, 2004. The UMIN Center became part of theFaculty of Medicine, as the Department of HealthCommunication, School of Public Health, which wasestablished in April 2007.

Clinical Activities
Although the UMIN Center is one of the central
medical examination and treatment institutions of the
University of Tokyo Hospital, the center does notprovide direct patient care services, but provides
services for medical researchers and practitioners
throughout Japan. We currently have about 470,000
registrants, and approximately 120,000,000 monthly
website accesses, which is currently in the scale of theworld’s highest access rates. The service extends tostudy / education / medical examination and treatment/ hospital duties and encompasses many divergences
as indicated below:
 Research: http://www.umin.ac.jp/research
AC:
Information for Academic Conferences
ELBIS:
Electronic Library for Biomedical
Sciences
FIND:
Fund Information Database
INDICE: Internet Data and Information Center ofClinical Research

ROCOLS: Recruiting System for Our Colleagues’
and Students’
CTR:
Clinical Trial Registry
ICDR:
Individual Case Data Repository Education: http://www.umin.ac.jp/education
SUPERCOURSE:
Online Lectures Compiled by Pittsburgh
Univ., U.S.A
EPOC:
Evaluation System of Postgraduate
Clinical Training
Debut:
Dental Training Evaluation andTabulation System
Web-QME: Medical Education Evaluation System
ARIA:
Online Recruiting System for General
Use Medical Examination and Treatment
http://www.umin.ac.jp/uhosp/
 Intoxication database Medical supplies and materials database Classification for Nursing
 Ministry of Education, Culture, Sports,
Science and Technology document public
information system National university hospital-related medical
dispute report Lists for people and committees
 Various government official appointments,
administrative websites and ML
 General Services(1) General information and search Medical / biology related websites
 Medical terminology A medical research organization / medical
institution database(2) Services for information providersWeb service for publicWeb service for members
Website preservation service(3) Communication support
 E-mail Listserv
 Discussion board
 File exchange

491

Teaching Activities
Please refer to Department of Health Communication
for information about graduate and undergraduate
education.

Research Activities
Please refer to Department of Health Communication
for information about research activities.

References
Please refer to Department of Health Communication.

492

Center for Epidemiology andPreventive Medicine
Director & Professor
Tsutomu Yamazaki, M.D., Ph.D. (Clinical Research Support Center)

Associate Professor
Yuichi Ikeda, M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)

Associate & Deputy Director
Yumiko Ohike, M.D., Ph.D.

Associates
Lumine Matsumoto, M.D., Ph.D. , Atsuko Ozeki, M.D., Ph.D. , Keiko Niimi, M.D., Ph.D.,
Satoshi Suzuki, M.D., Ph.D., Yukari Masuda, M.D., Ph.D.
Yoshiko Mizuno,M.D., Ph.D. (Department of Biostatistics and Bioinformatics)
Kazutaka Ueda, M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)

Homepage:

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

Introduction and Organization
Following the inauguration of a new Central
Clinical Service Building (Central Care 2) inNovember 2006 (Heisei 18) in the University ofTokyo Hospital, the Center for Epidemiology andPreventive Medicine was established on January 1,
2007, within the Central Clinical Facilities and therelevant regulations were revised. On January 9, theWorking Group for the Establishment of the Center
for Epidemiology and Preventive Medicine wasorganized; on April 1, Steering Committee for the
Establishment of the Center for Epidemiology andPreventive Medicine was organized; preparation foroffering its services continued until May 31; on June 4,
the department started offering its services on a trial
basis (in-hospital services) and was officiallyinaugurated 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 interven-tions, 2) to integrate a vast amount of clinical data andhealth-related information to develop more efficientmodels for disease management, 3) by doing theabove 1) and 2), to promote preventive medicine andmedicine for health promotion in an effort tocontribute to the improvement of public health, and 4)
to train medical personnel who can put the above 1),2) and 3) into practice.
In the administrative organization of the Center for
Epidemiology and Preventive Medicine, its Director
directly under the Director of the Hospital is responsible for the entire organization. The managementof the Department is also supported by the Departmentof Ubiquitous Preventive Medicine. In addition,
examinations in the Department are administered incollaboration with three Central Clinical Facilities(Clinical Laboratory Center, Radiological Center, andDepartment of Endoscopy and Endoscopic Surgery)and six Clinical Divisions (Breast and Endocrine
Surgery, Gynecologic Surgery, Ophthalmology and
Vision Collection, Oral-Maxillofacial Surgery,493

Dentistry and Orthodontics , Neurology, and GeriatricMedicine).
The staff of the Center for Epidemiology andPreventive Medicine is composed of ten physicians(seven regular physicians and three physicians fromthe related departments). One of the regularphysicians also performs upper gastrointestinalendoscopy and colonoscopy in the Department ofEndoscopy and Endoscopic Surgery. Our department
also has eight regular nurses and five regularsecretaries. When our department was established, thenumber of staff was increased 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 of Endoscopy and Endoscopic Surgery,
the Radiological Center and the Clinical Laboratory
Center.

Clinical activities
In addition to basic examinations which are open to
the public, our department provides these ten options:1) comprehensive
cardiovascularexaminations,2) comprehensive cerebrovascular examinations,3) check up for dementia, 4) colorectal cancer
screening, 5) uterine cancer screening, 6) breast
cancer screening, 7) lung cancer screening, 8) tumor
marker diagnosis, 9) estimation of gastric cancer risk,and 10) oral/dental examinations. While meeting theneeds of examinees, we have increased the number ofthe optional examinations and provided higher levelsof 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 plenty of time to perform
comprehensive medical examinations. Formally, theexaminee is notified in writing of the results withinapproximately three weeks after the examination. We
also offer each examinee a free consultation so that we
can help him/her understand the results or decide
whether or not to have further work-up.

Teaching activities
We started clinical teaching for medical students

in April 2017. Following the lecture of preventive
medicine, students observe examinations andexplanations by physicians to the examinees. They
learn how to apply preventive medicine to practice.
We also offer education in epidemiology to graduate
students in 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) 2017 from April 1, to
March 31, 2018, the total number of examinees (whohad basic examinations and optional examinations)was 7,529including 2,798 in basic examinations, 526
in complete cardiovascular examinations, 646 incomplete cerebrovascular examinations, 72 in checkup dementia, 307 in colorectal cancer screening, 551
in uterine cancer screening, 670 in breast cancer
screening, 577 in lung cancer screening, 1,135 intumor marker diagnosis, 199 in estimation of gastriccancer risk, 41 in oral/dental examinations, and 10 inupper gastrointestinal endoscopy (later).
When examinees visit other departments in our
hospital for a work-up or treatment, we write a letterof referral by request. In the FY 2017, we issued 771
letters of referral to other departments in our hospitaland 29 to other hospitals.
We have expanded our public relations efforts and15,000 brochure were delivered during the FY 2017.
We also prepared posters which were placed within
our hospital and on the campus of the University ofTokyo as well. Our homepage (the above URL) has

494

been constantly updated to provide the latest
information for examinees.

References
Academic Papers in English
1. Tagami M., Hirano T., Yamazaki T., Shiba T. ;RESERCH Study Group. Effect of ezetimibe
add-on therapy over 52 weeks extension analysis
of prospective randomized trial (RESEARCH
study) in type 2 diabetes subjects. Lipid HealthDis. 16(1):122,2017
2. Tokushige A., Ueda S., Tomiyama H., Ohishi M.,
Kohro T., Higashi Y., Takase B., Suzuki T., IshizuT., Yamazaki T., Furumoto T., Kario K., Inoue T.,
Koba S., Takemoto Y., Hano T., Sata M., Ishibashi
Y., Node K., Maemura K., Ohya Y., Furukawa T.,
Ito H., Yamashina A. Association Between Waistto-Height Ratio and Endothelial Dysfunction in
Patients With Morbidity -A Report From the
FMD-J Study. Circ J.2017 Epub ahead of print.
3. Matsumoto L., Suzuki K., Mizuno Y., Ohike Y.,
Ozeki A., Ono S., Takanashi M., Sawaki D.,
Suzuki T., Yamazaki T., Tsuji S., Iwata A.
Association of subclinial carotid atherosclerosis
with immediate memory and other cognitive
functions. Geriatr Gerontol Int.2017 Epub aheadof print.
4. Maruhashi T., Soga J., Fujimura N., Idei N.,
Mikami S., Iwamoto Y., Iwamoto A., Kajikawa M.,
Matsumoto T., Oda N., Kishimoto S., Matsui S.,
Hashimoto H., Aibara Y., Yusoff FBM., Hidaka T.,
Kihara Y., Chayama K., Noma K., Nakashima A.,
Goto C., Tomiyama H., Takase B., Kohro T.,
Suzuki T., Ishizu T., Ueda S., Yamazaki T.,
Furumoto T., Kario K., Inoue T., Koba S.,
Watanabe K., Takemoto Y., Hano T., Sata M.,
Ishibashi Y., Node K., Maemura K., Ohya Y.,
Furukawa T., Ito H., Ikeda H., Yamashina A.,
Higashi Y. Endothelial Function Is Impaired in
Patients Receiving Antihypertensive Drug
Treatment Regardless of Blood Pressure Level:
FMD-J Study (Flow-Mediated Dilation Japan).
Hypertension. 70(4):790-7,2017
5. Masudo R., Yasukawa K., Nojiri T., Shimosaka H.,
Sone S., Oike Y., Ugawa A., Yamazaki T.,
Shimokado K., Yatomi Y., Ikeda H. Evaluation ofhuman nonmercaptalbumin as a marker foroxidative stress and its association with various
parameters in blood. J Clin Biochem Nutr. 61(2):79-84,2017
6. Niimi K, Ishibashi R, Mitsui T, Aikou S,
Kodashima S, Yamashita H, Yamamichi N, Hirata
Y, Fujishiro M, Seto Y, Koike K. Laparoscopic
and endoscopic cooperative surgery for gastrointestinal tumor. Ann Transl Med. 2017 Apr;
5(8):187. doi: 10.21037/atm.2017.03.35. Review.
7. Sato H, Suzuki JI, Aoyama N, Watanabe R,
Kaneko M, Shiheido Y, Yoshida A, Wakayama K,
Kumagai H, Ikeda Y, Akazawa H, Komuro I,
Isobe M, Izumi Y.: A Periodontal pathogen
Porphyromonas
gingivalis
deteriorates
Isoproterenol-Induced myocardial remodeling in
mice. Hypertens Res.40(1):35-40, 2017
8. Suzuki JI, Sato H, Kaneko M, Yoshida A, Aoyama
N, Akimoto S, Wakayama K, Kumagai H, Ikeda Y,
Akazawa H, Izumi Y, Isobe M, Komuro I.:
Periodontitis and myocardial hypertrophy.
Hypertens Res.40(4):324-28, 2017
9. Watanabe R, Suzuki JI, Wakayama K, Maejima Y,
Shimamura M, Koriyama H, Nakagami H,
Kumagai H, Ikeda Y, Akazawa H, Morishita R,
Komuro I, Isobe M.: A peptide vaccine targetingangiotensin II attenuates the cardiac dysfunction
induced by myocardial infarction. Sci Rep.doi:10.
1038/srep43920, 2017
10. Kamo T, Akazawa H, Suda W, Saga-Kamo A,
Shimizu Y, Yagi H, Liu Q, Nomura S, Naito AT,
Takeda N, Harada M, Toko H, Kumagai H, Ikeda
Y, Takimoto E, Suzuki JI, Honda K, Morita H,
Hattori M, Komuro I. Dysbiosis and compositional alterations with aging in the gut
microbiota of patients with heart failure. PLoS
One.12(3):e0174099, 2017
11. Nagata N, Iwanari H, Kumagai H, Kusano-Arai O,
Ikeda Y, Aritake K, Hamakubo T, Urade Y.:
Generation and characterization of an antagonistic
monoclonal antibody against an extracellulardomain of mouse DP2 (CRTH2/GPR44) receptors
for prostaglandin D2. PLoS One.12(4):e0175452,
2017
12. Takanashi M, Taira Y, Okazaki S, Takase S,
Kimura T, Li CC, Xu PF, Noda A, Sakata I,
Kumagai H, Ikeda Y, Iizuka Y, Yahagi N,

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Shimano H, Osuga JI, Ishibashi S, Kadowaki T,
Okazaki H. Role of Hormone-sensitive Lipase in
Leptin-Promoted Fat Loss and Glucose Lowering.
J Atheroscler Thromb. doi:10.5551/jat.39552,
2017
13. Aoyama N, Suzuki JI, Kobayashi N, Hanatani T,
Ashigaki N, Yoshida A, Shiheido Y, Sato H,
Kumagai H, Ikeda Y, Akazawa H, Komuro I,
Izumi Y, Isobe M. Periodontitis deteriorates
peripheral arterial disease in Japanese population
via enhanced systemic inflammation. Heart
Vessels.doi:10.1007/s00380-017-1003-6, 2017
14. Aoyama N, Suzuki JI, Kumagai H, Ikeda Y,
Akazawa H, Komuro I, Minabe M, Izumi Y, Isobe
M. Specific periodontopathic bacterial infection
affects hypertension in male cardiovasculardisease patients. Heart Vessels. doi:10.1007/
s00380-017-1042-z, 2017
15. Lu Q, Schnitzler GR, Vallaster CS, Ueda K,
Erdkamp S, Briggs CE, Iyer LK, Jaffe IZ, Karas
RH. Unliganded estrogen receptor alpha regulates
vascular cell function and gene expression. Mol
Cell Endocrinol.442:12-23,2017

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Division of Tissue Engineering
Director & Professor
Tsuyoshi Takato, M.D., Ph.D. (until June)

Kazuto Hoshi, M.D., Ph.D. (from July)

Vice Director
Kazuto Hoshi, M.D., Ph.D. (until June)

Atsuhiko Hikita, M.D., Ph.D. (from July)

Project Associate Professors
Atsuhiko Hikita, M.D., Ph.D.,

Takumi Matsumoto, M.D., Ph.D.,

Research Associates
Yukiyo Asawa, D.V.M., Ph.D.,

Makoto Komura, M.D., Ph.D.,

Fumiko Yano, D.D.S., Ph.D.,

Homepage

http:// square.umin.ac.jp/t-e/

Introduction and Organization
Division of Tissue Engineering was established as a
special medical office in The University of Tokyo
Hospital, in October 2001 and has a fully equipped
800 m2 laboratory on the 8th floor of the In-patient
Ward B. Division of Tissue Engineering consists of
Department of Bone & Cartilage Regenerative
Medicine, Department of Vascular Regeneration,
Department of Advanced Nephrology & Regenerative Medicine, Department of Cartilage & BoneRegeneration, Project for Regeneration Medicine of
Hematopoiesis, Corneal Tissue Regeneration Project,and Laboratory for Pediatric Regenerative Medicine.
We have invited talented personnel of various fields
from home and abroad. One project associate
professor and one or two project research associates
who are assigned to each department are conducting
research with many post graduate students. Aiming at
clinical application within a few years, the researchers
continue their studies to make the center function as atranslational research center.
Tie-up with companies, technical transfer, patenting developed technologies, producing materials
for treatment at a GMP level, safety evaluation studies
and organization for clinical trials are necessary inorder to realize regenerative medicine, which is now

recognized as a national project. As foundation andoperation of venture companies as well as industryuniversity-government cooperation is essential to thesuccess, it seems that state-level efforts are necessary.
It is expected that broad progress in tissue engineering
technologies and regenerative medicine contributes totreatment and drug discovery of all medical fields
regardless of specialties.
October, 2001 Division of Tissue Engineeringfounded as a special medical office in the Universityof Tokyo Hospital.
June, 2002 Department of Corneal Tissue Engineering founded by a donation from HOYA health careCO., Ltd.
July, 2002 Department of Vascular Regeneration
founded by a donation from Daiichi PharmaceuticalCo., Ltd.
July, 2002 Department of Bone & Cartilage
Regenerative Medicine founded by a donation from
TAKEDA Chemical Industries., Ltd.
September, 2002 Department of Regeneration
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.

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November, 2002 Department of MENICON
Cartilage & Bone Regeneration founded by a donationfrom MENICON Co., Ltd.
March, 2003 The Cell Processing Center set up on
the 8th floor of the In-patient Ward B.
June, 2005 Department of Corneal Tissue Regeneration was renewed by a donation from AMNIOTEC Co., Ltd.
July, 2005 Department of Bone & Cartilage
Regenerative Medicine was renewed by a donationfrom TAKEDA Chemical Industries Co., Ltd.
September, 2005 Department of Regeneration
Medicine for Hematopoiesis was renewed by adonation from KIRIN Brewery Co., Ltd.
November, 2005 Department of Clinical Renal
Regeneration was renewed by a donation fromMOCHIDA Pharmaceutical Co., Ltd.
November, 2005 By a donation from FUJISOFTABC Co., Ltd. Department of MENICON Cartilage &Bone Regeneration was renewed to Department ofFuji Software ABC Cartilage & Bone Regeneration.
January, 2007 Laboratory for Pediatric Regenerative Medicine was founded by department of pediatricsurgery.
July, 2007 Department of Bone & Cartilage
Regenerative Medicine was renewed by a donationfrom Eli Lilly Japan K.K.
March, 2012 Department of Advanced Nephrology and Regenerative Medicine founded by a donationfrom Zenjinkai.
April, 2016 The Cell Processing & Banking
Center set up on the 4th floor of the Molecular & Life
Innovation Building.
November 2017 Change of the department name:
Department of Cartilage & Bone Regeneration
became Department of Cell & Tissue Engineering.

Research activities
As for bone and cartilage regeneration, we aim todevelop easy, precise, non-invasive systems to detect
osteoblastic and chondrogenic 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 and angiogenesis simultaneously, to screen for compounds thatinduce bone and cartilage regeneration, to develop
non-viral gene transfer methods by nano-micelletechnology and to generate, to devise methods toprecisely control 3D shape of biomaterials, and totransplant regenerated bone and cartilage. To achievethese goals, we are conducting research on bone andcartilage biology, developmental biology, stem cellbiology and regenerative medicine. Regarding theclinical study “Development of implant-type tissueengineered cartilage for patients with nasal deformity
in cleft lip and palate”, which was authorized to of
conduct on Mar 18th 2011, we have completed thetransplantation on 3 patients as had been planned. The
outcomes have been good so far with no majorcomplications.
As for renal regeneration, we aim at specificmethod to differentiate human iPS cells to kidney cells.
We also try to clarify the epigenetic regulation of
BMP7. To achieve these goals, we are conducting
epigenetic analysis of human kidney derived iPS cells.
Moreover, we are trying to establish 3-D culture
system for safe clinical application of human iPS cells,
and determining new target of cancer therapy bycomprehensive epigenetic analysis of cancer dereived
iPS cells.
In the department donated by FUJISOFT ABC, we
aim to produce regenerated cartilage and bone withhigh safety and usefulness, to realize production
system and establish practical quality control and topromote the application of regenerated cartilage andbone. To achieve these goals, we are conducting
research on adult stem cell biology in mesenchymal
tissues, application of molecular biology on cartilage
repair for regenerative medicine, development ofnovel scaffolds in cartilage and bone regeneration,
development of 3-D reconstruction system forregenerated tissues, evaluation on biochemical andbiophysical properties of regenerated tissues in vivo
and clinical trials and application of regenerated
cartilage and bones. Based on the findings andknowledge gained through our clinical study“Development of implant-type tissue-engineered
cartilage for patients with nasal deformity in cleft lip
and palate” conducted previously, we carried out an
investigator-initiated clinical trial “A clinical trial forthe validation of safety and efficacy of the implant-

498

type tissue-engineered cartilage using autologous
cells”.
In the laboratory for pediatric regenerative medicine,
we are doing research to fabricate an engineered
airway by tissue engineering technique to fabricate
generic technology for clinical study. In addition,
fundamental researches to perform a clinical study ofthe cytokine therapy for the trachea malacia arecarried out.
Basic Research on human ES cells
Besides, to promote basic research on humanembryonic stem cells with our eyes set on applicationsin the future, Department of Clinical Renal Regeneration is carrying forward the application procedures toobtain human ES cells from Institute for Frontier
Medical Sciences, Kyoto University, which will beapproved shortly.

References
1.

2.

3.

Clinical Studies
Of particular note is clinical studies started as aresult of basic research. In Department of Bone &Cartilage Regenerative Medicine, a clinical study onbone implants into non-loading parts (IRB approval
number #1310) was conducted on 10 patients
successfully and a large-scale clinical trial was started
across the nation. In project for cartilage regeneration,
an investigator- initiated clinical trial “A clinical trial
for the validation of safety and efficacy of theimplant-type tissue-engineered cartilage using autologous cells” have been carried out. As stated above, weare proceeding translational research aiming at clinicalapplication of tissue engineering and regenerative
medicine. Contribution to the Hospital

4.

5.

6.

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.

7.

8.

Makii Y, Asaka M, Setogawa S, Fujiki S, Hosaka
Y, Yano F, Oka H, Tanaka S, Fukui N, Yanagihara
D, and Saito T. Alteration of gait parameters in amouse model of surgically-induced knee osteoarthritis. J Orthop Surg (Hong Kong) (in press).
Goto H, Nishio M, To Y, Oishi T, Miyachi Y,
Maehama T, Nishina H, Akiyama H, Mak TW,
Makii Y, Saito T, Yasoda A, Tsumaki N, andSuzuki A. Loss of Mob1a/b in mice results inchondrodysplasia due to YAP1/TAZ-TEADsdependent repression of SOX9. Development (inpress).
Oichi T, Taniguchi Y, Soma K, Chang SH, Yano F,
Tanaka S, and Saito T. A mouse intervertebral
disc degeneration model by surgically-induced
instability. Spine (Phila Pa 1976) 2017 Oct 9.
doi: 10.1097/BRS.0000000000002427 [Epubahead of print].
Huang KC, Yano F, Murahashi Y, Takano S,
Kitaura Y, Chang SH, Soma K, Ueng S, Tanaka S,
Ishihara K, Okamura Y, Moro T, and Saito T.
Sandwich-type PLLA-nanosheets loaded with
BMP-2 induce bone regeneration in critical-sizedmouse calvarial defects. Acta Biomaterialia 59:
12-20, 2017. doi: 10.1016/j.actbio.2017.06. 041.
Saito T, and Tanaka S. Molecular mechanisms
underlying osteoarthritis development: Notch andNF-kappaB. Arthritis Res Ther 19:94, 2017. doi:
10.1186/s13075-017-1296-y.
Kawata M, Taniguchi Y, Mori D, Yano F, Ohba S,
Chung UI, Shimogori T, Mills SS, Tanaka S, andSaito T. Different regulation of limb development by p63 transcript variants. PLOS One
12:e0174122, 2017. doi: 10.1371/journal.pone.
0174122.
Watanabe S, Ogasawara T, Tamura Y, Saito T,
Ikeda T, Suzuki N, Shimosawa T, Shibata T,
Chung UI, Nangaku M, and Uchida S. Targeting
gene expression to specific cells of kidney
tubules in vivo, using adenoviral promoter
fragments. PLOS One 12: e0168638, 2017. doi:
10.1371/journal.pone.0168638.
Taniguchi Y, Kawata M, Chang SH, Mori D,
Okada K, Kobayashi H, Sugita S, Hosaka Y, Inui
H, Taketomi S, Yano F, Ikeda T, Akiyama H,

499

9.

10.

11.

12.

13.

14.

15.

Mills AA, Chung UI, Tanaka S, Kawaguchi H,
and Saito T. Regulation of chondrocyte survival
in mouse articular cartilage by p63. Arthritis
Rheumatol 69:598-609, 2017. doi: 10.1002/art.
39976.
Matsumoto T, Nakamura I, Juji T, and Ito K.
Severe pes planovalgus successfully treated in apatient with mutilating rheumatoid arthritis using
a new surgical approach involving medial
malleolar resection and medial displacement of
the talus: A case report. Mod Rheumatol 27(6):1083-1088, 2017.
Chang SH, Matsumoto T, Naito M, and Tanaka S.
Stenosing tenosynovitis of the flexor hallucis
longus tendon associated with the plantar
capsular accessory ossicle at the interphalangeal
joint of the great toe. Case Rep Orthop 2017:
2146762, 2017.
Ikegami M, Matsumoto T, Chang SH, Kobayashi
H, Shinoda Y, and Tanaka S. Anterior impingement syndrome of the ankle caused by osteoid
osteoma in the talar neck treated with arthroscopy and 3D C-arm-based imaging. Case Rep
Orthop 2017:2171627, 2017.
Matsumoto T, Nishino J, Izawa N, Naito M,
Hirose J, Tanaka S, Yasui T, Saisho K, andTohma S. Recent trends in treatment, outcomes,
and incidence of orthopedic surgery in patientswith rheumatoid arthritis: An observational
cohort study using the National Database of
Rheumatic Diseases in Japan from 2004 to 2014.
J Rheumatol 44(11):1575-1582, 2017.
Naito M, Matsumoto T, Chang SH, Ikegami M,
Hirose J, and Tanaka S. Recalcitrant lateralpremalleolar bursitis of the ankle associated withlateral ankle instability. Case Rep Orthop 2017:
4854812, 2017.
Riedl M, Glisson RR, Matsumoto T, Hofstaetter
SG, and Easley ME. Torsional stiffness after
subtalar arthrodesis using second generation
headless compression screws: Biomechanicalcomparison of 2-screw and 3-screw fixation. Clin
Biomech 45:32-37, 2017.
Komura M, Komura H, Komuro H, Ikebukuro K,
Hikita A, Hoshi K, and Takato T. Tracheal
cartilage growth by intratracheal injection ofbasic fibroblast growth factor. J Pediatr Surg

16.

17.

18.

19.

20.

21.

22.

2017 Feb; 52(2):235-238. doi: 10.1016/j.jpedsurg.
2016.11.011.
Hikita A, Chung UI, Hoshi K, and Takato T.
Bone regenerative medicine in oral andmaxillofacial region using a 3D printer. Tissue
Eng Part A 2017 Jun; 23(11-12):515-521. doi:
10.1089/ten.TEA.2016.0543.
Yonenaga K, Nishizawa S, Nakagawa T, Fujihara
Y, Asawa Y, Hikita A, Takato T, and Hoshi K.
Optimal conditions of collagenase treatment for
isolation of articular chondrocytes from aged
human tissues. Regenerative Therapy 2017 Jun;
6:9-14.
Horie N, Hikita A, Nishizawa S, Uto S, Takato T,
and Hoshi K. Impairment of the transition fromproliferative stage to prehypertrophic stage inchondrogenic differentiation of human induced
pluripotent stem cells harboring the causative
mutation of achondroplasia in fibroblast growth
factor receptor 3. Regenerative Therapy 2017
Jun; 6:15-20.
Ishibashi M, Hikita A, Fujihara Y, Takato T, andHoshi K. Human auricular chondrocytes withhigh proliferation rate show high production of
cartilage matrix. Regenerative Therapy 2017
Jun; 6:21-28.
Hoshi K, Fujihara Y, Saijo H, Asawa Y,
Nishizawa S, Kanazawa S, Uto S, Inaki R,
Matsuyama M, Sakamoto T, Watanabe M,
Sugiyama M, Yonenaga K, Hikita A, and Takato
T. Implant-type tissue-engineered cartilage forsecondary correction of cleft lip-nose patients:
An exploratory first-in-human trial. J Clin Trials
2017; 7:315.
Hoshi K, Fujihara Y, Saijo H, Kurabayashi K,
Suenaga H, Asawa Y, Nishizawa S, Kanazawa S,
Uto S, Inaki R, Matsuyama M, Sakamoto T,
Watanabe M, Sugiyama M, Yonenaga K, Hikita A,
and Takato T. Three-dimensional changes ofnoses after transplantation of implant-type tissueengineered cartilage for secondary correction ofcleft lip-nose patients. Regenerative Therapy
2017; 7:72-79.
Ohno M, Fuchimoto Y, Hsu HC, Higuchi M,
Komura M, Yamaoka T, Umezawa A, Enosawa S,
and Kuroda T. Airway reconstruction using
decellularized tracheal allografts in a porcine

500

model. Pediatr Surg Int 2017 Oct; 33(10):10651071. doi: 10.1007/s00383-017-4138-8. Epub
2017 Aug 17.

501

Department of Clinical Research
GovernanceDirector & Project Professor
Takashi Moritoyo M.D.,Ph.D.

Research Associate
Keiko Ueda, M.D.,Ph.D. (From May, 2016 to July, 2017)

Homepage

http://www.h.u-tokyo.ac.jp/english/centers-services/organization/l4/
researchgovernance.html

History and Overview of theOrganization
The Department of Clinical Research Governance
was established independently from the ClinicalResearch Support Center on January 1, 2015, for the
management of clinical research. The aim of thedepartment is an appropriate and rapid response tovarious issues surrounding clinical research in recent
years, to prevent problems related to research ethics
and research misconduct, and to promote highly
reliable clinical research. The intention of the
Department of Clinical Research Governance is toestablish a system that would enable the University ofTokyo Hospital to take the initiative in managing andpromoting clinical research so as to ensure thereliability of clinical research and compliance with the
ethics of clinical research promoted by university
hospitals providing advanced medical care.
The Department of Clinical Research Governance iscomposed of three offices: 1) Office of TR Strategy
Promotion, 2) Office for Clinical Research Education,and 3) Office of Clinical Quality Assurance &Compliance. These offices mutually cooperate topromote and strengthen governance functions within
the hospital.
The following activities are carried out by the
Office of TR Strategy Promotion: (1) formulating
comprehensive strategies for research and develop-

ment at the University of Tokyo Hospital; (2) adopting
the role of administrative headquarters when publicly
applying for large-scale research projects; (3) serving
as a liaison for consultations regarding the acquisitionof research funds and intellectual properties; (4)examination financial self-reliance strategies of theclinical research base; (5) discovering needs and seeds
in clinical practice; (6) investigating research
activities at the University of Tokyo Hospital andcreating a database; (7) collecting clinical research
information from external organizations; (8) activities
related to conflicts of interest at the University ofTokyo Hospital; (9) clerical work related to the
Advanced Medicine Development Support Management Committee; and (10) clerical work related to theSpecial Clinical Research Steering Committee. It was
reorganized in December, 2017, and the name of theoffice was changed to Office of Strategic Planning andPromotion.
The activities of the Office for Clinical Research
Education are as follows: (1) educational activities forclinical researchers; and (2) the dissemination ofworkshop summaries. It was reorganized in December,
2017, and the name of the office was changed to
Office of Research Integrity and Promotion.
The activities of the Office for Clinical Research
Education are as follows: (1) Auditing of clinicalresearch and clinical trials, (2) Give guidance andadvice on the reliability of clinical trials, (3) Perform
trend-analysis of audit findings and compliance issues,

502

report and make recommendations to the hospital
director to become a high reliability organization,(4) Provide support for the preparation of GCP
inspections by regulatory authorities, and integrated
management of findings, (5) Integrated managementof outsourced auditing, (6) Integrated managementof audit results of the University of Tokyo Hospital,(7) Collect information for corrective action andpreventive action after audits and investigations, (8)Collecting and analyzing regulatory information on
reliability of clinical research/trials, and providing
education/training, and (9) Secretariat of the Auditing
Working Group for the Translational ClinicalResearch Core Centers (AMED).
The Department of Clinical Research Governanceconsists of one manager (a full-time post from August,2015) and two staff members of the Office of TR
Strategy Promotion (one special researcher/URA andtwo clerical staff [temporary]), as of March 2018. The
Office for Clinical Research Education consists of one
member. The Office of Clinical Quality Assurance
consists of one head (project senior specialist) andthree staff members (auditors), three temporary staff(one auditor, one audit-assistant, three support staff).

Medical Care and Activities
The Office of TR Strategy Promotion has undertaken the following activities.
1) Organization coordination activities: assisting theSpecial Clinical Research Steering Committee, assisting the Special Clinical Research Checkup Committee
and assisting the preparation of reports on clinicalresearch activities at core hospitals under the Medical
Service Law (approved on March 25, 2016) and forsurveys conducted by the Ministry of Health, Labourand Welfare.
2) Activities related to TR Promotion: playing the roleof administrative headquarters for Projects of Translational and Clinical Research Core Centers.
3) Others: investigations of research paper publication
activities and hosting of the “Forum for Developmentof Seeds for Advanced Medicine, 2018” (administrative office).
The Office of Clinical Quality Assurance &Compliance was newly established in April 2015 andhas completed following activities in the third year,
2017.
1) Audit activities: (1) As regards to the University ofTokyo Hospital, the office conducted 3 audits for 2
investigator-initiated clinical trials (multi-center), and
6 audits for 3 clinical research (multi-center). (2) One
audit
for
investigator-initiatedclinicaltrial(multi-center) was conducted at the university otherthan the University of Tokyo. (3) We also provided
assistance in the preparation of audit SOPs and audit
plan, etc. for other some clinical trials and research.
(4) When research funding for the research/trials weresecured, the audits were outsourced to the CRO under
supervision the Office.
2) Support for inspections/investigations: Regarding
TR Core Centers surveys by AMED, and ClinicalResearch Core Hospital investigations, the Officeattended to explain the system and structure of quality
assurance, etc.
3) Consolidate information: The office collects all theinformation on audit results including directly
outsourced by principal investigators, and has been
centrally managing the GCP inspections findings
conducted at the University of Tokyo Hospital.
4) Advisory: Provides advice on compliance andreliability related matters to the Central Coordinating
Unit, Site Coordinating unit, and prepares advisory
records.
5) TR program: In June/2017, the University of Tokyo
Hospital was appointed as the secretariat of the new
initiative, [inter-site network audit working group]of Translational Research Program among 10 TR Core
Site Centers. The Working Group consists of one tothree auditors from each Center. The kick-off meeting
was held on December 1st, 2017, to discuss objectives
and the 5-year plan. Worked on three themes (1)Auditors education and training, (2) Collect issues inauditing and solve them, and (3) Optimal state of audit& quality assurance, it has started in March/2018.
6) Networking: (1) As a part of UCHT Allianceactivity, visitation took place among the eight member
universities in the Kanto Koshinetsu region toevaluate the implementation system. (2) Participatedin the study to evaluate the reliability as a part of the
National University Hospital Clinical Research
Promotion Initiative (NUH-CRPI). (3) Participated in

503

the Japan Society of Quality Assurance (JSQA). (4)Participated in the working group of Japan Society ofClinical Trials and Research to draw up guideline torespond to Clinical Trials Act.

References
1. Yamamoto T., Furihata K., Hisaka A., Moritoyo
T., Ogoe K., Kusayama S., Motohashi K., Mori A.,
Iwatsubo T., Suzuki H. Notable Drug-Drug
Interaction Between Etizolam and Itraconazole inPoor Metabolizers of Cytochrome P450 2C19. J.
Clin. Pharmacol.57:1491-1499, 2017

504

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

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

Homepage

http://kokoro.umin.jp/

Introduction and Organization
The Department of Child Psychiatry wasestablished in April 2005 as the clinical counterpart to
the Clinical Education Center of Mental Development,
both of which are funded by the special grant forfaculty development. The major aim of the Clinical
Education Center is to train mental health specialists
in various fields with a fundamental grounding inchild psychiatry and neurosciences. Much of theservices provided are based on the 37 years ofexperience in intervention and treatment for developmentally disabled children established in the former
child psychiatry division of Department of Neuropsychiatry. Our department uses a multidisciplinary
approach by working in collaboration not only with
the Department of Neuropsychiatry, Department ofPediatrics and Graduate School of Education in the
University of Tokyo but also several other educational
and/or clinical facilities on mental development ordevelopmental disorders. The Department of Child
Psychiatry complemented the Clinical Education
Center by providing fieldwork for clinical training andoffered clinical services to patients with various
development problems also.
The Clinical Education Center of Mental Development was closed in March 2010 because of time limitof the fund, and Department of Child Neuropsychiatry,
Graduate School of Medicine was established in April
2010. The Department of Child Psychiatry, as theclinical counterpart to the department in graduate
school, focuses on clinical activity related to research
as well as quality practice of child psychiatry andeducation of leading child psychiatrists and allied

professionals. In addition to professors of the graduate
school, 3 psychiatrists and 3 psychologists (2 full-timeones for a definite term and 1 part-time one) areofficially assigned to the Department of Child
Psychiatry. One psychiatric social worker works
mainly for the Department of Child Psychiatry since2013 also.

Clinical activities
In the year 2017, the Department of Child
Psychiatry consisted of 13 psychiatrists and 6
psychologists (full-time and part-time). Althoughpatients with various disorders are seen, the focus of
the department is mainly on patients with developmental disorders. We offer services to patients with abroad range of developmental disorders including
Autism Spectrum Disorder (ASD), Attention-Deficit/
Hyperactivity Disorder (ADHD), Learning Disabilities(LD), Intellectual Disability (ID), tic disorders, andchild & adolescent Obsessive-Compulsive Disorders(OCD).
Number of new patients in 2017 was 239, andalmost the same as that in 2016. A large part of the
new patients consisted of patients with ASD, ADHD
or tic disorders. Out of 239 patients, children ofelementary school age were 105, and children of
junior high school age were 30. In other words,
children of elementary or junior high school age weremore than half of the patients. Number of preschool
children was 73, and slightly higher than that in 2016,
suggesting our response to increasing needs for early
diagnosis and intervention.
The follow-up clinic consisted of general clinic and505

special clinic (Tic/OCD clinic). At the general clinic, arigorous diagnosis based on detailed assessment anddecision about treatment course are provided forchildren and adolescents with any kinds of mental
problems. After fine adjustment of treatment course
within a given period, the patients are referred tocommunity hospitals/clinics or intervention/education
facilities with a detailed report. The special clinic
meets a need for high level services and works withresearch for special diseases.
Services for the general child psychiatry outpatientsare provided by psychiatrists in the areas of pharmacotherapy, psychotherapy, psychoeducation and also
work closely with the schools and community.
Psychologists have charge of psychological consultation as well as psychological examination. Patients
involved in those are mainly individuals with
developmental disabilities, and individualized treatment focusing on developmental viewpoint is plannedfor each. Psychological consultation includes services
in the following areas: (1) evaluation of cognitive andbehavioral development, (2) individualized treatmentof the disabled individual (3) counseling of parents
and providing information to the disabled individual’s
support network (relatives, schools) and environmental coordination. In addition to psychologists,
psychiatric social worker participates in actual
environmental coordination. Cognitive behavior
therapy for obsessive-compulsive symptoms oranxiety is sometimes provided also.
As for intervention for preschool children with ASD,
intensive individualized therapy consisting of weekly
10 sessions was provided for children aged 3 years or
younger.
Parent-training for parents with ADHD children,which started in 2011, was provided. This program
aimed that the parents learn deeper understanding ofdifficult children and appropriate strategy of copingwith them.
In addition to these outpatient services, “inpatient
assessment on developmental disorders” program
started in 2010. This program is provided in theinpatient ward of neuropsychiatry for adolescents oradults who have mental problems such as depression
and wish a detailed examination about possibility ofhidden developmental disorders including ASD and
ADHD.

We also focus on psychiatric liaison activity withother departments in the University hospital,
especially pediatrics.

Education
Undergraduates of the University of Tokyo haveopportunities to participate in an assessment anddiagnosis session at the general first visit outpatient
clinic and intervention for preschool children.
Graduate students in clinical psychology course fromthe University of Tokyo participate in intervention forpreschoolers also.
One month training course is offered to juniorresidents especially in pediatric specialty course. This
course includes intake interview of first visit patients,
observation of assessment and treatment for follow-up
patients and intervention for preschoolers, and visit tocommunity hospital and intervention/guidance
facilities for child and adolescent mental health. For
general psychiatrists including senior residents of the
Department of Neuropsychiatry, round for developmental disorders and an inpatient program of assessment about developmental disorders are provided asopportunity to get knowledge and experience ofdevelopmental disorders.
In response to the increasing interest to adults with
developmental disorders, a seminar of developmental
disorders was held in July 2017, and about 200
medical doctors, psychologists, and allied professionals attended.

Research
We participate in investigation of etiology anddevelopment of effective treatment on ASD and
ADHD, which are organized in collaboration with the
Department of Neuropsychiatry and other research,educational and clinical facilities. In addition, research
related specifically to the clinical activities in the
Department of Child Psychiatry is currently being
investigated.
Clinical evaluation and treatment
Effectiveness study of early intervention for autisticpreschoolers is being undertaken. We focused oninvestigating early intervention including treatment
for children and parent support.

506

Effectiveness of a program of group cognitive
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.
We continued survey of tics and related symptoms
in community preschoolers and development ofobjective assessment for tics also.
Neuropsychological research
Neuropsychological data on ASD, ADHD andTourette syndrome are being collected. Analysis of therelations among neuropsychological findings and theclinical evaluation as well as comparisons between
patients and their healthy siblings are being
conducted.
Genetic research
As we are interested in gene-environment interaction, we are examining influence of age of parents
and assisted reproduction technologies on emergenceof ASD. We are analyzing samples of individuals froma multiplex family of ASD by exome sequencing also.
We are collecting and analyzing DNA samples ofpatients with Tourette syndrome and their parents also.
Neuroimaging
Studies include structural MRI, Near-Infrared Spectroscopy (NIRS) and functional MRI with exploring
the pathogenesis of developmental disorders such as
ASD. One of the intensive study is the examination of
prefrontal blood flow in ASD and ADHD by NIRS
which is non invasive and easily applicable to children
and developmentally disabled individuals. Possibilityof NIRS as a predictor of efficacy of methylphenidate
for children with ADHD is intensively examined also.
Functional MRI study of adults with ADHD andadults with Tourette syndrome by delayed reward task
is in process.

Publications
1.

2.

3.

4.

Eriguchi Y, Kuwabara H, Inai A, Kawakubo Y,
Nishimura F, Kakiuchi C, Tochigi M, Ohashi J,
Aoki N, Kato K, Ishiura H, Mitsui J, Tsuji S, Doi
K, Yoshimura J, Morishita S, Shimada T,
Furukawa M, Umekage T, Sasaki T, Kasai K,
Kano Y. Identification of candidate genes
involved in the etiology of sporadic Tourette
syndrome by exome sequencing. Am J Med
Genet B Neuropsychiatr Genet. 2017; 174(7):712-723.
Owada K, Kojima M, Yassin W, Kuroda M,
Kawakubo Y, Kuwabara H, Kano Y, Yamasue H.
Computer-analyzed facial expression as asurrogate marker for autism spectrum social core
symptoms. PLoS One. 2018; 13(1): e0190442.
Yoshikawa A, Nishimura F, Inai A, Eriguchi Y,
Nishioka M, Takaya A, Tochigi M, Kawamura Y,
Umekage T, Kato K, Sasaki T, Kasai K, Kakiuchi
C. Novel rare variations in genes that regulate
developmental change in N-methyl-d-aspartate
receptor in patients with schizophrenia. Hum
Genome Var. 2018; 5: 17056.
Yoshikawa A, Nishimura F, Inai A, Eriguchi Y,
Nishioka M, Takaya A, Tochigi M, Kawamura Y,
Umekage T, Kato K, Sasaki T, Ohashi Y,
Iwamoto K, Kasai K, Kakiuchi C. Mutations of
the glycine cleavage system genes possibly affectthe negative symptoms of schizophrenia throughmetabolomic profile changes. Psychiatry Clin
Neurosci. 2018; 72(3):168-179.

507

Department of Pain and Palliative
Medicine
Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/pailiative/

History and outline of organization
About a half of the cancer patients die by cancer
though of the recent innovations of anti-cancer
treatments. It mainly depends on the efficacy of thefirst-line strategies whether cancer is curable or not.
Almost all the cancer patients whose initial treatment
was unsuccessful die after the distressing struggle
against their disease within several years. It is clear
for such patients that both sufficient anti-cancer
treatments and appropriate approaches to improvetheir quality of life (QOL) are simultaneously indispensable.
However in our nation, most attention has been
entirely paid to the improvement of cure rate andsurvival time of cancer patients. On the other hand, we
have to consider that their QOL is scarcely
concentrated until quite recently.
Palliative care means the combination of active
therapeutic approach and total human care for thepatients no matter which their cancer does or does not
respond to anti-cancer treatments. Pain relief, othersymptom management, psychological, social andspiritual cares are as a top priority for these patients. It
is also emphasized that palliative care is necessary to
be applied in the cancer treatment even for patients inearly stage of their diseases as well as the progressiveor terminal phase of their clinical courses.
In Department of Pain and Palliative Medicine of The
University of Tokyo Hospital, we pain and palliative
care team takes a leading role not only to control
physical symptoms of cancer patients but also to carefor the mental and social support at the same time, andto improve the overall QOL of patients. Moreover, we
also promote the education, research and innovation ofpain and palliative medicine of our hospital anduniversity.
Palliative care is described clearly in the law "Cancer

Control Act" approved by the National Diet on June
2006 that "The medical treatment to aim at relieving
many kinds of pain and problems of cancer patients is
applicable from the early course of the illness".

Consultation
In The University of Tokyo Hospital, we pain andpalliative care team are composed of many kinds ofspecialists containing three full-time staff doctors, twofull-time doctors, and two certificated cancer andhospice care nurses who take an initiative in thismultidisciplinary team. We visit to bedsides, consultation rooms and everywhere in the hospital, and offer
palliative care to cancer patients who have received
cancer care in cooperation with patients’ attending
doctors, ward staff, therapists of rehabilitation, social
workers and every kind of professionals.
The annual number of consultation by our pain andpalliative care team is getting increased. In 2016, thenumbers achieved to more than total 900 cases andfurther increased in 2017. To date we have become tocollaborate with almost all departments treating
cancer in our hospital. These results indicate that thehospital understands the significance of palliative carewell and relies on our team.

Education
In the Department of Pain and Palliative Medicine,junior residents of the first and second year can learn
the basic knowledge and practice of palliative care by
selecting an optional subject for one, two, four oreight months. And then they can participate in the pain
and palliative care team and attend the daily teamconference on weekdays.

508

1) Palliative care training program
The training course (selection) for two months ( or *for one month )･ Program to acquire basic knowledge and practice ofpalliative care for targeting all junior residents. *Only in "Comprehensive Internal Medicine”
selection.
The training course (selection) for four or eightmonths･ Program to acquire basic knowledge, practice, andskills of communication for doctors who need to beclinical oncologists or pain and palliative carespecialists.
2) CurriculumContents of training･ All junior residents are assigned to the pain andpalliative care team. They chiefly participate inpalliative care practice as a member of the team.
･ In the course for four and eight months, they learn
to make palliative care plans for inpatients, discuss
palliative care of the cases with patients’ attending
doctors, ward staff, and execute these palliative careplans.
Goal to attain･ Palliative care for inpatients (around 40 cases aday): They acquire the outline of control of physicaland psychiatric symptoms of the patients with
common diseases in our country such as digestivecancers. They also learn the outline of spiritual andfamily care.
･ Cancer registry: In The University of Tokyo
Hospital, it is not unusual that the patient whom thepain and palliative care team treats is often in an
end stage, and his or her condition changes
physically and mentally day by day. Residents
should input the clinical data about palliative careof such patients concisely to the database. Theyacquire the outline of data management of thepalliative care connected directly to a clinicalresearch.
･ Communicative competence: The clinician often
has to break "Bad news" to his patients time after
time along the course of their illness. It is very
difficult for the clinician to provide the appropriate
information about diagnoses, recurrence, progression and prognosis of illness to his patients.

The oncologist has to deal with patients’ strong grief
and feeling of loss when their illness is obviously progressive as well as has to manage both their accepting
realities and expecting hopes. We practice according
to the guidelines of communication that is recommended by the Japanese Psycho-Oncology Society.
Educational･ In the intensive course for the first-year residents,
we prepare lectures about:# pain management# diagnoses and management of delirium# Introduction of guidelines in the field of palliative
medicine and their use# Basic medication for palliative care
# Spirituality and whole person care for Japanesepatients facing death
Daily and weekly schedule･ Conference: Monday-Friday (every weekday);9:00-10:30am･ Consultation: Monday-Friday (every weekday);from the end of morning conference, up to the completion of all the requested consulting of the day.
･ The cancer registry: They input data in the ward
round with the HIS (Hospital information system)
terminal on each floor.
The instruction system･ Inpatient care: Residents participate in the
consultation team (pain and palliative care team)that contains medical instructors. We pain andpalliative care team take charge of about 40-50
inpatients usually.
･ Multidisciplinary conference: Psychiatrists, pain
clinicians/Anesthesiologists, orthopaedicians, pharmacists, medical social workers and others
participate in the daily or weekly conference
besides the regular member of the pain andpalliative care team. Residents can discuss actively
the multidisciplinary palliative care plans which ourteam should carry out. Participants from each
occupation also guide the care plans from their
viewpoints of experts.

Research
The clinical information accumulated from thepalliative care consultation is input to the concise
database simultaneously and utilized for various kinds

509

of clinical researches to submit to the international
medical journal such as "International Journal of
Radiation Oncology Biology Physics", "Journal ofPain and Symptom Management" and so on.
To date, we the Department of Palliative Medicine
have contributed to the progress of following fields ofinvestigations. Please refer to our homepage forresults in details and acquisition of the research fund.
1) Evaluation and quality assurance of special pain
and palliative care team2) Cancer Survivorship
3) Investigating cognitive dysfunction induced bypain4) Cancer treatments-induced neurological side
effect5) Synergistic influence between sleep disorder andpain6) Assessment of neuropathic pain
7) Relationships among our university hospital andlocal hospitals and clinics
8) Palliative care supporting metastatic breast cancer
patient9) In palliative medicine field, clinical researchesand questionnaires

Publications
1. Matsuishi Y, Hoshino H, Shimojo N, Enomoto Y,
Kido T, Jesmin S, Sumitani M, Inoue Y.
Development of the Japanese version of the
Preschool Confusion Assessment Method for the
ICU (psCAM-ICU). Acute Medicine & Surgery
2017; 5: 102-5
2. Abe H, Sumitani M, Matsubayashi Y, Tsuchida R,
Oshima Y, Takeshita K, Yamada Y. Validation ofpain severity assessment using the painDETECT
questionnaire. Int J Anesthesiol Pain Med 2017;
3: 1-5
3. Inoue R, Sumitani M, Ogata T, Chikuda H,
Matsubara T, Kato S, Shimojo N, Uchida K,
Yamada Y. Direct evidence of central nervous
system axonal damage in patients with postoperative delirium: a preliminary study of pNF-H
as a promising serum biomarker. Neuroscience
Letters 2017; 653: 39-44
4. Ichinose A, Sano Y, Osumi M, Sumitani M,
Kumagaya S, Kuniyoshi Y. Somatosensory

feedback to the cheek during virtual visualfeedback therapy enhances pain alleviation forphantom arms. Neurorehabilitation & Neural
Repair 2017; 31: 717-25
5. Oka, H, Matsudaira K, Fujii T, Kikuchi N, Haga Y,
Sawada T, Katsuhira J, Yoshimoto T, Kawamata K,
Tonosu J, Sumitani M, Kasahara S, Tanaka S.
Estimated risk for chronic pain determined using
the generic StarT Back 5-item screening tool. J
Pain Res 2017; 10: 461-7
6. Kogure T, Sumitani M, Ikegami K, Abe H,
Hozumi J, Inoue R, Kawahara K, Yamada Y.
Donepezil, an acetylcholinesterase inhibitor, canattenuate gabapentinoid-induced somnolence inpatients with neuropathic pain: a retrospective
chart review. J Pain Palliat Care Pharmacother2017; 31: 4-9
7. Osumi H, Sumitani M, Kumagaya S, Morioka S.
Optimal control of reaching is disturbed incomplex regional pain syndrome (CRPS): asingle-case study. J Pain Res 2017; 10: 167-73
8. Osumi M, Ichinose A, Sumitani M, Wake N, Sano
Y, Yozu A, Kumagaya S, Kuniyoshi Y, Morioka S.
Restoring movement representation and alleviating phantom limb pain through neurorehabilitation with a virtual reality system. Eur J
Pain 2017; 21: 140-7
9. Kogure T, Sumitani M, Abe H, Hozumi J, Inoue R,
Mietani K, Kawahara K, Yamada Y. Ischemic
ulcer pain is both nociceptive and neuropathic
pain based on a discriminant function analysis
using the McGill Pain Questionnaire. J Pain
Palliat Care Pharmacol 2017; 31: 98-104
10. Osumi M, Sumitani M, Abe H, Otake Y,
Kumagaya S, Morioka S. Kinematic evaluation
for impairment of skilled hand function inchemotherapy-induced peripheral neuropathy. J
Hand Ther 2017; 14: S0894-1130(16)30238-1
11. Isomura T, Sumitani M, Matsudaira K,
Kawaguchi M, Inoue R, Hozumi J, Tanaka T,
Oshima H, Mori K, Takemoto S, Inui H, Tahara K,
Yamagami R, Hayakawa K. Development of theJapanese version of the Leeds Assessment of the
Neuropathic Symptoms and Signs Pain Scale(LANSS-J): Diagnostic Utility in a clinical setting.
Pain Prac 2017; 17: 800-7(And, 17 Japanese articles)

510

Department of Cancer Resource
CenterChief
Sachiyo Nomura, M.D.,Ph.D.

Associate chief
Takako Wakeda, M.D.,Ph.D.

Counseling staff
Nobuko Yamaji, RN., Megumi Yasuda, RN.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/cancer_support/

Introduction and Organization
As part of national efforts to address cancer,
the government has been establishing a network of“cancer care hub hospitals.” In response to its being
designated as a regional cancer care hub hospital in2008, the University of Tokyo Hospital established theCancer Patient Support Center to provide consultations to cancer patients and their families as well as
residents in neighboring communities with the aim ofleading them to appropriate departments and facilities.

Medical Services
Provision of information if patient contracts cancer
If a person gets cancer, the first thing theyneed to do is collect information on cancer. The
Cancer Counseling and Support Center provides
information and booklets on different types of cancer.
Furthermore, the person needs to accurately
understand the doctors’ explanations to select the besttreatment for oneself from the various options
presented by doctors. At the Cancer Counseling andSupport Center, we explain difficult medical terms in
simple language, and we help patients understand theirdoctors’ advice.

Various kinds of advice related to the medical careof cancer
If a person contracts cancer, besides the
medical problem of what kind of treatment to undergo
and where, there are also issues related to medicalcare when receiving treatment, such as medical
expenses, how to get along after being discharged
from hospital, job, and nursing services. The Cancer
Counseling and Support Center provides patients withadvice and support so that they can resolve such social
worries.
Provision of information on second opinions
The Center provides information on how to
get a second opinion and on facilities that provide
second opinions.
Various kinds of advice related to the appearancechanges caused by cancer treatment
Cancer treatment often causes appearancechanges such as hair loss and skin pigmentation. The
center provides patients with practical advice andsupport about wig and cover make-up.
Provision of general information and advice on
cancer
The Center sends out and provides
information to people who do not have cancer but who

511

want to find out about cancer, for instance thetreatment and screening for it.

Open hours
If you have any queries, please contact us on
03-5800-9061 between 9am-4pm weekdays (except 12
noon-1pm). Our center provide advices for nothing.

Research activities
Our research field covers the relation between
appearance changes caused by cancer therapy andPatients’ quality of life.

References and Presentation
1. Diagnosis and treatment of breast cancer(Review) Takako W. Ido-no-Nippon (0287-6760)
vol.76-8 Page62-67, Aug. 2017
2. Development of appearance care services at the
University of Tokyo hospital. Wakeda T., Nomura
S., Tsuge M., Miura E., Yasuda M., Haruki H.,
Kikuchi T., Takeda A. The 55th Annual Meetingof Japan Society of Clinical Oncology, Oct. 2017

512

Department of Genome
Informatics
Director & Professor
Takashi Kadowaki, M.D., Ph.D.

1. Organization
The Department of Genome Informatics started asa special unit conducting research on human genetics
and clinical epidemiology in 2003. Our section
functions as the unit to establish clinical andepidemiological data sampling/management and toaccomplish an appropriate and efficient application of
results of recently advanced human genetics andgenomics. In addition, the unit contributes to training
and educating specialists of clinical epidemiology andhuman genetics. Our section also supported designingof clinical / genetic studies. It consists of one
professor and different specialties participating in thedepartment. They include diabetologists, nephrologist,
cardiologists and epidemiologists.

2. Activities
In collaboration with RIKEN, we have identified
genetic variations conferring susceptibility to type 2
diabetes, myocardial infarction, renal dysfunction,
and atherosclerosis obliterance (ASO) in theJapanese population. We are now performing agenome-wide association study to identify variations
conferring susceptibility to type 2 diabetes in theJapanese population. About 500,000 variants directly
genotyped were imputed using the 1000 Genomes
Project Phase 3 reference panel in 36,000 cases andmore than 155,000 controls. We identified novel type2 diabetes associated loci, which had distinct minor
allele frequency spectra between Japanese andEuropeans, such as the missense variants in genes
relatedtoinsulinsecretion.
Trans-ethnic
comparisons of the molecular pathways from the

GWAS results highlighted both ethnically shared anddistinct impacts of a series of pathways on type 2
diabetes. These findings illustrated the etiology oftype 2 diabetes in Japanese and Europeans. We also
found that one gene was associated with diabetic
nephropathy and two genes were associated withdiabetic retinopathy.
We conducted whole genome sequence andanalyzed the sequence data of the subjects with type2 diabetes in collaboration with RIKEN and BioBank
Japan.
We are exploring the genetic andenvironmental factors by selecting case and control
from BioBank Japan for genome-wide analysis
concerning deterioration of diabetes and diabetic
complications (diabetic nephropathy and diabetic
retinopathy). We are developing the methods topredict diabetic complications and deterioration ofdiabetes by bioinformatics algorithms including thePenalized regression method, often used in machinelearning and public OmiX database.
The insulin receptor gene mutations were analyzed
in four patients with severe insulin resistance 1).
Using online databases, we analyzed insulin receptor
gene missense mutations and demonstrated that
mutations causing Donohue syndrome were more
frequently located in the fibronectin type III domain(FnIII) than those causing the milder insulin
resistance. We revealed that the mutant insulin
receptor genes in the FnIII reduced insulin
proreceptor processing, by functional analysis using
cultured cells. In silico structural analysis revealed
that missense mutations predicted to severely impairhydrophobic core formation and stability of the FnIII
domains. These results suggest the importance of the513

FnIII domains, provide insight into the molecularmechanism of severe insulin resistance, and will aid
early diagnosis.
In cardiology and vascular medicine, we focused onatherosclerotic diseases such as coronary stenosis andmyocardial infarction. It is important to accumulate
and analyze data obtained in practice and genetic data
to gain insight into a clinical picture. Analyzing datacollected provide detailed genetic factors of thecoronary atherosclerotic diseases and their clinicaloutcome.
We used panel analysis applying next-generation
sequencer and revealed the genetic diagnosis on
extreme phenotypes of diseases related to life-styles
including, maturity onset diabetes of the young andlipodystrophy and predicted the prognosis andselected effective therapies.

3.

3．References
1. Suzuki K, Akiyama M, Ishigaki K, Kanai M,
Hosoe J, Shojima N, Hozawa A, Kadota A,
Kuriki K, Naito M, Tannno K, Ishigaki Y,
Hirata M, Matsuda K, Iwata N, Ikeda M,
Sawada N, Yamaji T, Iwasaki M, Ikegawa S,
Maeda S, Murakami Y, Wakai K, Tsugane S,
Sasaki M, Yamamoto M, Okada Y, Kubo M,
Kamatani Y, Horikoshi M, Yamauchi T,
Kadowaki T. Identification of 28 novel
susceptibility loci for type 2 diabetes in theJapanese population. Nat Genet. in revision
2. Zhao W, Rasheed A, Tikkanen E, Lee JJ,
Butterworth AS, Howson JMM, Assimes TL,
Chowdhury R, Orho-Melander M, Damrauer S,
Small A, Asma S, Imamura M, Yamauch T,
Chambers JC, Chen P, Sapkota BR, Shah N,
Jabeen S, Surendran P, Lu Y, Zhang W, Imran A,
Abbas S, Majeed F, Trindade K, Qamar N,
Mallick NH, Yaqoob Z, Saghir T, Rizvi SNH,
Memon A, Rasheed SZ, Memon FU, Mehmood K,
Ahmed N, Qureshi IH, Tanveer-Us-Salam, Iqbal
W, Malik U, Mehra N, Kuo JZ, Sheu WH, Guo X,
Hsiung CA, Juang JJ, Taylor KD, Hung YJ, Lee
WJ, Quertermous T, Lee IT, Hsu CC, Bottinger
EP, Ralhan S, Teo YY, Wang TD, Alam DS, Di
Angelantonio E, Epstein S, Nielsen SF,
Nordestgaard BG, Tybjaerg-Hansen A, Young R;

4.

5.

6.

CHD Exome+ Consortium, Benn M, FrikkeSchmidt R, Kamstrup PR; EPIC-CVD
Consortium;
EPIC-Interact
Consortium;
Michigan Biobank, Jukema JW, Sattar N, Smit R,
Chung RH, Liang KW, Anand S, Sanghera DK,
Ripatti S, Loos RJF, Kooner JS, Tai ES, Rotter JI,
Chen YI, Frossard P, Maeda S, Kadowaki T,
Reilly M, Pare G, Melander O, Salomaa V, RaderDJ, Danesh J, Voight BF, Saleheen D.
Identification of new susceptibility loci for type 2
diabetes and shared etiological pathways withcoronary heart disease. Nat Genet. 2017
Oct;49(10):1450-1457.
Hosoe J, Kadowaki H, Miya F, Aizu K,
Kawamura T, Miyata I, Satomura K, Ito T, Hara
K, Tanaka M, Ishiura H, Tsuji S, Suzuki K,
Takakura M, Boroevich KA, Tsunoda T,
Yamauchi T, Shojima N, Kadowaki T. Structural
Basis and Genotype-Phenotype Correlations of
INSR Mutations Causing Severe Insulin Resistance. Diabetes. 2017 Oct;66(10):2713-2723.
Yamaguchi J, Tanaka T, Saito H, Nomura S,
Aburatani H, Waki H, Kadowaki T, Nangaku M.
Echinomycin inhibits adipogenesis in 3T3-L1
cells in a HIF-independent manner. Sci Rep. 2017
Jul 26;7(1):6516.
Sasaki M, Sasako T, Kubota N, Sakurai Y,
Takamoto I, Kubota T, Inagi R, Seki G, Goto M,
Ueki K, Nangaku M, Jomori T, Kadowaki T. Dual
Regulation of Gluconeogenesis by Insulin and
Glucose in the Proximal Tubules of the Kidney.
Diabetes. 2017 Sep;66(9):2339-2350.
Yamada T, Shojima N, Noma H, Yamauchi T,
Kadowaki T. Weekly Versus Daily Dipeptidyl
Peptidase 4 Inhibitor Therapy for Type 2
Diabetes: Systematic Review and Meta-analysis.
Diabetes Care. 2018 Apr;41(4):e52-e55.

514

Department of Clinical Genomics
Director & Professor
Masaomi Nangaku, M.D., Ph.D.

Organization
The Department of Clinical Genomics started as a
special unit providing clinical genomics services in
2003. The department functions as the core unit toprovide genetic counseling services and to support anappropriate and efficient application of results ofgenetic testing. The department also provides a
training program for physicians preparing for boardcertified clinical geneticists. Many medical staffs withdiverse specialties including pediatricians, obstetricians, neurologists, cardiologists diabetologists andsurgeons participate in the activities of the
Department.

Activities
The room (Room 200) is specifically allocated in
the outpatient clinic. Genetic counseling is performed
by a team of board-certified clinical geneticist andcertified genetic counselors in cooperation with otherclinical departments. All cases are reviewed anddiscussed at the conference which is held once every
month.
We also provide support to clinical departments byconducting genome analysis for establishing genetic
diagnosis.
We also participate in Marfan’s Syndrome Clinic,
which is managed collaboratively by the Departmentsof Cardiovascular Surgery, Cardiovascular Medicine,
Pediatrics, Spinal Surgery and Ophthalmology.
Clinical sequencing for incurable malignant solid
tumors is also in progress as an Advanced Medical
Treatment B by using a multiplex genome sequencing,named "Todai OncoPanel”. In collaboration with
Clinical Laboratory Center, Pharmaceutical Services,
DepartmentsofPlanning
Information
andManagement, and several clinical departments,

pharmacogenetics tests including those for proton
inhibitor, warfarin, irinotecan, and tacrolimus, areconducted.

Publications
1. Hosoe J, Kadowaki H, Miya F, Aizu K,
Kawamura T, Miyata I, Satomura K, Ito T, Hara
K, Tanaka M, Ishiura H, Tsuji S, Suzuki K,
Takakura M, Boroevich KA, Tsunoda T,
Yamauchi T, Shojima N, Kadowaki T. Structural
Basis and Genotype-Phenotype Correlations of
INSR Mutations Causing Severe Insulin
Resistance. Diabetes. 2017 Oct;66(10):27132723.
2. Sato NS, Maekawa R, Ishiura H, Mitsui J, Naruse
H, Tokushige SI, Sugie K, Tate G, Shimizu J,
Goto J, Tsuji S, Shiio Y. Partial duplication of
DHH causes minifascicular neuropathy: A novel
mutation detection of DHH. Ann Clin Transl
Neurol. 2017 May 22;4(6):415-421.
3. Yamashita T, Mitsui J, Shimozawa N, Takashima
S, Umemura H, Sato K, Takemoto M, Hishikawa
N, Ohta Y, Matsukawa T, Ishiura H, Yoshimura J,
Doi K, Morishita S, Tsuji S, Abe K. Ataxic formofautosomal
recessive
PEX10-related
peroxisome biogenesis disorders with a novelcompound heterozygous gene mutation andcharacteristic clinical phenotype. J Neurol Sci.
2017 Apr 15;375:424-429.
4. Harigaya Y, Matsukawa T, Fujita Y, Mizushima
K, Ishiura H, Mitsui J, Morishita S, Shoji M,
Ikeda Y, Tsuji S. Novel GBE1 mutation in a
Japanese family with adult polyglucosan bodydisease. Neurol Genet. 2017 Feb 24;3(2):e138.
5. Matsukawa T, Koshi KM, Mitsui J, Bannai T,
Kawabe M, Ishiura H, Terao Y, Shimizu J,

515

Murayama K, Yoshimura J, Doi K, Morishita S,
Tsuji S, Goto J. Slowly progressive d-bifunctional
protein deficiency with survival to adulthood
diagnosed by whole-exome sequencing. J Neurol
Sci. 2017 Jan 15;372:6-10.

516

Medical Genome Research Support
CenterDirector and Professor
Masaomi Nangaku, M.D., Ph.D.

The Medical Genome Research Support Centerstarted as a core facility at the University of Tokyo
Hospital in 2011. Next generation sequencers(NGSs) including three Illumina HiSeq2500s, one
Pacific Biosciences RS II, an Oxford Nanopore
MinION system, and one Illumina MiSeq, and a
Droplet Digital PCR system have been installed.
Robotics for preparation of samples has also been
installed. Computer servers for processing ofmassive amount of genome data have been installedin the server room, which are connected to NGs via
network system isolated from the internet.

Publications
1.

2.

Activities
The core facility offers genome sequencing
employing NGSs for other laboratories in the
University of Tokyo Hospital. The core facility
further offers genome sequencing employing NGSs
for laboratories outside of the University of Tokyo.
Approximately 2,000 samples per year have been
analyzed.

3.

Research Accomplishments
Collaborative researches have achieved multiple
accomplishments in molecular genetic studies on
Charcot–Marie–Tooth diseases types 2A2A, 2K, and2Z, spinocerebellar ataxia type 42, focal segmental
glomerulosclerosis 9, candidate genes involved insporadic Tourette syndrome, and the causative genefor progressive neurodegenerative encephalopathy
with atypical infantile spinal muscular atrophy(TBCD). Five case reports based on mutational
analyses have also been published.

4.

5.

Ando M, Hashiguchi A, Okamoto Y, Yoshimura
A, Hiramatsu Y, Yuan J, Higuchi Y, Mitsui J,
Ishiura H, Umemura A, Maruyama K,
Matsushige T, Morishita S, Nakagawa M, Tsuji
S, Takashima H. Clinical and genetic diversities
of Charcot-Marie-Tooth disease with MFN2
mutations in a large case study. J Peripher Nerv
Syst. 2017 Sep;22(3):191-199.
Yoshimura A, Yuan J.-H., Hashiguchi A,
Hiramatsu Y, Ando M, Higuchi Y, Nakamura T,
Okamoto Y, Matsumura K, Hamano T, Sawaura
N, Shimatani Y, Kumada S, Okumura Y,
Miyahara J, Yamaguchi Y, Kitamura S,
Haginoya K, Mitsui J, Ishiura H, Tsuji S,
Takashima H. Clinical and mutational spectrumof Japanese patients with Charcot-Marie-Tooth
disease caused by GDAP1 variants. Clin Genet.
2017 Sep;92(3):274-280.
Ando M, Okamoto Y, Yoshimura A, Yuan J-H,
Hiramatsu Y, Higuchi A, Hashiguchi a, Mitsui J,
Ishiura H, FukumuracS, Matsushima M, Ochi N,
Tsugawa J, Morishita S, Tsuji S and Takashima
H. Clinical and mutational spectrum of Charcot–
Marie–Tooth disease type 2Z caused by
MORC2 variants in Japan. Eur J Neurol. 2017
Oct;24(10):1274-1282.
Kimura M, Yabe I, Hama Y, Eguchi K, Ura S,
Tsuzaka K, Tsuji S, Sasaki H. SCA42 mutation
analysis in a case series of Japanese patientswith spinocerebellar ataxia. J Hum Genet. 2017
Sep;62(9):857-859.
Udagawa T, Jo T, Yanagihara T, Shimizu A,
Mitsui J, Tsuji S, Morishita S, Onai R, Miura K,

517

Kanda S, Kajiho Y, Tsurumi H, Oka A, Hattori
M, Harita Y. Altered expression of Crb2 in
podocytes expands a variation of CRB2 mutations in steroid-resistant nephrotic syndrome.
Pediatr Nephrol. 2017 May;32(5):801-809.
6. Eriguchi Y, Kuwabara H, Inai A, Kawakubo Y,
Nishimura F, Kakiuchi C, Tochigi M, Ohashi J,
Aoki N, Kato K, Ishiura H, Mitsui J, Tsuji S,
Doi K, Yoshimura J, Morishita S, Shimada T,
Furukawa M, Umekage T, Sasaki T, Kasai K,
Kano Y. Identification of candidate genes
involved in the etiology of sporadic Tourette
syndrome by exome sequencing. Am J Med
Genet B Neuropsychiatr Genet. 2017 Oct;174(7):712-723.
7. Ikeda T, Nakahara A, Nagano R, Utoyama M,
Obara M, Moritake H, Uechi T, Mitsui J, Ishiura
H, Yoshimura J, Doi K, Kenmochi N, Morishita
S, Nishino I, Tsuji S, Nunoi H. TBCD may be acausal gene in progressive neurodegenerative
encephalopathy with atypical infantile spinal
muscular atrophy. J Hum Genet. 2017 Apr;
62(4):473-480.
8. Hosoe J, Kadowaki H, Miya F, Aizu K,
Kawamura T, Miyata I, Satomura K, Ito T, Hara
K, Tanaka M, Ishiura H, Tsuji S, Suzuki K,
Takakura M, Boroevich KA, Tsunoda T,
Yamauchi T, Shojima N, Kadowaki T.
Structural Basis and Genotype-Phenotype Correlations of INSR Mutations Causing Severe
Insulin Resistance. Diabetes. 2017 Oct;66(10):2713-2723.
9. Sato NS, Maekawa R, Ishiura H, Mitsui J,
Naruse H, Tokushige SI, Sugie K, Tate G,
Shimizu J, Goto J, Tsuji S, Shiio Y. Partial
duplication of DHH causes minifascicular
neuropathy: A novel mutation detection of DHH.
Ann Clin Transl Neurol. 2017 May 22;4(6):415-421.
10. Yamashita T, Mitsui J, Shimozawa N,
Takashima S, Umemura H, Sato K, Takemoto M,
Hishikawa N, Ohta Y, Matsukawa T, Ishiura H,
Yoshimura J, Doi K, Morishita S, Tsuji S, Abe
K. Ataxic form of autosomal recessive PEX10related peroxisome biogenesis disorders with anovel compound heterozygous gene mutationand characteristic clinical phenotype. J Neurol

Sci. 2017 Apr 15;375:424-429.
11. Harigaya Y, Matsukawa T, Fujita Y, Mizushima
K, Ishiura H, Mitsui J, Morishita S, Shoji M,
Ikeda Y, Tsuji S. Novel GBE1 mutation in a
Japanese family with adult polyglucosan bodydisease. Neurol Genet. 2017 Feb 24;3(2):e138.
12. Matsukawa T, Koshi KM, Mitsui J, Bannai T,
Kawabe M, Ishiura H, Terao Y, Shimizu J,
Murayama K, Yoshimura J, Doi K, Morishita S,
Tsuji S, Goto J. Slowly progressive dbifunctional protein deficiency with survival toadulthood diagnosed by whole-exome sequencing. J Neurol Sci. 2017 Jan 15;372:6-10.

518

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

519

of a portion of the first floor and the basement of an
administration building came to a decision by theconference.
2003 May. The construction of Cooperative Unit ofMedicine and Engineering Research was completed.
The cost of the construction was shared by theparticipation groups.
2003 May 22. The first research meeting of
Cooperative Unit of Medicine and Engineering
Research took place and research activities started.
2004 September 3. The second research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2005 September 13. The third research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2006 December 21. The fourth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2007 December 13. The fifth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2009 December 3. The sixth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2011 February 2. The seventh research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2011 December 17. The eighth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place2013 January 25. Development forum of advanced
medical seeds took place
2014 January 24. Development forum of advanced
medical seeds took place
2015 January 22. Development forum of advanced
medical seeds took place
2016 February 2. Development forum of advanced
medical seeds took place2017 February 2. Development forum of advanced
medical seeds took place2018 February 1. Development forum of advanced
medical seeds took place

Research activities
Development of Advanced Stereotactic Radiation
Cancer Therapy System
Department of Radiology
Nuclear Professional School, Department of Nuclear
Engineering and Management
Department of Chemical System Engineering
High Precision Stereotactic X-ray Cancer Therapy
System. Development of Advanced Compact Electron
Linear Accelerator for Cancer Inspection and Therapy
The aim of this research is to apply the in-vivo
visualization technique developed by our group in
high-precision radiation therapy and to develop the
motion prediction system for a real-time
tumor-tracking radiation therapy. For the visualizationof the treatment area during treatment, afour-dimensional cone-beam computed tomography(4D CBCT) reconstruction algorithm is developed bytaking the anatomy or tumor motion analysis into
account. In-treatment 4D CBCT requires the
projection images acquired during treatment. The
projection images are analyzed online, and comparedwith the reprojection images from the treatment
planning CT or registration CT. The time lag due tothe analysis can be compensated by the prediction
using a multi-channel singular spectrum analysis. Thissystem will remove a delay problem during thereal-time tumor-tracking radiation therapy, and will
provide a safer radiation therapy than the current ones
because this will be able to detect an irregularbreathing motion of the tumor.
Research and development of micro-neurosurgicalrobotic systems
Department of Neurosurgery, The University of Tokyo
Hospital
Mitsuishi Laboratory, Department of MechanicalEngineering, School of Engineering
Development of micro-neurosurgical robotic systems
and advanced microscopic image processing forautonomous surgical task recognition.
Laboratory of Cavitation & Lithotripsy
Department of Urology, Faculty of Medicine
Department of Mechanical Engineering, School ofEngineering

520

Development of a new method of lithotripsy using
high intensity focused ultrasound induced cavitation.
Development of Support Systems for Risk
Reduction in the Clinical Process
Chemical System Engineering
Center for Epidemiology and Preventive Medicine
Our specific targets are research and education on the
integration of biological and clinical information
including genome. In particular, we focus onestablishmentof
personalized
medicineastranslational research, selection of drug targets byproteomics,
interpretationoftranscriptional
regulations and drug development by targetingtranscriptional factors in metabolic and cardiovasculardiseases. Also, analyses of genomic functions, clinicalsafety monitoring by clinical database andassessments of clinical information systems are
conducted.
Development of diagnostic system of orthopedic
biomechanics
The Department of Orthopaedic Surgery, The
University of Tokyo.
Graduate School of Information Science andTechnology, The University of Tokyo.
To develop a non-invasive method for predicting bonestrength by finite element method analysis. Newly
administration of Teriparatide to the rheumatoid
patients and analyses of its effects by finite element
method with bone metabolic markers, bone density,and computed tomography.
Division of Neutron Capture Therapy & Immunotherapy for Cancer
Department of Cardiothoracic Surgery, Graduate /School of Medicine
Department of Radiology, University of Tokyo
Hospital
Department of Nuclear Engineering and Management,
School of Engineering
Endowment Department, Department of Immunotherapeutics (Medinet)
In order to control and eliminate human cancers, wedevelop the neutron capture therapy (NCT) using
small neutron accelerator equipped to hospital andalso aim to augment cancer therapy combined withimmunotherapeutic approaches. We develop thetumour specific drug delivery systems entrappedboron or gadolinium compounds as neutron capture
agents.
Development of new method of detecting andimaging chemical probes for biomolecules
Laboratory of Chemistry and Biology,
Graduate School of Pharmaceutical Sciences
Department of Cardiovascular Medicine
To develop chemical probes for imaging of
biomolecules. To visualize arteriosclerotic andischemic lesions by using fluorescent probes and MRI
contrast media.
Development of adhesion barrier materials using a
new animal model of liver-peritoneal adhesion
Artificial Organ and Transplantation Division,
Department of Surgery, Graduate School of Medicine,
University of Tokyo
Hepato-Biliary-Pancreatic
Surgery
Division,
Department of Surgery, Graduate School of Medicine,
University of Tokyo
Organs and Biosystems Engineering Laboratory,
Institute of Industrial Science, The University of Tokyo
Division of Biomedical Equipment and Biomaterials,
Center for Disease Biology and Integrative Medicine,
Graduate School of Medicine, The University of Tokyo
Department of Chemical System Engineering,
Graduate School of Engineering, The University ofTokyo
Department of Bioengineering, Graduate School ofEngineering, The University of Tokyo
Adhesions between liver and other organs are an
important issue in the cases of second surgeries suchas hepatic resection. Adhesions extend operative
duration; in addition, they increase the risk ofsurgeries. Thus, it is important to avoid adhesions at afirst surgery. However, no one report both the animalmodel and adhesion barrier materials of liver adhesion.
We try to develop a new adhesion model by hepatic
resection, instead of a usual peritoneal abrasion model.
Also, we develop new materials for preventing theadhesions.
Development of new therapy of life style-relateddeseases by Applied Metabolic Biotechnology

521

Department of Cardiovascular Medicine, Graduate
School of Medicine
Department of Diabetes and Metabolic Diseases,
Graduate School of Medicine
Department of Chemistry and Biotechnology, Schoolof Engineering
To establish the system and methods for engineering
the novel model mice of life style-related diseases
using RNAi technology and biotechnology. To
elucidate the mechanisms by which adipose tissue
derived factors, adipokines, contribute to thedevelopment of the metabolic syndrome. To explore
the molecular mechanisms of sarcopenia.
Development of bone and cartilage regeneration byscaffold and mechanical stress
Department of Orthopaedic Surgery, Faculty of
Medicine, The University of Tokyo
Division of Science for Joint Reconstruction,
Graduate School of Medicine, The University of Tokyo
Ishihara & Takai Lab, Department of Materials
Science, Graduate School of Engineering, The
University of Tokyo
Laboratory of Regenerative Medical Engineering,
Center for Disease Biology and Integrative Medicine,
Faculty of Medicine, The University of Tokyo
Department of Oral and Maxillofacial Surgery,
Faculty of Medicine, The University of Tokyo
Inhibition of aseptic loosening of artificial joints bynano-grafting of a novel biocompatible polymer MPC.
Creation of biocompatible biomaterials optimized forbone,
cartilage
andvascularregeneration.
Regeneration of bone and cartilage tissue in vitro
promoted by physical stimulation
Development of a non-viral gene delivery system bysupramolecular nanotechnology.
Department of Materials Science, Graduate School ofEngineering, The University of Tokyo
Department of Bone & Cartilage Regenerative
Medicine, Graduate School of Medicine, The
University of Tokyo
Department of Orthopaedic Surgery, Faculty of
Medicine, The University of Tokyo
Department of Oral and Maxillofacial Surgery,
Faculty of Medicine, The University of Tokyo

Division of Clinical Biotechnology, Center for Disease
Biology and Integrative
Medicine, Graduate School of Medicine, The
University of Tokyo
Division of Tissue Engineering, The University ofTokyo Hospital
Development of a non-viral siRNA delivery system bysupramolecular nanotechnology. Production ofregenerated cartilage and bone with high safety andusefulness. Establishment of practical production
and quality control systems. Promotion of the clinicalapplication of regenerated cartilage and bone.
Development of easy, precise, non-invasive systems todetect osteoblastic and chondrogenic differentiation.
Determination of a finite set of signaling factors
sufficient for induction of osteoblasts andchondrocytes. Development of a method to induce
osteogenesis and angiogenesis simultaneously.
Development of a cell-sheet culture system for bone
and cartilage. Screening for compounds that inducebone and cartilage regeneration
Development of gene therapy of cardiovasculartherapy by polymeric micelles.
Department of Vascular Surgery, Division of Tissue
Engineering, The University of Tokyo Hospital
Kataoka Laboratory, Department of Materials Scienceand Engineering, Graduate School of Engineering,
The University of Tokyo
To achieve effective and safe in vivo gene therapy ofcardiovascular and vascular diseases, we aredeveloping non-viral gene vectors based on nanoscaled polymer assemblies (polymeric micelles).
Polymeric micelles, which are spontaneously formed
from block copolymers, have a core containing
packaged genes surrounded by biocompatiblepoly(ethylene glycol) (PEG) palisades, and a varietyof pilot molecules can be installed on the surface ofpolymeric micelles. This "virusmimicking" nanoparticles might achieve efficient gene transfer to thetargeted tissues or cells because of protection of theloaded DNA from nuclease attack, their lowered
non-specific interaction with proteins and cells andfacilitated internalization by the targeted cells throughspecific interaction of the pilot molecules. Currently,
our research has been focused on in vivo gene transfer
to artery walls and muscles using polymeric micelles

522

incorporated genes.
Intervention study of exercise therapy for patientswith gluteal claudication after abdominal aortic or
iliac arterial surgery.
Mechano-Informatics,
Graduate
SchoolofInformation Science and Technology, The Universityof Tolyo
Department of Vascular Surgery, Faculty of Medicine,
The University of Tokyo
After minimally invasive endovascular aortic and iliac
repair for aneurysm with stent grafts and coilembolization, we apply intervention with exercise
therapy in case of postoperative gluteal claudication.
We aim to explore the mechanism of improving
gluteal claudication and establish the optimal exercise
therapy, by analyzing the biomechanical motion ofwalking with motion capture method before and after
the exercise therapy.
Analysis of the role of nitric oxide in themechanisms of renal and vascular injuries by theprobes for active oxygen and nitric oxide.
Department of Cardiovascular Medicine
Laboratory of Chemistry and Biology, Graduate
School of Pharmaceutical Sciences
It has been elucidated that the oxidative stress andnitric oxide have injurious and protective roles forrenal and vascular dysfunction, respectively. However,
it is difficult to detect them correctly in cells because
they are unstable. We aim to develop the way to detect
active oxygen and nitric oxide by using the in vivo
and in vitro models of renal and vascular dysfunction.

3.

4.

5.

6.

7.

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8.

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Kumagai H, Ikeda Y, Akazawa H, Komuro I,
Minabe M, Izumi Y, Isobe M: Detrimental effectsof specific Periodontopathic bacterial infection ontachyarrhythmia compared to bradyarrhythmia.
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Ashigaki N, Yoshida A, Shiheido Y, Sato H,
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Kimura T, Li CC, Xu PF, Noda A, Sakata I,
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H : Role of Hormone-sensitive Lipase in
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19. Kamo T, Akazawa H, Suda W, Saga-Kamo A,
Shimizu Y, Yagi H, Liu Q, Nomura S, Naito AT,
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Y, Takimoto E, Suzuki JI, Honda K, Morita H,
Hattori M, Komuro: Dysbiosis andcompositional alterations with aging in the gut
microbiota of patients with heart failure. PLoS
One. 2017 22; 12(3):e0174099.
20. 小倉奈々、葛山晴子、関本真理子、堀江亜由
美、堀川さとこ、永松明美、山田奈央子、渡部歌織、山崎力 ：Six Sigma の手法を用いた
原資料の分類・保管の品質向上の取り組み
薬理と治療 45: 698-701.2017
21. Huang KC, Yano F, Murahashi Y, Takano S,
Kitaura Y, Chang SH, Soma K, Ueng SWN,
Tanaka S, Ishihara K, Okamura Y, Moro T, Saito
T: Sandwich-type PLLA-nanosheets loadedwith BMP-2 induce bone regeneration in
critical-sized mouse calvarial defects. Acta
Biomater 2017, 59:12-20
22. Saito T, Tanaka S: Molecular mechanisms
underlying osteoarthritis development: Notch and
NF-κB. Arthritis Res Ther 2017,19(1):94
23. Taniguchi Y, Kawata M, Ho Chang S, Mori D,
Okada K, Kobayashi H, Sugita S, Hosaka Y, Inui
H, Taketomi S, Yano F, Ikeda T, Akiyama H, Mills
AA, Chung UI, Tanaka S, Kawaguchi H, Saito T:
Regulation of Chondrocyte Survival in Mouse

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Articular Cartilage by p63. Arthritis Rheum
2017,69(3):598-609
24. Kyomoto M, Moro T, Yamane S, Takatori Y,
Tanaka S, Ishihara K: A hydrated phospholipid
polymer-grafted layer prevents lipid-relatedoxidative
degradationofcross-linked
polyethylene. Biomaterials 2017,112:122-132
25. TanakaS:RANKL-Independent
Osteoclastogenesis: A Long-Standing Controversy.
J Bone Miner Res 2017,32(3):431-433
26. Oka H, Matsudaira K, Fujii T, Kikuchi N, Haga Y,
Sawada T, Katsuhira J, Yoshimoto T, Kawamata K,
Tonosu J, Sumitani M, Kasahara S, Tanaka S:
Estimated risk for chronic pain determined using
the generic STarT Back 5-item screening tool. J
Pain Res 2017,10:461-467
27. Kawata M, Taniguchi Y, Mori D, Yano F, Ohba S,
Chung UI, Shimogori T, Mills AA, Tanaka S,
Saito T : Different regulation of limb developmentby p63 transcript variants. PLoS One
2017,12(3):e0174122
28. Mi P, Yanagie H, Dewi N, Yen HC, Liu X, Suzuki
M, Sakurai Y, Ono K, Takahashi H, Cabral H,
Kataoka K, Nishiyama N: Block copolymerboron cluster conjugate for effective boron
neutron capture therapy of solid tumors, J Control
Release. 2017 Mar 21;254:1-9. doi: 10.1016/j.
jconrel.2017.03.036.
29. Hironobu Yanagie, Syushi Higashi, Ichiro
Ikushima, Koji Seguchi, Ryuji Mizumachi, Yuji
Murata, Yasuyuki Morishita, Atsuko Shinohara,
Shoji Mikado, Nakahiro Yasuda, Mitsuteru
Fujihara, Yuriko Sakurai, Kikue Mouri, Masashi
Yanagawa, Tomoya Iizuka, Minoru Suzuki,
Yosinori Sakurai, Shin-ichiro Masunaga, Hiroki
Tanaka,Takehisa
Matsukawa,
Kazuhito
Yokoyama, Novriana Dewi, Koichi Ogura,
Yasumasa Nonaka, Hirotaka Sugiyama, Tetsuya
Kajiyama, Sho Yui, Ryohei Nishimura, Koji Ono,
Sinichi Takamoto, Jun Nakajima, Minoru Ono,
Masazumi Eriguchi, Kenichiro Hasumi, andHiroyuki Takahashi : Selective Enhancement ofBoron Accumulation in Tumours with Intraarterial Administration of Boron-Entrapped
Water-in-Oil-in-Water Emulsion as a Novel Boron
Carrier in VX-2 Rabbit Hepatic Cancer Model for
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30. Miyata Y, Ishizawa T, Kamiya M, Yamashita S,
Hasegawa K, Ushiku A, Shibahara J, Fukayama
M, Urano Y, Kokudo N: Intraoperative imaging
ofhepatic
cancersusing
γ-glutamyltranspeptidase-specificfluorophoreenabling real-time identification and estimation ofrecurrence. Sci Rep. 2017; 7, 3542.
31. Sasaki M, Sasako T, Kubota N, Sakurai Y,
Takamoto I, Kubota T, Inagi R, Seki G, Goto M,
Ueki K, Nangaku M, Jomori T, Kadowaki T1:
Dual Regulation of Gluconeogenesis by Insulin
and Glucose in the Proximal Tubules of theKidney. Diabetes 2017; 66: 2339-2350.
32. Nawaz A, Aminuddin A, Kado T, Takikawa A,
Yamamoto S, Tsuneyama K, Igarashi Y, Ikutani M,
Nishida Y, Nagai Y, Takatsu K, Imura J, Sasahara
M, Okazaki Y, Ueki K, Okamura T, Tokuyama K,
Ando A, Matsumoto M, Mori H, Nakagawa T,
Kobayashi N, Saeki K, Usui I, Fujisaka S, Tobe
K: CD206+ M2-like macrophages regulate
systemic glucose metabolism by inhibiting
proliferation of adipocyte progenitors. Nat
Commun 2017; 8: 286.
33. Oshima H, Tanaka S, Takatori Y, Tanaka T,
Ishikura H, Moro T: Clinical and radiographic
outcomes of total hip arthroplasty with a specificliner in small Asian patients: Influence of
patient-related, implant-related, and surgicalfactors on femoral head penetration. J
Arthroplasty 2017; 32: 3065-3070.
34. Moro T, Takatori Y, Tanaka S, Ishihara K, Oda H,
Kim YT, Umeyama T, Fukatani E, Ito H,
Kyomoto M, Oshima H, Tanaka T, Kawaguchi H,
Nakamura K: Clinical safety and wear resistanceof the biocompatible phospholipid polymergrafted highly cross-linked polyethylene liner. J
Orthop Res 2017; 35(9): 2007-2016.
35. Watanabe K, Moro T, Kyomoto M, Saiga K,
Taketomi S, Kadono Y, Takatori Y, Tanaka S,
Ishihara K: The effects of presence of a backside
screw hole on biotribological behavior ofphospholipid
polymer-graftedcross-linked
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36. Yamane S, Kyomoto M, Moro T, Hashimoto M,
Takatori Y, Tanaka S, Ishihara K:
Wearresistanceofpoly(2-methacryloyloxyethyl
phosphorylcholine)-graftedcarbonfiber
reinforced poly(ether ether ketone) liners against
metal and ceramic femoral heads. J Biomed Mater
Res B Appl Biomater 2018; 106(3):1028-1037.
37. Kyomoto M, Moro T, Yamane S, Watanabe K,
Hashimoto M, Tanaka S, Ishihara K: A
phospholipid polymer graft layer affords highresistance for wear and oxidation under load
bearing conditions. J Mechan Behav Biomed
Mater 2018; 79: 203-212.
38. Kyomoto M, Moro T, Yamane S, Watanabe K,
Hashimoto M, Tanaka S, Ishihara K: A hydrated
phospholipid polymer gel-like layer for increased
durability of orthopedic bearing surfaces.
Langmuir (in press).
39. Kyomoto M, Shoyama Y, Saiga K, Moro T,
Ishihara K: Reducing fretting-initiated crevice
corrosion in hip simulator tests using azirconia-toughened alumina femoral head. J
Biomed Mater Res B Appl Biomater (in press).
40. Tanaka T, Moro T, Takatori Y, Oshima H, Ito H,
Sugita N, Mitsuishi M, Tanaka S: Evaluation of
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526

Department of Disaster Medical
Management
Professor
Naoto Morimura, M.D.,Ph.D.

Lecturer
Masataka Gunshin, M.D.

Homepage

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

Introduction and Organization
Responding to the Great East Japan Earthquake in2011, the University of Tokyo Hospital has decided to
set out to establish “disaster medical management
studies” in terms of need not only to provide medical
treatment at the time of disaster but also to develop a
new academic field that provides bird’s-eye view on
overall disaster medicine. In March 2012, we made anannouncement to establish “Department of Disaster
Medical Management” in the Public Comment.
In July 2012, Associate Professor Dr. Hiroyuki
Nakao was assigned the post as the first General
Manager of the Department of Disaster Medical
Management. Afterwards, in January 2015, Professor Dr. Tadashi Iwanaka, the Hospital Vice Director,
was assigned the post as the second General Manager.
In April 2015, Professor Dr. Masaomi Nangaku, theHospital Vice Director in charge of crisis managementand disaster prevention, was assigned the post as thethird General Manager. In April 2017, Professor Dr.
Naoto Morimura was assigned the post as the fourth
General Manager of the Department of Disaster
Medical Management and was appointed as the chairman of the in-hospital Disaster Prevention Committee.
This department belongs to the Central ClinicalFacilities Division and is involved in activities within
this hospital and inside/outside of the University.
In order to establish disaster medical management
studies, we are aiming at 1) fostering leaders who candevelop plans for disaster medicine and educate

personnel engaged in disaster medicine, 2) relationship building with relevant institutions for establishinga system for the University of Tokyo Hospital to leaddisaster medicine and 3) developing a system as abase of formation of organizations at the time ofdisaster.

Clinical activities
Since 2012, the Disaster Prevention Committee carries
out planning and conduct the University of Tokyo
Hospital Comprehensive Disaster Drill regularly.
Drills of launching a new earthquake early warning
system, building hospital headquarter for disaster
control, reporting in-hospital damage situation,
establishing triage and casualty clearing station, triage
and rescue of mass casualties, were performed yearlywith cooperation of the University of Tokyo, theMetropolitan Tokyo Fire Department, and the Ministryof Health Labor and Welfare.

Teaching activities
As educational activities inside and outside of the
University, we are holding and teaching MIMMS,
Major Incident Medical Management and Support,
courses accredited by English ALSG, Advanced Life
Support Group, regularly for the purpose of developing leadership of health care professionals who canprovide ideal medical care in times of disaster. Also,
we are cooperating holding and teaching MCLS, Mass
Casualty Life Support, courses of Japan Association

527

for Disaster Medicine, and JATEC, Japan Advanced
Trauma Evaluation and Care, courses of Japanese
Association for Acute Medicine, and so on.

Research activities
We are seeking ways of cooperation between
institutions through workshops with relevant
institutions from the perspective that day-to-day
cooperation with relevant institutions can be alsoutilized at the time of disaster. We consider that it canbe also utilized for cross-business formation oforganizations at the time of disaster.
Other than that, we are holding outside researchgroups and cooperating for building up a functional
emergency medical system at the time of disaster.

References
1. Naoto Morimura: “Actuals of emergency medical
responses for the multiple acts of terror in Paris in2015” Journal of the Japanese Association for theSurgery of Trauma 31; 1: 56-62. 2017
2. Naoto Morimura: “Fact of medical responses forthe multiple acts of terror in Paris” Journal ofJapan Surgical Association 77; 306. 2016
3. Naoto Morimura, Chiaki Toida, Yasushi Asari, et al.:“Introduction of new index of disaster medicine
supply demand balance, Risk Resource Ratio, forthe purpose of plotting out regional disaster medical
management plan” Japanese Journal of Disaster
Medicine 21; 1: 10-17. 2016
4. Chiaki Toida, Takashi Muguruma, Naoto Morimura,et al.: “Disaster medicine and intensive care
medicine. Problems of pediatric intensive care
medicine at the time of disaster including thebusiness continuity plan” Journal of the JapaneseSociety of Intensive Care Medicine 22; 3. 2016
5. Jun Hattori, Naoto Morimura, Yasushi Asari, et al.:“Planning for the burn patients assumed in case of ahuge earthquake in the metropolitan area, using
disaster medicine risk resource ratio” Japanese
Journal of Disaster Medicine 20; 3: 561. 2016
6. Kohei Takahashi, Naoto Morimura, Hidenori
Nakagawa, et al.: “Planning for the crush
syndrome patients assumed in each disaster center
hospital, using disaster medicine risk resource
ratio” Japanese Journal of Disaster Medicine 20;

3: 561. 2016
7. Kyoko Hattori, Jun Hattori, Naoto Morimura, etal.: “The next disaster medicine. Planning forthe perinatal medical care at the time of disaster,using disaster medicine risk resource ratio”
Japanese Journal of Disaster Medicine 20; 3: 461.
2016
8. Naoto Morimura, Chiaki Toida, Yasushi Asari, etal.: “The next disaster medicine. Calculation ofnecessary quantity of support and patterns ofordering priority of support for disaster center
hospitals, based on disaster medicine risk resource
ratio” Japanese Journal of Disaster Medicine 20;
3: 460. 2016
9. Naoto Morimura: “Emergency medical responsesof APHP and SAMU for the multiple acts of terror
in Paris” Journal of Japanese Society for
Emergency Medicine 19; 2: 205. 2016

528

International Medical Center
Director and Associate Professor
Sumihito Tamura, M.D., Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/english/international-patients/index.html

Introduction and Organization
One of the University of Tokyo’s significant
challenges is globalization. The International Medical
Center was launched as a significant step forward inenhancing The University of Tokyo Hospital’s
development as an international hub. Designateddirector position has been assigned.

Activities and challenges
The University of Tokyo Hospital offers sophisticatedsurgery and state-of-the-art treatment in variety offields. One of the roles of the International Medical
Center is to establish a system through which we
provide medical expertise to patients from overseas.
The International Medical Center will cater to thevarious requirements that must be met when accepting
overseas patients, including multilingual support,
translation of medical documents, and offeringsolutions to financial challenges, so that each department can focus solely on providing sophisticatedtreatment to those patients.
As well as receiving patients, another important
aspect is the globalization of clinical education. We
hope to establish a system in which non-Japanese
doctors accepted for residencies, or those who come toreceive cutting-edge medical training can carry out
operations, interventions or demonstrations without
being hindered by their nationality. Similarly, we hopeto establish a system through which overseas doctors
can learn new techniques alongside Japanese doctors,
and to provide an environment where doctors fromvarious countries can mingle with young doctors
working at our hospital, as well as student physiciansin participatory clinical training. We have been
actively accepting advanced clinical trainees granted

permission by the Ministry of Health, Labor andWelfare under the Exceptional Cases of the Medical
Practitioners ‘Act, Article 17, regarding Advanced
Clinical Training of Foreign Medical Practitioners, etc.
Internal hospital rules to accept consultant level
foreign medical doctors as Invited Faculty member
has also been settled.
Lastly, heightening the capability of physicians andmedical staff to cater to international needs is an
important factor in globalizing The University ofTokyo Hospital. To this end, the International Medical
Center will attempt to cultivate personnel by hosting
various international exchanges and language-training
programs so as to further develop the hospital’s
capabilities to become an international hub in thefield.

529

Department of Clinical Nutrition
Therapy
Head of the Department
Naoto Kubota (Associate Professor)

Assistant Head of the Department
Hideaki Ijichi (Lecturer)
Rie Sekine

Homepage

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

Introduction and Organization
In 1922, a stall in the outpatient department of thehospital and hospital ward shop sold milk, baked goods,
cider and ice cream. In 1925, a service contract between
the hospital and the Kojinkai Foundation resulted in thestart of a patient food service. In 1936, a “special
therapeutic diet” approach for newborn infants,
diabetes, nephropathy in which a physician prescribed
the food composition individually for each patient was
instituted for the first time in Japan. In 1950, a nationalhospital complete food service system was announced,
and the nutrient content provided was standardized.
The nutrient content provision for patient meals at thetime was 2400 kcal/day. In 1952, the inpatient meal
service was officially outsourced to a foundation.
In 1957, the first nationwide meeting of nationaluniversity-hospital head dietitians was held at the
University of Tokyo with the aim of improving patients’
diets.
In 1958, the complete food service was abolished.
Implementation of a standard food service and staffing
with a dietitian became required conditions, and thefood service section was staffed by a part-time section
chief and a dietitian. In 1962, a request from thenationwide meeting of national-university-hospitalhead dietitians, which primarily conducted its activities
at the University of Tokyo, was realized, and the
managerial dietitian system was established by a partial
revision of the Nutritionists Act. In 1972, nutritional

guidance was actively provided to inpatients andoutpatients with the aim of obtaining approval tocharge fees, and in 1978 a medical diet charge andnutrition guidance charge were established. In 1988, atimely tray service achieved by using hot and cold
food-tray carts was instituted in order to dispel the “tooearly, cold, unappetizing” reputation of hospital meals.
In 1991, the name of the food service section waschanged to the “Department of Nutrition Management”,
a change that had a long been sought by nationwide
national-university-hospital managerial dietitian staff
members. At the same time, the nutrition sections of themain hospital and branch hospital were consolidated,
and the head of the Department of Nutrition
Management, who was a managerial dietitian, assumed
the section manager post to form a system composed of
5 managerial dietitians at the main hospital and 3
managerial dietitians at the branch hospital.
In 1994, as a result of a partial revision of the
National Health Insurance Act, the standard foodservice approval system was abolished, and a diettherapy notification system on admission was set up.
An on-admission nutrition guidance fee was alsoestablished.
In 1998, the first diet therapy exhibit organized by
the Department of Nutrition Management was
conducted as part of the diabetes week events that theTokyo Diabetes Association held to the side of the freespace in the vestibule of the outpatient department. In

530

the first year there were 3527 visitors a week.
In 2001, integration of the branch hospital with themain hospital resulted in an 8-managerial- dietitiansystem. In 2004, the Department of Nutrition
Management was separated from the medical service
division. In 2005, the introduction of the self-pay
system for inpatient meals meant that inpatients began
to be charged for their meals. During the same year one
managerial dietitian (limited-term employment) was
added to the staff.
In 2006, charges for the performance of nutrition
management were newly established, and that meant
providing nutrition management for all patients. The
increase in work was accompanied by the addition of
one managerial dietitian (limited-term employment) to
the staff. Team care was introduced the same year, andin-hospital activity in the form of an all-department
nutrition support team (NST) was inaugurated. Eachhospital ward was staffed with a physician, managerial
dietitian, and nurse in charge of an NST, and whenevernecessary members from other fields (pharmacists,
medical technologists, physical therapists) joined, andthey held a hospital ward meeting once a week. In 2010,
an NST committee was created as a result of theestablishment of charges for NSTs. The NST director
up until that time became a member of the committee
and played an active role as the center of in-hospital
NST activities. The addition of one managerial dietitianto the staff (full time) as a full-time employee tocalculate the billing charges for the NST was approved.
In 2011, the inauguration of a nutritional guidanceservice for recipients of health checkups in the
Department of Epidemiology and Preventive Medicine
was accompanied by the addition of one managerial
dietitian (limited-term employment) to the staff. In
2012, charges for conducting nutrition management
were abolished. They were incorporated into the basic
hospital-admission fee, and the nutrition management
system by physicians, managerial dietitians, and nurses
was improved.
In 2013, the Department of Nutrition Management
was reorganized as the Department of ClinicalNutrition Therapy. A physician (Professor, the head of
the Central Clinical Services Administration) assumed
the concurrent post of head of the Department, and thehead of the Department of Nutrition Management
assumed the post of Assistant Head of the Department;

they undertook responsibility for managing the foodservice, maintaining activities of the NST, andstrengthening its functions. In 2014, two physicians,
full-time department head (associate professor) and
lecturer, were assigned and improvements were madeto NST activities and to the nutrition therapy, education,and research system. As a result of a managerial
strategic personnel distribution, 5 new managerial
dietitians (full-time) have also been assigned this fiscal
year. Along with the increase in work of managerial
dietitians for strengthening the nutrition management
system and expanding the number of clinical trials in
P1 unit, another managerial dietitian (limited-term
employment) was added to the staff in May 2015.
Long-coveted introduction of the New Cook Chill
System was eventually admitted by the University ofTokyo and the process was started in October 2016.
Renovation of the main kitchen was started in June
2017. During the renovation, the makeshift kitchen wasplaced on the 1st floor (the main kitchen) and the 3rdbasement floor (the washing room and the formularoom) of the Inpatients Ward A and the menu wasrestricted for the makeshift kitchen use. In February
2018, the New Cook Chill System in the University ofTokyo Hospital began. The menu was considerably
modified for the new cooking system.

Clinical Activities
The Department is proactively conducting
nutritional guidance in regard to metabolic diseases,
including diabetes, chronic kidney disease, dyslipidemia, and obesity, perioperative guidance,
including in regard to postgastrectomy diets,
hepatobiliary and pancreatic disease diets, and cardiac
disease diets, etc., mothers’ classes, etc.
The records of achievements in 2015 show that there
were 2819 instances of inpatient nutritional guidance(455 without charge) and 5503 instances of outpatient
nutritional guidance (275 without charge). The results
for group nutritional guidance showed that during theyear there had been 292 outpatient diabetes classes and
217 inpatient diabetes classes (for some of which there
was a charge), and that there had been 115 best-weightclasses, classes after gastric cancer operations for 81
patients, and mother’s classes for 139 mothers.
In July 2012, a physician, managerial dietitian, and531

nurse formed a dialysis prevention team, and started
calculating fees for diabetes and dialysis prevention
guidance and management in the outpatient clinic. The
managerial dietitian and nurse provide guidance on
Wednesday and Thursday afternoons, and there were
131 guidance sessions in 2015.
In April 2014, the department started calculating
charges for NST and counted 1261 instances in the firstfiscal year, which reached 1529 instances in 2015.
In November 2014, a procedure manual ofnutritional management was revised and an original
two-step nutritional screening by physicians,
managerial dietitians, nurses and pharmacists wasintroduced. In this system, the high-risk patients ofmalnutrition are now screened through the common
criteria in our hospital and monitored by the medical
team. The high-risk patients picked up through thistwo-step screening are weekly referred to the NST ofeach floor. In April 2015, alternative initial screening
criteria specific for pediatric and pregnant patientswere added to the procedure manual of nutritional
management, respectively.
When a new electronic health record system wasintroduced in January 2017, food service system(Nutrimate Ver. 9.0) and nutritional guidance system
was also updated. Mobile terminals specific for
managerial dietitian were provided on every floor of
Inpatients ward A&B, which enhanced the practiceefficiency. In the fiscal year of 2017, 8485 instanceswere monitored in the two-step screening and floor
NST system.

Educational Activities
The Department accepts managerial dietitian clinicaltrainees. In 2017, the department accepted 48 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 (5days/ week/ term). Participants are mainly managerial
dietitians, pharmacists, nurses, medical technologists,and physical therapists, and candidates are trainees
whose aim is acquiring the qualifications certified byacademic societies or to become a full-time employee
to calculate the billing charges for the NST. There were
15 participants (2 managerial dietitians, 4 pharmacists,
8 nurses, 1 physical therapist) in 2017.
In 2017, the department was involved in the
curriculum of Clinical Clerkship, the medical education program of the Faculty of Medicine, the Universityof Tokyo. 105 medical students at M4 grade
participated in the two-day practice course.
To disseminate NST activities fully in the hospital,
the department organizes NST Seminar for Doctor-intraining and Clinical Nutrition Seminar throughout theyear. The department also organizes NST Conference
and Joint Conference of Team Medicine for casediscussions to facilitate cooperation with each floor
NST and other medical teams. In 2015, the department
started “Nutritional Management e-learning” for all
employee to learn basic knowledge of nutritional
management procedure. The ratio of completion
reached 99.0% in March 2016. In October 2016, “TheManual of The Department of Clinical Nutrition
Therapy 2015-2016” was published. In December 2016,
the exchange training program between the Departmentof Nutrition Management of The Institute of Medical
Science and our department was initiated. At the samemonth, “The Pocket Manual of The Department ofClinical Nutrition Therapy 2016-2017” was published.
In March 2018, “The Manual of The Department ofClinical Nutrition Therapy 2017-2018” was published.

Research・Joint research with the Department of Stomach andEsophageal Surgery
Research topics: “Evaluation of nutrition indexes
after proximal gastrectomy”“Multi-center randomized controlled study of theeffects of early post-gastrectomy oral feeding
support”“A randomized study of post-operative invasivenessand systematic post-operative functional assessmentin esophageal cancer comparing the operation
procedures”
・Joint research with the Department of Hepatobiliaryand Pancreatic Surgery
Research topic: “Assessment of perioperative532

improvement in nutrition status by an open trial of
an immune-enhancing diet in patients who haveundergone pancreaticoduodenectomy”

References<Publications (English)>
1. Asano T, N Kubota, Koizumi N, Itani K, Miyake
T, Yuhashi K, Liao H, Mitsuishi M, Takeishi S,
Takahashi T, Ohnishi S, Sasaki S, Sakuma I,
Kadowaki T: Novel and simple ultrasonographic
methods for estimating the abdominal viseceral fat
area. Int. J. Endocrinol. vol. 2017, Article ID
8796069, 12 pages, 2017
2. Kubota T, Kubota N, Kadowaki T: Imbalanced
insulin actions in obesity and type 2 diabetes: Keymouse models of insulin signaling pathway. Cell
Metabolism 25(4):797-810, 2017
3. Marangoni RG, Masui Y, Fang F, Korman B, Lord
G, Lee J, Lakota K, Wei J, Scherer PE, Otvos L,
Yamauchi T, Kubota N, Kadowaki T, Asano Y,
Sato S, Tourtellotte WG, Varga J: Adiponectin isan endogenous anti-fibrotic mediator and therapeutic target. Sci. Rep. 7(1):4397, 2017
4. Masamoto Y, Arai S, Sato T, Kubota N, Takamoto
I, Kadowaki T, Kurokawa M: Adiponectinenhances quiescence exit of murine hematopoietic
stem cells and hematopoietic recovery throughmTORC1 potentiation. Stem Cells 35:1835-1848,
2017
5. Sakurai Y, Kubota N, Takamoto I, Obata A,
Iwamoto M, Hayashi T, Aihara M, Kubota T,
Nishihara H, Kadowaki T: Role of insulin receptor
substrates in the progression of hepatocellular
carcinoma. Sci Rep. 2017 Jul 14;7(1):5387.
6. Sasaki M, Sasako T, Kubota N, Sakurai Y,
Takamoto I, Kubota T, Inagi R,Seki G, Goto M,
Ueki K, Nangaku M, Jomori T, Kadowaki T: Dualregulation of gluconeogenesis by insulin andglucose in the proximal tubules of the kidney.
Diabetes 66(9): 2339-2350, September 2017.
7. Suyama S, Lei W, Kubota N, Kadowaki T, Yada T:
Adiponectin at physiological level glucoseindependently enhances inhibitory postsynaptic
current onto NPY neurons in the hypothalamicarcuate nucleus.Neuropeptides 2017, in press Mar
22. pii: S0143-4179(17)30006-9. doi: 10.1016/j.

npep.2017.03.003. [Epub ahead of print]
8. Nakatsuka T, Tateishi K, Kudo Y, Yamamoto K,
Nakagawa H, Fujiwara H, Takahashi R,
Miyabayashi K, Asaoka Y, Tanaka Y, Ijichi H,
Hirata Y, Otsuka M, Kato M, Sakai J, Tachibana
M, Aburatani H, Shinkai Y, Koike K. Impact ofhistone demethylase KDM3A-dependent AP-1
transactivity on hepatotumorigenesis induced by
PI3K activation. Oncogene. 36(45):6262-6271,
2017.
9. Mizuno S, Isayama H, Nakai Y, Yoshikawa T,
Ishigaki K, Matsubara S, Yamamoto N, Ijichi H,
Tateishi K, Tada M, Hayashi N, Koike K.
Prevalence of Pancreatic Cystic Lesions Is
Associated With Diabetes Mellitus and Obesity:
An Analysis of 5296 Individuals Who Underwent
a Preventive Medical Examination. Pancreas.
46(6):801-805, 2017.
10. Nakagawa H, Suzuki N, Hirata Y, Hikiba Y,
Hayakawa Y, Kinoshita H, Ihara S, Uchino K,
Nishikawa Y, Ijichi H, Otsuka M, Arita J,
Sakamoto Y, Hasegawa K, Kokudo N, Tateishi K,
Koike K. Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands. Proc Natl
Acad Sci U S A. 114(19):E3806-E3815, 2017.

Center for Disease Biology andIntegrative Medicine

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Laboratory of Molecular
Biomedicine for Pathogenesis
Professor
Toru Miyazaki, M.D., Ph.D.

Associate Professor
Satoko Arai, Ph.D.

Assistant Professor
Nobuko Mori, D.V.M., Ph.D.

Project Associate Professor
Shigeru Matsuoka, Ph.D. (Laboratory for New Generation Drug Discovery)

Official Website

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

Research
Our laboratory focuses on clarification of thepathogenesis of various diseases and the related
physiological machineries in cellular and molecular
aspects. Based on our technical advantage in genemanipulation via gene knockout and transgenesis, wegive high priorities to in vivo analyses. This willdefinitively contribute to the direct therapeutic
application of our findings. Since our rationale is tochallenge to uncharacterized disease mechanisms andphysiologies, we will not restrict our interest, strategy
or technique employed, in certain specific field.
Rather, we will expand our research area by
establishing different collaborations with a broad
spectrum of researchers. We believe this fits to thepolicy of the CDBIM, which aims the development of
a comprehensive science including the fundamental
and clinical medicines, and the biotechnology. Overall,
we will attempt to discover novel biological insights
rather than to study details of previously characterized
physiologies, by targeting molecules newly identified
by ourselves. Now, we are focusing on the following
major projects.

AIM (Apoptosis Inhibitor of Macrophage) as a masterswitch to various modern diseases.
The rapid change in lifestyles and eating habits intoday’s society are thought to be the cause of various
disorders; metabolic syndrome and lifestyle-relateddiseases increase the risk of developing obesity,
diabetes, and cardiovascular disease; a fatty liver leads
to NASH and liver disease, may result in liver cancer;
autoimmune disease followed by obesity, chronic
renal failure, and Alzheimer’s disease are considered
as well. We hypothesize that such various modern
disorders, seemingly unrelated at first sight, share thecommon underlying pathological condition andmechanism, and the group of molecules exists as themaster switch, regulating the varied conditions.
We found a soluble apoptosis inhibitor factor
largely produced by tissue macrophage, named AIM(apoptosis inhibitor of macrophage). Our recent
studies showed that AIM plays an important role inregulating the pathological condition of the modern
diseases.
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

535

progression of obesity. However, when this process
undergoes effectively and excessively under the obese
condition, oppositely to control the progression ofobesity, chronic inflammation of adipose tissue andinsulin resistance are triggered and Type II diabetes
and atherosclerosis are worsen.
Moreover, because AIM binds to IgM in bloodstream, it leads to production of various autoantibodies, especially under the obese condition.
This suggests that the obesity is the cause of
autoimmune disease. Other studies showed that liverdisease, cancer, and kidney disease worsen under low
concentration of AIM. It is suggested that theconcentration of AIM in bloodstream differentiates theoutcome and the risk of getting various diseases.
Finding the mechanism on the regulation of AIM
activity will shed light on developing a diagnostics
and potential treatments to modern diseases. We will
focus on the details of involvement of AIM to thevarious diseases by generating a mouse model. Also,
cohort study is carried out using and analyzing thehuman specimen, aiming to develop a novel drug
treatment.

Similar meetings are organized by our laboratory
every year, e.g. Taiwan-Japan Joint Meeting in 2013
(hosted by National Taiwan University, National Yang
Ming University, and the University of Tokyo), theCREST joint meetings in 2014 and 2015 (hosted by
Kumamoto University and the University of Tokyo)
and, Scientific Meeting in 2016 (hosted by Shimane
University and the University of Tokyo). We will keepplanning such Joint Meetings in the future.

Lab Activities

Seminar hosted by our lab (co-sponsorship: MPUTC,
Laboratory of Animal Resources)
Title: Homeostasis of Peripheral CD4 ⁺ T Cells
Maintained by CoroninⅠ. / Dr. Mayumi Mori
(University of Basel, Switzerland)
In September 2017, we organized an invited lecture
by Dr. Mayumi Mori. She introduced her recent work
regarding Coronin I that is involved in maintenance of
peripheral T cells.

Laboratory for New Generation Drug Discovery
This endowed laboratory was established in 2017
for the purpose of the drug development aiming at theclinical application of AIM protein and relatedmaterials. In this laboratory, we investigate theprocess development for the AIM protein
manufacturing under the GMP condition. In addition,
we are trying to find small molecules that can activate
AIM through developing the high throughput
screening system and the structural analysis of AIM.
Joint Meeting
In 2017, several medical laboratories from National
Defense Medical Center and our laboratory jointly
held a Work Shop in Taipei. The members from theboth universities including the teaching staffs,
graduate students and researchers, fully enjoyed thisretreat, having intense research sessions with lively
discussions, which can lead to future collaborations.
We could also strike up a friendship through thedinners and recreations during the two days.

List of labs:
Prof. Wan-Wan Lin’s Laboratory, National Taiwan
University
Prof. Shie-Liang Hsieh’s Laboratory, National Yangming University
Prof. Ken-ichi Yamamura’s Laboratory, The University of Kumamoto
Prof. Toru Nabika’s Laboratory, Shimane University
Prof. Seiji Yamaguchi, Shimane University
Prof. Ann Chen’s Laboratory, National Defense
Medical Center
Prof. Toru Miyazaki’s Laboratory, The University ofTokyo

DBELS (Disease Biology Excellent Lecture Series)
We present a lecture series by top scientists in avariety of research fields related to disease biology. Sofar, eleven lecturers have been invited from many
places including Kyoto Univ., Hokkaido Univ., Riken
Institute, Tokyo Univ. of Science, Washington Univ.
(USA), Univ. of Basel (Switzerland), and Weill
Medical College of Cornell University (USA).
DBELS-EXTRA
This is a lecture series on the latest experimental
techniques for medical research, founded as anextension of DBELS. We offer monthly lecture series,

536

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.

Tomita T, Arai S, Kitada K, Mizuno M, Suzuki Y,
Sakata F, Nakano D, Hiramoto E, Takei Y,
Maruyama S, Nishiyama A, Mastuo S, Miyazaki
T & I to Y. “Apoptosis inhibitor of macrophageameliorates fungus-induced peritoneal injury
model in mice”, Sci Rep, 7, 6450, 2017.
Koyama N, Yamazaki T, Kanestuki Y, Hirota J,
Asai T, Mitsumoto Y, Mizuno M, Shima T,
Kanbara Y, Arai S, Miyazaki T & Okanoue T.

3.

4.

“Activation of apoptosis inhibitor of macrophage
is a sensitive diagnostic marker for NASHassociated hepato cellular carcinoma”, J Gastroenterol, doi:10.1007/s00535-017-1398-y, 2017.
Kimura H, Suzuki M, Konno S, Shindou H,
Shimizu T, Nagase T, Miyazaki T & Nishimura
M. “Orchestrating Role of Apoptosis Inhibitor of
Macrophage in the Resolution of Acute Lung
Injury”, J Immunol, 199, 3870-3882, 2017.
Miyazaki T, Yamazaki T, Sugisawa R, Gershwin
ME & Arai S. “AIM associated with the IgM
pentamer: attackers on stand-by at aircraft
carrier”, Cell Mol Immunol 14, 1-12, 2018.

537

Laboratory ofStructural Physiology
Professor
Haruo Kasai, M.D.,Ph.D.

Lecturers
Noriko Takahashi, M.D., Ph.D.

Research Associates
Sho Yagishita, M.D. Ph.D.

Research Associates
Makiko Negishi, 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

Teaching activities
We have 2 master and 7 doctor course students in2017. We gave all together 8 lectures of physiology
for undergraduate students, and 5 lectures ofphysiology and neuroscience for master course
students. Four undergraduate students join the activityof our laboratory for free quarter (FQ).

538

representative work (Ref. 5) of this year in somedetail.
Dendritic spines are postsynaptic to most excitatory
synapses in the brain, and their structural changes area major cellular basis for learning and memory. Spine
generation and elimination are robust processes, evenin the adult brain, and spine enlargement and shrinkage play key roles in the plasticity of dendritic spines.
We previously used two-photon glutamate uncaging tostimulate individual spines and demonstrated that
dendritic spine enlargement underlay long-term potentiation (LTP) at the level of single spines. We also
reported that spine shrinkage and elimination can be
induced when glutamate uncaging was paired withaction potentials in the presence of GABAergic inhibition. Spine structures are dynamically maintained by
the regulation of actin fibers (F-actins). Cofilin is ahighly abundant actin-regulatory protein, which binds
to and alters the physical properties of F-actin.
Dephosphorylated cofilin at its serine-3 residue(dp-cofilin) cleaves F-actin to generate new barbed
ends that are sites for actin polymerization and depolymerizes F-actin at its pointed end to reduce fiber
length. These bidirectional enzymatic activities ofcofilin are inhibited by its phosphorylation at the serine-3 residue, as phosphorylated cofilin (p-cofilin)
dissociates from F-actin. Thus, the entire lifecycle of
F-actin is regulated by cofilin. Dendritic spine enlargement and shrinkage are likely also regulated by
the phosphorylation and dephosphorylation of cofilin18. We previously showed that bidirectional structural plasticity is controllable in individual spines bymodulating cofilin phosphorylation.
It has been reported that spine shrinkage tends
to spread as in the case with LTD. In contrast, spine
the diffusional properties of cofilin, which can be assessed by its retention time in the spine, must differ
during enlargement and shrinkage. Recently, cofilin
has been shown to accumulate during spine enlargement, and long-term spine enlargement was inhibitedby shRNA-mediated cofilin knockdown. Both constitutively active and inactive-phosphomimetic cofilinmutants failed to resume long-term spine enlargement
and the cofilin accumulation. Considering phosphorylated cofilin cannot bind with F-actin directly, the accumulated cofilin was thought to be dephosphorylated

before binding F-actin, although both phosphorylation
and re-dephosphorylation of cofilin are necessary forlong-term spine enlargement. On the other hand, an
accumulation of phosphorylated cofilin was reported
after LTP stimulation using immunohistochemistry.
To resolve these discrepant findings, the objective of
this study was to address whether dephosphorylated or
phosphorylated cofilin accumulates in the stimulated
spine after enlargement. In addition, we sought to determine whether spine shrinkage is generated only by
the diffusion of dephosphorylated cofilin along thedendrite.
We investigated the diffusional properties of cofilin, the actin-severing and depolymerizing actions ofwhich are activated by dephosphorylation. Cofilin
diffusion was measured using fluorescently labeledcofilin fusion proteins and two-photon imaging. We
show that cofilins are highly diffusible along dendrites
in the resting state. However, during spine enlargement, wildtype cofilin and a phosphomimetic cofilinmutant remain confined to the stimulated spine,whereas a nonphosphorylatable mutant does not.
Moreover, inhibition of cofilin phosphorylation with acompetitive peptide disables spine enlargement, suggesting that phosphorylated-cofilin accumulation is a
key regulator of enlargement, which is localized toindividual spines. Conversely, spine shrinkage spreads
to neighboring spines, even though triggered byweaker stimuli than enlargement. Diffusion of exogenous cofilin injected into a pyramidal neuron soma
causes spine shrinkage and reduced PSD95 in spines,
suggesting that diffusion of dephosphorylated endogenous cofilin underlies the spreading of spine shrinkage and long-term depression (Ref. 5).

References
1. Nagaoka, A., Takehara, A., Hayashi-Takagi, A.,
Shirai, F., Ishii, K., Noguchi, J., Ichiki, K. &Kasai, H. (2016) Abnormal intrinsic dynamics ofdendritic spines in a fragile X syndrome mousemodel in vivo. Scientific Reports 6: 26651.
2. Takehara, H., Nagaoka, A., Noguchi, J., Akagi, T.,
Kasai, H. & Ichiki, T. (2016) Implantablemicrofluidic device with hydrogel permeable
membrane for delivering chemical compounds
and imaging neural cells in living mice. Journal

539

3.

4.

5.

6.

of Photopolymer Science and Technology 29:513518.
Jakkampudi, S., Abe, M., Komori, N., Takagi, R.,
Furukawa, K., Katan, C., Sawada, W., Takahashi,
N. & Kasai, H. (2016) Design and synthesis of a
4‑nitrobromobenzene derivative bearing an
ethylene glycol tetraacetic acid unit for a newgeneration of caged calcium compounds with
two-photon absorption properties in the near-IR
region and their application in vivo. ACS Omega
1(2): 193-201.
Kunii, M., Ohara-Imaizumi, M., Takahashi, N.,
Kobayashi, M., Kawakami, R., Kondoh, Y.,
Shimizu, T., Simizu, S., Lin, B., Nunomura, K.,
Aoyagi, K., Ohno, M., Ohmuraya, M., Sato, T.,
Yoshimura, S., Sato, K., Harada, R., Kim, Y.,
Osada, H., Nemoto, T., Kasai, H., Kitamura, T.,
Nagamatsu, S., & Harada, A. (2016) The opposite
roles of SNAP23 in the exocrine and endocrine
pancreas. J. Cell Biol. 215:121-138.
Noguchi, J., Hayama, T., Watanabe, S., Ucar, H.,
Yagishita, S., Takahashi, N. & Kasai, H. (2016)
State-dependent diffusion of actin-depolymerizing
factor/cofilin underlies the enlargement andshrinkage of dendritic spines. Scientific Reports 6:32897.
Dagliyan, O., Karginov, A., Yagishita, S., Gale,
M., Wang, H., DerMardirossian, C., Wells, C.,
Dokholyan, N., Kasai, H. & Hahn, K. (2017)
Engineering Pak1 allosteric switches, ACS
Synthetic Biology 6:1257-1262.

540

Laboratory of Biomedical
Equipment and Biomaterials
Professor
Takashi Azuma, Ph.D.

Associate Professor
Taichi Ito, Ph.D.

Assistant Professor
Naoki Tomii, Ph.D., Seiichi Ohta, Ph.D.

Homepage

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

Introduction and Organization
The Division is composed of two laboratories, Azuma
laboratory and Ito Laboratory. The Division tightly
collaborates with Faculty of Engineering. Prof. Azuma
is also charged at Department of MechanicalEngineering and Bioengineering, where the laboratory
members include an assistant professor, two associates
and 3 graduate students. Prof. Ito charged at
Department of Chemical System Engineering andBioengineering. The current laboratory members
include one assistant professor, two associates, and 13
graduate students School of Engineering andMedicine.

Teaching activities
Prof. Azuma and Prof. Ito are sharing duties forundergraduate and graduate students of both Graduate
School of Medicine and Graduate School of Engineering. They give lectures on biomedical engineering at
Graduate School of Medicine. Prof. Azuma has also
lectures on Overview of Bioimaging，Overview of
Mechano-Bioengineering, Bioengineering exercise
for social implementation at Graduate School ofEngineering. Prof. Ito gives a lecture concerning
biosystem engineering, separation technology I,
biotechnology II, Basic Biology, and Overview ofChemical Bioengineering at the Chemical System

Engineering course and Bioengineering course at
Graduate School of Engineering School.

Research activities
Prof. Azuma’s laboratory aims to develop clinicalimaging and therapeutic systems. In particular, we aredeveloping an advanced imaging system using
ultrasound with large interaction and low invasivenesswith the living body, minimally invasive treatmentusing ultrasound, and a combination device withdrugs.
1. Ultrasonic imaging
An ultrasonic CT (Computed Tomography)
We are developing clinical testing equipment for
ultrasonic CT screening and diagnosis system aiming
at the early detection of breast cancer. Ultrasound CT
uses ultrasound which is minimally invasive and has
many interactions with the living body (large amountof information that can be acquired) as the imaging
method. The amount of obtained information is large
in proportion to the computation cost. We aredeveloping high precision image reconstruction
algorithm utilizing parallel computing and application
technology extracting new biological information.
2. Ultrasound therapy1) Development of minimally invasive treatment
equipment and systems

541

We are developing an intracranial ultrasonicirradiation system and conduct research aiming to
induce action potential and stimulated motion byadding mechanical stimulus to nerve cells. In addition,
we are also developing therapy monitoring method
aiming at high accuracy of minimally invasive
treatment.
2) Ultrasonic drug delivery system
We are also developing ultrasonic drug delivery as atherapeutic application of ultrasound. In particular, we
aim to realize the enhancement of drug permeabilityof the cerebrovascular barrier by combining
ultrasound and microbubbles.
Biomaterials are one of important keys in medicine
and medical engineering. In the field of tissue
engineering, scaffold materials are extremely
important. In the drug delivery field, drugs areencapsulated in various materials which achieve ideal
release kinetics. The functions of these biomaterials
and phenomena inside and outside biomaterials invivo are complicated both in terms of chemistry andbiology. Ito Laboratory is trying to design and develop
novel biomaterials for tissue engineering and drugdelivery by the combination of medicine and chemicalsystem engineering. Especially we focus on hydrogels
which can be utilized for islet regeneration and drugdelivery in peritoneum.
1) Development of Hydrogels for medical uses
- Development of novel in situ crosslinked hydrogels
for a medical use using hyaluronan, chitosan,
dextran, alginate, gelatin, carboxymethyl cellulose
and synthetic dendritic polymers.
2) Development of particles for medical uses
- Nano-sized semi-conductor and metal particles forimaging- Micro-sized particles composed of PLGA, PEG,
Albumin.
3) Challenge to establish novel treatments using new
medical hydrogels and particles.
- Peritoneal adhesion prevention- Hemostats- Drug delivery for peritoneal dissemination,
Mesothelioma, Liver cirrhosis- Hydrogel scaffolds for regeneration of islets andbones- Artificial Oxygen Carriers

References(1) A. Ishijima, K. Minamihata, S. Yamaguchi, S.
Yamahira, R. Ichikawa, E. Kobayashi, M. Iijima, Y.
Shibasaki, T. Azuma, T. Nagamune, I. Sakuma,“Selective intracellular vaporisation of antibodyconjugated phase-change nano-droplets in vitro”,
Sci. Rep. 2017(7) 44077(2) H. Lin, T. Azuma, X. Qu, and S. Takagi, "Robust
contrast source inversion method with automatic
choice rule of regularization parameters forultrasound waveform tomography", Jpn. J. Appl.
Phys., 2016(55) 07KB08(3) X. Qu, T. Azuma, T. Yogi, S. Azuma, H. Takeuchi, S.
Tamano, S. Takagi, "Synthetic aperture ultrasoundimaging with a ring transducer array: preliminary exvivo results", J. Med. Ultrasonics, 2016(43) 461471(4) Tatsuto Kageyama, Tatsuya Osaki, Junko Enomoto,Dina Myasnikova, Tadashi Nittami, Takuro Hozumi,
Taichi Ito, and Junji Fukuda, In situ cross-linkablegelatin-CMC hydrogels designed for rapid
engineering of perfusable vasculatures, ACS
Biomaterials Science and Engineering, 2016, 2(6)1059-1066(5) Seiichi Ohta, Syota Hiramoto, Yuki Amano, Mayu
Sato, Yukimitsu Suzuki, Marie Shinohara,
Shigenobu Emoto, Hironori Yamaguchi, Hironori
Ishigami, Yasuyuki Sakai, Jyoji Kitayama, andTaichi Ito, Production of cisplatin-incorporating
hyaluronan nanogels via chelating ligand-metal
coordination, Bioconjugate Chemistry, 2016(27)504-508

542

Laboratory of Clinical
Biotechnology
Professor
Yuichi Tei/ Ung-il Chung, M.D.,Ph.D.

Associate Professor
Shinsuke Ohba, D.D.S., Ph.D.

Assistant Professor
Hironori Hojo, Ph.D.

Homepage http://www.tetrapod.t.u-tokyo.ac.jp/index_en.html
http://www.cdbim.m.u-tokyo.ac.jp/english/index.php
Introduction and Organization
The Laboratory of Clinical Biotechnology at theCenter for Disease Biology and Integrative Medicine(CDBIM) was launched in April 2003 under the
direction of Professor Kazunori Kataoka. As thisLaboratory is expected to serve as a bridge at The
University of Tokyo (UTokyo) for medical bioengineering, where medicine and engineering areclosely intertwined with each other, we are conducting
research on medical bioengineering through oncampus collaborations with the Graduate School ofEngineering, the Graduate School of Medicine, andThe University of Tokyo Hospital and its affiliateddivisions such as the Division of Tissue Engineeringand the Cooperative Unit of Medicine andEngineering Research. We also aim to recruit and train
professionals — including
physicians,
dentists,
pharmacists, veterinarians, life science researchers,
engineering researchers, and engineers — who are
equipped with a deep understanding of medical
bioengineering. To achieve this, we have utilized
undergraduate and graduate education programs suchas the Graduate Program for Leaders in Life
Innovation (GPLLI) of UTokyo.
Professor Kataoka, who directed the laboratory
until March 2016, worked on the development andclinical applications of nanotechnology-based drugdelivery systems and imaging.
Professor Yuichi Tei (Ung-il Chung) has served
as Director of the Laboratory of Clinical Biotechnology since November 2016. With a particularfocus on skeletal tissues (bones and cartilage), we are
currently studying molecular mechanisms underlying
cell fate specification as well as signaling factor-based
systems to manipulate cell differentiation andproliferation. We are also working on the developmentof novel biomaterials that will fulfill thecharacteristics required for in vivo use as scaffolds. By
integrating these studies, we aim to develop novel
systems for skeletal tissue engineering and regenerative medicine, in which cell differentiation andproliferation are regulated directly and locally in situ.
Professor Tei has a cross-appointment with the
Department of Bioengineering, Graduate School ofEngineering, and he also serves as Research Leader of
The University of Tokyo Center for Innovation (COI)
Self-Managing Healthy Society. In collaboration withthe program, we are also working on the establishmentof an Open Innovation Platform and the promotion ofindustry-academia collaborations for the social
implementation of research products.

Education
The development of advanced medical systems, such

543

as regenerative medicine and medical devices, is an
important and globally growing research field inwhich medical biology and engineering are integrated
and play important roles. Since the medicineengineering cooperation that has occurred to date has
been mainly research collaborations, the developmentof theoretical systems as well as education systems forthe integrated field have been delayed. This oftencauses a mismatch between clinical needs andtechnological seeds. The delay is likely due todifficulties in identifying basic principles that underlie
both of the quite different fields of medical biology
and engineering, when they are integrated.
Through multi-discipline and cross-sectional
research projects integrating medical biology andengineering, we aim to train biomedical professionals
who themselves integrate medicine and engineering;that is, engineers who understand medical needs andmedical researchers who understand technologicalseeds. We are offering students with varying
backgrounds opportunities to study a broad spectrumof biomedical engineering — from basic principles ofliving organisms to advanced medical systems — on
the basis of each student's expertise. We alsocollaborate with The University of Tokyo COI
Self-Managing Healthy Society, in order to utilize theOpen Innovation Platform in which all stakeholders
from industry, government, academia, and the private
sector join the program as equals from the start, as apractical education tool for developing the
aforementioned biomedical professionals.

Research
We pursue two scientific interests with a particularfocus on skeletal tissues (bones and cartilage): (1) the
manipulation of progenitor cell differentiation andproliferation based on the understanding of molecularmechanisms underlying cell fate specification, and (2)the development of novel biomaterials fulfilling thecharacteristics required for in vivo use as scaffolds.
We aim to develop novel systems for skeletal tissue
engineering and regenerative medicine in which celldifferentiation and proliferation are directly regulated
in situ. The following four projects are ongoing.

1. Understanding of epigenome dynamics and gene
regulatory networks during cell fate specification
processes
Organogenesis depends on cell fate specification andthe subsequent differentiation and maturation of
specified cells. Gene transcription underlies a series ofprocesses; appropriate genes are transcribed withappropriate amounts and at the appropriate timing for
inducing cell activities and characteristics. In thiscontext, the epigenome works as a main switch forgene expression. Transcription factors, which bind to
the genome in a sequence-dependent manner, in turnincrease the amount of transcripts, in a manner that is
analogous to turning up the volume of a radio.
Against this background, we seek to understandthe mechanisms of cell fate specification, celldifferentiation, and cell maturation during skeletal
development with a particular focus on epigenome
dynamics and genomic targets of transcription factors.
We also plan to apply the knowledge gained to thedevelopment of regenerative therapies for skeletal
tissue defects. Here we rely on the following
approaches: (1) observations of intracellular events bydirect and comprehensive techniques, (2) the construction of hypotheses driven by these observations,and (3) verification of the hypotheses. Thus, theapproach starts with the collection of genome-scaledata on gene expression, epigenome, and transcription
factor binding sites by taking advantage ofnext-generation sequencers. The data are analyzed bybioinformatics approaches, leading to the constructionof a new biological hypothesis. Each hypothesis isverified by molecular-biological approaches andmouse genetics. With this research strategy, we areinvestigating the regulatory landscape on the genomethat determines the specification of bone- andcartilage-forming cells, osteoblasts and chondrocytes,
respectively, and their phenotypes. A series of studies
reveals transcriptional networks that mediate
pluripotency and the differentiation of pluripotent
stem cells (Stem Cells 31:2667, 2013), epigenome
dynamics and modes of action of master transcription
factors that specify osteoblasts and chondrocytes, andthe gene regulatory networks mediated by thosemaster transcription factors (Cell Reports 12:229,
2015; Developmental Cell 37:238, 2016; Development
143:3012, 2016; Trends in Genetics 32:774, 2016). A544

fuller understanding of cell fate specification
processes during skeletal formation, we believe, will
enable the development of novel therapeutic strategies,in which bone and cartilage repair and regeneration
are induced by the manipulation of the specification
processes.

We have also worked on the development of
direct reprogramming methods in which osteoblasts
and chondrocytes are directly generated from somatic
cells including fibroblasts, without the use of stem
cells (Arthritis & Rheumatology 50:3561, 2004;
FASEB Journal 21:1777, 2007).

2. The development of tissue-development modelingsystems using pluripotent stem cells
It would be ideal to study the mechanisms of tissue
formation and maintenance in in vivo working cells.
However, the number of cells that can be obtained invivo is often not sufficient for molecular-levelmechanistic studies; this is a technical limitation in
studying skeletal development and regeneration.
Pluripotent stem cells (PSCs; i.e., embryonic stem
cells — ES cells and induced pluripotent stem
cells — iPS cells), which have the ability to self-renew
and differentiate into all of the lineages present in thebody, are a promising tool for study; reproducing
organogenesis and metabolism in vitro potentiallyovercomes the above limitation. Considering thesafety, cost, and biological conciseness, it would bebetter to induce tissues from PSCs under definedconditions by using small molecules while avoiding
differentiation into lineages of no interest.
We have therefore been developing protocols for
directing mouse and human PSCs toward osteoblasts
under defined conditions using only small molecules,
while recapitulating in vivo osteoblast development(Stem Cell Reports 2:751, 2014). We are attempting toapply the protocols to the generation of PSC-derived
bone-like tissues, in which distinct cell populations
regulating bone formation and maintenance(osteoblasts, osteocytes, and osteoclasts) function
three-dimensionally on culture dishes (Science
Advances 3:e1602875, 2017). Such culture systems in
combination with human PSCs could enable us toreproduce human bone development and metabolism
in a physiologically relevant manner. These systems
will also allow us to visualize bone metabolism invitro with imaging techniques, contributing to drug
discoveries for the treatment of various bone diseases
such as osteoporosis, and to our understanding of thediseases' pathophysiology and of the molecularmechanisms underlying skeletal formation andmaintenance.

3. The identification of bioactive factors that inducebone/cartilage formation and their application tobone/cartilage repair
Skeletal formation is regulated by various signaling
pathways and transcription factors. The manipulationof key pathways and/or factors would enable us to not
only induce skeletal formation and regeneration, butalso suppress the progression of skeletal degeneration.
Thus, we are carrying out molecular-biological andmouse genetic studies to elucidate the roles ofosteogenic and chondrogenic signaling pathways aswell as the modes of their actions. Based on thesebasic findings, we are also working on theidentification and application of bioactive moleculesthat induce osteogenesis and chondrogenesis.
We have been focusing on: (1) hedgehog (Hh)signaling-mediated cell fate specification duringosteoblast development (Development 131:1309,
2004； Journal of Biological Chemistry 282:17860,
2012; Journal of Biological Chemistry 288:9924,
2013), and (2) transcriptional regulation mediating
osteoblast differentiation and maturation (Developmental Cell 14:689, 2008; PLOS ONE, 2014). Thesestudies further extend to the development of the small
molecule-based treatment of bone fractures, using the
Hh signaling-activator molecule SAG (Biochemical
and Biophysical Research Communications 479:772,
2016) and bone regenerative therapy with SAG-loaded
calcium phosphate artificial bones (Biomaterials
34:5530, 2013). By combining biological findings
with engineering techniques, we are working on boneregeneration by plasmid delivery using polymericnanomicelles as nucleic acid carriers (Molecular
Therapy 15:1655, 2007) and the suppressive treatmentof cartilage degeneration by mRNA delivery(Scientific Reports 6:18743, 2016).
We have also identified novel small moleculesthat induce bone and cartilage formation (Biochemical
and Biophysical Research Communications 357:854,
2007; Annals of Rheumatic Diseases 72:748, 2013),

545

through the screening of compound libraries withcell-based sensors enabling the high-throughput
detection of osteoblast and chondrocyte differentiation(Biochemical and Biophysical Research Communications 376:375, 2008; Journal of Bone and Mineral
Metabolism 28:627, 2010).
4. The development of tissue-inductive implant
devices integrating tissue-regeneration signals andhighly functional and biocompatible biomaterials
In the current aging society, the treatment of tissue
defects in locomotive organs is a crucial task toachieve the extension of healthy life expectancy.
There is an urgent need for low-invasive reconstruction therapies that recover lost or damaged tissues
with the same functional and aesthetic qualities as
those in healthy states. The transplantation of donor
tissues obtained from patients’ healthy sites has been
widely used for tissue reconstruction (autologoustransplantation). However, this strategy often causes
post-operative pain and the cosmetic disturbance ofdonor sites. Although reconstruction with biomaterials
avoids donor site problems, its tissue induction
capacity is generally inferior to that of autologoustransplantation.
As signaling networks mediating the formation
and regeneration of tissue and organs are being
elucidated by recent advances in stem cell biology,
some biomaterial-based systems are being developed
for delivering signaling factors to target tissues. We
are studying these approaches as mentioned above. In
addition, the emergence of three-dimensional (3D)
printers has rapidly improved the techniques available
for controlling the shapes of scaffold materials. By
controlling the 3D shape of biomaterials, we havebeen attempting to improve the performance of
biomaterials for tissue repair. We developed custommade calcium phosphate artificial bone (CT-bone) thatis manufactured using 3D printers and have appliedthem to clinical settings in cooperation with the
Department of Oral and Maxillofacial Surgery, The
University of Tokyo Hospital (Journal of Artificial
Organs 9:234, 2006; Journal of Artificial Organs
12:200, 2009; Regenerative Therapy 5:1, 2016). We
have also worked on the development and applicationof tetrapod-shaped calcium phosphate artificial bone
(Tetrabone), which is fabricated at 1-mm size by

injection molding, and a custom-made titanium meshcage fabricated by laser sintering (Acta Biomaterialia
8:2340, 2012; Biomaterials 35:3229, 2014).
However, either signaling factors or biomaterials
alone are not sufficient for the clinically sufficient
regeneration of tissues, and interface units integratingthem are necessary for fully utilizing their performance. A candidate for the integrating interface unit isa high-performance hydrogel unit, which maintains
the spatial arrangement of signaling factors and candeliver them to target cells at a selected timing bytemporally controlled degradation. However, conventional hydrogels do not provide the characteristics
required for an integrating interface unit.
In cooperation with Associate Professor
Takamasa Sakai at the Department of Bioengineering,
UTokyo, we are developing a high-performancehydrogel unit that fulfills the necessary characteristics,
based on knowledge and techniques that we haveaccumulated regarding the design and fabrication ofnovel hydrogels (Macromolecules 41:5379, 2008;
Science 343:873, 2014; Advanced Materials 27:7407,
2015; Nature Biomedical Engineering 1:44, 2017).
The high-performance hydrogel unit would integratesignaling factors with shape-controlled scaffold
materials, leading to the development of implant
devices that work as scaffolds for tissue repair andalso as carriers of bioactive factors. Through a seriesof these studies, we are aiming to create a"four-dimensional scaffold system" that achieves
efficient tissue regeneration by controlling cellproliferation and differentiation in temporal andspatial manners. The system will not only beapplicable to the regeneration of other tissues; it will
also contribute to the development of basic
technologies for the temporal-spatial control of in situ
tissue formation, which is versatile in the prevention,
diagnosis, and treatment of various diseases.

Publications
1.

Zujur D, Kanke K, Lichtler AC, Hojo H, Chung
UI, Ohba S. Three-dimensional system enabling
the maintenance and directed differentiation ofpluripotent stem cells under defined conditions.
Sci Adv 2017;3(5):e1602875.

546

2.

3.

4.

5.

6.

7.

Hayashi K, Okamoto F, Hoshi S, Katashima T,
Zujur D, Li X, Shibayama M, Gilbert EP, Chung
UI, Ohba S, Oshika T, Sakai T. Fast-forminghydrogel with ultralow polymeric content as an
artificial vitreous body. Nat Biomed Eng 2017;1:
44.
Hojo H, Chung UI, Ohba S. Identification of thegene-regulatory landscape in skeletal development and potential links to skeletal regeneration.
Regenerative Therapy 2017;6:100-7.
Harata M, Watanabe M, Nagata S, Ko EC, Ohba
S, Takato T, Hikita A, Hoshi K. Improving
chondrocyte hargests with poly(2-hydroxyethyl
methacrylate) coated materials in the preparation
for cartilage tissue engineering. Regenerative
Therapy 2017;7:61-71.
Onodera S, Saito A, Hasegawa D, Watanabe K,
Morita N, Nomura T, Shibahara T, Ohba S,
Yamaguchi A, Azuma T. Multi-layered mutatin
in hedgehog-related genes in Gorlin syndrome
may affect the phenotype. PLOS ONE 2017;12(9): e0184702.
Kawata M, Taniguchi Y, Mori D, Yano F, Ohba S,
Chung UI, Grove E, Shimogori T, Mills AA,
Tanaka S, Saito T. Different regulation of limb
development by p63 transcript variants. PLoS
ONE 2017;12(3):e0174122.
Honnami M, Choi S, Liu IL, Kamimura W,
Taguchi T, Ichimura M, Urushisaki Y, Shimohata
N, Ohba S, Amaya K, Koyama H, Nishimura R,
Chung UI, Sasaki N, Mochizuki M. Repair ofsegmental radial defects in dogs by using
tailor-made titanium mesh cages with plates
combined with calcium phosphate granules andbasic fibroblast growth factor-binding ion
complex gel. J Artif Organs 2017;20(1):91-8.

547

Laboratory of Microenvironmental
and Metabolic Health Sciences
Professor
Makoto Murakami, Ph.D.

Associate Professor
Seiichiroh Ohsako, Ph.D., D.V.M.

Research Assistant
Yoshitaka Taketomi, Ph.D.

Project Assistant
Hiroyasu Sato, Ph.D.

Home Page

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

Introduction
Laboratory of Environmental Health Sciences of theCenter for Disease Biology and Integrative Medicine
moved from the 3rd floor of the Medical Faculty of
Medicine Building 1 to the 8th floor of the ClinicalResearch Center A on October 2016, and renamed thelaboratory to “Laboratory of Microenvironmental andMetabolic Health Sciences” on April 2017, aiming at
examining biochemistry and biology of lipids as wellas environmental toxicology. One professor, one
associate professor, one research assistant, one project
assistant, two project researchers, one temporal
researcher, one visiting researcher, one doctoral student,
and two graduation trainees conducted the researches
together during the year of 2017.
This laboratory belongs to the Department of Social
Medicine, cooperates to the Departments International
Health Sciences and Social Public Health, and isengaged in education and research on relationships.

Research activities
Laboratory of Microenvironmental and Metabolic
Health Sciences is constituted by two major research
projects; “lipid biology” by a group of Murakami(professor) and “environmental toxicology” by a groupof Ohsako (associate professor).
1. Lipid biology (Murakami’s group)
The main theme of this research project is to clarify
the role of lipids in health and diseases. Lipids
represent the largest source of energy in livingorganisms, are main components constituting cell
membranes, and also act as signal molecules. Lipids areenvironmental nutritional factors ingested from foods,
as well as tissue microenvironmental regulators thatspatiotemporally coordinate biological responses after
being metabolized to specific bioactive lipids. By
performing comprehensive lipid analysis (lipidomics)
on gene-manipulated mice for lipid-metabolizing
enzymes, particularly those in the phospholipase A2(PLA2) family, we aim to elucidate the molecularpathophysiology of diseases (e.g. metabolic andimmune diseases) that are increasing in modern society.
Based on this, we will promote the research of Qualityof Lipids (QOL) for Quality of Life (QOL) and aim atbuilding a theoretical foundation for diagnosis,
prevention and treatment of diseases involving
alteration of lipid metabolism.
We performed following researches in 2017.

548

1) Metabolic diseases
We have recently reported that two particularadipocyte-derived secreted PLA2s (sPLA2s), PLA2G5(sPLA2-V) and PLA2G2E (sPLA2-IIE), hydrolyze
different phospholipids in lipoprotein particles andthereby distinctly regulate systemic metabolism (Satoet al, Cell Metab 2014). In this year, we have extended
this approach and identified PLA2G2D (sPLA2-IID) asa novel regulator of systemic metabolism toward
metabolic health. Polyunsaturated fatty acids (PUFAs)
have health benefits by ameliorating inflammation andobesity and by increasing thermogenesis in brown andbeige adipocytes, yet the molecular entity of aparticular PLA2 that supplies PUFAs for metabolic
homeostasis remained unclear. We show that
PLA2G2D, a resolving sPLA2 (Miki et al, J Exp Med2013), is constitutively expressed in M2 macrophages
in white adipose tissue (WAT) and shows a reciprocal
correlation with obesity. Studies using global andmacrophage-specific Pla2g2d-/- mice revealed that
PLA2G2D, by supplying a pool of endogenous PUFAs,
ameliorates diet-induced obesity and insulin resistanceand counteracts the pro-inflammatory M1 macrophagebias in WAT. Moreover, PLA2G2D increases energy
expenditure and thermogenesis by facilitating
adipocyte browning. Thus, our results underscore therole of the M2 macrophage-driven PLA2G2D-PUFA
axis in metabolic health (manuscript in preparation).
2) Colonic diseases
Lipid mediators play pivotal roles in colorectal
cancer and colitis. We have recently shown that
PLA2G4A (cPLA2) and PLA2G10 (sPLA2-X)
protects from colitis by mobilizing distinct lipids, i.e.
arachidonate-derived PGE2 and 3 PUFAs (EPA andDHA), respectively (Murase et al, J Biol Chem 2016).
In this year, we have extended this approach andidentified PLA2G3 (sPLA2-III) as a novel regulator ofcolon diseases. Pla2g3-/- mice are highly resistant tothree different types of colon carcinogenesis.
Furthermore, Pla2g3-/- mice are less susceptible todextran sulfate-induced colitis, implying that theamelioration of colonic inflammation by Pla2g3
ablation may underlie the protective effect againstcolon cancer. Lipidomics analysis of the colon revealed
significant reduction of pro-inflammatory or protumorigenic lysophosholipids in Pla2g3-/- mice.
Overall, our results establish a role of PLA2G3 in the

promotion of colorectal inflammation and cancer,
expand our understanding of the divergent roles ofmultiple PLA2 enzymes in the gastrointestinal tract,and point to PLA2G3 as a novel druggable target forcolorectal diseases (Murase et al, Sci Rep 2016).
3) Skin diseases
Lipids play crucial roles in skin homeostasis anddiseases. We have recently shown that PLA2G2F(sPLA2-IIF) mobilizes lysoplasmalogen, a uniquelysophospholipid that promotes epidermal hyperplasic
diseases such as psoriasis and skin cancer (Yamamoto
et al, J Exp Med 2015). In this year, we have identified
the mechanistic action of PNPLA1, a member of theintracellular iPLA2 family whose mutations cause
autosomal recessive congenital ichthyosis, as a longsought ω-O-acylceramide synthase. PNPLA1 isexpressed in differentiated keratinocytes and plays acrucial role in the biosynthesis of ω-O-acylceramide, aparticular lipid component essential for skin barrier.
Global or keratinocyte-specific Pnpla1-deficientneonates die due to impaired skin permeability barrier
with severe transepidermal water loss, decreased
intercellular lipid lamellae in the stratum corneum, andaberrant keratinocyte differentiation. In Pnpla1–/–
epidermis, unique linoleate-containing lipids including
ω-O-acylceramides are almost absent, with reciprocal
increases in their putative precursors, indicating thatPNPLA1 catalyzes the ω-O-esterification with linoleic
acid to form ω-O-acylceramides. Supplementation with
ω-O-acylceramide partially rescues the differentiation
defects of Pnpla1–/– keratinocytes. Thus, our findings
provide valuable insight into the skin barrier formationand ichthyosis development, and may contribute tonovel therapeutic strategies for treatment of epidermal
barrier defects (Hirabayashi et al, Nat Commun 2017).
4) Allergic diseases
We have currently shown that PLA2G3 secreted
from mast cells promotes mast cell maturation by
driving the paracrine PGD2 circuit in cooperation withmicroenvironmental fibroblasts (Taketomi et al, Nat
Immunol 2013). In collaboration with Prof. H. Arai
(Faculty of Pharmaceutical Science, the University ofTokyo), we have found a novel role of PAF-AH2, aunique PLA2 that hydrolyzes oxidized phospholipids,in mast cell activation and thereby allergic responses.
By employing lipidomics, we identify ω3 EPA/DHA
epoxides as novel mast cell-derived lipid mediators that549

are constitutively produced by PAF-AH2. Genetic or
pharmacological inactivation of PAF-AH2 reduces thesteady-state production of ω3 epoxides, leading toattenuated FcRI-induced mast cell activation andanaphylaxis. Mechanistically, the ω3 epoxides promote
IgE-mediated activation of mast cells by downregulating Srcin1, a Src-inhibitory protein thatcounteracts FcRI signaling, through a pathway
involving PPAR. Thus, the PAF-AH2–ω3 epoxide–
Srcin1 axis presents new potential drug targets forallergic diseases (Shimanaka et al, Nat Med 2017).
As another collaborating research with a Koreangroup, we have found that the SIRT1-LKB1-AMPK
pathway negatively regulates FcRI signaling in mast
cells (Li et al, Sci Rep 2017).
5) Bone biology
Osteoclasts, responsible for bone resorption, aremultinucleated cells formed by cell-cell fusion ofmononuclear pre-osteoclasts. We found that theincreased biosynthesis and exposure of phosphatidylethanolamine on the cell surface, which were regulated
by LPEAT2 and ABCB4/ABLG1, respectively, arecrucial for osteoclast fusion (Irie et al, Sci Rep 2017).
2.

Environmental Toxicology (Ohsako’s group)
The aim of this research project is to push up theimportance of so-called environmental toxicology
originated form hygiene, toxicology, environmental
health science and so on, which use predominantly
experimental animals, cell cultures, and humansamples, but not subordinate biostatics andbioinformatics. Here show three examples performedin this year.
1) Epigenetic Molecular Epidemiology
Many epidemiological studies reported that theabnormal external genitalia of newborns, such as
hypospadias, are increasing since the second half of thelast century worldwide. We found the CYP1 familygene expression as estimated chemical exposure level,
as well as DNA methylation using foreskin or blood
samples collected at the time of surgical operation of
the hypospadias to clarify the relationship between
disease and environmental factors. Expression level of
the CYP1 family in the hypospadias group is higher
than that in the fimosis group. Minimum promoter
methylation level of the SRD5A2 gene is correlatedwith its expression levels in hypospadias group. These
results suggest that there is some relation between onset
and chemical exposure (Ohsako et al, AECT, 2017).
2) Affordable Genome-wide Methylation Analysis
The MSD-AFLP method is an exhaustive
methylation analysis method that can be performed at
low cost and high sensitivity (Aiba et al., BMC Mol
Biol, 2017). We used this method to capture
epigenomic changes in response to environmental
factors. In addition, a method of amplifying only
methylated genomic DNA short fragments using amethylation-sensitive
restriction
enzymewaspublished (Kurita et al., Gene Environ, 2018).
3) EST (Embryonic Stem Cell Test)
Using a toxicity test using a differentiation culture
system from human and mouse ES cells which has beendeveloped in our previous studies, we are developing a
toxicity prediction system for chemicals which are
difficult to extrapolate data of animal experiments andactual effects to humans. At present, we collaborate
with Dr Ichihara lab in Tokyo University of Science toanalyze the developmental neurotoxicity of acrylamide,
which has been found to be unintentionally generated
and contained in food cooking in recent years and has
become a problem. We carried out EST using mouse ES
cells.

Teaching activities
The Laboratory of Microenvironmental Health
Sciences has important missions to train postdoctoral
fellows to become promising scientist leaders in thefield of life sciences and environmental toxicology andto give biochemistry, molecular biology, toxicology
and environmental health courses for graduate andundergraduate students. The following lectures havebeen provided to students.
Graduate education
Lectures, Seminar, and laboratory practice, as wellas guidance for the dissertation for the Master’s andDoctor’s degrees have been provided.
Master Course in the Graduate School of Medical
Sciences: Metabolic Health Sciences (Lecture)
Master and Doctor Courses in the Graduate School

550

of International Health: International Environmental
Medicine (Lecture and Laboratory Practice)
Master Course in the School of Public Health:Environmental Health Medicine (Lecture)

Publications
1.

2.

3.

4.

5.

6.

7.

8.

Shimanaka Y, Kono N, Taketomi Y, Arita M,
Okayama Y, Tanaka Y, Nishito Y, Mochizuki T,
Kusuhara H, Adibekian A, Cravatt BF, Murakami
M, Arai H. ω3 fatty acid epoxides are autocrine
mediators that control the magnitude of IgEmediated mast cell activation. Nat. Med. 23, 12871297, 2017.
Murase R, Taketomi Y, Miki Y, Nishito Y, Saito M,
Fukami K, Yamamoto K, Murakami M. Group III
phospholipase A2 promotes colitis and colorectal
cancer. Sci. Rep. 7, 12261, 2017.
Aikawa S, Kano K, Inoue A, Wang J, Saigusa D,
Nagamatsu K, Hirota Y, Fujii T, Tsuchiya S,
Taketomi Y, Sugimoto Y, Murakami M, Arita, M,
Kurano M, Ikeda H, Yatomi Y, Chun J, Aoki J.
Autotaxin-lysophosphatidic acid-LPA3 signalingat the embryo-epithelial boundary controls
decidualization pathways. EMBO J. 36, 21462160, 2017.
Li X, Lee YJ, Jin F, Park YN, Deng Y, Kang Y,
Yang JH, Chang JH, Kim DY, Kim JA, Chang YC,
Ko HJ, Kim CH, Murakami M, Chang HW. Sirt1
negatively regulates FcεRI-mediated mast cell
activation through AMPK- and PTP1B-dependent
processes. Sci. Rep. 7, 6444, 2017.
Irie A, Yamamoto K, Miki Y, Murakami M.
Phosphatidylethanolamine dynamics are requiredfor osteoclast fusion. Sci. Rep. 7, 46715, 2017.
Hirabayashi T, Anjo T, Kaneko A, Senoo Y,
Shibata A, Takama H, Yokoyama K, Nishito Y,
Ono T, Taya C, Muramatsu K, Fukami K, MuñozGarcia A, Brash AR, Ikeda K, Arita M, Akiyama
A, Murakami M. PNPLA1 has a crucial role inskin barrier function by directing acylceramide
biosynthesis. Nat. Commun. 8, 14609, 2017.
Murakami M. Lipoquality control by thephospholipase A2 family. Proc. Jpn. Acad. Ser. B.
93, 677-702, 2017. (Review)
Yamamoto K, Miki Y, Sato H, Murase R, Taketomi
Y, Murakami M. Methods Enzymol. 583, 101-117,
2017. (Review)

9.

Kurita H, Aiba T, Saito T, Ohsako S. A new
method to specifically amplify the genomic DNA
ragments neighboring 5-methylcytosine for the
genome-wide CpG methylation analysis. Genes
Environ. 10, 40:1, 2018.
10. Ohsako S, Aiba T, Miyado M, Fukami M, Ogata T,
Hayashi Y, Mizuno K, Kojima Y. Expression ofxenobiotic biomarkers CYP1-family in preputial
tissue of patients with hypospadias and phimosis
and its association with DNA methylation level of
SRD5A2 minimal promoter. Arch. Environ.
Contam. Toxicol. 74, 240-247, 2018.
11. Aiba T, Saito T, Hayashi A, Sato S, Yunokawa H,
Maruyama T, Fujibuchi W, Kurita H, Tohyama C,
Ohsako S. Methylated site display (MSD)-AFLP,a sensitive and affordable method for analysis of
CpG methylation profiles. BMC Mol. Biol. 18, 7,
2017.

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Laboratory of Animal Resources
Professor
Atsu Aiba, Ph.D.

Associate Professor
Kazuki Nakao, Ph.D., Hidetoshi Kassai, Ph.D.

Assistant Professor
Michinori Koebis, Ph.D., Harumi Nakao, Ph.D., Hiromitsu Kono, Ph.D.

Homepage

http://lar.cdbim.m.u-tokyo.ac.jp/index.html

Introduction and Organization
Our laboratory was established as the Division ofAnimal Research affiliated with the Faculty of
Medicine in April 1971. The building for animal
experimentation was completed and the accommodation and experimentation of laboratory animals
started in 1973. In 2003, the laboratory was
reorganized as the Section of Animal Research of theCenter for Disease Biology and Integrative Medicine(CDBIM). In 2008, the Laboratory of Animal
Resources was established to strengthen research activities in addition to the Section of Animal Resources.
The members of our laboratory and section are 6
teaching staffs, 5 technical support staffs, an assistantmanager of CDBIM, an administrative staff, a project
academic support specialist, 3 assistant laboratory
animal technicians, and 4 assistant clerks. In addition,
about 15 contracted employees are involved in animal
breeding and maintenance of the animal facility.
The laboratory animals in our facility include
macaque monkeys, dogs, swine, rabbits, rats, mice,and marmosets. The number of registered users of ourfacility was 806 at the end of academic year 2017.
We provide quality care for all animals in our facility
and assist animal experimentation carried out by the
researchers. The office of our section is in charge ofthe secretariat of the Institutional Animal Care and the
Use Committee (IACUC) of the Graduate School of
Medicine, the University of Tokyo. The committee(Chair, Prof. Atsu Aiba) reviews the plans of animal

experimentation and helps researchers carry out
animal experiments in accordance with law,regulations and University policies governing the useof animals.

Teaching activities
We are responsible for the education of laboratory
animal science to the 2nd-year students (M0) of theFaculty of Medicine. The lecture includes animal
welfare, refinement of animal experiments, animal
breeding, infectious diseases of laboratory animals
and zoonoses. We also give a lecture on mouse
molecular genetics and molecular embryology.
We are also involved in lectures by IACUC for the
researchers at the Graduate School of Medicine.

Research activities
Our laboratory focuses on understanding themolecular mechanisms which underlie the synaptic
plasticity, activity dependent formation of neuronal
circuitry, and learning and memory. We also study cell
metabolism. We generate knockout mice and transgenic mice of signal transduction molecules including
the glutamate receptors and mammalian target of
rapamycin (mTOR). We applied proteomics analysis
to these mice. We also try to generate murine models
for human genetic diseases. We have also established
new gene targeting technology using the CRISPR/
CRISPR-associated (Cas) system.

552

1. Embryo transfer of marmoset embryos
Common marmoset (Callithrix jacchus) is a nonhuman primate and recently used for human model,
especially focusing on brain function. We haveestablished the techniques for embryo transfer tooviducts. We expected the higher efficiency of thedevelopment of genome edited embryos by thistechnique.
2. Generation of knock-in mice by CRISPR/Cas
systemThe CRISPR/Cas system has rapidly emerged recently
as a new tool for genome engineering, and is expected
to allow for controlled manipulation of specificgenomic elements in a variety of species. A number ofrecent studies have reported the use of CRISPR/Cas
for gene disruption (knockout) or targeted insertion offoreign DNA elements (knock-in). Despite the ease of
simple gene knockout, small insertions or nucleotide
substitutions in mouse embryos, targeted insertion oflarge DNA elements remains an apparent challenge.
We tried to quantify knock-in efficiency using
sgRNAs or crRNA/tracrRNA targeting for mouse
Grm1 locus, single stranded oligo DNAs as donors
and Cas9. We have succeeded to maximize knock-in
efficiency (63.0%), when purified Cas9 protein was
injected with crRNA/tracrRNA and donor DNA.
3. Generation of calsyntenin triple KO mice
Calsyntenins are membrane proteins belonging tocadherin superfamily. In C. elegans, a calsynteninhomolog CASY-1 is required for taste avoidance
learning. There are three mouse calsyntenins(CLSTN1, 2, and 3), which are predominantly expressed in the central nervous system (CNS). To
investigate the role of CLSTNs in the CNS, we plan togenerate Clstn triple KO mice. We have injected Cas9mRNA with sgRNA targeting Clstn 1, 2 and 3 into
mouse embryos and have obtained founder mice
which carry several mutant alleles of Clstn genes. By
crossing these mice, we have established Clstn triple
KO mice. Clstn triple KO mice are viable. We
examined long-term potentiation (LTP) in the TKO
hippocampus and found that they induce normal LTP.
We found that TKO mice showed reduced
parvalbumin positive neurons, which might be relatedwith abnormal behavior which TKO showed.

4. Generation of 22q11.2 DS syndrome modelmouse
22q11.2 deletion syndrome (22q11.2DS) is a genetic
syndrome caused by a heterozygous deletion ofchromosomal region 22q11.2. Most patients have adeletion of 3 Mb in this region, whereas 7% of
patients have a smaller, nested deletion of 1.5 Mb.
Genes of human chromosome 22q11.2 have beenhighly conserved in mouse chromosome 16qA13. This
syndrome has been shown to increase the risk ofdeveloping schizophrenia, intellectual disability,
autism spectrum disorders and other psychiatricdisorders. Particularly, about 30% of patients with thissyndrome
developschizophrenia.
We havesuccessfully generated mice with 3 Mb deletion(Del(3Mb)/+) by genome editing techniques using
CRISPR/Cas9 system. We have also established themice with 1.5 Mb deletion (Del(1.5Mb)/+) and 1.4
Mb deletion (Del(1.4Mb)/+) by genome editing. We
are currently analyzing these mice.

References
1. Endo M, Ubulkasim G, Kobayashi C, Onishi R,
Aiba A, Minami Y.
Critical role of Ror2 receptor tyrosine kinase inregulating cell cycle progression of reactive
astrocytes following brain injury.
Glia, 65(1), 182-197, 2017.
2. Ishii T, Ueyama T, Shigyo M, Kohta M, Kondoh T,
Kuboyama T, Uebi T, Hamada T, Gutmann DH,
Aiba A, Kohmura E, Tohda C, Saito N.
A Novel Rac1-GSPT1 Signaling Pathway
Controls Astrogliosis Following Central Nervous
System Injury.
J Biol Chem, 292(4), 1240-1250, 2017.
3. Ueda J, Murata Y, Bundo M, Oh-Nishi A, Kassai
H, Ikegame T, Zhao Z, Jinde S, Aiba A, Suhara T,
Kasai K, Kato T, Iwamoto K.
Use of human methylation arrays for epigenome
research in the common marmoset (Callithrix
jacchus).
Neurosci Res, 120, 60-65, 2017.
4. Nakamura T, Ueyama T, Ninoyu Y, Sakaguchi H,
Choijookhuu N, Hishikawa Y, Kiyonari H, Kohta
M, Sakahara M, de Curtis I, Kohmura E, Hisa Y,
Aiba A, Saito N.

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Novel role of Rac-Mid1 signaling in medial
cerebellar development.
Development, 144(10), 1863-1875, 2017.
5. Kanayama M, Hayano T, Koebis M, Maeda T,
Tabe Y, Horie S, Aiba A.
Hyperactive mTOR induces neuroendocrine
differentiation in prostate cancer cell withconcurrent up-regulation of IRF1.
Prostate, 77(15), 1489-1498, 2017.

554

Laboratory of Molecular Radiology
Professor
Kiyoshi Miyagawa, M.D., Ph.D.

Lecturer
Noriko Hosoya, M.D., Ph.D., Atsushi Enomoto, Ph.D.

Associate
Takaaki Yasuhara, Ph.D., Claudia Juliane Krause, Ph.D. (Project)

Homepage

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

Introduction and Organization
When the Center for Disease Biology and Integrative
Medicine was established in 2003, the Department ofRadiation Oncology established in 1967 and theRadiation Research Institute established in 1992 werejoined to form the Section of Radiation Biology as apart of Divisions of Research Resources and Support.
In 2008, the Laboratory of Molecular Radiology was
also established to strengthen research activities inthis section. The scientists and staffs belong to boththe section and the laboratory.
The aim of this laboratory is to facilitatetranslational research from frontier life science toapplied radiology by introducing molecular biology
into conventional radiology.
To maintain the facility of radiation research,
responsible staffs at two facilities are elected from oursection. This year, the hospital radioisotope researchfacility was continued to be closed to prepare theopening of the new facility in the newly-constructed
Clinical Research Building.

Education
We are responsible for the education of basic radiation
medicine for the 3rd year medical students. The
students are expected to start with understanding of
the physics and the chemistry for radiation and thenunderstand the basic biology of radiation. Furthermore,they learn how to handle radioactive materials by the

2-day practical course.
In addition to these courses, the 4th year medical
students are expected to learn how to use clinicalradiation technology safely in hospitals. The
background for this addition is that clinical problems
arising from the lack of knowledge of radiation effects
have been increasing. Furthermore, the education ofradiation emergency medicine is included in thiscourse. Even though radiation casualty is rare, allclinicians should know how to treat patients exposed
to radiation. The importance of this education has
been widely recognized since the accident at the
Fukushima nuclear power plant.
We also take part in the education of radiation
health science for the 3rd year students specialized in
integrated health sciences. Radiation protection isemphasized in this course.
For graduate students, the education of molecularbiology of the DNA damage response to radiation and
DNA repair is more intensively integrated.
In addition, education courses for users of radioactive materials frequently take place.

Research
We focus on the mechanism underlying the cellularresponse to DNA double-strand breaks (DSBs).
Among various types of DNA damage, DSBs are themost deleterious if not repaired properly. To protect
the genome, at least four signaling cascades are
known to function as the repair machineries against

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DSBs.
While
nonhomologous
endjoining,
microhomology-mediated end joining, and singlestrand annealing are error-prone repair pathways,
homologous recombination (HR) is an error-freepathway in principle using newly replicated DNA as atemplate for the repair. There is accumulating
evidence that defective HR plays a role in tumor
development. For example, BRCA1 and BRCA2,
tumor suppressors in hereditary breast and ovariancancers, are known to mediate the damage response to
DSBs and promote HR.
Rad51, a key player at early stages of HR, catalyzes
the invasion of a single-strand DNA end into an intact
homologous duplex. BRCA2 plays a mediator role atthis stage by directly binding to Rad51 and promoting
the formation of the filament consisting of thesingle-strand DNA and Rad51.
SYCP3 is a component in the synaptonemal
complex which is formed between homologous
chromosomes to ensure their connection in meiosis.
Expression of SYCP3 was observed in adrenal, liver,stomach, and kidney tumors, confirming that SYCP3
is a cancer testis antigen. Treatment of SYCP3nonexpressing cells with a methylation inhibitor
induced its expression, indicating that methylation
alteration in cancer is responsible for its ectopic
expression.
Since biological significance of cancer testis
antigens in somatic cells is largely unknown, weinvestigated the effects of SYCP3 expression on
cellular functions in somatic cells. This study revealed
that SCYP3-expressing cells are hypersensitive toradiation and cisplatin and are characterized byincreased aneuploidy. As these phenotypes are
consistent with those of defective HR, we screened themolecule that co-localizes with SYCP3 by immunefluorescence. Consequently, we identified that thetumor suppressor BRCA2 co-localizes with SYCP3.
We also confirmed that these proteins form a complex.
Furthermore, we found that binding of SYCP3 to
BRCA2 inhibits the HR repair activity mediated bybinding of BRCA2 to Rad51.
Since cells with BRCA1 or BRCA2 mutations are
hypersensitive to PARP inhibitors, their clinical trials
are internationally ongoing. However, the problem isthat the application of the trial is limited due to low
incidence of their mutations. Our findings implicatethat SYCP3-expressing cancers, even if they do notharbour BRCA mutations, are sensitive to PARP
inhibitors, providing novel insight into cancer therapy
based on the synthetic lethal approach in which both
two pathways essential for cell viability are disrupted
by an intrinsic genetic alteration and a specificpathway inhibitor.
In addition to Rad51, 5 Rad51 paralogs, Rad54, andRad54B are also involved in early stages of HR.
While Rad51 paralogs and Rad54 were shown toassist the Rad51-dependent cascade, the involvementof Rad54B in HR is not closely associated with
Rad51and Rad54. This fact led us to hypothesize that
Rad54B has a role distinct from other HR factors. We
found that levels of Rad54B are inversely correlatedwith protein levels of p53 both after DNA damage andRad54B knockout cells. Protein interaction analysis
revealed that Rad54B promotes proteasome-dependentdegradation of p53 by directly binding to MDM2/
MDMX, an E3 ubiquitin ligase complex targeting p53.
Furthermore, we found that overexpression of Rad54B
facilitates genomic instability by negatively regulatingcell-cycle checkpoints medicated by p53. Consistent
with this biological function, high levels of Rad54B
were shown to correlate with poor prognosis incolorectal cancers. In addition, increases in its
expression are also observed in other types of cancers.
Thus, our studies on the mechanisms underlying
HR contribute to the establishment of important
strategies against cancer. Radiation and many DNAdamaging chemotherapeutic agents induce DNA DSBs,
which can be normally repaired by the intrinsic repair
pathways. The induced breaks therefore do not always
lead to apoptosis. If we will understand the details of
the repair pathways, the molecules in this pathway
will be the therapeutic targets. From the clinical pointof view, we are continuing the research exploring theprinciple in this field.

Publications
1. Enomoto A, Yamada J, Morita A, Miyagawa K:
Bisdemethoxycurcumin enhances X-ray-induced
apoptosis possibly through p53/Bcl-2 pathway.
Mutation Res 815:1-5, 2017
2. Kobayashi W, Hosoya N, Machida S, Miyagawa
K, Kurumizaka H: SYCP3 regulates strand

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invasion activities of RAD51 and DMC1. Genes
Cells 22:799-809, 2017
3. Sato H, Niimi A, Yasuhara T, Permata TBM,
Hagiwara Y, Isono M, Nuryadi E, Sekine R, Oike
T, Kakoti S, Yoshimoto Y, Held KD, Suzuki Y,
Kono K, Miyagawa K, Nakano T, Shibata A:
DNA double-strand break repair pathway
regulates PD-L1 expression in cancer cells. Nat
Commun 8:1751, 2017

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Laboratory ofBiomedical Informatics
Associate Professor
Takeshi Imai, Ph.D.

Homepage

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

Introduction and Organization
When the Center for Disease Biology andIntegrative Medicine was established in 2003, Sectionof Biomedical Informatics was launched as one of thedepartments in Division of Research Resources &Support. In 2017, Laboratory of Biomedical
Informatics was established as a part of Division of
Research in the Center. Because of the parallel
establishments, the both of organizations are made upof the same faculties.
The objective of Laboratory of Biomedical
Informatics which is placed in the interdisciplinary
field between medicine, engineering and informatics
is to offer feedback to clinical medicine andcontributions toward the healthcare and our society
through studies such as analyses of medical
information, gaining medical findings in secondary
use of medical information, and developing andapplying diagnosis support systems. Besides thestudies, our laboratory takes a roll of graduate
education for the doctor’s program in the Departmentof Biomedical Informatics at the Division of Social
Medicine, the master’s program in the Medical
Science Graduate Program, and the School of Public
Health, the Graduate School of Medicine.
Section of Biomedical Informatics, Division of
Research Resources & Support has an operation of the
Office for Information Services, Graduate School of
Medicine to maintain MERCS (Medical Research
infrastructure with Computer System). The operations
include: (1) handling the incidents of CERT andmaintaining network infrastructure, (2) offering
software service of medical research supports, (3)operating mailing service for Faculty of Medicine, (4)operating DNS service and allocating global IP
addresses for UT-Net connections, (5) operating websites and servers of Faculty of Medicine and the
Graduate School of Medicine, (6) offering learning
devices at the medical library, and so on.

Teaching activities
In 2017, we took charge of lectures: “Description
and Processing of Medical Knowledge” in the 2-year
master course in the Medical Science Graduate
Program, “Computer Processing of Medical
knowledge and AI application” in School of Public
Health course, and “Applying Techniques of Artificial
Intelligence to Processing Clinical Information” in theM2 undergraduate course.
We accept students in the 2-year master course in
the Medical Science Graduate Program, and 4-year
Medical Sciences doctoral course, cooperating withteaching staffs in other laboratories in the field of
medical informatics. Four students in the master’s
program and one student in M.D./Ph.D. education
program are enrolled in our laboratory in FY2017.
Additionally, six undergraduate students took practiceeducation in our laboratory through M3 Elective
Clerkship program.

Research activities
Our primary research domains are: (1) methods toknowledge representation and processing knowledge
in healthcare, (2) analysis of electronic medical
records and gaining medical knowledge with natural

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language processing and machine learning, (3)developing
diagnosis
supportsystem,(4)
standardization in the field of healthcare informatics,
and so on.
In these domains, major research topics are listed
below:(1) DevelopmentofMedicalKnowledge
Infrastructure.
A large amount of medical information has
been accumulated with the prevalence ofcomputerization in medicine. Correspondingly,
the needs of secondary use of the accumulated
information for diagnosis support system andgaining medical knowledge have been
increasing. Ontology, knowledge database,which is assembled mass of information
describing the relationship of terms andconcepts marshaled in a structured manner, isrequired for the study besides the techniques ofmachine learning and knowledge deduction. We
have developed the clinical ontologies inparticular fields such as anatomy, diseases, andabnormal status, as a funded research by the
Ministry of Health, Labor and Welfare, Japan.
For example, the ontology for diseases has beendeveloped with approximately 6,000 diseases,that they are described as causal chains ofabnormal states. We have also participated in“Research and development of intellectual
information system infrastructure in medicine”
project, sponsored by AMED since 2015. As
further developing the ontology, we haveworked on the study that clinical information ofa targeted patient is automatically mapped on
chronic disease ontology in order to perceive
changes of disease states.
(2) Development of Diagnosis Support System for
General Physicians.
It is difficult in community medicine topromote cooperation between medical experts
and the core medical institutions. The expertsof regional communities are required to havecomprehensive diagnosis skills and technicalknowledge in the domain they specialize in.
However, given the difficulty of such asituation that physicians take all the
responsibilities, depending on only theirknowledge and experiences, the need of
diagnosis support system is pointed out. In thisstudy, we have developed support system, thatgives physicians in outlying regions access torefer to information matching experiences andknowledge matured general physicians have, tosolve the issues. This project has been launchedsponsored by AMED since January 2017. The
current developed system is made up of
approximately 20,000 case reports in internal
medicine. The reports are transformed into
knowledge database, described as chains ofclinical states, so that the system can suggest alist of candidate diseases corresponding to aquery, with certainty scores and reasons. We
also have worked on a study to automaticallyextract knowledge from raw texts in casereports using natural language processing forthe continuous updating of the system. In future,
we plan to achieve the social implementation of
the support system.
(3) Analysis of Electrocardiogram (ECG) by Deep
Learning.
Automatic analyzers of ECG data used inmost hospitals are rule-based models that
outputs ECG data in waveforms with clinicalannotations. However, it still has difficulties onclassification on abnormal findings. In fact, it ispointed out that it has a low sensitivity or
potential for a false-positive diagnosis.
Therefore, it needs an enhancement in its
classification performance. We have developed
another classification model using deeplearning, intended for standard 12-leads ECG
data. The current clinical annotations used fortraining our model is the ones given by theautomatic analyzers; however we plan to apply
diagnosis confirmed by echocardiogram as
annotation data in future, so that our proposedmodel can be specialized in more specificabnormal findings and achieve comparable
performance to diagnosis by experts.
In addition to the researches, we have worked onother studies such as developing a classification modelfor ‘Sho’ which is the differentiation concept ofsyndrome in Kampo medicine and a prescription

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selection support system for non-specialists in
Kanmpo medicine, and developing prescription
support system in medical care for hypertension
patients based on the clinical guidelines. Furthermore,
we also have promoted a project aimed at theapplication of ICD-11 released in June 2018 fordomestic use in Japan.

Publications
1.

2.

3.

4.

5.

6.

7.

Ma X, Imai T, Shinohara E, Sakurai R, Kozaki K,
Ohe K. A Semi-Automatic Framework to Identify
Abnormal States in EHR Narratives. Stud HealthTechnol Inform. 2017;245:910-914.
Kagawa R, Kawazoe Y, Shinohara E, Imai T, Ohe
K. The Impact of “Possible Patients” on
Phenotyping Algorithms: Electronic Phenotype
Algorithms Can Only Be Reproduced by Sharing
Detailed Annotation Criteria. Stud Health Technol
Inform. 2017;245:432-436.
Iwai S, Kawazoe Y, Imai T, Ohe K. Effects of
Implementing a Tree Model of Diagnosis into a
Bayesian Diagnostic Inference System. Stud
Health Technol Inform. 2017;245:882-886.
Kozaki K, Yamagata Y, Mizoguchi R, Imai T,
Ohe K. Disease Compass- a navigation system fordisease knowledge based on ontology and linked
data techniques. J Biomed Semantics. 2017 Jun
19;8(1):22. doi: 10.1186/s13326-017-0132-2.
Kagawa R, Kawazoe Y, Ida Y, Shinohara E,
Tanaka K, Imai T, Ohe K. Development of Type 2
Diabetes Mellitus Phenotyping Framework Using
Expert Knowledge and Machine Learning
Approach. J Diabetes Sci Technol. 2017
Jul;11(4):791-799.
Kasai S, Yokota S, Noguchi T, Ida Y, Kitagawa Y,
Imai T, Kawazoe Y, Tanaka Y, Ohe K. Analysis
of Medication Process using Transaction Log in
Oral Drug Administration Ordering System. Japan
Journal of Medical Informatics. 2017; 37(4):187-196. (In Japanese)
Kagawa R, Kawazoe Y, Shinohara E, Imai T, Ohe
K. Study of the features of EHR data fordevelopmentofthedisease-independent
framework for e-phenotyping techniques. Japan
Journal of Medical Informatics. 2017; 37(suppl.):754-759. (In Japanese)

8. Kawazoe Y, Kagawa R, Imai T, Ohe K. Current
status and limitations of EHR Phenotyping. Japan
Journal of Medical Informatics. 2017; 37(suppl.):169-172. (In Japanese)

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Department of Medical Education
Studies
Professor
Masato Eto, M.D., Ph.D.

Lecturer
Daisuke Son, M.D., Ph.D.

History and organization
International Research Center for Medical
Education (IRCME), established in 2000, hadfunctioned as a center for the whole university andkept relations with Graduate School of Medicine invarious ways. IRCME became an affiliated center for
education and research under the control of Graduate
School of Medicine since April 2013. IRCME
previously consisted of two departments of International Cooperative Study in Medical Education, andPlanning & Cooperation for International Cooperative
Projects and Information on Medical Education.
Names of two new departments are Department ofMedical Education Studies and Department ofInternational Cooperation for Medical Education.
The mission of Department of Medical Education
Studies includes promotion of medical education not
only in Faculty of Medicine of the University ofTokyo but also of the whole country. Specific contents
are as follows:(1) Research in medical education and dissemination
within and outside of the University
Medical and health professions education needs tocontinue revisions to meet health care needs of thecountry or the region. However, since every country
or region has different culture or social system,
experiences to apply updated evidences to the realsettings to revise the system.
(2) Support to undergraduate and postgraduate education in the University
Through the support to education in Faculty of

Medicine and Its University Hospital, we show theeffective ness of such teaching practice and apply it toother medical schools in Japan for future reform.

Activities
This department promotes research related to
medical education field. As the studies of medical
education develop very rapidly all over the world, thedepartment expands research to construct theories andemphasizes activities of educational practice or
improvement.
In the University, this department provides
information and member(s) as to the education ofFaculty of Medicine in such as academic affair
committee, medical education reform working group,and clinical clerkship. Moreover, the department
offers educational activities such as PBL (problembased learning) and clinical skill practical training.
The department operates OSCE (objective structured
clinical examination). The department also runs andmanages “Tsutsuji no kai” under the consortium with
Tokyo Medical Dental University to develop
simulated patients indispensable for education of
medical interview.

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Department of International
Cooperation for Medical
Education
Lecturer
Hirotaka Onishi, M.D., M.H.P.E., Ph.D.

Homepage

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

History
International Research Center for Medical Education(IRCME), established in 2000, had functioned as acenter for the whole university and kept relations with
Graduate School of Medicine in various ways.
IRCME became an affiliated center for education andresearch under the control of Graduate School of
Medicine since April 2013. IRCME previously
consisted of two departments of Inter¬national
Cooperative Study in Medical Education, andPlanning & Cooperation for International Cooperative
Projects and Information on Medical Education.
Names of two new departments are Department ofMedical Education Studies and Department ofInternational Cooperation for Medical Education.

Overview of the Department
The Department of International Cooperation for
Medical Education is a department handlingcomprehensive practices and research, both in thefield of international cooperation in healthprofessions-education-related area and in the fieldlinking policies and actual practices such as
international health, community medicine, and generalpractice. Specifically, it is as follows.
(1) International Cooperation in the Field of HealthProfessions Education: We explore how education andpolicies in the health and medical fields should bebased through participation in international
cooperation projects in countries mainly in Asia. We

try to become the core center for the research in thisarea by conducting practical efforts as an expert on the
project under Japan International Cooperation Agency,
by accumulating experiences in the area such as
evaluation
method,policyrecommendation,
coordination of stakeholders, and by disseminating the
research results.
(2) Study on Learner Assessment: When certifying thecompletion of the program, it is very important toinvestigate how the learner's assessment is conductedand how the decision is made. Various changes areseen in the concept of assessment itself. As forresearch, development of work-based assessment
methods, verification of reliability and validity,
improvement of methods for setting pass / failjudgment criteria are examples.
(3) Practice and research in the field linking healthpolicy and clinical practice: Our projects consists of
how to train the carrier of integrated community-basedcare, how to set goals in elderly care, how to develop
lifelong learning e-learning system.

References
1. Nomura O, Onishi H, Kato H. Medical students
can teach communication skills–a mixed methods
study of cross-year peer tutoring. BMC medical
education, 17(1), 103, 2017

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Global Nursing Research Center
Director, Professor
Hiromi Sanada, R.N., P.H.N., W.O.C.N., Ph.D.

Vice Director, Professor
Kiyoko Kamibeppu, R.N., P.H.N, Ph.D.
Noriko Yamamoto-Mitani, R.N, Ph.D.

Project Associate Professor
Makoto Oe, R.N., P.H.N., Ph.D.

Project Assistant Professor
Mami Takahashi, Ph.D., M.B.A., R.Ph.

Project Researcher
Mariko Sakka, R.N., Ph.D., Mayu Fukuda, R.N., Ph.D.

Homepage

http://gnrc.m.u-tokyo.ac.jp/en/

Introduction and Organization
With a falling birthrate and a super-aging society,Japan is in need of a paradigm shift toward a medical
and nursing care that supports the aging, as well as
those dealing with chronic health conditions, to lead
lives with maximum independence and well-being. In
order to provide a healthy life expectancy for its
people, it will be necessary for Japan to face its
forthcoming challenges and bring about the realizationof a ‘care’ society that lightens the difficulty of theliving and brings a self-reliant way of life to theJapanese nation. Nursing, which plays a central role inproviding care, must develop into a new field as ascience for the realization of this ‘care’ society.
Currently, however, the dominant paradigm employedin various nursing fields embraces a structure that
supports the training of clinical nurses, not thedevelopment of a science aimed at producing a'medical and nursing care that supports.’ Thus, GNRC
seeks to promote research into an innovative,
transdisciplinary nursing science that systematizes thistype of care. In particular, our focus is to create atransdisciplinary research and educational environ-ment that fosters young leaders in nursing research
who will promote care innovation and develop nursing
systems for implementation.
In order to achieve this, we must work toward
integrating nursing with fields it has yet to fully
collaborate with, such as bio-engineering, molecularbiology, human engineering, philosophy, educational
psychology, information science, and policy science.
Moreover, as the field of nursing science continues todevelop, further attention must be paid to both thedevelopment of the necessary human resources thatwill be required to promote this transdisciplinary
research, as well as the networks necessary to create
collaborative relationships among industry, government, and academia. In short, our aim is to create along-term research system that allows young
researchers to conduct transdisciplinary work that
ranges from fundamental research to studies withcommercial application.
Thus, the Global Nursing Research Center has been
established as an affiliated research center, which isthe first of its kind in nursing science. The GNRC willseek to execute the following three goals over the next
four years:

5631) Establish an innovative nursing research field basedon transdisciplinary integration;2) Carry out cutting-edge research and present it to theworld with young researchers pursuing the sciences;
3) Build up a foundation of these new fields throughrepeated research trials that will strengthen the newresearch and education systems.

Establishing an Innovative Nursing Research
Field
1. Division of Care Innovation
The Division of Care Innovation promotes various
research activities, such as robotics nursing, biologicalnursing, visualized nursing, clinical nursing technology and reverse translational research, with the aimof ‘developing and producing patient care productsthat lighten unfavorable conditions of daily life due tothe health impairment of each person.’
2. Division of Nursing Systems
The Division of Nursing Systems promotes suchresearch activities as health-quality outcome researchand care quality management, in order to provide‘nursing practice solutions that reflect important
cultural and social concerns, constructing Japan-origin
nursing theories that support high quality practices,and making policy proposals.’
3. Achievements
In 2017, four international joint research projects andfive industry-government-academia research projects
were undertaken. In addition, two patent applications
were submitted, and 26 original English articles were
published.

Executing Innovative Research
1. International Invited Faculty
In 2017, we invited two project professors: Claudia K.
Y. Lai, Honorary Professor & Founding Director ofCentre for Gerontological Nursing at Hong Kong
Polytechnic University, and Edward Ko Ling Chan,
Professor at Hong Kong Polytechnic University. In
addition, we also invited researcher Pamela S. Hinds,
Professor at George Washington University (USA).
They each gave post-doctoral seminars.

2. Post-doctoral Program
Post-doctoral (PD) researchers engage in focusedresearch projects, the findings of which will be madeknown to the public. In addition, PD researchers musttake five essential seminars that cover comprehensive
research knowledge, skills, and global awareness forthe training of youth for leadership.
These five required seminars are, as follows: (1) How
to Write a Research Paper in English, (2) Leadershipin Nursing Research, (3) Qualitative Research
Methods, (4) Health Quality Outcome Research, and(5) Introductory Seminar to Nursing Science andEngineering.
Further, there are an additional five optional seminars:(1) Skin Assessment, (2) Ultrasonography, (3)Qualitative Sketch Techniques, (4) Biological Nursing,and (5) 3D Measurement and Modeling Hands-on
Seminar for Nursing Science and Engineering.
In 2017, two PD researchers participated in thisprogram, and one of them completed the program as a
one-year course.
3. Other Universities’ Young Researchers
In 2017, our PD seminars were opened to young
researchers from other universities, and by the end of
the year, a total of 359 researchers were able to attend.
Furthermore, we conducted research consultations or
technical assistance and training for 12 of these young
researchers.
Five GNRC faculty members attended the 2017
summer program, held at the University of
Nottingham, where they provided lectures aboutwound assessment methods using the DESIGN tool,ultrasonography and thermography. A joint research
project was undertaken in order to further study theseassessment methods.

Building Future Research
1. Inaugural Symposium
Professor Claudia K. Y. Lai of Hong Kong
Polytechnic University, and Professor Christine
Moffatt, of the University of Nottingham, were invited
to the Inaugural Symposium of the GNRC, which washeld in 2017. One hundred eighty-six people attended
this symposium.

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2. Global Nursing Research Center FundThe Global Nursing Research Center Fund wasestablished for the purpose of fostering young
researchers.
3. Visiting Foreign Universities
In 2018, we visited National University of Singapore,
National Taiwan University, Chinese University ofHong Kong, and Hong Kong Polytechnic University,
which were high-ranking universities in Asia, andinspected their education and research systems. The
purpose of this visit was to establish education andresearch systems which can permit high quality andworld-class innovative nursing research in the GNRC.

References
1. Murayama R, Uchida M, Oe M, Takahashi T, Oya
M, Komiyama C, Sanada H. Removal of
peripheral intravenous catheters due to catheter
failures among adult patients. Journal of Infusion
Nursing. 2017; 40(4): 224-231.
2. Matsui Y, Murayama R, Tanabe H, Oe M, Motoo
Y, Wagatuma T, Michibuti M, Kinosita S, Sakai K,
Konya C, Sugama J, Sanada H. Evaluation of thepredictive validity of thermography in identifying
extravasation with intravenous chemotherapy
infusion. Journal of Infusion Nursing. 2017;40(6): 367-374.
3. Abe-Doi M, Oe M, Murayama R, Takahashi M,
Zushi Y, Tanabe H , Takamoto I, Suzuki R,
Yamauchi T, Kadowaki T, Komiyama C, Sanada
H. Development of an automatic puncturing andsampling system for a self-monitoring blood
glucose device. Diabetes technology andtherapeutics. 2017; 19(11): 651-659.
4. Noyori S, Nakagami G, Noguchi H, Yabunaka K,
Mori T, Sanada H. "A New Ultrasonographic
Image Displaying System to Support Vein
Detection", Journal of Robotics and Mechatronics,
Vol. 29, No. 2, pp. 306-316, Apr. 2017.
5. Watanabe A, Noguchi H, Oe M, Sanada H, Mori T.
“Development of a Plantar Load Estimation
Algorithm for Evaluation of Forefoot Load of
Diabetic Patients during Daily Walks Using a Foot
Motion Sensor,” Journal of Diabetes Research,
vol. 2017, Article ID 5350616, 8 pages, 2017.

doi:10.1155/2017/5350616
6. Takahashi T, Murayama R, Oe M, Nakagami G,
Tanabe H, Yabunaka K, Arai R, Komiyama C,
Uchida M, Sanada H. Is thrombus with
subcutaneous edema detected by ultrasonography
related to short peripheral catheter failure? Journalof Infusion Nursing. 2017; 40(5): 313-322.
7. Oya M, Murayama R, Oe M, Yabunaka K, Tanabe
H, Takahashi T, Matsui Y, Otomo E, Komiyama C,
Sanada H. Continuous thermographic observation
may predict extravasation in chemotherapytreated patients. European Journal of Oncology
Nursing. 2017; 28: 56-61.
8. Tamai N, Minematsu T, Tsunokuni S, Aso K,
Higashimura S, Nakagami G, Sanada H. Detectionof albumin using skin blotting as a measure ofskin barrier function. J Nurs Sci Eng. 2017 Jul;
4(2):116-120.
9. Yoshida M, Igawa Y, Higashimura S, Suzuki M,
Niimi A, Sanada H. Translation and reliability andvalidity testing of a Japanese version of theIntermittent Self-Catheterization Questionnaire
among disposable and reusable catheter users.
Neurourol Urodyn. 2017;36(5):1356-62.
10. Higashiguchi T, Ohara H, Kamakura Y, Kikutani T,
Kuzuya M, Enoki H, Sanada H, Matsuzaki M,
Maruyama M. Efficacy of a New Post-Mouthwash
Intervention (Wiping Plus Oral Nutritional
Supplements)
forPreventing
Aspiration
Pneumonia in Elderly People: A Multicenter,
Randomized, Comparative Trial. Ann Nutr Metab.
2017;71(3):253-60.
11. Goto T, Nakagami G, Nakai A, Noyori S, Sasaki S,
Hayashi C, Miyagaki T, Akamata K, Sanada H.
Utility of a three-dimensional wound measurement device in pressure ulcers. Chronic Wound
Care Management and Research. 2017;2017(4):129-33.
12. Koyano Y, Nakagami G, Iizaka S, Sugama J,
Sanada H. Skin property can predict the development of skin tears among elderly patients: aprospective cohort study. International Wound
Journal. 2017;14(4):691-7.
13. Takehara K, Amemiya A, Mugita Y, Tsunemi Y,
Seko Y, Ohashi Y, Ueki K, Kadowaki T, Oe M,
Nagase T, Ikeda M, Sanada H. The Association
between Tinea Pedis and Feet-Washing Behavior

565

in Patients with Diabetes: A Cross-sectional Study.
Advances in Skin and Wound Care. 2017;30(11):510-6.
14. Yusuf S, Okuwa M, Rassa S, Laitung B, Kasim S,
Irwan M, Sanada H, Nakatani T, Sugama J.
Relationship between sandals and diabetic footulcers in an outpatient clinic in Indonesia. The
Diabetic Foot Journal. 2017;20(2):83-8.
15. Haryanto H, Aris, i D, Suriadi S, Imran I, Ogai K,
Sanada H, Okuwa NM. Relationship between
maceration and wound healing on diabetic footulcers in Indonesia: a prospective study. International Wound Journal. 2017;14(3):516-22.
16. Kon Y, Ichikawa-Shigeta Y, Iuchi T, Nakajima Y,
Nakagami G, Tabata K, Sanada H, Sugama J.
Effects of a Skin Barrier Cream on Managementof Incontinence-Associated Dermatitis in Older
Women: A Cluster Randomized Controlled Trial.
Journal of Wound Ostomy and Continence
Nursing. 2017;44(5):1-6.
17. Miura Y, Yamabe A, Nakagami G, Sanada H.
Relationship between health literacy andadherence to exercise classes in health carefacilities. Journal of Clinical Gerontology andGeriatrics. 2017;8(2):52-7.
18. Nozawa K, Tamai N, Minemtsu T, Kitamura A,
Saegusa M, Amaike K, Sanada H. Situation of
occurrence and morphological characteristics ofperessure ulcers among inpatients with mental
illness. Journal of Japanese Society of Wound,
Ostomy, and Continence. 2017;21(1):10-24.
19. Koyano Y, Nakagami G, Sanada H. Reliability
and validity of the Japanese version ofIncontinence-Associated Dermatitis and its
Severity (IADS). Journal of Japanese Society ofWound, Ostomy, and Continence. 2017;21(1):1-9.
20. Goto T, Nakagami G, Takehara K, Nakamura T,
Kawashima M, Tsunemi Y, Sanada H. Examining
the accuracy of visual diagnosis of tinea pedis andtinea unguium in aged care facilities. J Wound
Care. 2017;26(4):179-83.
21. Nakagami G, Mori M, Yoshida M, Kitamura A,
Hayashi A, Miyagaki T, Sasaki S, Sugama J,
Sanada H. Inter-rater and intra-rater reliability
outcomes of a rapid bacteria counting system withpressure ulcer samples. Journal of Wound Care.
2017;26(Sup2):S27-S31.

22. Uehata Y, Yoshida M, Yabunaka K, Minematsu T,
Tamai N, Sugama J, Sanada H. Relationship ofskin hardness of the temporal region to nutritional
status. Journal of Nursing Science andEngineering. 2017;4(1):49-57.
23. Yabunaka K, Nakagami G, Kitamura A, Sanada H.
Pocket-sized versus laptop type ultrasonography
devices for imaging normal subcutaneous tissue.
Journal of Nursing Science and Engineering.
2017;4(1):21-6.
24. Yamanaka H, Okada S, Sanada H. A multicenter,randomized, controlled study of the use ofnutritional supplements containing collagen
peptides to facilitate the healing of pressure ulcers.
Journal of Nutrition and Intermediary Metabolism.
2017;8(2017):51-9.
25. Komagata K, Yabunaka K, Nakagami G, Ikeda M,
Takehara K, Takemura Y, Sanada H. Confirming
the placement of nasogastric tubes by handcarried ultrasonography device. Journal of
Nursing Science and Engineering. 2018;5(1):52-7.
26. Iwasaki T, Yamamoto-Mitani N, Sato K, Yumoto
Y, Noguchi-Watanabe M, Ogata Y. A purposeful
yet non-imposing approach: How Japanesehomecare nurses establish relationships with older
clients and their families. Journal of Family
Nursing. J Fam Nurs. 2017;23(4):534-561.

566

Office ofInternational Academic Affairs
HeadYasuyuki Seto

Assistant Professors
Joseph Green
Christopher Holmes
Keiko Nanishi

Homepage http://koryu.m.u-tokyo.ac.jp
Status and functions
The Office of International Academic Affairs isunder the direct authority of the Dean of the Faculty of
Medicine. Its three most important roles, as defined by
the Committee on International Academic Affairs, arei) international educational exchange, ii) international
contacts in research and scientific fields, and iii)
international cooperation in health care and medicine.

Activities
This document reports on the office's activities inthese areas over the 2017 academic year (April 1, 2017
through March 31, 2018).
1. International Educational Exchange
1.1 Student counseling about education and research
In 2017, there were 150 foreign students (37countries) officially registered in the Graduate Schoolof Medicine. Many inquiries were received during thisperiod from prospective applicants for foreign student
and trainee status; responses were sent to 51 suchinquiries.
Many currently enrolled foreign students received
counseling at this office concerning their studies andlife at the University of Tokyo and the requirementsfor obtaining scholarships and degrees.

In addition, a large number of University of Tokyo
students wish to supplement their training with basic
clinical experience overseas before graduation, as wellas the type of short-term training (1-3 months)
frequently called clinical electives overseas. Inquiries
from these students were either answered by thisoffice or referred to appropriate centers.
Every year, 25 or more University of Tokyo
students go overseas to study, and the office makes its
best efforts to accommodate their needs.
It has become a tradition to hold a Spring
get-together of foreign students and University ofTokyo students who will study or have studied abroad.
This event is attended by the Dean of the Faculty of
Medicine, teaching staff, administrative staff, andstudents; about 70 people attended in 2017, at CapoPELLICANO.
A formal agreement for academic exchange
between the University of Pennsylvania and the
University of Tokyo was renewed in May 2004. Since
that time, seventeen University of Tokyo students
have taken research electives at the University ofPennsylvania, and two students from the University ofPennsylvania have taken clinical electives at the
University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and Johns Hopkins University in567

December 2002. Since the start of the program in
2002, thirty University of Tokyo students have visited
to attend clinical electives at Johns Hopkins
University, and four students from Johns Hopkins
University have taken clinical electives at the
University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and the University of Michigan
Medical School in January 2005. Since the start of the
program in 2005, twenty-three University of Tokyo
students have attended clinical electives at the
University of Michigan Medical School, and twelve
students from the University of Michigan have taken
clinical electives at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and Munich University in
February 2005. Since the start of the program in 2005,
sixteen University of Tokyo students have visited toattend research electives at Munich University, andeleven students from Munich University have taken
clinical electives at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and the College of Medicine of
National Taiwan University in October 2012. Since
the start of the program in 2012, seven University ofTokyo students have visited to attend clinical electives
at National Taiwan University and ten students from
National Taiwan University have taken clinicalelectives at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the
University of Tokyo and the University of Chicago
Medicine in June 2014. Since the start of the programin 2014, four University of Tokyo students havevisited to attend clinical electives at the University of
Chicago Medicine and a student from the Universityof Chicago Medicine have taken clinical electives at
the University of Tokyo.
1.2 Counseling about short-term and longer overseas
study programs for University of Tokyo medical
students and researchers.
Every year, about 35 requests from students forcounseling regarding pre-graduation or post-

graduation studies abroad are received by the Officeof International Academic Affairs. The office responds
to these requests by providing information, advice,and letters of recommendation.
2. Education and research
2.1 Education
In 2016, Dr. Green taught courses open to allstudents in the Graduate School of Medicine:
Introduction to Scale Development 1 and 2. Dr. Green
also taught two other graduate-level classes:
International Epidemiology 1 and 2.
Mr. Christopher Holmes taught Medical English 1
and 2, which are required for all medical students.
The Office also organized classes in English for the
Health Sciences. In 2016, Mr. Holmes also arranged
and led ad hoc sessions in Oral Presentation Training
and extracurricular activities in English for medical
students and graduate students. These sessions wereopen to all students and teaching staff in the Graduate
School of Medicine and the Faculty of Medicine.
Dr. Green and Dr. Nanishi conducted several
international health studies.
2.2 Publications
1: Kikuchi K, Yasuoka J, Nanishi K, Ahmed A,
Nohara Y, Nishikitani M, Yokota F, Mizutani T,
Nakashima N. Postnatal care could be the key toimproving the continuum of care in maternal andchild health in Ratanakiri, Cambodia. PLoS One.
2018 Jun 11;13(6):e0198829.
2： Amira Mohammed Ali, Anwar Ahmed, Amira
Sharaf, Norito Kawakami, Samia M Ab-deldayem,
Joseph Green. The Arabic Version of The
Depression Anxiety Stress Scale-21: Cumulative
scaling and discriminant-validation testing. Asian
J Psychiatr 2017 Dec 18;30:56-58. Epub 2017 Jul
18.
3: Yasuoka J, Nanishi K, Kikuchi K, Suzuki S, Ly P,
Thavrin B, Omatsu T, Mizutani T. Barriers for
pregnant women living in rural, agriculturalvillages to accessing antenatal care in Cambodia:
A community-based cross-sectional study
combined with a geographic information system.
PLoS One. 2018 Mar 19;13(3):e0194103.
4: Hongo H, Green J, Nanishi K, Jimba M
Development of the revised Japanese Maternal

568

Breastfeeding Evaluation Scale, short version.
Asia Pac J Clin Nutr. 2017 May;26(3):392-395.
5: Sunguya BF, Mlunde LB, Urassa DP, Poudel KC,
Ubuguyu OS, Mkopi NP, Leyna GH, Kessy AT,
Nanishi K, Shibanuma A, Yasuoka J, Jimba M.
Improving feeding and growth of HIV-positive
children through nutrition training of frontline
health workers in Tanga, Tanzania. BMC Pediatr.
2017 Apr 4;17(1):94
6: Binns CW, Lee MK, Kagawa M, Low WY, Liqian
Q, Guldan GS, Hokama T, Nanishi K, Oy S, Tang
L, Zerfas A. Dietary Guidelines for the Asia
Pacific Region. Asia Pac J Public Health. 2017
Mar;29(2):98-101.

569

MD Scientist Training Program
Professor and Director
Haruhiko Bito, M.D., Ph.D.

Assistant Professor

Yuki Sugaya, M.D., Ph.D.
Ikuko Honda, Ph.D.

Homepage:

http://www.ut-mdres.umin.jp/ (in Japanese)

Introduction and Organization
The MD Scientist Training Program (MDSTP) was
founded in 2008 to achieve the goal of systematicallyproviding an intensive basic medical research training
framework to the next generation of MD scientists
during their MD training at the School of Medicine,
The University of Tokyo. Capitalizing on the advances
made by launching a reliable and sustainable program
through the leadership of its first directors, Prof.
Shigeo Okabe (2008-2010) and Prof. Masahide
Kikkawa (2011-2014), the Program currently consistsof its director Prof. Haruhiko Bito and two assistantprofessors Yuki Sugaya and Ikuko Honda, and over 70
students who are seeking extracurricular basic medical
research training through the Program’s framework.
With the help of two assistants for clerical work, it
provides a variety of support programs to assist the
research activities of medical students. From 2011 on,
the MDSTP at the University of Tokyo has cooperated
with its sister programs at Kyoto University, Osaka
University and Nagoya University, and has received
governmental funding support to dramatically boost
its activities.
The number of the enrolled students during the launchyear (2008) of the MDSTP was 6. Since then, theProgram has expanded and now enrolls more than 70
students (during Year 3 to 6 of the Medical School).
Around 5 to 10 students write research honors theses
during their final year, which they defend to become
certificated as MDSTP graduates. The number of
research publications in scientific journal or awards atinternational scientific meetings, which resulted fromthese theses, is growing.

Achieving basic medical researchtraining in parallel with medical
education
The Program offers a platform of activities aimed atproviding an early exposure to basic medical researchand to basic skills required for achieving leadership inacademic medicine.
During the first 2 years after the entrance to the
University of Tokyo, we initially organize a lecture
series entitled ‘Introduction to Medical Biology’. In
this lecture series, top researchers of various fields at
the University of Tokyo provide exciting but
intelligible talks to students with little medical
knowledge. This helps students to get introduced
various research subjects in various fields of medical
research and strongly motivate them to find bythemselves a laboratory suitable to their aspirations.
Furthermore, we offer an opportunity to read the
textbook ‘Molecular Biology of the Cell’ in English,
in a small group setting, to get an exposure toscientific English, and to be formally introduced tobasic molecular and cellular biology, the foundation ofcurrent medical research.
From Year 3 on, as the students choose the labs andprincipal investigators with whom to do science with,
the Program organizes journal clubs for basic medical

570

research and courses of medical researchcommunications are held every 2 weeks. In the journalclub, students are trained to critically read recent
scientific papers published in top journals, often in thepresence of the first authors, if they are available. In
medical research communications courses, thestudents discuss scientific topics and research issues
with a native English speaker with a strong researchbackground.
Students who have shown their research abilities arehighly recommended to write their honors researchtheses by the end of the summer of Year 6. After
successfully defending their theses, they are certified
as qualified MDSTP trainee and, as such, they become
eligible for an exemption of a part of an entrance
examination for the Graduate School of Medicine. The
Dean’s Prize is awarded to the best thesis.

Enhancing awareness andproviding opportunities forexcellence in basic medical
research
1) Providing assistance for research and clinicalexperience in foreign laboratories and hospitals
We encourage students to plan and seek for basic
medical research experience in other countries during
their MD training. Based on research proposals
submitted to the Program, travel supports are provided
on a competitive basis. In 2017, a total of 6 students
received the Program’s support for carrying out basic
medical research abroad (in U.S., Europe andAustralia) for more than a month and to present theirresearch achievements at international scientificmeetings. We also support exposure to clinicaltraining in foreign hospitals with the Osamu Otsubo
Tetsumon Fellowship, initiated in 2008 with an
Endowment donated by Dr. Osamu Otsubo. In 2017, a
total of 10 students were awarded a fellowship andgained invaluable experience as student clinical clerks
in many university hospitals abroad.
2) Organizing an MD scientist training program
retreat
A MDSTP retreat was held on March, 17-18, 2018 topresent ongoing research progress in a closed meeting

among peers. More than 45 participants, mostly
medical school students, but also some medical
interns, graduate students and Program-affiliatedprofessors attended it. Lively discussions among peers
were exciting throughout the meeting and thefeedback from all participants was outstanding andunequivocal in emphasizing the critical importance fora research progress retreat to promote their future
research projects. One important aspect of the retreat
was to provide students, interns and professors to
discuss opportunities in various career paths available
in the basic medical research field.
3) Cooperating with other medical universities acrossJapan
With the availability of governmental support from2011 on, the MDSTP at the University of Tokyo has
been in close touch with sister organizations at Kyoto
University, Osaka University and Nagoya University.
With a view to enhancing collaborative efforts inimproving the basic medical research training at the 4
medical schools, Annual Joint Retreats were held topromote communication and networking among the
medical students with research minds. The latest
retreat was organized on December, 9-10, 2017 inKobe, at the occasion of Consortium of Biological
Sciences 2017 (ConBio2017). More than 90 people
including medical school students and teachers fromall over Japan participated in this retreat andenthusiastically discussed about their research andfuture career as researchers. Four celebrated MD
scientists presented their research achievements andcarrier path in a joint forum of this meeting.
The MSDTP also currently cooperates with 9 otheruniversities in eastern Japan to organize annual
research students’ retreats. In 2017, this was held on
August, 16-17 in Isawa, Yamanashi under the auspices
of Yamanashi University. Around 70 people
participated in the retreat and presented their ongoing
research progress and future plans.

Activities (2017)
The number of registered students: 74 (3rd grade: 25,
4th: 20, 5th: 18, 6th: 11)571

Lectures for students in Years 1 and 2
Introduction to Medical Biology: 13 lectures
Group reading of Molecular Biology of the Cell: 11
lectures
Seminar for students (in Year 3 or above)
Journal Club for basic medical research: 3 lectures
Medical Research Communications: 36 lectures
Presentation of research progress: 3 times (including
the retreat of MD scientist training program in the
University of Tokyo)
The number of students receiving travel supports forresearch and clinical activities abroad: 16
The number of Year 6 students who passed theirhonors thesis defense: 5 (the Dean’s Prize wasawarded to 2 students)

572

Museum of Health and Medicine
Director
Kazuhiko Ohe

Associate
Atsushi Kitade

Homepage

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

History and overview
The origins of the School of Medicine and the
University of Tokyo Hospital can be traced back to theestablishment of the Kanda Otamaga-Ike Vaccination
Center in 1858. In 2008, it celebrated its 150th
anniversary. The Museum of Health and Medicine wasplanned as part of commemorative projects tocelebrate the 150th anniversary of the founding of the
School and the Hospital, and was opened on January
20, 2011. One of the themes for the commemorative
projects marking the 150th anniversary was the“development of communication between healthscience and care and society,” and the Museum of
Health and Medicine forms one of the pillars of this.
In establishing the Museum of Health andMedicine, we renovated the School of Medicine’s
Central Building (Medical Library), which hadoriginally been instituted as part of thecommemorative projects celebrating the 100th
anniversary of the founding of the School and the
Hospital. The Museum has about 400m2 areas,
including about 70m2 of a permanent gallery and230m2 of special exhibition rooms.
The aims of the Museum are to: (1) provide healthand medical information to the public, (2) educate
students studying medicine, health care services andrelated areas, (3) research the history of medicine andhealth care through archives, instruments andtechnology, and (4) preserve and investigate valuable
medical archives and instruments, etc.
In addition to the permanent gallery exhibiting
accomplishments related to the School and the
Hospital and its contributions made to modern andcontemporary development in Japan, a feature of theexhibitions is that a large space has also been set aside
for special exhibitions to promote understanding
among the public regarding the latest advances inmedical science and health care. Planning andsupervision of the permanent exhibition and special
exhibition is done with the cooperation of the various
research units within the School and the Hospital,
other departments within the University, industry, andmuseums. Special exhibitions will be changed several
times a year.
The first permanent exhibition since the openingof the Museum was a display of medical texts andinstruments from the early Meiji era, an Ishihara’s
Color Blind Test Chart and a gastroscope developed at
the University. The first special exhibition was related
to the beginnings of the School and the Hospital,
Entitled “the Challenge to Infectious Diseases”. It
introduced the history of vaccinations against
smallpox, research into infectious diseases conductedin the University and by its graduates since the Meiji
era (1868-1912), and the latest knowledge about
infectious diseases. The second was “the Secret of
Vessel System”, which introduced the circulatory
system. The third “diagnosis of cancer”, the fourth“Our brain”, the fifth “Locomotive syndrome”, thesixth “Diabetes Mellitus”, the seventh "Pediatrics",
the eighth "Forensic Medicine”, the ninth “the Colon”
followed, the tenth “Virus”, and the eleventh“Kidney”.
Since the opening of the Museum, more than
127,131 people had visited by the end of FY2017.
It is closed due to preparations for the removal.

573

After April, 2019, we are going to re-open our
museum.

Overview of operations
The opening hours are 10:00-17:00. 12:00-13:00 is
lunch break. The Museum is closed every Monday andduring the New Year holidays (however, it will open if
Monday is a public holiday). Admission is free.

574

Office for Human Research Studies(OHRS)
Professor (Director of OHRS)
Yutaka Yatomi, M.D., Ph.D.

Professor (Vice Director of OHRS)
Akira Akabayashi, M.D., Ph.D.

Lecturer
Yuzaburo Uetake, M.D., Ph.D.

Homepage: http://www.m.u-tokyo.ac.jp/ethics/ethcom/gakugai2/index.html
http://www.u-tokyo-ohrs.jp/
Top page of online application system: https://u-tokyo.bvits.com/esct/
Introduction and Organization
The Office for Human Research Studies (OHRS) wasestablished in October 2009 for the advancement ofresearch ethics standards. OHRS aims to protect therights, health, and dignity of research participants.
Based on this principle, OHRS is providing research
ethics support services to researchers at Graduate
School of Medicine and Faculty of Medicine, theUniversity of Tokyo and the University of Tokyo
Hospital to enable them to better perform their studies
in an ethical manner. Our primary task is the management of the Ethics Committee secretariat. Additionally,
OHRS plans and manages research ethics seminars,
provides ethics education to researchers throughconsultation and develops human resources for future
research ethics specialists.

Activities
・Management of Ethics Committee
・Prior review of research activity documents (except
for clinical trial, GCP), at Graduate School of
Medicine and Faculty of Medicine, the Universityof Tokyo and the University of Tokyo Hospital.
Correspond in response to various research ethics
inquiries.

・ Coordination of various matters with Ethics
Committee members, and other similar bodies anduniversities.
・Examination of case documents in connection with,-High risk elective operations,-Medical treatments to implemented for the firsttime at the University of Tokyo Hospital,-Examination of the clinical use of the unapproved
medicines and medical devices,・Preperation and maintenance of the organ transplantation manuals for the liver, kidney and hearttransplants.
◇ Specific items reviewed and examined by each
Ethics Committee in fiscal year 2017
・Research Ethics Committee (except for clinical
trial, GCP):
427 new applications, 1227 minor alterations ofapproved studies, and 19 documentary examinations
・New clinical documentary examinations: 69

575

Research activities
At present, OHRS is a business section. For more
information about the research, see the contents of
Department of Biomedical ethics, which is acooperative department.

Though OHRS adopts various inclusive applications,the number of studies applied to and reviewed by
ethics committees over the last several years is on therise.
The management duties of the Ethics Committee
secretariats are complicated and diversified, making it
difficult to be able provide adequate services toappropriately respond to such increasing needs.
OHRS operates an online application system andcontributes to the convenience of applicants and toenable them to efficiently plan their researchobligations.

Teaching and training activities
OHRS plans and manages research ethics seminars
with Department of Clinical Research Governance inthe University of Tokyo Hospital.
We provide a broad outline overview regarding ethics
education aimed generally for all researchers andstudents who are engaged in clinical studies throughsuch seminars. The ethics seminars were held monthly
in fiscal year 2017 with 2589 people attended.
OHRS makes efforts to educate researchers through its
research ethics support services. Additionally, the skill
development and support of the secretariat staff is oneof our important tasks.
OHRS also aims to advance research ethics standards
by cooperating and consulting with Ethics Consultant
specified by each laboratory.

576

The Office for Clinical Practiceand Medical Education
Professor
Tatsuya Yamasoba, M.D.,Ph.D.

Research Associate
Shoko Horita, M.D.,Ph.D.

Homepagenone

Introduction and Organization
The Office for Clinical Practice and Medical
Education was established in April 2015, to support
and promote medical education, especially clinicalpractice at grade 5 and 6. The office used to be theClinical Clerkship Support Center, which wasestablished to meet the change from bedside learning
to clinical clerkship in February 2013. Our aim is to
run the clinical clerkship (CC) smoothly, as well as toimprove the curriculum and evaluation methods incooperation with teachers and students. In addition,
we try to support each student in cooperation withtutors, the instruction department and the office forstudent assistance in the faculty of medicine. The
Information and Communication Technology (ICT)system has launched in January 2018, which greatly
improved the efficiency of clerical works. The office
now consists of a general manager (professor), a
research associate, and three specialist/staffs.

Activities
Before the CC begins in January for 4th grade medical
students, we have a meeting to explain the details tothe students, and then make a schedule of the CC
based on the questionnaire. Just before the CC starts,
we hold a ceremony to name students “student
doctors”, which the dean of the medical faculty of The
University of Tokyo, and the director and the chief
nursing officer of The University of Tokyo Hospitalattend.

After the CC starts, we support teachers,
students and the external cooperative institutions to
run the clerkship smoothly by making necessary
contacts with them. In addition, we handle withproblems and considerations occurred during thepractice if needed. Particularly, we manage andsupport students who need helps, with the instruction
department, tutors, and the office for student
assistance in the faculty of medicine. The new ICT
system permits the evaluations of the students in the
CC to be revealed real-time, hence the students areable to look their scores, at the earliest on the final dayof each practice.
Twice a year, we hold a meeting withteachers who are in charge of the CC. In this meeting,we provide teachers the feedbacks about the practicefrom students, and exchange the information andopinions among the teachers, thus improving the CC.
On the other hand, we have opportunities withstudents (working group on medical education), todiscuss the CC and try to respond to comments fromthem.

Educations
Together with the IRCME, we take charge of “medical
practice: the introduction” for 4th grade students and“tutorial PBL” for 2th grade students, teaching
medical interview, physical examination and medical
professionalism. We also take charge of tutorials andindividual consultations related to the CC.

577

Research activities
Presently the “Research of the coherence between thestudents’ daily life and the outcome at the graduation”
is being conducted. The results-in-progress are being
released in the domestic and international conferencesof medical education in 2018.