Table of Contents
From the Editors ......................................................................................................................................... 1
RERF NewsThe 35th Scientific Council Meeting .................................................................................................... 1
The 43rd Board of Directors Meeting ................................................................................................... 4
Staff News ............................................................................................................................................. 5
Visiting Scientists .................................................................................................................................. 6
Student Researcher ................................................................................................................................ 7
2008 Distinguished Lecture Series ....................................................................................................... 8Award Received by an RERF Scientist ................................................................................................. 8
Conference and Workshop Reports
Symposium on Health Effects of Radiation and Smoking, by Ritsu Sakata ........................................ 9
RERF Symposium on Bioinformatics, by Susan M. Geyer................................................................ 10
Science Article
Preferential Gene Alterations in Adult-onset Papillary Thyroid Cancer among Atomic-bomb
Survivors: Chromosomal Rearrangements vs. Point Mutations,by Kiyohiro Hamatani et al. ............................................................................................................ 12
Human Interest Notes
Start of Health Examinations of A-bomb Survivors Overseas, by Akio Awa ..................................... 19
In Memory of Dr. Chiyoko Satoh, by Norio Takahashi ...................................................................... 22
Mourning the Death of Former Vice Chairman Sheldon Wolff, by Seymour Abrahamson ............... 23
In Memoriam ...................................................................................................................................... 24
Facts and Figures ...................................................................................................................................... 25
Research Protocols and Publications
Research Protocols approved in January–September 2008 ................................................................ 26
Recent Publications ............................................................................................................................. 27

This newsletter is published by the Radiation Effects Research Foundation (formerly the Atomic
Bomb Casualty Commission), established in April 1975 as a private, nonprofit Japanese foundation.
It is supported by the government of Japan through its Ministry of Health, Labour and Welfare andthat of the United States through the National Academy of Sciences under contract with the
Department of Energy.
RERF conducts research and studies—for peaceful purposes—on the medical effects of radiation on humans with a view toward contributing to the maintenance of the health and welfare of
atomic-bomb survivors and to the enhancement of the health of all mankind.
Editor-in-Chief: Evan B. Douple, Associate Chief of ResearchTechnical Editor: Yuko Ikawa, Public Relations & Publications Office
Editorial Policy
Contributions to Update receive editorial review only and do not receive scientific peer review.
The opinions expressed herein are those of the authors only and do not reflect RERF policies orpositions.
Contact: Mailing address: RERF Public Relations & Publications Office, 5-2 Hijiyama Park,
Minami-ku, Hiroshima 732-0815 Japan
Telephone: 81-82-261-3131; Facsimile: 81-82-263-7279
Internet: www.rerf.jp

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From the Editors, RERF News

From the Editors
Konnichiwa!
As the red Japanese maple leaves start falling andsignal that the year 2008 is coming to an end, wewelcome our readers to the second issue of Update
Volume 19. It seems that time has passed quickly since
the glowing sunflowers welcomed our many visitors
to RERF’s Open House back in August. A total of
approximately 1,750 persons, including school
children, foreign tourists, A-bomb survivors, andother interested Japanese citizens, participated inOpen House activities in the two laboratories andlearned about the important work going on here. That

turnout was one of the largest totals in the last 14
years and was considered to be a big success.
Please find enclosed reports of this year’s ScientificCouncil meeting and the Board of Directors meeting.
In addition to staff news and information regarding
visiting researchers, this issue includes reports on
two symposia conducted at RERF, a science article,
and a summary of a report by the RERF Committee
on Biological Samples. Again, we hope that you
enjoy this edition and that you will let us know how
we might improve our reporting of RERF’s many
scientific activities.
Sincerely,

Evan B. Douple
Editor in Chief

Yuko Ikawa
Technical Editor

Report on the 35th Scientific Council Meeting
The 35th Scientific Council (SC) meeting, cochaired by Dr. Teruhiko Yoshida (National Cancer
Center Research Institute) and Dr. Theodore
DeWeese (Johns Hopkins University) was convenedon March 3–5, 2008 in Hiroshima to review thescientific program of RERF. The review of departmental research activities was restructured this year
to concentrate primarily on the Departments ofClinical Studies, Epidemiology, and Statistics.
Along with this transition to a focused review, RERF
also invited three special scientific councilors withexpertise in the areas selected for in-depth review
to augment the review process. These included Dr.
Sarah Darby of Oxford University, Dr. Fred Mettler,
Jr. of the University of New Mexico, and Dr. Kazuo
Tajima of Aichi Cancer Center Research Institute, whoprovided added strength to the in-depth reviews.
Dr. Toshiteru Okubo, Chairman of RERF,
warmly greeted the scientific councilors and guests
and noted that there had been several retirements
and additions to the professional staff and leadership of RERF over the last year. He also mentionedthat the Senior Review Panel had met several times,
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had received the report of the 34th SC and that the
RERF leadership awaits the final report from thePanel. Finally, Dr. Okubo highlighted the fact that
there is renewed focus toward thematic working
groups at RERF that enhance collaboration amongscientists of different departments and mentionedthat monthly scientific colloquia also enhance interdepartmental interactions.
Dr. Roy Shore, Chief of Research at RERF,
provided a review of the responses to the 34th SC
recommendations, as well as a review of the statusof research at RERF. Dr. Shore noted that the mandated reduction in force diminishes the needed flexibility to recruit young scientists. He highlighted
how several of the unique research resources of
RERF, such as the longitudinal biospecimen collection and data from the cohort studies, were increasing the external collaborative opportunities of
RERF. He also mentioned the newly introduced
performance review process of the scientific staff
and department chiefs.
The Departments of Clinical Studies, Epidemiology, and Statistics then provided departmental
RERF Update Volume 19, Issue 2, 2008

RERF News
overviews including responses to the 34th SC’s
recommendations and multiple presentations on
research programs, highlighting program achievements, ongoing research activities, and future plans.
The Departments of Radiobiology/Molecular Epidemiology, Genetics, and Information Technology
and the Public Relations program provided alimited summary of ongoing efforts.
The SC began their review by stating they
believe that “RERF is one of the pre-eminent leaders in radiation risk research in the world and has
the expertise, populations, and data sets to conduct
investigations that cannot be carried out elsewhere.
The support and assistance of the Japanese Ministry of Health, Labour and Welfare and the U.S.
Department of Energy as well as guidance of the
National Academy of Sciences continue to be critical to the mission of RERF. Without such support
and the assistance of the survivors and theirfamilies, the ability of RERF to conduct substantive
research that has great impact around the world
would not be possible.” Their principal assessments
and general recommendations were:• Continued important progress has been madein several areas over the last two years or so.
The leadership should be highly commended
for this improvement. In particular, there isclear evidence of increased collaboration among
RERF scientists as noted in the programmatic
reviews. This effort has improved several of theresearch projects and provides a good working model for developing young scientists.
• We would like to stress the movement toward
greater use of biospecimens in RERF research
efforts. The biospecimens collected by RERF
represent a singularly unique resource fromwhich appropriately designed projects can becreated to yield new mechanistic information.
• We would encourage the leadership of RERF
to engage in an internal strategic planning process aimed at clarifying the short, medium andlong term goals of RERF, the research directions needed to reach those goals and the necessary projects that will be pursued.
• Strategic focus also allows teams to more
effectively prioritize work by themselves andlessens the likelihood of inefficient use of resources. The SC notes that departments havea very large portfolio of projects, suggesting
the need for more prioritization of research
projects within RERF departments. The model
for research project prioritization needs toinclude clear metrics, milestones, and timelines
for progress.
• An efficient programmatic structure is necessary for any research organization to maintainhigh level activity, to bring the best people
together on a given project, and to minimize
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2
duplication of effort. It may be helpful for the
RERF leadership to consider an ad hoc,project-oriented team approach of cross- orinter-disciplinary experts that is conducted
outside the conventional departmental structure. Such programmatic constructs, using coreresources of the departments to support them,provides an effective mechanism of conducting collaborative research.
• A closer affiliation with Japanese universities
and other institutions should be promoted.
Such affiliations could facilitate access to facilities, students, and new scientific disciplines
and ideas, as well as to other skilled investigators outside RERF.
To highlight a few of the numerous recommendations to departments:• The Department of Clinical Studies should becommended for its continued diligence in managing the Adult Health Study (AHS) and F1
Clinical Study (FOCS) cohorts. These studies
remain an essential backbone of RERF anddirectly inform ongoing clinical, epidemiologic, statistical, and radiobiological research.
They also provide necessary biospecimens forbasic and translational discovery efforts.
• The efforts to expand the AHS cohort by 2,300
subjects is endorsed as helpful, particularlycollecting data from those subjects with lowdose exposures and incorporating medicalfamily history.
• The FOCS study should be continued as a longitudinal study since an increase in cancer andother outcomes is expected in the next two
decades.
• The working group on medical exposures
should continue its work to standardize theapproach and methodology for this problem,
though it is understood that individual dosimetry for diagnostic exposures will probably belimited to average dose for the type of examination and will have more uncertainty than the
A-bomb doses.
• With the finding of cataracts occurring at relatively low doses, radiation exposure of eyes
becomes a critically important issue. This finding is important for radiation protection of
nuclear workers, for the many physicians
using fluoroscopy for interventional purposes,
and for the patients who receive millions of
cranial CT scans each year that may have relatively high eye doses. Continued cataract
investigations will provide greater predictive
capability to assess the risk of radiationinduced cataract onset and the likelihood of
resulting visual dysfunction.
• In the new Life Span Study (LSS) mail surRERF Update Volume 19, Issue 2, 2008

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RERF News
vey, important missing covariates will be obtained as well as important updated information on radiation effects and smoking history
to inform future studies. Overall, significant
effort should be expended to insure collectionof information on as many members of thiscohort as possible.
• The studies of dose-response curves for noncancer diseases are a strength of the Epidemiology Department and appear to be yielding
new and valuable information, particularly inthe area of heart disease.
• Laboratory and clinical studies to investigate
potential mechanisms of non-cancer effects
will be especially important. Biologicalmechanisms by which low-dose radiation
exposure may induce cardiovascular diseaserisks are currently unclear, and an extensive
search is needed to explore alternative models. A workshop (including at least radiobiologists and cardiologists) may be helpful todiscuss how best to elucidate mechanisms.
• The SC agrees with and fully supports thestated objectives for the Department of Statistics. Last year the SC recommended that theStatistics Department should expand its collaborative work with other departments. It was
clear that considerable effort had been directed
towards this end.
• One stated aim of the Statistics Department is
to aid in the development of complete, accurate, and accessible research databases. Thisaim should become a priority for RERF as awhole. A detailed strategy should be developed
to achieve this and to produce appropriate
documentation for it.
• RERF should set up a biospecimen repository
using the most contemporary processing, storage, annotation and backup systems. We suggest that RERF focus on best practices learned
from institutions of repute with high volume
biospecimen banks. RERF also should establish a vetting process that prioritizes specimen
distribution and applications. We would suggest that substantial energy be spent in having afunctioning and thorough system in place soon.
• The SC feels that the Genetics Department has
made substantial contributions to the goals andmission of RERF, as well as to the larger scientific community. There is every hope andexpectation that they will continue to do so.
• In the past 60 years, the central dogma ofradiation carcinogenesis has been the straightforward hypothesis that radiation-induced
DNA damage causes mutations responsible fordevelopment and progression of cancer. However, the working hypothesis of the immunology group challenges this dogma by offering
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an alternative mechanism of immune theory ofradiation induction of cancer as well as noncancer diseases. It is interesting to note that thisneo-classic immune theory of carcinogenesis is
now gaining recognition in the oncology fields.
The RERF leadership appreciates the tremendous
effort that the research and support staff of RERF
put into the development of materials and presentations for the Scientific Council. We believe the Council produced a very constructive report that will prove
to be of much value to us.
RERF Scientific Councilors
Dr. Theodore L. DeWeese, Professor and Chair,
Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Co-chairperson
Dr. Teruhiko Yoshida, Chief, Genetics Division,
National Cancer Center Research Institute, Cochairperson
Dr. Ohtsura Niwa, Deputy Director, ResearchCenter for Charged Particle Therapy, National
Institute of Radiological Sciences
Dr. Yoshiharu Yonekura, President, National Institute of Radiological Sciences
Dr. Takashi Yanagawa, Professor, The Biostatistics
Center, Kurume University
Dr. Katsushi Tokunaga, Professor, Department of
Human Genetics, Division of International
Health, Graduate School of Medicine, The
University of Tokyo
Dr. Marianne Berwick, Professor and Chief, Division of Epidemiology, Associate Director, Cancer Research and Treatment Center, Universityof New Mexico
Dr. John J. Mulvihill, Professor of Pediatrics, University of Oklahoma Health Sciences Center
Dr. David G. Hoel, Distinguished University Professor, Department of Biostatistics, Bioinformatics
and Epidemiology, Medical University of South
Carolina (Absent)
Dr. Michael N. Cornforth, Professor and Directorof Biology Division, Department of Radiation
Oncology, University of Texas Medical Branch,
GalvestonSpecial Scientific Councilors
Dr. Sarah C. Darby, Professor of Medical Statistics, Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford
Dr. Fred A. Mettler, Jr., Professor, University of
New Mexico, Chief, Radiology and Nuclear
Medicine
Dr. Kazuo Tajima, Director, Aichi Cancer Center
Research Institute
RERF Update Volume 19, Issue 2, 2008

4

RERF NewsThe 43rd Board of Directors Meeting in Washington, D.C.
The 43rd meeting of the RERF Board of Directors was held on June 18 and 19, 2008, at a meetingroom of the National Academy of Sciences’ KeckCenter in Washington, D.C. On June 17, the day
before the Board meeting, the report of the Senior
Review Panel on Future Planning for RERF, a panel
established by the Japanese and U.S. governments
in 2006 for the purpose of reviewing future plansfor RERF, was presented to the representatives of
the two governments by the panel’s Japanese andAmerican co-chairs at the Japanese Embassy inWashington, D.C. The Board discussed with keeninterest the actions that RERF would take in responseto the report as well as important issues that could
affect RERF’s future direction, such as the organization’s change of status to a public-interest foundation.
The FY2007 research activities report and audit
report, the FY2007 settlement of accounts and audit
report, the FY2008 research activities plans, and the
FY2008 working budget, which is similar to that ofthe previous year, were approved as presented.
At its meeting in the previous year, the Board
determined the policy of following up the cohort ofchildren of A-bomb survivors. At this year’s meeting, the Board approved, following the recommendations of the Senior Review Panel, RERF’s proposal to begin preparations during this fiscal yearwith a view to resuming the follow-up in FY2009 or
shortly thereafter.
As the Senior Review Panel submitted its reportto the two governments the day before the Board
meeting, as mentioned above, RERF invited the two
co-chairs to attend the Board meeting and explain
the panel’s following recommendations: 1) continuation of RERF’s cohort studies for the next 20 years;2) necessity of negotiations between the two governments and RERF pertaining to the future of RERF
after the completion of its cohort studies; 3) necessity of talks between the two governments toward
their agreement concerning relocation of theHiroshima facilities with a view to achieving its
future vision; and 4) recruitment of young researchers and expansion of international research collaborations.
The Board welcomed these recommendations andagreed on the necessity of negotiations over the next
two years on the specifics of each recommendation
between the three parties (the two governments andRERF) and of formulating and implementing future
strategies based on the negotiations.
With regard to the change to a public-interest
foundation, the Board requested that deliberation takeplace soon between the governments regarding suchbasic issues as organizational composition (includReturn to Table of Contents

ing establishment of a Council), and then determinedthat the Board would proceed with detailed procedures based on the deliberation results.
The Board discussed the appointment of directors, scientific councilors and others, and approved
the proposed one-year extension of Mr. David Williams’ appointment as an American supervisor
because efforts to nominate his successor before themeeting had failed, and the appointment of Mr.
Takashi Kono, a certified public accountant and tax
accountant at the Hiroshima General Law/Accounting Office, as the successor to Dr. Tomio Hirohata,
the Japanese supervisor. The Board also approved
the appointment of Dr. Kiyoshi Miyagawa (Professor, Laboratory of Molecular Radiology, Center for
Disease Biology and Medicine, Graduate School of
Medicine, The University of Tokyo) as the successor to Dr. Teruhiko Yoshida, a scientific councilor.
The Board reappointed Dr. John J. Mulvihill for
another term as a scientific councilor, and decided
to conduct a mail ballot to appoint a successor to Dr.
Theodore L. DeWeese, a scientific councilor who
had expressed his intention to resign from his post,
as soon as a successor is nominated.
The Board agreed to hold its next meeting over
the three-day period from June 24 through 26, 2009,
in Hiroshima.
List of Participants
Directors:
Dr. Toshiteru Okubo, Chairman
Dr. Roy E. Shore, Vice Chairman and Chief ofResearch
Mr. Takanobu Teramoto, Permanent Director
Mr. Masaaki Kuniyasu, Former Ambassador Extraordinary and Plenipotentiary to the Republicof Portugal
Dr. Yasuhito Sasaki, Director General, Radiology
Center, International University of Health andWelfareDr. Senjun Taira, Permanent Director, Japanese
Association of Quarantine Inspection Hygiene
Mr. James W. Ziglar, President and Chief Executive Officer, Cross Match Technologies, Inc.
Dr. James D. Cox, Professor and Head, Division ofRadiation Oncology, The University of Texas
M.D. Anderson Cancer Center
Dr. John E. Burris, President, Beloit College
Supervisors:
Dr. Tomio Hirohata, Professor Emeritus, Department of Public Health, Faculty of Medicine,
Kyushu University
Mr. David Williams, Senior Financial Advisor,
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RERF News
National Academy of Sciences
Co-chairmen Senior Review Panel on Future
Planning for RERF:
Dr. Sadayoshi Kitagawa, Director General, Japan
Public Health Association
Dr. Paul Gilman, Senior Vice President and Chief
Sustainability Officer, Covanta Energy Corporation
Co-chairman Scientific Council:
Dr. Theodore L. DeWeese, Professor and Chair,
Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine
Representatives of Supporting Agencies:
Mr. Osamu Okabe, Director, General Affairs Division, Health Service Bureau, Ministry of Health,Labour and Welfare (MHLW)
Mr. Takahiro Maeda, Chief, Relief Budget Unit,
General Affairs Division, Health Service Bureau,
MHLW
Dr. Masaharu Tantou, Group Leader, General
Affairs Division, Health Service Bureau, MHLW
Mr. Masahiro Mori, First Secretary, Embassy of
Japan
Mr. Glenn S. Podonsky, Chief Health, Safety andSecurity Officer, Office of the Secretary ofEnergy, U.S. Department of Energy (DOE)

Since April 2008, two scientists have been recruited to RERF and have recently moved toHiroshima. We have asked them to tell you a little
about themselves and their interest in the work of
RERF.
Munechika Misumi
I received my B.S. Degree in Environmental Studies from Nagasaki University and an M.S. in Statistics from North Carolina State University in Raleigh,North Carolina, with a biomedical concentration.
While at the North Carolina State University I was
encouraged to study the mathematical modeling ofradiation health effects by the director of the Biomathematics Program, Dr. Charles Smith, who had
spent some time working at RERF as a Gilbert W.
Beebe Fellow. I accepted the position of RERF
Research Scientist and began my work in the Department of Statistics in June, 2008. Prior to my arrival in Hiroshima I was an Assistant Professor of
Biostatistics in the Graduate School of Medicine of
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5
Mr. Michael A. Kilpatrick, Deputy Chief for Operations, Office of Health, Safety and Security,
DOE
Dr. Michael J. Ardaiz, Department of Energy Chief
Medical Officer, Office of Health, Safety andSecurity, DOE
Dr. Joseph F. Weiss, Japan Program Manager,
Office of International Health Studies, Office of
Health, Safety and Security, DOE
Ms. Julie Liu, U.S. Department of State
Dr. Warren R. Muir, Executive Director, Division
on Earth and Life Studies, National ResearchCouncil (NRC), National Academy of Sciences(NAS)
Dr. Kevin D. Crowley, Director, Nuclear and Radiation Studies Board, Division on Earth and Life
Studies, NRC, NAS
Ms. Laura Llanos, Financial and Administrative
Associate, Nuclear and Radiation Studies Board/
RERF Program, Division on Earth and Life Studies, NRC, NAS
RERF:
Mr. Eiji Akimoto, Chief of Secretariat
Dr. Evan B. Douple, Associate Chief of Research
Dr. Nori Nakamura, Chief Scientist
Dr. Kazunori Kodama, Chief Scientist
Mr. Douglas C. Solvie, Associate Chief of Secretariat

Kyushu University. I have had an interest in multistage models of carcinogenesis and am especiallypleased to be at RERF and joining my new colleagues
in analyzing the very special resource of data andcontributing to the mission of RERF. Currently I am
working on the application of measurement error
models to RERF data, and I am looking at the molecular-level effects of radiation in carcinogenic
processes with the scientists in the Radiobiology/
Molecular Epidemiology Department.
Kotaro Ozasa
I recently joined RERF as the Chief of the Epidemiology Department in November of this year. Prior
to arriving in Hiroshima, I was an Associate Professor in the Department of Epidemiology for Community Health and Medicine in Kyoto Prefectural University of Medicine’s Graduate School of Medical
Science. I had received my M.D. and Ph.D. also fromthe Kyoto Prefectural University of Medicine. My
major research interests have focused on epidemioRERF Update Volume 19, Issue 2, 2008

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RERF News
logical studies such as large-scale cohort studies to
elucidate cancer pathogenesis, studies on Japanesecedar pollinosis, and evaluation of the effectivenessof influenza vaccinations. Other projects and activities in which I have been involved include the Kyoto
Prefectural Cancer Registry projects, health-education efforts, and anti-smoking countermeasures.
During my career I participated in the 1991 Summer
Program of the New England Epidemiology Institute in Boston, Massachusetts in the U.S. and I served
for five months in 1997 as an Honorary Lecturer inthe Department of Public Health Medicine in the

United Medical and Dental School of Guy’s and St.
Thomas’ Hospitals in London, U.K.
I am pleased to join the research scientists of
RERF and look forward to assisting my fellow
epidemiologists continue their important work. I am
especially indebted to the contributions of my predecessor, former Acting Chief, Dr. Fumiyoshi
Kasagi, as well as the other Epidemiology department chiefs who have established a long legacy of
research based on the important RERF cohorts. I
thank all of RERF staff who have accepted me
warmly!

Visiting Scientists
Sung Ho Moon
I am a radiation oncologist from the Proton
Therapy Center in the Research Institute and Hospital of the National Cancer Center in South Korea. I
received my M.D. from Seoul National University
College of Medicine and my Master of Medical Science from the Seoul National University Graduate
School. I arrived at RERF in Hiroshima for researchtraining on the biological effects of radiation withspecial emphasis on the interaction between radiation and histone deacetylase inhibitors on breast cancer cell lines. During my two-month stay I have benefited from the RERF’s International Exchange Program and appreciate very much the researchfacilities and collegial staff of RERF’s Departmentof Radiobiology/Molecular Epidemiology.
David Richardson
After several months of preparation, I arrived in
Hiroshima in late May. The visit was an opportunity
to engage in some specific analytical projects, butalso an opportunity to meet the staff at RERF, learn
about the organization, and to develop a better understanding of the consequences of the atomic bombings of Hiroshima and Nagasaki and the experiencesof the survivors who have participated in thisimportant research program.
I was stationed for the summer in the offices of
the Department of Epidemiology at RERF, where I
had proposed to work on analyses of associations
between ionizing radiation dose and mortality due
to lymphatic and hematopoietic cancers. In recent
years, I have had a particular interest in leukemia
and lymphoma and the temporal patterns of these
diseases following exposure to ionizing radiation.
While there has been a lot of epidemiologicalresearch on leukemia mortality among A-bomb survivors, the focus has been on leukemia of all types,
considered in aggregate. Over the summer I drafted
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a report on mortality by type of leukemia among the
A-bomb survivors in the Life Span Study. During
this period, I also finalized a report on lymphoma
mortality among male A-bomb survivors. Both reports are now in the form of manuscripts under review.
As an academic (Assistant Professor in the
Department of Epidemiology, School of Public
Health, University of North Carolina), it is unusual
for me to have a period of months to focus on a single
project with no distractions; and, it is extremely
unusual to be surrounded by others with a sharedinterest in radiation epidemiology. We are a rare
breed. Being located at RERF meant that I had an
opportunity to participate in weekly meetings andinformal discussions. The experience was tremendously productive. I learned a great deal from thosemeetings, and the experience sparked new ideas
and suggested new research questions. Furthermore,
I had the pleasure of getting to know some of
the RERF staff personally. I want to thank everyone
at RERF for this generous opportunity and, inparticular, for the hospitality shown by the RERF
staff.
Jacob Adams
I (Jacob Adams, M.D., M.P.H., an Assistant Professor of Epidemiology in the Department of Community and Preventive Medicine at the Universityof Rochester School of Medicine and Dentistry) spent
the summer and early fall at RERF in the Department of Epidemiology investigating the potential
association between radiation dose and chronic
kidney disease mortality. This investigation was
inspired by prior investigations in the Life Span
Study (LSS) by Drs. Yukiko Shimizu, Kazunori
Kodama, Kiyohiko Mabuchi, and others that repeatedly showed an association between cardiovasculardisease mortality and radiation dose. While at the
RERF Update Volume 19, Issue 2, 2008

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RERF NewsRERF between June 11th and September 30th, I
worked very closely with Eric Grant to clean andrecode the data he used from the LSS database andto learn how to use Epicure. In addition to evaluating a possible association between radiation dose andchronic kidney disease, I also evaluated the validityof self-reporting of hypertension in the 1965, 1978,
and 1991 LSS surveys compared to measured bloodpressure and medication data in those survivors who
participated in the concurrent AHS visits.
I am especially interested in the late effects ofcancer therapy, particularly radiation therapy on the
cardiovascular system. I found my experience at
RERF to be invaluable to my career development as
it provided me the opportunity to learn how to model
excess relative risk using the Epicure progam whilemodeling real data that I hope will contribute to two
publications with my collaborators at RERF. The
skills I learned will also allow me to further my analyses of the Rochester, NY area Thymus Irradiation
Cohort (a cohort originally started by Dr. Louis
Hempelmann) which I restarted in 2004 after 17
years of dormancy as part of an NIH (National Institute of Health) career development award. Dr.
Roy Shore, RERF’s Vice Chairman and Chief ofResearch, served as an advisor for my study. I wantto thank Dr. Shore and the NCI (National Cancer
Institude) Radiation Epidemiology Branch for sup-port of my career and for encouraging me to apply
for a visiting research fellowship at RERF. I want toalso thank the RERF staff and scientists, especiallyin the Department of Epidemiology, for their support and wonderful hospitality. I look forward tomaintaining contact with RERF while working on
the above-mentioned manuscripts and exploring
potential collaborations, including one already suggested by Dr. Yoichiro Kusunoki and Dr. Kei Nakachiin the Department of Radiobiology/Molecular
Epidemiology.
Yoshisuke Nonaka
I arrived in RERF in April, 2008 as a visiting scientist and to continue my postdoctoral fellowship in
the Department of Epidemiology as part of a Partnership Program between RERF and Kurume University. Prior to my arrival I had been a postdoctoral
fellow in the Biostatistics Center of Kurume University where I was studying statistical modelingbased on the regularized local likelihood methods
as applied to clinical data. I was also developing andapplying the mixed-effect model to repeat-measurement data. I received my Ph.D. in Mathematics from
Kyushu University in 2004. At RERF, I have beenworking on selection of relative-risk models using
information criteria related to the RERF Life Span
Study.

Student Researcher
Javad Mohammadi-Asl
I arrived at RERF in Hiroshima in August 2008,
with my wife and three sons from Iran where I am aPh.D. student in the Medical Genetics Departmentof the Tehran University of Medical Sciences. I am
also currently a faculty member in the Biochemistry
Department of the Ahwaz Joundi-Shapor Universityof Medical Sciences in Ahwaz, Iran, where I had
received my B.Sc. in Genetics. I had also received
an M.Sc. in Human Genetics from Tehran University of Medical Sciences. I am especially pleased to
be able to work with RERF scientists in the Radiobiology/Molecular Epidemiology Department where

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I am studying promoter methylation of RASSF1A,
P16, MGMT, and TSHR genes, BRAF gene mutations, RET mRNA expression, and PTC1 and PTC3
rearrangement on malignant thyroid nodules. RERF’s
excellent facilities and collegial research staff havebeen of great value to me as I continue my researchand pursuit of the Ph.D. I would like to thank RERF
for accepting me and my family and I really appreciate the assistance of Drs. Kiyohiro Hamatani, Kei
Nakachi, Roy Shore, and Evan Douple, as well asother RERF staff who have helped me during mystay in Hiroshima.

RERF Update Volume 19, Issue 2, 2008

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RERF News2008 Distinguished Lecture Series
The third lecturer of this year’s Distinguished
Lecture Series was Dr. Albrecht Wieser from theHelmholtz Zentrum and German Research Center
for Environmental Health in Munich. Dr. Wieser’s

lecture on April 23, 2008, was entitled “Comparisonof EPR (electron paramagnetic resonance), FISH
(fluorescence in situ hybridization), and film badge
reconstructed doses for Mayak workers.”

Award Received by an RERF Scientist
Receiving “Presentation of the Year” award
at 15th annual meeting of the JapaneseSociety of Immunotoxicology
Tomonori Hayashi, Chief, Immunology Laboratory
Department of Radiobiology/Molecular Epidemiology

The 15th annual meeting of the Japanese Societyof Immunotoxicology was held in Tokyo on September 11 and 12, 2008, and my presentation titled“Elevation of aging-associated inflammatory markers among atomic-bomb survivors” received the“Presentation of the Year” award, which is granted
to one from among all presentations each year. This
year’s meeting was held jointly with the 52nd meeting of the Japan Society for Occupational HealthResearch Group on Allergy and Immunotoxicology,
at which research results regarding natural immunity and mucosal immunity and those targeting awide variety of substances including drugs andmedicines, dietary components, environmental
chemicals, and nano-particles were comprehensively
reported, and hence this scientific meeting was
precisely suited for its theme “New developments
in immunotoxicology.”
In the presentation I reported on the presence ofsignificant positive correlations between radiationdose and inflammation-related substances on thebasis of results from analysis on impairment of
immune function with increased radiation dose, conducted through use of such inflammation-related

Return to Table of Contents

markers as peripheral inflammatory cytokines(IL-6, TNF-α, and others) and reactive oxygen species (ROS). A majority of the previous reports on
association between radiation dose and inflammatory response came from in vitro studies, with any
reported findings involving only the acute phase
after radiation exposure. There are thus no previous
reports targeting a cohort as many years after radiation exposure as that in my report. The relevant study
was the first to have reported on the possibility that
increased cancer/non-cancer risk with increased
radiation dose might be caused by radiationenhanced immunological aging, and that was presumably the reason for the recognition the annual
meeting bestowed upon our study. Needless to say,the report resulted from research activities based on
the understanding and cooperation of RERF’s Adult
Health Study participants. I received the award on
behalf of the staff of the Department of Clinical Studies; Dr. Yoichiro Kusunoki, who has long studied
effects of radiation exposure on immunity, the technicians at the Immunology Laboratory, Dr. Kei
Nakachi, Department Chief, who has brought new
perspective to immunology research and contributed
to that field’s further development, and many otherpeople contributed. I would like to express my heartfelt appreciation to all of them for their cooperationand support.
I will continue to make efforts to promote immunology research, and everyone’s continued guidance
would be greatly appreciated.

RERF Update Volume 19, Issue 2, 2008

9

Conference and Workshop Reports

Symposium on Health Effects of Radiation and Smoking
10 March 2008, Hiroshima Laboratory
Ritsu Sakata, Research Scientist
Department of Epidemiology, Hiroshima
Tobacco smoke contains many carcinogens, andsmoking’s association with development of many
cancers, such as of the lung and stomach, has been
confirmed. Based on studies of effects of smoking
on mortality in various regions around the world, italso has become clear that smoking is the mostimportant cause of early death in many populations
over the past several decades. Because of just suchserious health effects, smoking is considered to be afactor that must be considered in estimating healtheffects of radiation. Studies on the effects of smoking in Japanese populations have shown, after
adjustment for amount of smoking, less significant
health effects from smoking than in populations ofEurope and the United States. It is still unclear
whether this difference is due to the fact that smoking became prevalent somewhat later in Japan thanin other countries or because of the presence of otherfactors that modify smoking effects.
In the mail surveys and interviews that RERF has
conducted thus far, questions on smoking have beenasked repeatedly. Although several studies have been
conducted using the results of those surveys, mostof the studies only used responses from a single
survey; no study has been conducted using multiple
responses from the same subjects. Thus, clearly there
is potential for making better use of the results.
To discuss methods for more effective use of
RERF data on smoking status, the “Symposium on
Health Effects of Radiation and Smoking” was heldat the Hiroshima Laboratory on March 10, 2008.
Invitees from outside research organizations to thesymposium included Drs. Sarah Darby and Paul

McGale of the Clinical Trial Service/Epidemiological Research Unit at Oxford University, who wereinvolved in a study on British physicians, one of themost important studies in the world concerning
effects of long-term smoking on mortality, and Dr.
Tomotaka Sobue of the Center for Cancer Control
and Information Services, National Cancer Center,
who has been involved in many cohort studies on
health effects of smoking in Japan.
First, Dr. Darby showed the latest results ofanalysis in the 50-year follow-up study of British
physicians. She reported that smoking increased
age-specific mortality from all diseases and that,when mortality was examined by disease, smoking
also increased age-specific mortality from many ofthe diseases. She also reported that there weredifferences by birth cohort in mortality risks of smokers and non-smokers: the difference in mortality
between smokers and non-smokers is larger in the
population born in the first half of the 20th century
than in the population born in the latter half of the
19th century. It was also reported that quitting smoking even between the ages of 50–64 was effective in
reducing subsequent mortality risks.
Chief Scientist Kazunori Kodama then made an
introductory presentation concerning RERF cohorts,
results from several past studies of health effects ofsmoking, and research on interaction between smoking and radiation. At the end of the morning session,
Dr. Sobue presented information on changes overtime in terms of cancer mortality in Japan; whereas
lung cancer mortality has started to decrease in
England and the United States, a similar reduction
in lung cancer mortality in Japan has been
delayed compared with other developed
countries. He also showed yearly changes
in amount of tobacco consumption in Japan and the United States. Comparisonof results of studies on lung cancer risks
related to smoking in European countries,
the United States, and Japan showed thatthe risks observed in Japanese populations were lower. Reasons for the lower
risks were explained as possibly due to asmaller amount of smoking, high lungcancer risk among non-smokers, effectmodification from other lifestyle factors,
or low genetic susceptibility.
In the afternoon session, details of data
Participants of the Symposium on Health Effects of Radiation andSmokingobtained by RERF and Oxford UniverReturn to Table of Contents

RERF Update Volume 19, Issue 2, 2008

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Conference and Workshop Reports
sity were presented. First, information on smoking
maintained at RERF was explained. Research Scientist Eric Grant of the Department of Epidemiology reported the number of respondents in past mailand interview surveys, the number of subjects who
responded on multiple occasions, age distribution of
respondents, and information regarding lifestyle factors other than smoking that has been obtained fromsuch mail surveys. Then, the author of this article,
also of the Department of Epidemiology, introduced
distribution of smoking status and number of cigarettes smoked by survey, and explained that, because
questions in some cases varied by survey, analysis
required special care. This was followed by apresentation by Dr. McGale, who stated that almost
perfect follow-up had been achieved in the study ofBritish physicians, and that the response rate of
all five past mail surveys conducted for the study
exceeded 90%.
Lastly, all the symposium participants engaged

in discussion on future plans for collaborative
research. It was agreed that, in order to make fulluse of smoking information maintained at RERF, acollaborative study should be conducted utilizing
Oxford University’s extensive experience. Based onsuch a collaborative study, it will become possible
not only to incorporate smoking information in risk
estimation of radiation exposure but also to apply to
Japanese populations the same analytical methods
used in the study on British physicians. This will
enhance the possibility of further comparison andmay provide valuable additional information on theeffects of smoking on public health in Japanese populations. It also will likely be necessary to fully utilize mail and interview survey data, obtained thanks
to the cooperation of many subjects and RERF staff.
I would like to express my appreciation for theopportunity to hear presentations on the use ofsmoking data by leading scientists and to be involvedin collaborative studies.

RERF Symposium on Bioinformatics
24–25 March 2008, Hiroshima Laboratory
Susan M. Geyer, Associate Senior Scientist
Department of Statistics
High-throughput technologies that can yield massive amounts of data are often referred to as “ ‘omics”
technologies, such as genomics, proteomics, andmetabolomics. Those technologies are widely usedin current medical research. They can provide information to build better predictive models of diagnosis and prognosis and to identify and characterize
key signaling networks in cell culture or in vivo. But
the technologies present researchers with a greatchallenge: the task of extracting meaningful statistical and biological information from huge numbersof variables measured simultaneously, along withconsiderable noise. Using the technologies, a single
sample can have hundreds or even thousands ofmeasurements, usually obtained by running a single
microarray. There are great opportunities here at
RERF to use such technologies to explore radiation
effects as well as other biological questions. The
RERF is uniquely poised to benefit from these ‘omics
technologies because of its biospecimens resources,
virtually unparalleled in the world, provided generously by the atomic-bomb survivors in Hiroshima
and Nagasaki. Multiple biosamples collected on
thousands of subjects provide many potential opportunities for research in this area.
The complex new research technologies involvReturn to Table of Contents

ing high-dimensional data require tools to effectively
manage and analyze large amounts of data. In that
context, the area of bioinformatics provides manysuch tools for handling those issues, and the researchin computational and systems biology provides new
ways of analyzing data and looking for meaningful
patterns and associations.
The goal of this symposium was to bring together
experts to provide a forum for the discussion of
bioinformatics here at RERF and in general. The
symposium was considered a first step to exploring
potential applications and methods that could beapplied to the RERF atomic-bomb survivor cohort
data, which could also generate benefits forbioinformatics research in general. Another goal ofthis symposium was to provide an opportunity forexperts in bioinformatics to meet with RERF researchers, where the invited speakers could obtain abetter understanding of the resources and the research
conducted here and we could all explore potential
collaborations for the future.
The first day of the symposium consisted of two
sessions: one on bioinformatics with talks given by
the invited bioinformatics scientists, and one by
RERF directors and department chiefs regarding theactivities of the various research departments at
RERF Update Volume 19, Issue 2, 2008

Conference and Workshop Reports
RERF and the research areas of interest that may
benefit from bioinformatics initiatives and ‘omics(e.g., genomics, proteomics, metabolomics) research.
The invited speakers were leaders in bioinformatics
from the United States and Japan, and included: Dr.
John Quackenbush from Harvard University, Dr.
Peter Li from Mayo Clinic, Dr. Hiroshi Mizushimafrom Tokyo Medical and Dental University, Dr.
Tatsuya Akutsu from Kyoto University, and Dr.
Toshio Kojima from RIKEN Genomic Sciences
Center. Each speaker gave interesting and thoughtprovoking presentations on varying areas ofbioinformatics. After hearing about the research ideas
and interests of the invited speakers, the RERF directors and department chiefs presented different
aspects of the research and resources here at RERF;
this naturally led to discussion of the potential forthe applications of the research and ideas presented
earlier. On the second day of the symposium, we hada roundtable discussion with the invited speakers,
the RERF directors, and many research scientists
from RERF representing all research departments.
The discussion focused on research interests as wellas the necessary resources. Specific challenges andtasks were also identified in order for RERF to more
effectively utilize bioinformatics research.
The result of the bioinformatics symposium wasan increased knowledge among research scientists
at RERF regarding bioinformatics and its intersection with the high dimensional data technologies suchas genomics and proteomics. In meeting with theinvited bioinformatics speakers, the RERF researchleadership was able to identify steps that would need
to be taken as well as challenges in incorporating
this science into RERF’s research initiatives. I be-

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11
lieve that the invited speakers also benefited fromhearing about the interesting research done here andwere impressed by the virtually unparalleled biological resources at RERF and the opportunities they
provide. In the end, we felt that this symposium wasan important first step toward exploring the potential to fully implement the research initiatives ofbioinformatics and computational biology here at
RERF.
Lastly and most importantly, we would like toexpress our sincere appreciation and gratitude to all
who helped to make this symposium possible, theRERF leadership and researchers who made informed and interesting presentations and participatedin and contributed so much to the discussions. Special thanks also are given to the staff members of theStatistics Department, the Secretariat, and the Information Technology Department who were an integral part in helping to organize this symposium.

RERF Symposium on Bioinformatics held at theHiroshima Laboratory

RERF Update Volume 19, Issue 2, 2008

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Science Article

Preferential Gene Alterations in Adult-onset Papillary
Thyroid Cancer among Atomic-bomb Survivors:
Chromosomal Rearrangements vs.
Point Mutations
Kiyohiro Hamatani,1 Reiko Ito,1 Masataka Taga,1 John Cologne,2 Hidetaka Eguchi,3 Yuzo
Hayashi,4 Kei Nakachi1
Departments of 1Radiobiology/Molecular Epidemiology and 2Statistics, RERF; 3Translational Research Center, Saitama Medical University, International Medical Center,
Saitama; 4Hidamari, Geriatric Health Service Facility

Introduction
Thyroid cancer is one of the malignancies most
associated with ionizing radiation in humans. The
excess relative risk of papillary thyroid cancer inatomic-bomb (A-bomb) survivors was 1.2 per Gy,
and it increased with increased radiation dose.1 A
histopathological study has revealed that the thyroid
cancers found in A-bomb survivors were largely
conventional papillary in nature, and this is also thecase of spontaneous thyroid cancer in the Japanese
population at large. Solid variant papillary thyroid
cancer was not found in A-bomb survivors, although
this cancer has been frequently found among postChernobyl children.2,3 However, it still remains toclarify molecular mechanisms of how radiation
exposure affects the development of thyroid cancer.
Gene alterations that lead to constitutive activation of the MAP kinase-signaling pathway are frequently found in papillary thyroid cancer. Thosealterations are mutually exclusive, non-overlapping
events that involve rearrangements of the RET and
NTRK-1 (neurotrophic tyrosine kinase receptor 1)
genes and point mutations in the RAS and BRAF
genes.4–6
In papillary thyroid cancer, the RET protooncogene is known to be activated by fusion of the
RET TK domain with the 5′ terminal sequence of
one of different heterologous genes via rearrangements that generate a series of chimeric-transforming oncogenes collectively described as RET/PTCs.
To date, at least 12 rearranged forms of the RET gene
have been isolated, of which RET/PTC1 and RET/
PTC3 are by far the most common.7 RET/PTC rearrangements were commonly found in childhood papillary thyroid cancer regardless of radiation history.8,9
RET/PTC rearrangements, especially RET/PTC3,
were frequently encountered in papillary thyroid
cancers with relatively short latency among children
Return to Table of Contentsfrom contaminated areas at the Chernobyl nuclear
accident in 1986. Amongst those early-onset carcinomas, solid variants and follicular variants of papillary thyroid carcinomas were found at an unusually high frequency. Among children in Chernobyl
contaminated areas, RET/PTC3 appeared to bestrongly associated with solid variant-type carcinomas and with a short latency period after exposure.9,10
On the other hand, in the Japanese general adult
population, typical frequency of RET/PTC seems to
be of the magnitude of 10 to 40%, though a wide
variation, ranging from 2.6 to 70%, has been observed in different geographic areas.11–13 RET/PTC
rearrangements, especially RET/PTC1, were reported
as being detected at higher frequency in papillary
thyroid cancer from adult patients with a history ofradiotherapy than in those without radiation history,14
but another report disputed such findings.15 Interestingly, we also found that RET/PTC1 rearrangement
could be induced in human thyroid cells by Xirradiation in vitro and in vivo as tissue transplants
in scid mice, and that the rearranged RET oncogene
was constitutively expressed for two months after
X-irradiation in vivo (50 Gy).16 Those findings may
provide supporting evidence that activation of the
RET oncogene via rearrangements plays a crucialrole in radiation-associated papillary thyroid carcinogenesis.
BRAF V600E mutation has thus far been describedas occurring with a frequency ranging from 29% to
83% in papillary thyroid cancer among an adult general population.17 The alteration is detected in a partof micropapillary thyroid carcinoma, suggesting that
BRAF point mutation is an important event involvedin the early step of adult-onset papillary thyroid
carcinogenesis. Regarding the relationship withradiation exposure, the BRAF V600E gene mutation wasstudied in post-Chernobyl childhood papillary thyRERF Update Volume 19, Issue 2, 2008

13

Science Article
roid cancer. A very low frequency of BRAFV600E
mutations in this papillary thyroid cancer has beenreported (range: 0–12%).18–22 However, prevalenceof BRAF V600E mutation was originally low (range:
0–6%) in papillary thyroid cancer among children,
unrelated to their history of radiation exposure.18,19,22
In order to clarify mechanistic relationships
between radiation exposure and the development ofpapillary thyroid cancer, we have conducted experiments to identify which types of gene alterations,e.g., chromosomal rearrangements or point mutations, preferentially occurred in adult-onset papillary thyroid cancer among A-bomb survivors.
Toward this end, we analyzed RET/PTC rearrangements and BRAF V600E point mutations in 71 adultonset papillary thyroid cancer cases among A-bomb
survivors, since the major initial event of this cancer
is either RET/PTC rearrangements or BRAF mutations, which appear to occur mutually exclusive.
Material and Methods
Study subjects and tissue specimens
Study subjects comprised 71 adult-onset papillary thyroid cancer cases consisting of 50 exposedand 21 non-exposed subjects found among A-bomb
survivors in Hiroshima and Nagasaki.
All study materials were formalin-fixed and paraffin-embedded papillary thyroid cancer tissue specimens surgically resected during 1956–1993. This
study has been conducted under approval of the
Human Investigation Committee and the Ethics
Committee for Genome Research at the Radiation
Effects Research Foundation (RERF).
DNA and cDNA preparation
RNA and DNA were extracted from microdissected

non-cancerous or cancerous regions using the High
Pure RNA Paraffin Kit (Roche Diagnostics GmbH;Manheim, Germany) and QIAamp DNA Micro Kit(QIAGEN; Hilden, Germany), respectively, as described previously.23,24 Reverse transcription (RT)was performed with random primers (9 mer) using 100
ng total RNA as template, as described previously.23
Detection of RET/PTC rearrangements and
BRAF V600E mutation
RET/PTC1 and RET/PTC3 were analyzed by
BamH I digestion of obtained fragments after
RT-PCR amplification with primers sandwiched thefusion point, as described previously.25 RET rearrangements other than RET/PTC1 or RET/PTC3 were
examined by improved 5′ RACE method. BRAF genemutation causing amino acid substitution of glutamic
acid for valine at codon 600 (BRAF V600E) was determined by restriction fragment length polymorphism(RFLP) using TspR I (New England Biolabs; Beverly,MA) and direct sequencing, as described previously.24
Statistical analyses
Mann-Whitney’s U test was used for non-parametric two-sample comparisons of continuous variables. Fisher’s exact test was used for categoricalvariables. The Cochran-Armitage test was used for
non-parametric trend analysis. All statistical analyses
were performed with SPSS software (version 12.0).
Results
There was no statistical significant difference inpathological and epidemiological characteristics
between exposed and non-exposed subjects (Table1). In addition to eight papillary thyroid cancer

Table 1. Pathological and epidemiological characteristics of study subjects by radiation exposure status
Life Span Study (LSS) cohort†
Exposed (Dose > 0 mGy)
(n=50)

Non-exposed(n=21)P

GenderMale (n)Female (n)

6
44

2
19

1

Histological subtype

Conventional PTC (n)Follicular variant (n)

47
3

21
0

0.6

Median age ATB*

(yr)
(range)

22
1–47

22
0–52

0.3

Median age at diagnosis(yr)(range)

50
18–89

48
24–84

0.9

Median time after exposure(yr)(range)

24
11–46

–

–

Median radiation dose(mGy)(range)203
0.4–2758––*ATB: at the time of the bombings.
†

LSS cohort: 120,000 atomic–bomb survivors (including non–exposed subjects) in Hiroshima andNagasaki at baseline.

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RERF Update Volume 19, Issue 2, 2008

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Science Article
patients with only RET/PTC1 and one with both RET/
PTC1 and RET/PTC3 who were detected among 50
exposed patients, we identified a novel type of RET/
PTC rearrangement as well as rare RET/PTC8 in
A-bomb survivors exposed to high radiation dose
(1.5 Gy and 2 Gy, respectively), expression of which
was confirmed by RT-PCR (Figure 1). Although theexposed patients showed a higher frequency of RET/
PTC rearrangements than did non-exposed ones, thisdifference was not statistically significant (Table 2).
On the other hand, frequency of BRAF V600E mutation was marginally lower in exposed patients thanthat in non-exposed ones (P = 0.06, Table 2).
In 50 exposed papillary thyroid cancer cases, there
was no case having both RET/PTC rearrangement
and BRAF point mutation, suggesting that thesealterations are mutually exclusive. To examine therelationship between RET/PTC rearrangements and
BRAF V600E mutation and radiation dose, exposed papillary thyroid cancer patients were divided into threegroups harboring RET/PTC rearrangements (11cases), BRAF point mutation (28 cases), and otherunknown gene alterations (11 cases) by dose tertiles.
RET/PTC rearrangements were more frequently
found in patients with increased radiation dose (Ptrend= 0.002, Figure 2). On the other hand, prevalence of
BRAF V600E mutation significantly decreased withradiation dose (Ptrend = 0.00006). In addition, papillary thyroid cancer patients having wild-type RET
and BRAF showed a marginally significant increasing trend with radiation dose (P = 0.08, Figure 2).
RET/PTC rearrangements and BRAF V600E mutation were further studied in relation to time sinceradiation exposure (Figure 3). BRAF V600E mutation
significantly increased with increased time since
exposure, while unidentified alterations in papillary
thyroid cancer having wild-type RET and BRAF drastically decreased with increased time since exposure.
In contrast, RET/PTC rearrangements showed a peakat time since exposure around 22 years. These findings revealed that the cases with RER/PTC rearrangements developed cancer sooner following exposure
than did the cases with BRAF mutation.
Age at diagnosis and age at the time of the bombings (ATB) were compared between 11 papillary thyroid cancer patients having RET/PTC rearrangements
and 28 patients having BRAF V600E mutation. As
shown in Figure 4, age at diagnosis in the cases with
RET/PTC rearrangements was significantly younger
than in the cases with BRAF mutation (P = 0.005,
Figure 4A). Furthermore, the papillary thyroid cancer cases with RET/PTC rearrangements tended toshow younger age ATB than did those with BRAF
mutation (P = 0.06, Figure 4B).

Figure 1. Expression of RET/PTC rearrangements in papillary thyroid cancer (PTC)
from A-bomb survivors. Lanes 2–8 indicate RT-PCR products from RNA in
PTC cancer specimens of A-bomb survivors. Lanes 2, 3, 4, and 7 showed no
detectable expression of RET TK domain; lane 5, novel RET/PTC (RET/PTCX)
rearrangement; lanes 6 and 8, RET/PTC1; lane 9, H2O (negative control);lane 10, cell line TPC1 harboring RET/PTC1. Lane 1 indicates pUC19-MspI
digest for DNA size marker.

Table 2. Frequency of RET/PTC rearrangements and BRAF V600E mutation by radiation exposure status
LSS cohort
Exposed (Dose > 0 mGy)
(n=50)

Non-exposed(n=21)P

RET/PTC rearrangements

Absence (n)Presence (n)Frequency (%)

39
11
22

20
1
5

0.09

BRAF V600E mutation

Absence (n)Presence (n)Frequency (%)

22
28
56

4
17
81

0.06

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RERF Update Volume 19, Issue 2, 2008

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Science Article

Figure 2. A relative frequency of RET/PTC and BRAFV600E alterations in papillary thyroid
cancer patients grouped by radiation exposure dose levels (non-exposed anddose tertiles). Exposed papillary thyroid cancer patients were divided into threegroups by dose tertiles. †One case in the non-exposed group had both RET/PTC and BRAF V600E. Relative frequency of genes in the non-exposed group
was calculated by using 22 for the number of gene alterations. The open, dotted, and closed bars indicate PTC with RET/PTC rearrangement, with BRAF V600E
mutation, or with other unknown alterations, respectively.

Figure 3. A scheme of gene alteration types in adult-onset papillary thyroid cancer among
A-bomb survivors varying with year elapsed since radiation exposure.

Discussion
In papillary thyroid carcinogenesis, constitutive
activation of the MAP kinase-signaling pathway,
namely rearrangements of RET and NTRK1 tyrosine
kinase receptor genes and mutations in RAS and
BRAF oncogenes, seems to be required for transformation.26 Recent in vitro and in vivo experiments
have also demonstrated the requirement of activation of the RET/PTC-RAS-BRAF-MAPK pathway
Return to Table of Contents

in thyroid tumorigenesis.27–29 Interestingly, mutual
exclusion of these genetic alterations in the MAP
kinase-signaling pathway was reported; one event
among BRAF mutation, RAS mutations, and RET/
PTC rearrangements4,5,20 or one among BRAF mutation, RET/PTC rearrangements, and NTRK1 rearrangements6 was singularly found, indicating that one
such gene alteration is an important early event indevelopment of papillary thyroid cancer. FurtherRERF Update Volume 19, Issue 2, 2008

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Science Article

Figure 4. Comparison of age at diagnosis (A) and age ATB (B) by gene alteration status.
The square and circle indicate RET/PTC rearrangement and BRAF V600E mutation, respectively. The star shows wild-type RET and BRAF.

more, a recently identified AKAP9-BRAF rearrangement did not coexist with BRAF mutation in radiation-associated papillary thyroid cancer.21 Those datasuggest that a single genetic event in the MAP
kinase-signaling pathway may be sufficient forthyroid cell transformation and tumorigenesis.
In this study, pathological and epidemiologicalcharacteristics, specifically radiation-related ones, ofpapillary thyroid cancer having RET/PTC rearrangements contrasted clearly with those of papillary thyroid cancer having BRAF V600E mutation. Noting that
17 (81%) and 1 (5%) of 21 non-exposed papillary
thyroid cancer patients having BRAF V600E mutation
and RET/PTC rearrangement in this study, respectively, are in agreement with other data on nonexposed adult-onset Japanese papillary thyroid
cancer,12,17,30–32 we for the first time have shown that
RET/PTC rearrangements showed significantly
increased frequency with increased radiation dose.
In contrast, BRAF V600E mutation was less frequent incases exposed to higher radiation dose. Papillary thyroid cancer subjects harboring RET/PTC rearrangements developed this cancer earlier than did caseswith BRAF V600E mutation. Taken together, our findings imply that RET/PTC rearrangements, not
BRAF V600E mutation, are closely associated withradiation-associated adult-onset papillary thyroid
cancer. Furthermore, these findings have suggested
that radiation did not alter basic pathways, but preferentially induced specific events: e.g., preferential

Return to Table of Contents

occurrence of RET/PTC rearrangements in the earlystage of papillary thyroid carcinogenesis.
The existence of a molecular mechanism otherthan RET/PTC rearrangement is suggested from
Figures 2 and 3: Unidentified gene alterations otherthan RET/PTC and BRAFV600E tended to be more
frequent with increased radiation dose. RET/PTC
rearrangements showed a peak at 20 to 30 years sinceradiation exposure and relatively low frequency of
20% in <20 years since exposure, in contrast to 53%
of other unidentified gene alterations. Because RET/PTC and BRAFV600E account for 82% of non-exposed
papillary thyroid cancer and about 60–70% of
papillary thyroid cancer in the Japanese general
population, 12,17,30–32 this increase of unidentified
alterations in <20 years is thought to be caused byradiation. This unidentified mechanism may be
involved in radiation-associated papillary thyroid
cancer, which occurred earlier after radiation exposure than did papillary thyroid cancer having RET/
PTC. Figure 5 summarizes our hypothesis of development of radiation-associated adult-onset papillary
thyroid cancer among A-bomb survivors.
We anticipate that our molecular oncology study
will not only contribute to understanding mechanisms of radiation thyroid carcinogenesis but also
linked to “molecular event-based risk estimation” ofpapillary thyroid cancer in A-bomb survivors, e.g.,radiation-induced risk of papillary thyroid cancer
with RET/PTC rearrangements.

RERF Update Volume 19, Issue 2, 2008

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Science Article

Figure 5. A hypothetical scheme of the development of radiation-associatedpapillary thyroid cancer among A-bomb survivors.

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12. Suárez HG. Genetic alterations in human epithelial thyroid tumors. Clin Endocrinol 48:531-46, 1998.
13. Chu EL, Wu WM, Tran KT, et al. Prevalence and distribution of ret/ptc 1, 2, and 3 in papillary thyroid carcinoma in New Caledonia and Australia. J Clin Endcrinol Metabol 85:2733-9, 2000.
14. Bounacer A, Wicker R, Caillou B, et al. High prevalence of activating ret proto-oncogene rearrangements, inthyroid tumors from patients who had received external radiation. Oncogene 15:1263-73, 1997.

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RERF Update Volume 19, Issue 2, 2008

18

Science Article

15. Elisei R, Romei C, Vorontsova T, et al. RET/PTC rearrangements in thyroid nodules: Studies in irradiated andnot irradiated, malignant and benign thyroid lesions in children and adults. J Clin Endocrinol Metabol 86:32116, 2001.
16. Mizuno T, Iwamoto KS, Kyoizumi S, et al. Preferential induction of RET/PTC1 rearrangement by X-ray
irradiation. Oncogene 19:438-43, 2000.
17. Xing M. BRAF mutation in thyroid cancer. Endocr-Relat Cancer 12:245-62, 2005.
18. Kumagai A, Namba H, Saenko VA, et al. Low frequency of BRAF T1796A mutations in childhood thyroid carcinomas. J Clin Endocrinol Metabol 89:4280-4, 2004.
19. Lima J, Trovisco V, Soares P, et al. BRAF mutations are not a major event in post-Chernobyl childhood thyroid
carcinomas. J Clin Endcrinol Metabol 89:4267-71, 2004.
20. Nikiforova MN, Ciampi R, Salvatore G, et al. Low prevalence of BRAF mutations in radiation-induced thyroid
tumors in contrast to sporadic papillary carcinomas. Cancer Lett 209:1-6, 2004.
21. Ciampi R, Knauf JA, Kerler R, et al. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway
activation in thyroid cancer. J Clin Invest 115:94-101, 2005.
22. Powell N, Jeremiah S, Morishita M, et al. Frequency of BRAF T1796A mutation in papillary thyroid carcinoma
relates to age of patient at diagnosis and not to radiation exposure. J Pathol 205:558-64, 2005.
23. Hamatani K, Eguchi H, Takahashi K, et al. Improved RT-PCR amplification for molecular analyses withlong-term preserved formalin-fixed, paraffin-embedded tissue specimens. J Histochem Cytochem 54:773-80,
2006.
24. Takahashi K, Eguchi H, Arihiro K, et al. The presence of BRAF point mutation in adult papillary thyroid
carcinomas from atomic bomb survivors correlates with radiation dose. Mol Carcinogenesis 46:242-8, 2007.
25. Hamatani K, Eguchi H, Ito R, et al. RET/PTC rearrangements preferentially occurred in papillary thyroid
cancer among atomic bomb survivors exposed to high radiation dose. Cancer Res 68: 7176-82, 2008.
26. Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nature Rev Cancer 6:292-306, 2006.
27. Melillo RM, Castellone MD, Guarino V, et al. The RET/PTC-RAS-BRAF linear signaling cascade mediates
the motile and mitogenic phenotype of thyroid cancer cells. J Clin Invest 115:1068-81, 2005.
28. Mitsutake N, Miyagishi M, Mitsutake S, et al. BRAF mediates RET/PTC-induced mitogen-activated protein
kinase activation in thyroid cells: Functional support for requirement of the RET/PTC-RAS-BRAF pathway inpapillary thyroid carcinogenesis. Endocrinology 147:1014-9, 2006.
29. Ouyang B, Knauf JA, Smith EP, et al. Inhibitors of RAF kinase activity block growth of thyroid cancer cellswith RET/PTC or BRAF mutations in vitro and in vivo. Clin Cancer Res 12:1785-93, 2006.
30. Motomura T, Nikiforov YE, Namba H, et al. Ret rearrangements in Japanese pediatric and adult papillary
thyroid cancers. Thyroid 8:485-9, 1998.
31. Kitamura Y, Minobe K, Nakata T, et al. Ret/PTC3 is the most frequent form of gene rearrangement in papillary
thyroid carcinomas in Japan. J Hum Genet 44:96-102, 1999.
32. Kumagai A, Namba H, Akanov Z, et al. Clinical implications of pre-operative rapid BRAF analysis for papillary thyroid cancer. Endocrine J 54:399-405, 2007.

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RERF Update Volume 19, Issue 2, 2008

19

Human Interest Notes

Start of Health Examinations of A-bomb
Survivors Overseas
Akio Awa, Former Associate Chief of ResearchMore than 30 years have already passed sincehealth examinations of A-bomb survivors living in
the United States were initiated in 1977 by specialists in Hiroshima and Nagasaki. I presume that not
many people know the developments that lead toinitiation of the project. I describe here, as long as
my memory permits, the two episodes before initiation of the medical project. I hope that the stories
will be of some help for future generations.
Episode 1
When I was a graduate student at Hokkaido University, I studied in the United States for two years
from the spring of 1960. I joined the Tissue Culture
Laboratory (professor in charge: Dr. Charles Marc
Pomerat) of the Department of Anatomy at the
University of Texas Medical Branch at Galveston,
Texas. My main theme was a chromosome study
using tissue culture procedures. In those days, Dr.
Pomerat, my advisor, was a leading expert in researchon tissue culture in the United States. With the useof microphotography for taking images of cultured
cells alive, Dr. Pomerat had no equal in terms ofresearch on cellular morphology or activity. Dr.
Pomerat was also one of the founding members of
the American Tissue Culture Society, and served aspresident of the society. Unfortunately, however, Dr.
Pomerat stayed in Galveston only about threemonths. He was reportedly not on good terms withthe dean of the medical branch.
Dr. Pomerat had to look for a position at a different laboratory. Arrangements were then made by one
of Dr. Pomerat’s previous students to have theprofessor transfer to the Pasadena Foundation for
Medical Research (PFMR), to which this student
belonged. All necessary laboratory facilities weretransferred to PFMR. On July 4, 1960, an Independence Day, I moved to Pasadena, following my mentor. Thereafter, for one year and nine months until
the end of March 1962, I continued my research at
PFMR.
Pasadena is located about 20 km northeast of Los
Angeles (LA), in the north of which stands Mt.
Wilson, which is the site of a famous observatory. In
those days, having many beautiful Spanish-stylebuildings, Pasadena was famous as a place where
many California millionaires lived. Donations fromthose millionaires were sufficient for covering costs
for the operation of PFMR. Because of its affluence,
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Pasadena was known as a beautiful small city withwell-maintained cultural-arts facilities. On New
Year’s Day, an annual event called the “RoseParade” was held on the main street (Colorado
Boulevard). Many floats decorated with roses andcarrying beautiful girls paraded through the city, andsubsequent college football games sent football fansinto a frenzy.
On the other hand, since smog produced fromexcessive motorization at LA’s city center driftedwith the southwest wind into the Pasadena Valley,
the air in the city was polluted, which made the sunalways look dull. By the way, the term “smog” is acompound of smoke (= exhaust gas) and fog, andwas first used in this area. Now, smog is a familiar
term, symbolizing environmental pollution.
As part of its program for providing scientificcontributions to medicine and society, PFMR holds
a tissue culture training course for about one week
every summer. Dr. Pomerat was an excellent educator, and his lectures were quite easy to understand.
In addition, having remarkable skills of watercolor
painting, Dr. Pomerat could draw with ingenuity
various biomedical illustrations on the blackboard.
Many students from Japan visited Dr. Pomerat’s
laboratory for his guidance. When I was at PFMR,
there were two Japanese researchers other thanmyself (the three of us were all graduates from thesame university).
Because of limited staff and space, only eightpeople participated in the tissue culture course in thesummer of 1961. Training was conducted on a
one-to-one basis, starting with the basics of tissue
culture. I was involved in the training regarding chromosome analysis methods using cultured cells. In
this training course, I met a person who is the main
character of this episode.
The person was one of the trainees, Dr. Thomas
Noguchi. Dr. Noguchi was born on January 4, 1927.
He was eight school-years older than me. Dr.
Noguchi was a very hardworking person. After
graduating from the Nippon Medical School, he visited the United States and further studied medicine(pathology and anatomy). Mrs. Noguchi was an
American of Japanese ancestry. In the summer of
1961, when he underwent training at PFMR, Dr.
Noguchi had the position of pathological autopsy
expert at Loma Linda University, LA and judicial
autopsy expert at the LA County Medical Examiner’s
RERF Update Volume 19, Issue 2, 2008

Human Interest Notes

Participants of the first tissue culture course at PFMR
in the summer of 1961. Dr. Thomas Noguchi is the
fourth person from left in the second row.

Office. In the training course, Dr. Noguchi often
helped me when I found it difficult to make explanations in English. This was the start of exchanges
both in public and private between the Japanese scientists who studied at PFMR and Dr. Noguchi. I
learned various aspects of the United States fromDr. Noguchi. This broadened my perspective regarding the United States, which was very useful for mystay in that country.
After I returned to Japan in 1962, significant
events that made Dr. Noguchi a “man in the news”
developed one after the other, by which he drewattention from the world. The first incident was thesuicide of Marilyn Monroe, a Hollywood star, inAugust 1962. Since Dr. Noguchi conducted a postmortem, he attracted attention from the entire
nation. The second incident that made him even morefamous was the assassination in LA in July 1968 ofRobert Kennedy, then Democratic presidential candidate and younger brother of the late John Kennedy.
In this incident also, Dr. Noguchi, Chief Medical
Examiner for the county, was responsible for the
postmortem, and his every move attracted muchattention from the public. Even before and after thoseincidents, he conducted autopsies for many Hollywood stars. He was therefore given a nickname “thecoroner to the stars” by the British press. After
resigning from his position as Chief Medical
Examiner of LA County in 1982, Dr. Noguchi served
as professor of pathology at the University of California in Los Angeles (UCLA) and the University ofSouthern California (USC), prestigious universities
on the West Coast. He thus had a successful career
as an outstanding pathologist/autopsy expert until heretired in 1999.
Episode 2
During the three days from November 30, 1975,
an international symposium titled “AutomatedCytogenetics” was held in Pacific Grove, a place ofscenic beauty near San Francisco. I was invited tothe symposium, which was organized by Dr.
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20
Mortimer Mendelsohn, former Vice Chairman andChief of Research of the Radiation Effects Research
Foundation (RERF). I made a presentation titled“Cytogenetic study of A-bomb survivors and theirchildren in Hiroshima and Nagasaki.” After finishing the presentation, I visited Pasadena for the firsttime in 13 years and six months. At that time, Dr.
Yasushi Ohnuki, two years my senior at college, andDr. Tohru Okigaki, my contemporary at college, wereon the permanent staff of PFMR. In addition, I foundthat many of the staff members whom I had known
during the period of my assignment at PFMR werestill working there, making this revisit a more pleasant occasion. During PFMR’s seminar in the afternoon of December 4, I made a presentation on a topic
similar to the above-mentioned international symposium presentation. The seminar was covered indetail with photos by a local newspaper, the Pasadena Independence Star News.
Not long after I returned from Pasadena, I received
an airmail letter. The sender was Ms. Katsu (correctly, Kazue) Sueishi. The letter was beautifully
written using a writing brush on traditional Japanese
paper. I describe the essential points of the letter asfollows:“I read an article in the Pasadena IndependenceStar News covering recent findings on follow-up
health-examinations of A-bomb survivors andtheir children at the Atomic Bomb Casualty Commission (ABCC) and RERF. I was exposed toradiation from the atomic bomb in Hiroshima, but
I am now living in LA. Despite my concerns about
health disorders related to the atomic bomb, I cannot undergo health checkups as regularlyas A-bomb survivors living in Hiroshima andNagasaki. In LA, there are few physicians who
have enough information regarding atomic
bombs. Whenever I see a doctor, he/she finishes
his/her examination by saying, ‘Your concerns
over your health may be due to psychologicalreasons.’ In addition, medical expenses here arevery high, which makes me refrain from seeing
doctors regularly. This is the biggest problem forus, the members of A-bomb survivors’ group in
LA. Isn’t there any sensible resolution for our
problem?”
I wondered how I could respond to this earnest
appeal. No concrete solutions came to my mind. I
therefore wrote a letter to my friend at PFMR, asking him whether he can discuss this matter with those
involved in medicine in the United States, including
Dr. Noguchi. I also wrote a similar letter to Ms.
Sueishi. Thereafter, I exchanged airmail letters with
Ms. Sueishi several times. I believe that she reported
on subsequent progress of the matter, but I do nothave a clear memory about it. In those days, I was
RERF Update Volume 19, Issue 2, 2008

Human Interest Notes
extremely busy and could not provide Ms. Sueishi
with substantial support. Although I may soundapologetic, that was the time shortly after
reorganization of ABCC into RERF, and I was very
busy in drafting a budget for the first fiscal year for
RERF.
In July 1976, Dr. Noguchi and Ms. Sueishi visited Hiroshima. They also came over to RERF.
Although this was the first time that I met Ms.
Sueishi, I felt that I had already met her several times
before. I have heard that the two visited the local
governments and medical associations of Hiroshima
Prefecture and Hiroshima City and made their best
effort for the realization of the health-examination
project for A-bomb survivors living in the UnitedStates. Thanks to the effort of Dr. Noguchi and Ms.
Sueishi, as well as the untiring effort of those concerned in various circles in Hiroshima, in the summer of 1977, specialists from Hiroshima visited theWest Coast, including LA and San Francisco, where
many A-bomb survivors lived, for interviews andmedical examinations. From RERF, dosimetry experts participated in this project for the estimationof radiation doses of A-bomb survivors living in the
United States. The project has greatly contributed toeradication of concerns over health among thosesurvivors.
Now, I want to describe my personal views
regarding the project. Needless to say, the health-Return to Table of Contents

21
examination project for those living in the UnitedStates started with personal efforts of Dr. Noguchi
and Ms. Sueishi. The effort subsequently made by
the medical associations of Hiroshima and Nagasaki
and medical administrative specialists greatly contributed to the implementation of this project. This
attests to the fact that the power of a small thing likean ant, if supported by enthusiasm, can become big
enough to move a large rock. The health-examination project has been expanded over the years, andnow even A-bomb survivors living in Brazil canundergo relevant examinations. It is gratifying thatthe medical project is still helpful in maintenance ofthe health of A-bomb survivors abroad and alleviation of their psychological concerns. I feel proud that
I provided some help, even though a small amount,to the great efforts made by Dr. Noguchi and Ms.
Sueishi. The above is my subjective report, which,
to my regret, may lack objectivity. I would like to
ask those well-versed in this project to indicate mymistakes and make necessary corrections.
Note: Although the first letter from Ms. Kazue
Sueishi had been maintained in my files, its location
has been unknown since I transferred my private files
to my home at the time of my retirement. I am stilltrying to locate this letter … It is quite regrettable if
I have lost it.

RERF Update Volume 19, Issue 2, 2008

22

Human Interest Notes

In Memory of Dr. Chiyoko Satoh(1937–2008)
Norio Takahashi, Laboratory ofBiochemical Genetics, Department of Genetics
In mid-March, when the cherry blossoms werefirst starting to bloom, I received news of the deathof Dr. Chiyoko Satoh who had once served as Chiefof the Department of Genetics. The news was shocking to me, because I had heard only that she waswell.
It is true that time flies, and it has been nearly 30
years since I first met Dr. Satoh, when I visited RERF
to be interviewed for a job. That was in June 1978.
When I joined the Biochemical Genetics (BGS)
Laboratory of the Department of Clinical Laboratories (the laboratory was later incorporated into the
Department of Genetics), research on genetic effectsof A-bomb radiation using starch gel electrophoresis was at a peak. Everyday, electrophoresis was
performed as if the laboratory were some sort offactory. Dr. Satoh was the leader of these studies and,
under her guidance, research scientists labored hardto achieve progress in their own experiments anddata preparation.
Since DNA research was to be conducted after
the electrophoresis studies, we decided to prepare
immortalized cell lines using lymphocytes obtained
from study participants. Dr. Satoh and I embarked
on furthering our education (away from RERF, inOsaka) by studying techniques for cell immortalization and DNA analysis together under Dr. Tasuku
Honjo, then Professor at Osaka University. One of
my fondest memories is of us engaging in experiments day and night in a laboratory located in
Osaka’s Nakanoshima district under the guidance ofDr. Mieko Kodaira (currently, Associate SeniorResearch Scientist at the Department of Genetics). I
was impressed with Dr. Satoh, who, while staying at
a weekly rental apartment, pushed herself everyday
with the aim of introducing the new techniques toour laboratory.
Over the years, Dr. Satoh and I often attended thesame international scientific conferences, but wenever took the same airplane (even for short-distance
trips). She probably was avoiding such a situationout of consideration for her subordinates, to ensurethat they could relax by themselves, or she mightalso have felt that it was easier simply to travel byherself.
What I have written so far may give the impression that Dr. Satoh was a straight-laced woman, withno interests outside of work, but that was not at all

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Dr. Chiyoko Satoh in 1997 (fourth person from left in
front row) with staff members of the Biochemical
Genetics Laboratory

the case. All the staff members who worked at RERF
for a relatively long time surely know that she played
tennis. Not only in the evenings but also during
lunchtime, she could be seen in her tennis skirt playing energetically on RERF’s tennis court.
Dr. Satoh’s spirit of challenging new goals, whichshowed not only in the area of research but also in
her hobbies, might have been the secret to how she
maintained her youth. She especially loved scuba
diving and often showed me photographs that she
had taken while in the water. Even after her retirement from RERF, she apparently remained active inthese two hobbies; whenever we heard word of her,
the news was often in such context.
Dr. James Neel, Professor at the University ofMichigan, who was one of the founders of the American Society of Human Genetics and a giant in thefield of human genetics, visited RERF once a year
to make detailed review of BGS results. At suchtimes, Dr. Satoh used to exclaim, “Typhoon Neel iscoming.” However, Dr. Neel has since passed away.
Dr. Howard Hamilton (then Chief of the Departmentof Clinical Laboratories), who used to affectionately
call Dr. Satoh “Sugar,” has also died. Now, Dr. Satohis gone, and I truly feel as if the world has become alonelier place.
On the grounds of Fumon Temple, where Dr.
Satoh’s funeral was held, blossoms of a weeping
cherry tree were in full bloom. I felt they were suitable for bidding farewell to Dr. Satoh, who always
had a glamorous air about her. I join my hands inprayer for the repose of her soul.

RERF Update Volume 19, Issue 2, 2008

Human Interest Notes

23

Mourning the Death of Former Vice Chairman Sheldon Wolff(1928–2008)
Seymour Abrahamson, Former Vice Chairman
and Chief of Research
One important measure of a person’s life is thebeneficial influence he or she has had on the lives ofcountless others. For Professor Sheldon Wolff (Shelly
to all who knew him) that influence has been on a
grand scale. To me personally it has lasted over ahalf century.
Shelly was born in Peabody, Massachusetts,
earned his Bachelor of Science Degree, with highest
honors, at Tufts College in 1950 and then by 1953
he completed both a Master’s and PhD degree at
Harvard University. He studied with Professor Karl
Sax, one of the pre-eminent cytologists of thatera. The Biology Division of Oak Ridge National
Laboratory under the direction of Dr. Alexander
Hollaender was becoming the international centerof research in radiobiology and it was natural for Dr.
Hollaender to recruit this highly touted young PhD
to the program in 1953.
One of Shelly’s first publications in Science
showed that irradiated Vicia fava seeds required oxidative metabolism in order for induced chromosome
damage to be repaired. He had used chemicals toblock metabolism. (Human cytogenetics research
was still more than a decade from practical use. Infact the correct human chromosome number had yet
to be discovered.) It was, however, this report by
Shelly that allowed me to demonstrate in my PhD
thesis that the same held true for the fruitfly, Drosophila. This confirmed Shelly’s work. This was thestart of our long-lasting friendship.
Shelly spent from 1953 to 1966 at Oak Ridge
where he held a Senior Research Staff position andhis studies led to international prominence. His
laboratory attracted post-doctoral fellows who were
to become future leaders in the field as was true of
his students at the University of California, San Francisco (UCSF) where he moved in 1966 as Professorof Cytogenetics.
While there he and his students pioneered workon sister chromatid exchange (SCE) in mammaliancells, the chemical techniques that were developed
allowed the differentiation of the two chromatids andwas an important means of assaying chemical mutagen induced damage. Certain human diseases werealso shown to be associated with enhanced levels of
SCE’s. Three of his publications in this area reached
the status of Citation Classics.
Because of our interactions on various scientificcommittees we were able to co-author two publicaReturn to Table of Contents

Dr. Sheldon Wolff in his RERF office in 1998

tions that appeared in the journal Nature. The firstwas a demonstration that the larger the DNAcontent of a species the larger the radiation-induced
gene mutation rate. The second was an analysis of
the mechanism underlying radiation-induced genemutations indicating that chromosome deletions orother rearrangements were the primary cause of suchmutations in animal germ cells. In a sense, this confirmed the work of L.J. Stadler, the co-discoverer
with H.J. Muller of the phenomenon that X rays
induced mutations.
In 1983, Shelly became Director of the Laboratory of Radiobiology and Environmental Health at
UCSF, a position he held until his retirement fromthe University. And in 1984, he published anotherhighly influential paper in Science on adaptive response induced by low-dose exposure to ionizing
radiation. It is a very interesting observation for
estimating the low-dose risk, and we do not know as
yet whether or not such low-dose exposure itself is
detrimental or not.
His honors include but are certainly not limited
to: The E.O. Lawrence Memorial Award 1973, Gold
Medal recipient and Failla Lecturer of the Radiation
Research Society 1992, and the first Leonard Sagan
Belle Award in 1998 as a recognition of his researchthat had previously demonstrated unusual repair
mechanisms accompanied by low-dose radiation
exposures. In 1980–81, he served as President of theEnvironmental Mutagen Society (EMS) and Honorary Vice President of the Third International ConRERF Update Volume 19, Issue 2, 2008

24

Human Interest Notes
ference of Environmental Mutagens and was recipient of the EMS Award.
As the readers of this publication know, after hisretirement from the University of California, Dr.
Wolff was Vice Chairman and Chief of Research of
the Radiation Effects Research Foundation from1996–2000.
Shelly’s curriculum vitae involving scientificactivities on the national and international level runs
to over three and a half pages and includes work for
the National Academy of Sciences, National Insti-

tutes of Health, many programs of the Departmentof Energy and a number of different international
committees. He also served on the editorial boardsof nearly a dozen scientific journals. Shelly had awonderful sense of humor, a zest for life, and was aconnoisseur of fine food, excellent wines, and good
cigars.
Shelly died on June 5th 2008 as a result of pulmonary fibrosis. He is survived by Francis, his wifeof fifty-four years, his three children, Victor, Roger
and Jessica, and three grandchildren.

In Memoriam
The cohort of former employees of ABCC and
RERF is aging along with the A-bomb survivors.
From time-to-time we receive word that anotherformer employee has died. We plan to report the information that we receive, but often we do not havesufficient knowledge to write a proper obituary. So
we will rely on your help to send us the names ofany former employee who you know has recently
died. Also, please let us know if any of our information in Update is incorrect and feel free to provide
additional information for RERF’s records.
Ray Carl Anderson (September 24, 1917–May 20,
2008)
William “Jack” Schull alerted us to the passingof Ray Anderson who was Jack’s predecessor as headof the Genetics Department of ABCC. He served
ABCC between 1947–1949. He had been retired
from the faculty of the University of Minnesota andspent time between his lakeshore home in Northern
Minnesota and a home in Sun City, Arizona. He was
90 when he died this year in Sun City, Arizona. Dr.
Anderson was one of the four individuals who organized the ABCC in the autumn of 1947 (along with
Dr. James Neel, Dr. Masuo Kodani, and Mr. Richard

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Brewer). He had a Ph.D. in genetics as well as his
medical degree. He lived first in Hiro-machi since
there was no housing available in Hiroshima and his
office was located in the Red Cross Hospital in
Senda-machi and later shifted to the Gaisenkan in
Ujina area when the laboratory was constructed there.
He left Hiroshima in 1949 and went to the University of Minnesota Medical School where he became
a Professor of Pediatrics (Cardiology). His research
was associated with Dr. C. Walton Lillehei’s surgical group that pioneered open-heart surgery.
Dr. Anderson and his wife Hattie satisfied a 46year desire to visit Hiroshima in October 1995 when
they returned on a cruise ship from Vancouver. By astrange coincidence, and unknown to each other,
there was another passenger on the same cruise ship
who was also associated with ABCC—Dr. Isolde
Loewinger, who was Chief of Pediatrics from 1955–
1957. They had never met before. But since Dr.
Anderson had written to former RERF Chairman
Itsuzo Shigematsu about his arrival and Dr.
Loewinger to Mr. Mick Rappaport about hers, bothof them while on board were informed in a fax sent
by Mr. Richard Sperry that they shared somethingin common.

RERF Update Volume 19, Issue 2, 2008

25

Facts and Figures

Facts and Figures
In Update Volume 16 (2005), the Biosample
Archive of RERF was summarized in a table that
illustrated the large number of archived materials thathave been donated and stored at RERF. The
article also emphasized the importance of thosesamples to RERF’s research and their potential to be
used to improve our basic understanding of late-arising health consequences of prior acute radiation
exposures. With evolving analytical methodologies,
the samples continue to gain value and require
vigilant management and prudent usage in order to
optimize their scientific value.
Recognizing the importance of this treasure andits maintenance responsibilities, RERF has a 17member Committee on Biological Samples (CBS)that has been meeting to assess the collection, storage, and use of biological samples at RERF. During
2007 the CBS activities included: (1) updating
inventories of archived biosamples; (2) reviewing
the storage methodologies employed by RERF;(3) assessing current storage capacities and projectedstorage needs; (4) reviewing the status of safeguards;and (5) review of the current management of thearchives.
On May 15, 2008 the CBS released a 36-page
report: Committee on Biological Samples: Status
Report—2007 and Recommendations. The report
identifies and discusses several issues associated withthe archived biosamples at RERF. In addition, thecommittee reached a number of conclusions, including for example:• The holdings of the archive have been updatedwith details and improved accuracy, but
improvements could be made in the speed ofrecovery, frequency of updating, and accuracyof the inventory data.
• Overall growth of the archive is estimated to
be in the range of 5% per year, with a projecteddoubling of the holdings within 15 years.
• Significant improvements have been made insecuring uniform coverage of adequate electrical backup for all cold-storage units (mechani-

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cal freezers), but improvements could be madein remote monitoring of all of the storage units.
• The Hiroshima Laboratory is extremely limited in space and RERF will need to provide
additional renovated space to accommodate thegrowth of the archives.
• Ten-year projections of the required storage
space suggest that the current ~228 m2 will need
to be increased to ~424 m2, an ~86% increase.
• A restructuring of how the archive is managed
could increase the overall quality and utility of
RERF’s biorepository.
• While elements of quality assurance (QA) andquality control (QC) programs are in place, theprograms need to be uniformly applied andpracticed.
The report suggested a number of recommendations with respect to improving the archive inventory
process, increasing sample safeguards, expanding thestorage capacity, designing and implementing a regimented QA/QC program, and restructuring of thearchives to include a centralized management anddatabase. Finally, the report included an annex withtables listing the most recent biosample inventories,
a summary of biosample preparative protocols, anda report of a visit to the Mayo Clinic in Rochester,
Minnesota by Drs. Susan Geyer and Hiroaki Katayama
to observe and discuss how that important U.S.
research institution collects, stores, and utilizes
biosamples.
The CBS strongly recommended that RERF plana series of international workshops designed to obtain advice from experts on the collection, storage,
and utilization of RERF’s world-heritage biosamples.
The first of such workshops was held in March 2008
(RERF Symposium on Bioinformatics, see page 10).
The second was held in RERF October 10–11, 2008,
focusing on breast cancer research and will bereported on in the next issue of Update. As stated in
the past, RERF welcomes any and all constructive
input from the scientific community on the natureand use of this unique biosample repository.

RERF Update Volume 19, Issue 2, 2008

Research Protocols and Publications

26

Research Protocols Approved in
January–September 2008

at the time of the bombings, from the current 700 to
2,900.

RP 1-08 Establishment of a Recombinant
Mouse Model for Assessment of Genetic Effectsof Radiation at Low Doses
Noda A, Hirai Y, Kodama Y, Cullings HM, Nakamura
N
In this project, we propose to create geneticallymodified mice in which mutant cells arising in theirbody will generate green fluorescence. By using thesemice, genetic effects of radiation (transgenerational
effects) will be measured in their germ cells; spermatids, spermatocytes, spermatogonia, and oocytes.
This approach could pave the way to analyze genetic effects of radiation at low doses without
requiring a large number of F1 animals. To study thepossible negative selection of mutant embryos or
neonatal mice carrying the mutation, a fraction ofmutant germ cells will be used to produce fertilized
eggs which will be subsequently transplanted inpseudopregnant mice’s wombs to scrutinize thedevelopmental/growth process. Furthermore, mutant
cell frequency of somatic cells in F1 animals born toirradiated mice will be measured to test if genomic
instability might be observed as a delayed effect ofparental exposure.

RP 3-08 Mortality in Relation to Smoking andOther Lifestyle Factors in a Japanese Population
Sakata R, McGale P, Darby S, Grant EJ, Nishi N,
Boreham J, Sugiyama H, Soda M, Shimizu Y,
Tatsukawa Y, Yamada M, Moriwaki H, Kasagi F,
Suyama A, Geyer SM, Kodama K, Peto R
Existing studies of the effects of smoking in Japanese populations suggest that its impact on mortality is smaller than elsewhere, given the amountsmoked. At present it is not clear whether this is areflection of the fact that cigarette smoking became
common in Japan somewhat later than in other countries or whether there are other factors that modify
the impact of smoking, or appear to modify it. (Forexample, the lung cancer rate in non-smokers ishigher in Japan than in some other countries. Therefore, if the lung cancer rate among smokers were thesame in Japan as elsewhere, the relative risk would
appear smaller.) It is also not clear what the impact
is of using different methodologies to estimate thesmoking risk. The proposed study will address thoseissues in the Life Span Study population (including
members of the Adult Health Study) using data
already held at RERF. The project will be carriedout jointly between staff from RERF and the University of Oxford and it will draw on experience thathas recently been gained in analyses of the effect of
prolonged smoking in the British doctors’ study.

RP 2-08 Mail Survey 2008 on Epidemiological
Factors in the Extended Life Span Study Population
Nishi N, Nagano J, Grant EJ, Sugiyama H, Sakata
R, Hsu WL, Kasagi F, Fujiwara S, Akahoshi M,
Moriwaki H, Mabuchi K, Ron E, Suyama A, Kodama
K
A mail survey will be conducted on about 47,000
subjects in the Extended Life Span Study cohort(LSS-E85) who are alive at the time this study is
initiated, in order to obtain and update information
on epidemiological factors such as lifestyles, historyof radiotherapy, height, weight, financial situation,disease history, menstruation, and psychosocial
factors. Such information will be used as factors that
may confound or modify the health effects of radiation. Due to the large size, long-term follow-up, andadvanced age of the cohort, an effort to broaden thefocus to include overall aging markers is also proposed. Additional targeted data include present andpast history of major diseases as well as mental andphysical health status. A pilot study has shown thatboth the validity and reproducibility of the questionnaire are high and its implementation is feasible. To
support the approved research protocol entitled“Clinical health study for expanded group of younger
A-bomb survivors” (RP 3-07), applicants for theclinical health study will be sought among subjectsof the mail survey to increase the number of participants of the Adult Health Study under 10 years old
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RP 4-08 Investigation of Storage Conditions
for Cataract Tissue of A-bomb Survivors, and
Its Collection and Storage Program
Neriishi K, Blakely EA, Chang P, Nakashima E,
Ohishi W, Fujiwara S, Hida A, Akahoshi M, Hayashi
T, Ito R, Nakachi K, Minamoto A, Yokoyama T, Toda
S, Uematsu M, Tsuiki E, Kiuchi Y, Kitaoka T, Shirai
A, Cucinotta FA, Chylack LT
The goal of this project is to confirm reproducibility of the storage method for cataract tissues fromthe Adult Health Study (AHS) participants who
undergo cataract operations, and to collect and store
the tissue for future analyses. A recent study has
indicated that the odds ratio at 1 Sv of prevalence
for those who underwent cataract operations was 1.39
(95% confidence interval 1.24, 1.55). AHS participants who were young at the time of the bombingsare expected to reach the age of cataract operation
within the next decades. The removed cataract
tissues are expected to contribute significantly tofuture research on radiation-induced cataract. Whenenough numbers of tissues are collected, newresearch protocols, focusing on specific topics, will
RERF Update Volume 19, Issue 2, 2008

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Research Protocols and Publications
be separately prepared.

Recent Publications(Japanese): the original article is in Japanese.

RP 5-08 Breast Cancer Incidence among
Atomic-bomb Survivors, 1950–2005
Yonehara S, Nishisaka T, Nakashima M, Nishi N,
Furukawa K, Soda M, Suyama A, Ikeda T, Tokuoka
S, Mabuchi K, Land CE, Preston DL, Kodama K,
Kasagi F
Several breast cancer incidence studies based on
the RERF Life Span Study (LSS) population wereconducted during the period from 1950 through 1990.
Among those breast cancer cases, a highly significant linear dose response was observed in breast cancer incidence among exposed people; among women
exposed at less than 20 years of age, excess relativerisk per Sv for those with attained age of 35 or more
was around 2, whereas excess relative risk per Sv
for those with attained age of 20 years or more andless than 35 was shown to be remarkably high, at
16.8. Further, among women exposed at less than
20 years of age, excess relative risk of bilateral breast
cancer per Sv was also shown to be high, which suggested the presence among them of a group highly
sensitive to radiation-induced carcinogenesis.
However, more recent data indicate that both age at
exposure and attained age are important modifiersof the radiation-related risk of breast cancer, and therelative importance of these two factors is dependent on models, background rates, and other assumptions used. We thus need to pursue the risk analysis
to better understand the risk patterns in an extended
follow-up and try to identify morphological or otherfeatures contrasting early- vs. late-onset breast
tumors. In this study, we will examine new breast
cancer cases occurring in the LSS during the 15 years(from 1991 through 2005) following the previous
period and cases that occurred during the previous
study period but were registered after that period.
Ages at diagnosis of new breast cancer cases occurring during the period from 1991 through 2005 areat least 45 years old. We will examine new findings
and compare them with previous findings, andreview all breast cancer cases during the entire
period since the previous study, by classifying thembased on new histological classification criteria of
the World Health Organization (WHO).

Adiga SK, Toyoshima M, Shiraishi K, Shimura T,
Takeda J, Taga M, Nagai H, Kumar P, Niwa O.
p21 provides stage specific DNA damage control
to preimplantation embryos. Oncogene 2007
(September 13); 26(42):6141-9.
Asakawa J. Restriction landmark genome scanningfor the detection of mutations. Martin CC, ed.
Methods in Molecular BiologyTM—Environmental Genomics. Totowa, New Jersey: Humana Press
2007:pp 153-70.
Asia Pacific Cohort Studies Collaboration (RERF:
Nakachi K). The burden of overweight and obesity in the Asia-Pacific region. Obesity Reviews
2007 (May); 8(3):191-6.
Asia Pacific Cohort Studies Collaboration (RERF:
Nakachi K). Cardiovascular risk prediction tools
for populations in Asia. Journal of Epidemiology
and Community Health 2007 (February);61(2):115-21.
Asia Pacific Cohort Studies Collaboration (RERF:
Nakachi K). Impact of smoking and smoking cessation on lung cancer mortality in the Asia-Pacificregion. American Journal of Epidemiology 2007
(June 1); 165(11):1280-6.
Asia Pacific Cohort Studies Collaboration (RERF:
Nakachi K). Hypertension: Its prevalence andpopulation-attributable fraction for mortality fromcardiovascular disease in the Asia-Pacific region.
Journal of Hypertension 2007 (January); 25(1):739.
Asia Pacific Cohort Studies Collaboration (RERF:
Nakachi K). Blood cholesterol and vascular mortality by age, sex, and blood pressure: A metaanalysis of individual data from 61 prospective
studies with 55000 vascular deaths. Lancet 2007
(December 1); 370(9602):1829-39.
Baba T, Amasaki Y, Soda M, Hida A, Imaizumi M,
Ichimaru S, Nakashima E, Seto S, Yano K,
Akahoshi M. Fatty liver and uric acid levels predict incident coronary heart disease but not stroke
among atomic bomb survivors in Nagasaki.
Hypertension Research 2007; 30(9):823-9.
Cullings HM, Cologne JB. Risk from ionizing radiation. Melnick EL, Everitt BS, ed. Encyclopedia of Quantitative Risk Analysis and Assessment.
Chichester: John Wiley & Sons, Ltd. 2008 (July);

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RERF Update Volume 19, Issue 2, 2008

Research Protocols and Publications
4:1540-6. (RERF Report CR 1-08)
Fujiwara S, Nakamura T, Orimo H, Hosoi T, Gorai
I, Oden A, Johansson H, Kanis JA. Development
and application of a Japanese model of the WHO
fracture risk assessment tool (FRAX TM). Osteoporosis International 2008 (February 22);19(4):429-35.
Fujiwara S, Suyama A, Cologne JB, Akahoshi M,
Kasagi F, Kodama K. Health issues among offspring of A-bomb survivors. Hiroshima Igaku[Journal of the Hiroshima Medical Association]2008 (April 28); 61(4):283-6. (Proceedings of the
48th Late A-bomb Effects Research Meeting,2007) (Japanese)
Fujiwara S, Suyama A, Cologne JB, Akahoshi M,
Yamada M, Suzuki G, Koyama K, Takahashi N,
Kasagi F, Grant EJ, Lagarde F, Hsu WL, Furukawa
K, Ohishi W, Tatsukawa Y, Neriishi K, Takahashi
I, Ashizawa K, Hida A, Imaizumi M, Nagano J,
Cullings HM, Katayama H, Ross NP, Kodama K,
Shore RE. Prevalence of adult-onset multifactorial disease among offspring of atomic bomb
survivors. Radiation Research 2008 (October);170(4):451-7. (RERF Report 2-08)
Hamasaki K, Kodama Y, Kusunoki Y, Nakashima
E, Takahashi N, Nakamura N, Nakachi K.
Chromosome instability in colonally propagatedT lymphocytes in vitro from A-bomb survivors.
Hiroshima Igaku [Journal of the Hiroshima Medical Association] 2008 (April 28); 61(4):304-7.
(Proceedings of the 48th Late A-bomb Effects
Research Meeting, 2007) (Japanese)
Hamatani K, Eguchi H, Ito R, Mukai M, Takahashi
K, Taga M, Imai K, Cologne JB, Soda M, Arihiro
K, Fujihara M, Abe K, Hayashi T, Nakashima M,
Sekine I, Yasui W, Hayashi Y, Nakachi K. RET/
PTC rearrangements preferentially occurred inpapillary thyroid cancer among atomic bomb survivors exposed to high radiation dose. Cancer
Research 2008 (September 1); 68(17):7176-82.
(RERF Report 1-08)
Hayashi T, Fujiwara S, Kusunoki Y, Nakashima E,
Suzuki G, MacPhee DG, Kyoizumi S. Risks ofradiation-related diabetes differ among atomicbomb survivors with different HLA class II
haplotypes. Hansen JA, ed. Immunobiology of the
Human MHC. Seattle: IHWG Press 2007:pp 3403. (Proceedings of the 13th International Histocompatibility Workshop and Conference Volume
II)

28
Imaizumi M, Soda M, Maeda R, Nakashima E,
Ida H, Kawakami A, Nakamura T, Eguchi K.
Prevalence of Sjögren syndrome among Nagasaki
atomic bomb survivors. Annals of the Rheumatic
Diseases 2008 (May); 67(5):689-95. (RERF
Report 2-07)
Hirai Y, Inoue T, Noda A, Kodama Y, Nii K, Mizuno
M, Tokuoka S, Kodama K, Mabuchi K, Land CE,
Nakamura N. Involvement of heterozygotes ofbreast cancer-related genes in early-onset breastand ovarian cancers among A-bomb survivors.
Hiroshima Igaku [Journal of the Hiroshima Medical Association] 2008 (April 28); 61(4):360-2.
(Proceedings of the 48th Late A-bomb Effects
Research Meeting, 2007) (Japanese)
Horibe H, Kasagi F. ECG abnormality and total
mortality—Mortality risk by Minnesota code.
Ueshima H, ed. Evidence of Circulatory Disease
Based on NIPPON DATA. Tokyo: Japan Medical
Journal; 2008 (July), pp 143-51. (Japanese)
Imaizumi M, Ashizawa K, Neriishi K, Akahoshi M,
Nakashima E, Usa T, Tominaga T, Hida A, Sera
N, Soda M, Fujiwara S, Yamada M, Maeda R,
Nagataki S, Eguchi K. Thyroid diseases in atomic
bomb survivors exposed in utero. Journal of Clinical Endocrinology and Metabolism 2008 (May);
93(5):1641-8. (RERF Report 13-07)
Kasagi F, Kodama K, Ueshima H, Katayama H.
Health assessment system. Ueshima H, ed. Evidence of Circulatory Disease Based on NIPPON
DATA. Tokyo: Japan Medical Journal; 2008 (July),
pp 249-64. (Japanese)
Kanis JA, Oden A, Johnell O, Johansson H, De Laet
C, Brown J, Burckhardt P, Cooper C, Christiansen
C, Cummings S, Eisman JA, Fujiwara S, Gluer C,
Goltzman D, Hans D, Krieg M-A, La Croix A,
McCloskey E, Mellstrom D, Melton LJ III, Pols
H, Reeve J, Sanders K, Schott A-M, Silman
A, Torgerson D, van Staa T, Watts NB, Yoshimura
N. The use of clinical risk factors enhances theperformance of BMD in the prediction of hipand osteoporotic fractures in men and women.
Osteoporosis International 2007 (August);
18(8):1033-46.
Kanzaki H, Ouchida M, Hanafusa H, Yamamoto H,
Suzuki H, Yano M, Aoe M, Imai K, Date H,
Nakachi K, Shimizu K. The association between
RAD18 Arg302Gln polymorphism and the risk ofhuman non-small-cell lung cancer. Journal of Cancer Research and Clinical Oncology 2008 (February); 134(2):211-7.

Hida A, Akahoshi M, Takagi Y, Ashizawa K,
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RERF Update Volume 19, Issue 2, 2008

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Research Protocols and Publications
Kodama K, Kasagi F, Nishi N, Sugiyama H, Soda
M, Suyama A. Cancer registry and researches onlate health effects of atomic bomb radiation.
Hiroshima Igaku [Journal of the Hiroshima Medical Association] 2008 (April 28); 61(4):267-9.
(Proceedings of the 48th Late A-bomb Effects
Research Meeting, 2007) (Japanese)
Kohara K, Tabara Y, Nakura J, Imai Y, Ohkubo T,
Hata A, Soma M, Nakayama T, Umemura S,
Hirawa N, Ueshima H, Kita Y, Ogihara T, Katsuya
T, Takahashi N, Tokunaga K, Miki T. Identification of hypertension-susceptibility genes andpathways by a systemic multiple candidate geneapproach: The millennium genome project for
hypertension. Hypertension Research 2008
(February); 31(2):203-12.
Kusunoki Y. Differential process of memory T
cells—Overview. Clinical Immunology & Allergology 2008 (May); 49(5):485-94. (Japanese)
Mashimo Y, Suzuki Y, Hatori K, Tabara Y, Miki T,
Tokunaga K, Katsuya T, Ogihara T, Yamada M,
Takahashi N, Makita Y, Nakayama T, Soma M,
Hirawa N, Umemura S, Ohkubo T, Imai Y, Hata
A. Association of TNFRSF4 gene polymorphisms
with essential hypertension. Journal of Hypertension 2008 (May); 26(5):902-13.
Masunari N, Fujiwara S, Nakata Y, Furukawa K,
Kasagi F. Effect of angiotensin converting enzyme
inhibitor and benzodiazepine intake on bone loss
in older Japanese. Hiroshima Journal of Medical
Sciences 2008 (March); 57(1):17-25. (RERF
Report 21-04)
Nakachi K, Hayashi T, Hamatani K, Eguchi H,
Kusunoki Y. Sixty years of follow-up of Hiroshima
and Nagasaki survivors: Current progress in molecular epidemiology studies. Mutation Research2008 (July); 659(1-2):109-17. (RERF Report
10-07)
Nakamura N. Male infertility as a marker of genetic
effects of radiation: Will the detection of genetic
effects of radiation be easier if a phenotype related to multiple genes were chosen? Hoshasen
Seibutsu Kenkyu [Radiation Biology ResearchCommunications] 2008 (March); 43(1):1-9.
(Japanese)
Nakashima E, Akahoshi M, Neriishi K. Systolicblood pressure and systolic hypertension in adolescence of in utero exposed atomic-bomb survivors. Hiroshima Igaku [Journal of the Hiroshima
Medical Association] 2008 (April 28); 61(4):3003. (Proceedings of the 48th Late A-bomb Effects
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Research Meeting, 2007) (Japanese)
Nakashima E, Neriishi K, Minamoto A. Comparison of methods for ordinal lens opacity data fromatomic-bomb survivors: Univariate worse-eye
method and bivariate GEE method using global
odds ratio. Annals of the Institute of Statistical
Mathematics 2008 (September); 60(3):465-82.
(RERF Report 6-04)
Nishi N. Socioeconomic factors and circulatory disease—Relationship between job categories andcirculatory disease. Ueshima H, ed. Evidence ofCirculatory Disease Based on NIPPON DATA.
Tokyo: Japan Medical Journal; 2008 (July), pp
221-3. (Japanese)
Nishi N. Socioeconomic factors and circulatory disease—Relationship between urban/rural areas andcirculatory disease. Ueshima H, ed. Evidence ofCirculatory Disease Based on NIPPON DATA.
Tokyo: Japan Medical Journal; 2008 (July), pp
216-20. (Japanese)
Nishi N. Baseline cardiovascular risk factors andstroke mortality by municipality population sizein a 19-year follow-up study—NIPPON DATA 80.
Journal of Epidemiology 2008 (July); 18(4):13543.
Nishi N. Comments on “Solid cancer incidence inatomic bomb survivors: 1958–98.” Isotope News2008 (June); 650:17-21. (Japanese)
Nishi N, Sugiyama H, Hsu WL, Soda M, Kasagi F,
Mabuchi K, Kodama K. Differences in mortality
and incidence for major sites of cancer by education level in a Japanese population. Annals of Epidemiology 2008 (July); 18(7):584-91. (RERF
Report 7-07)
Ohishi W, Fujiwara S, Cologne JB, Suzuki G,
Akahoshi M, Nishi N, Takahashi I, Chayama K.
Risk factors for hepatocellular carcinoma in a Japanese population: A nested case-control study. Cancer Epidemiology, Biomarkers and Prevention
2008 (April); 17(4):846-54. (RERF Report 16-07)
Okubo T, ed. Report of Atomic Bomb Disease Research Project. Ministry of Health, Labour andWelfare Grants: FY2007 Report, 2008 (August
1):78 p. (Japanese)
Pierce DA, Vaeth M, Cologne JB. Allowance for
random dose estimation errors in atomic bomb
survivor studies: A revision. Radiation Research2008 (July); 170(1):118-26. (RERF Report 3-07)

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Research Protocols and Publications
Sueoka-Aragane N, Imai K, Komiya K, Sato A,
Tomimasu R, Hisatomi T, Sakuragi T, Mitsuoka
M, Hayashi S, Nakachi K, Sueoka E. Exon 19 of
EGFR mutation in relation to the CA-repeat polymorphism in intron 1. Cancer Science 2008 (June);
99(6):1180-7.
Sugiyama H, Nishi N, Kuwabara M, Ninomiya M,
Arita K, Yasui W, Kasagi F, Kodama K. Patternsof diagnosis and treatment among childhood cancer patinents in Hiroshima City. Hiroshima Igaku[Journal of the Hiroshima Medical Association]2008 (July); 61(7):557-62. (Japanese)
Takahashi N, Tsuyama N, Sasaki K, Kodaira M,
Satoh Y, Kodama Y, Sugita K, Katayama H.
Segmental copy-number variation observed inJapanese by array-CGH. Annals of Human
Genetics 2008 (March); 72(Pt 2):193-204. (RERF
Report 6-07)
Tatsukawa Y, Hsu WL, Yamada M, Cologne JB,
Suzuki G, Yamamoto H, Yamane K, Akahoshi M,
Fujiwara S, Kohno N. White blood cell count,especially neutrophil count, as a predictor of hypertension in a Japanese population. Hypertension
Research 2008 (July); 31(7):1391-7. (RERF
Report 16-06)
Tatsukawa Y, Nakashima E, Yamada M, Funamoto
S, Akahoshi M, Fujiwara S. Relationships between
incidence of noncancer diseases and radiation doseamong the atomic bomb survivors exposed inutero. Hiroshima Igaku [Journal of the Hiroshima
Medical Association] 2008 (April 28); 61(4):3556. (Proceedings of the 48th Late A-bomb Effects
Research Meeting, 2007) (Japanese)
Tatsukawa Y, Nakashima E, Yamada M, Funamoto
S, Hida A, Akahoshi M, Sakata R, Ross NP, Kasagi
F, Fujiwara S, Shore RE. Cardiovascular diseaserisk among atomic bomb survivors exposed inutero, 1978–2003. Radiation Research 2008
(September); 170(3):269-74. (RERF Report 4-08)

Neuroepidemiology 2008 (April 1); 30(3):152-60.
(RERF Report 14-06)
Yamada M, Soda M, Fujiwara S. Follicle-stimulating
hormone and oestradiol levels during perimenopause
in a cohort of Japanese women. International
Journal of Clinical Practice 2008 (July 31);62(10):1623-7. (RERF Report 10-04)
Yamada M, Wong FL. Effect of gender and smoking
on incidence of cardiovascular disease and peptic
ulcer in a Japanese population: The Radiation
Effects Research Foundation Adult Health Study.
Wesley MK, Sternbach LA, ed. Smoking and
Women’s Health. New York: Nova Science
Publishers, Inc.; 2008, pp 165-81.

Publications Using RERF Data
The following publications represent research done
by non-RERF scientists based on the data publicly
available from RERF.
Little MP, Hoel DG, Molitor J, Boice JD, Wakeford
R, Muirhead C. New models for evaluation ofradiation-induced lifetime cancer risk and its uncertainty employed in the UNSCEAR 2006 report.
Radiation Research 2008 (June); 169(6):660-76.
Sasaki MS, Nomura T, Ejima Y, Utsumi H, Endo S,
Saito I, Itoh T, Hoshi M. Experimental derivationof relative biological effectiveness of A-bomb neutrons in Hiroshima and Nagasaki and implications
for risk assessment. Radiation Research 2008
(July); 170(1):101-17.
Watanabe T, Miyao M, Honda R, Yamada Y.
Hiroshima survivors exposed to very low dosesof A-bomb primary radiation showed a high risk
for cancers. Environmental Health and Preventive
Medicine 2008 (September 15); 13(5):264-70.

Yamada M, Kasagi F. Late effects of atomic bomb—
Recent issues: “Aging-related diseases.” Hiroshima
Igaku [Journal of the Hiroshima Medical Association] 2008 (April 28); 61(4):271-4. (Proceedings of the 48th Late A-bomb Effects Research
Meeting, 2007) (Japanese)
Yamada M, Mimori Y, Kasagi F, Miyachi T, Oshita
T, Sudoh S, Ikeda J, Matsui K, Nakamura S,
Matsumoto M, Fujiwara S, Sasaki H. Incidence
of dementia, Alzheimer disease, and vascular dementia in a Japanese population: Radiation Effects
Research Foundation Adult Health Study.
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RERF Update Volume 19, Issue 2, 2008