Table of Contents
From the Editors.......................................................................................................................................... 1
RERF NewsThe 37th Scientific Council Meeting..................................................................................................... 1
National Geographic Television Films at RERF.................................................................................... 4
Staff News.............................................................................................................................................. 5
2010 Distinguished Lecture Series......................................................................................................... 7
Reports on Conferences and Workshops
Report of the 52nd Annual Meeting of the Japan Radiation Research Society,by Kazunori Kodama.......................................................................................................................... 8International Epigenetics Workshop, by Evan B. Douple...................................................................... 9
Science Articles
A Special Opportunity for RERF to Expand Studies of Immunosenescence and Other
Late Effects of Acute Ionizing Radiation Exposure in A-bomb Survivors, by
Yoichiro Kusunoki, Tomonori Hayashi, Evan B. Douple, and Kei Nakachi.................................... 13
Highlights of RERF Departments: Radiation Research Activities in the Department of  
Clinical Studies, by Saeko Fujiwara and Masazumi Akahoshi........................................................ 24
Human Interest Notes
An Intriguing Story of Mystery and Humanitarian Service, by Evan B. Douple................................ 35
In Memoriam........................................................................................................................................ 36
Research Protocols and Publications
Research Protocols Approved in October 2009–March 2010.............................................................. 37
Recent Publications.............................................................................................................................. 39

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

Yokuirasshaimashita!
Wewelcomeyoubackwiththeenthusiasticgreeting that is shouted by staff as you enter a typical
Japaneserestaurant.ThecharacteristicandbeautifulsongoftheUguisu(Japanesebushwarbler)intheHijiyama air once again reminds us that spring is
ending,thatthesakurahavefinishedblooming,and
thatScientificCouncilhasended(seeRERFNews)
andpreparationsfortheannualBoardMeetingare
underway.Inthisfirst2010Updateyouwilllearn
aboutthreesomewhatspecialeventsforRERF.First,
inNovemberRERFhostedforthefirsttimethe52nd
Annual Meeting of the Japan Radiation ResearchSociety (see Reports on Conferences and Workshops).Second,withplanningandactiveparticipationbyRERFemployees,includingpoundingricetomakemochi(seecoverphoto)andbreakingopenthenewbarrelofsake(kagami-wari),staffusheredinJanuarywithasuccessfulNewYearParty.And
third,inFebruary,aNationalGeographicTelevision
filmcrewspentalongdayfilmingthroughoutRERF

in preparation for a documentary film about theA-bombing of Hiroshima that will include some
coverageofRERFresearchactivities.
WeareespeciallypleasedtoannouncethatfourscientistsjoinedRERFsincethelastUpdate;please
read their self-introductions. A science article
describesthegoalsofanew,largeRERFcontractwithsignificantsupportfromaninstitutewithinthe
U.S. National Institutes of Health. The contract
representsauniqueopportunityforRERFscientists,
incollaborationswithscientistsandinstitutionsinJapanandtheU.S.,totestahypothesisthatradiation
enhancestheeffectsofagingontheimmunesystem.
AsecondsciencearticlebeginsaseriesofUpdate
reportsthatwillhighlightandsummarizetherecent
findingsandongoingactivitiesofRERFdepartments.
Thefirstarticleintheseriesfocusesontheresearch
activitiesoftheDepartmentofClinicalStudies.
Asalways,weinviteyoutosendyourquestions,
comments,orrecommendationsforhowwemight
improve Update. One such inquiry has led to thediscoverythatABCCmighthaveinfluencedthelife
of an adventurous Belgian physician (check out
HumanInterestNotes).Sountilthenextissue—Mataoidekudasai(goodbyeandpleasecomeagain)!

EvanB.Douple
Editor-in-Chief

Breaking open the new barrel of sake at the New Year
Party

The37thScientificCouncil(SC)metfromMarch3to5,2010inHiroshima,JapantoreviewRERF’sscientificprograms.Itwasco-chairedbyDr.Takashi
YanagawaandDr.JohnMulvihill.Dr.KazuoSakai
of the National Institute of Radiological Sciences
(Chiba)joinedusasanewmemberoftheSC.Toenhancethisyear’sin-depthreviewoftheDepartment of Clinical Studies (see a summary of thehighlightsofthisdepartmentonpage24ofthisissue
ofUpdate),theSCwasaugmentedbyspecialad hocReturn to Table of Contents

YukoIkawa
TechnicalEditor

scientificcouncilors,Drs.KojiMaemura(Hiroshima
University),YukihitoHigashi(NagasakiUniversity),
andDavidRush(TuftsUniversity),whoaddedexpertiseincardiovascularresearch,clinicalstudies,
andclinicalepidemiology.
Dr.ToshiteruOkubo,ChairmanofRERF,opened
themeetingwithawarmwelcometoallinattendanceandemphasizedtheimportanceoftheSC’sworkto
RERF.HeexplainedthatRERFmustconverttoan
approvedPublicInterestIncorporatedFoundationto
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RERF News
continue to qualify for funding under the Public
Interest Corporation Reform Bill. Other major
administrative activities have included employee
training in communication skills, leadership, and
problem-solving; continued implementation of
SeniorReviewPanelrecommendations;hosting,for
the first time, the annual meeting of the Japan
RadiationResearchSociety;andcontinuedmeetings
withtheLocalLiaisonCouncilsinHiroshimaand
Nagasaki.
FollowingDr.Okubo’scomments,Dr.RoyShore,
ChiefofResearchatRERF,providedresponsesto
therecommendationsofthe2009SCandanoverview of new research developments at RERF.A
number of improvements and changes have been
madeinresponsetothe2009SCrecommendations:
WehavebeguntousepresentationsofInitialConcept
Proposals(beforeformalresearchproposals)tohelp
direct the research focus to program priorities.
Researchmilestonesandtimelinesarebeginningto
beintroduced,andtheme-orientedresearchworkinggroupscontinuetofacilitateinterdepartmentalplanning and communication. Departmental seminars
with invitations extended to members of other
departmentsarebeingencouragedtopromotemore
cross-fertilizationofideaswithinRERF.Tokeepin
step with advancing technologies, an initial pilot
studyusinglarge-scalegenomicsequencinghasbeen
planned.ADataManagementandDocumentation
Committeewasformed,withinputfromalldepartments,torecommendproceduresforquality-control,documentation,andtransparentstorageandretrievalof data throughout RERF. That Committee will
interfacewiththeCommitteeonBiologicalSamplestoensureconsistencyandcomprehensivenessinthe
management of data and biosamples.The DepartmentofStatisticshasbeenupgradingitscapabilities
inbioinformaticsandisworkingwithresearchersinthebasicsciencedepartmentstoaddressissuessuchashandlinghigh-dimensionalmicroarraydata.
Neworcontinuingresearchdevelopmentspresented
attheSCmeetinginclude:• EffortstoenlargethenumbersofindividualsintheAdult Health Study clinical examination
programwhowereunderage10atthetimeofthe bombs are nearly completed, with about
1,800newlyrecruitedparticipants.
• A longitudinal clinical follow-up of about
12,000childrenofA-bombsurvivorsisbeingplannedandshouldbeunderwayduring2010.
Theprimarypurposeistodeterminewhetherparentalradiationexposurehasaneffectuponthe incidence of multifactorial diseases in
adulthoodintheF1generation,anissueabout
whichessentiallynoinformationiscurrently
available.
• In concert with the aforementioned clinical
study,newGeneticsDepartmentstudiesofthe
Return to Table of Contents

2
F1generationofhumansandofmicearebeginning to determine if radiation dose-related
increasesingenomicdeletionsandduplicationscanbedetectedwithhigh-densitymicroarrays.
• InvestigatorsintheDepartmentofRadiobiology/MolecularEpidemiologyrecentlyobtaineda substantial five-year contract from theNational Institute ofAllergy and Infectious
Diseases(NIAID)oftheU.S.NationalInstitutes of Health to conduct basic and applied
immunological studies in order to furtherdelineate determinants of radiation-induced
immunological changes and to assess their
health-related effects. RERF has established
collaborationswithscientistsinsevenU.S.and
sixJapaneseinstitutionsinordertobringthelatesttechnologiesandexpertisetobearonthe
goalsofthislargeproject(seesummaryofthisprojectonpage13ofthisissueofUpdate).
A synopsis of the general recommendations oftheSCis: TheSClooksforwardtoa“roadmap”establishingresearchpriorities,resourceallocations,
and research project timelines in relation to
RERF’sstatedfive-yeargoals.
 More collaboration among departments and
utilizationofinterdepartmentalworkinggroups
isencouraged.
 A centralized, comprehensive database is
needed that integrates all the information on
study participants and is linked to availablebiosamples.
 Increasedbioinformaticssupportneedstobe
developedandcoordinatedamongdepartments.
 The SC encourages a focus on major firstauthored publications, both for individual
careerenhancementandfortheoverallreputationofRERF.
 PlansforthetrainingandmentoringofjuniorscientistsatRERFwouldbeuseful.
Highlightsofafewofthenotesandrecommendations for departments and committees or workinggroupsare: Itisrecommendedthatattentionbefocusedonthe mechanisms that underlie the radiationassociatedexcessesofcardiovasculardiseasesand cataracts. RERF scientists are urged to
collaboratewithothergroupswithsuchexpertise.
 TheSCrecommendedthatourinitialstudyofthelifetimeriskofstrokestartingatmiddleage
be extended to younger ages and to other
cardiovasculardiseases.
 Withregardtocardiovasculardisease,theAdult
HealthStudyshouldconsiderincludingechocardiography and additional biomarkers for
RERF Update Volume 21, Issue 1, 2010

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RERF News
endothelialdysfunction.
 Newplanstoassesslatecognitivedysfunction
amongthoseexposed in uteroorinearlychildhoodarestronglysupported.
 Continuationofthebiodosimetryprogramwith
measurements of chromosome aberrations in
bloodandcarbonateradicalsinteethisencouraged,particularlyatlowerexposurelevels.
 Preliminarystudiesoftheuseofdirectsequencingareusefulinrelationtodetectingpotential
geneticeffects.
 Furtherworkisrecommendedtocharacterize
theradiationdoseresponseforimmunological
agingandtoinvestigatetheroleofsuchagingindiseaserisk.
 Studies of DNA methylation in pathology
specimens will need to carefully distinguish
radiation-associatedchangesfrompre-cancerouschanges.
 Further studies of RET/PTC and ALK mutational rearrangements in radiation-related
thyroid cancers are useful, and linkage with
histopathologicalandclinicalparameterswould
providefurtherclarity.
 Additionalprioritizationofworkintheepidemiology program is recommended.This will
facilitate the timely publication of important
mission-orientedpapersininternationalscientificjournals.
 Continued work to develop an inventory and
databaseofpathologyspecimensheldbythe
EpidemiologyDepartmentissupported.
 Increased publication of Statistics methodologicalpapersisencouraged.Developmentofa flexible methodological framework for theuseofindividualdataforassessingtherelationship of radiation dose and disease will be
particularlyuseful.
 Developingaconcerteddatamanagementand

documentation strategy for RERF is a very
importanteffortthatiscentraltothemissionof
RERF,andcriticalforthemaintenanceofits
worldheritageresource.
 The improvements being implemented in
radiation dosimetry are a high priority and
shouldbeexpedited.Whenthosearecompleted,newanalysesshouldbeconductedtodetermine
ifthedosimetryalterationsappreciablyaffectriskestimates.
 Therecentlydevelopedprimeronradiationand
health is highly commended. It is recommendedthatadditionalstrategiesbedevelopedtoreachouttomembersoftheRERFcohorts,
the community, and the international news
media.
In summary, the SC felt that RERF is makingprogressonanumberoffronts,andtheyencourage
additionalattentiontotheprioritizationandfocusof
researchactivities.
RERF Scientific Councilors
Dr. Takashi Yanagawa, Co-chairperson,Professor,
TheBiostatisticsCenter,KurumeUniversity
Dr. John J. Mulvihill, Co-chairperson,Professorof
Pediatrics, University of Oklahoma Health
SciencesCenter
Dr. Yoshiharu Yonekura,President,NationalInstituteofRadiologicalSciences
Dr. Katsushi Tokunaga,Professor,Departmentof
Human Genetics, Division of International
Health, Graduate School of Medicine, The
UniversityofTokyo
Dr. Kiyoshi Miyagawa, Professor, Laboratory of
MolecularRadiology,CenterforDiseaseBiology
andMedicine,GraduateSchoolofMedicine,The
UniversityofTokyo

Participants of the 37th Scientific Council meeting held at the Hiroshima Laboratory
Return to Table of Contents

RERF Update Volume 21, Issue 1, 2010

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RERF News
Dr. Kazuo Sakai, Director, Research Center for
Radiation Protection, National Institute ofRadiologicalSciences
Dr. Marianne Berwick, Professor and Chief,Division of Epidemiology,Associate Director,CancerResearchandTreatmentCenter,UniversityofNewMexico
Dr. David G. Hoel,DistinguishedUniversityProfessor,DepartmentofBiostatistics,Bioinformatics
andEpidemiology,MedicalUniversityofSouth
Carolina
Dr. Michael N. Cornforth,ProfessorandDirector
of Biology Division, Department of Radiation
Oncology,UniversityofTexasMedicalBranch
Dr. Sally A. Amundson, Associate Professor of
RadiationOncology,CollegeofPhysiciansand
SurgeonsofColumbiaUniversity

Dr. David Rush, Emeritus Professor of Nutrition,CommunityHealth(Epidemiology),andPediatrics,TuftsUniversity
Dr. Koji Maemura, Professor, Department of
CardiovascularMedicine,CourseofMedicaland
DentalSciences,GraduateSchoolofBiomedical
Sciences,NagasakiUniversity
Dr. Yukihito Higashi,AssociateProfessor,Department of Cardiovascular Physiology and Medicine, Division of Molecular Medical Science,
Programs for Biomedical Research, Graduate
School of Biomedical Sciences, Hiroshima
University

Thursday, 18 February:A busy day started for
RERFat7:00withthearrivalofafilmingcrewfrom
NationalGeographicTelevision(NGT).WhilethemagazineNational Geographicisknownaroundtheworldforitsremarkablephotographyandexcellentjournalism,Americans are also familiar with theaward-winningfilmdocumentariesandjournalism
created by NGT. The company produces 120
hoursofdocumentarytelevisioneachyearforthe
NationalGeographicChannel,PBS,andotherbroadcasters worldwide. Last year, NGT officials contactedRERFandindicatedthattheywereproducinganewseriesofscientificdocumentariesfocusingontheearth’smajorcatastrophes.Theyhadselectedthe
atomic-bombingofHiroshimaasthetopicofoneof

theirprogramsandwereinterestedinincludingthe
historic and scientific contributions ofABCC and
RERFduringthe65yearsfollowingthebombing.
Drs. RoyShore(RERFViceChairman)andEvan
Douple(AssociateChiefofResearch)metwiththe
co-producers, Pamela Wells and Holly Taylor, in
December 2009 at the NGT headquarters in
Washington, DC, and they came away impressed
withtheplansforthedocumentaryprojectthatNGT
officialsdescribedduringthepreliminarymeeting.
ThefilmcrewstartedfilmingtheprojectinSan
Francisco,wheretheyinterviewedA-bombsurvivors.
The crew then traveled to Hiroshima, where they
spent about one week filming. Ms.Taylor spent acoupleofhourson16February2010touringRERF

NGT team filming medical examinations of an AHS participant at the clinic

Special close-up lens used by NGT filming a recording of
tooth ESR signals

Return to Table of Contents

Special Scientific Councilors

RERF Update Volume 21, Issue 1, 2010

RERF News5

anddiscussingpotentialfilmingsites.Thesix-person
crew,includingRobLyall,DirectorofPhotography,
andGabeMonts,soundman,arrivedon18Februaryandspent13hourssettinguptheirequipmentand
filminginhigh-definitionTV.Thefilmingincluded
scenesofamedicalexamofanAdultHealthStudy
(AHS)participantwiththeassistanceofDr.Kazuo
NeriishiandnursesMichikoKuwamotoandJunkoHino,theextensivecabinetscontainingfilesintheclinicalrecordsroom,ESR(electronspinresonance)
toothdosimetrymeasurementswiththeassistance
ofToshieInoueandDrs.NoriNakamuraandYuko
Hirai,storageoflymphocytesinliquidnitrogenwiththeassistanceofDr.TomonoriHayashi,interviews
with Drs. Neriishi and Douple about the research
studiesandhistoryofABCCandRERF,andseveralviewswithintheRERFfacilities.
AfterdarknessreturnedtoHijiyamaandthemany
containersofequipmenthadbeenloadedbackintothe NGT vans, the film-crew members expressed
theirfeelingsofappreciationforthecooperationofso many RERF employees and for all they hadlearnedaboutRERF.Theywereveryimpressedwith
RERF’smanydedicatedemployees,theimportantcontributions of theA-bomb survivors, and theuniqueandhistoricworkthathasbeendonehere.
Those of us who were impressed by the professionalandcreativeskillofthededicatedfilmingcrew
membersareconfidentthattheNGTteam’sefforts
will result in a quality product, in the form of an
hour-long documentary, that we hope will help to
communicateapositiveimageofRERFaroundtheworld.ThatproductisexpectedtobecompletedthissummerandshouldappearontelevisioninOctoberorNovember.WethankallRERFemployeeswho
providedassistanceoralteredtheirworkschedulesto accommodate this important public-relationsactivity.

Wearepleasedtoreportthatfourscientistshave
joinedRERFsincethelastissueofUpdate.Seishi
KyoizumiwasappointedProjectResearchScientistin the Laboratory of Immunology, Department ofRadiobiology/Molecular Epidemiology (RME)
effectiveApril1,2010.HeisnostrangertoRERF
sincehestartedhiscareerasaresearchscientistin
RERFin1982.HeservedasChiefoftheImmunologyLaboratorybetween1994–2003inwhatwasthe
Department of Radiobiology and he served as
AssistantChiefoftheDepartmentofRME2003–
2004 before accepting a position as Professor of
NutritionalSciencesinYasudaWomen’sUniversity.
Junko Kajimura accepted a Research Scientist
positionintheLaboratoryofImmunologyofRME
effectiveApril 1, 2010. She was most recently aresearchassociateatYasudaWomen’sUniversityand
priortothatwasaresearchfellowintheResearchInstitute for Radiation Biology and Medicine at
HiroshimaUniversityfrom2005–2007.TwostatisticianshaverecentlyjoinedtheDepartmentofStatistics. Ravindra Khattree began work as a seniorscientistatRERFApril26andcomestoRERFfrom
OaklandUniversityinRochester,Michiganwhere
hehasbeenaProfessorofMathematicsandStatistics
since1991.Robert D. Abbott,formerlyProfessor
ofBiostatisticsintheDivisionofBiostatisticsand
EpidemiologyattheUniversityofVirginiaSchool
of Medicine in Charlottesville since 1982, startedwork as a senior scientist at RERF May 10. Both
statisticianswererecruitedbytheNationalAcademy
ofSciencesandRERFisespeciallyfortunatetohave

twoveryexperiencedscientistsjoinitsresearchteam.
Wehaveaskedthefournewmemberstointroduce
themselvesinthisissueofUpdate.
Harry M. Cullings waspromotedfromActing
ChieftoChiefoftheDepartmentofStatisticseffectiveApril 15, 2010. He began his employment at
RERFinOctoberof1999asaNationalAcademyof
Sciencesrecruit.Sincethen,hehasbeeninvolvedin
providingextensivestatisticalconsultationtoother
departmentsatRERFinsupportofvarioustypesof
studies and he was especially instrumental in theimplementationoftheDS02systemforcalculatingsurvivors’radiationdosesforuseinRERFstudies.

Return to Table of Contents

Seishi Kyoizumi
Forthepurposeofjoiningthe National Institute ofAllergyandInfectiousDiseases(NIAID)-fundedproject,IcamebacktoRERFfor
thefirsttimeinsixyears.Ispent those years on thefacultyoftheDepartmentof
Nutritional Management,
YasudaWomen’sUniversity, Seishi Kyoizumi, Projectbut I feel that I am more Research Scientist
adaptedforlifecenteringon
researchactivitiesthanforeducation-centeredlife.
EventhoughIfeltanxiousaboutaperiodofsix
years away from the cutting edge of scientific
research,Iwasabletoreadjustmybrainintoresearch
modeinearlyApril.(Ofcourse,Iexperienceslowing
RERF Update Volume 21, Issue 1, 2010

RERF Newsofthoughtappropriatelyformyage.)Thescientific
research community is basically competitive.
Researchersmustmakeimportantfindingsaheadofotherresearchersinordertobepraised.Inthefield
ofbiology,methodsthatcanefficientlynarrowdown
targets with the use of genome-wide high-speed
screening have become more common.A highbudgetapproachcanobtaintheoutcomefasterthan
low-budgetones.Whenemployingsuchmethodology,originalityinresearchwillbeshowninterms
ofeitherasubjectofresearch(phenomenon)orhow
toapproachthesubjectphenomenonwiththeuseofcollected data. In the case ofA-bomb survivor
studies,thesampleitselfisaveryvaluablepopulation.Meanwhile,agingofthepopulationisnoticeable.ThemissionofRERFresearchscientistsisto
verifyhypothesesasefficientlyaspossibleandobtain
correct findings. Specifically, the NIAID project,
whichaimsatelucidationofeffectsofimmunologicalagingandradiationexposureondiseasedevelopmentmechanismsonthebasisofepidemiological
findingsregardingdiseases,ishighlyoriginal.Ihopetomakehumblecontributionstotheaforementionedproject.
Junko Kajimura
By way of introduction,
mynameisJunkoKajimura,and I started work at theDepartment of Radiobiology/MolecularEpidemiology
onApril1ofthisyear.Asamatteroffact,thisisnotthe
firsttimeformetoworkat
RERF, since I belonged to
Junko Kajimura,the aforementioned departResearch Scientist
ment as a visiting scientist
duringtheperiodfrom2005
through2007.AfterworkingattheYasudaWomen’s
Universitystartingin2007,IcamebacktoRERF
forthepurposeofjoiningtheNIAID-fundedproject.
Iwillintroducemybackgroundinbrief.AfterI
received a Ph.D. at Hiroshima University, I was
employedasapostdoctoralfellowattheUniformed
ServicesUniversityoftheHealthSciences(USUHS)
inMaryland,U.S.andconductedresearchactivities
with a focus on microbial glycosylation for three
years.After returning home, I was employed as aresearch scientist at the Research Institute for
RadiationBiologyandMedicine,HiroshimaUniversity and engaged in research on translesion DNAsynthesis,whileservingasavisitingscientistatthe
DepartmentofRadiobiology/MolecularEpidemiology. Then, I served as a research associate at theYasuda Women’s University before returning to
RERF.
Inmychildhood,IlivedinthevicinityofHijiyama,and a park behind the RERF facilities, called
Return to Table of Contents

6“Hijiyamaamusementpark,”wasoneofmyfavorite
playgrounds.RERF’suniquequonset-hutbuildings
seemedverymysterioustomeatthattime,andIusedtowonderwhathappenedinsidethefacilitieswithmuchinterest.NowIamgivenanopportunitytobe
engagedinresearchactivitiesasafull-timeresearch
scientist at RERF, my childhood “mysterious
researchinstitute.”EventhoughareassurroundingHijiyama are noticeably different now due to theDanbaradistrictredevelopmentproject,Iamgoingtoworkonresearcheverydayatthebuildings,whicharemaintainedintheiroriginalstate.Ifeelthisisakindoffatefullink.
SinceIamnewtomypostandshortofperfection,I hope to perform day-to-day research operationsunder the direction of, and with support from,
researchscientistsandthestaff.Iwouldbegratefulforyoursupport.
Ravindra (Ravi) KhattreeAll my life I have beeninterested in statistics and
various aspects of it. I received an M. Stat. fromthe Indian Statistical Instituteand,in1985,receiveda
Ph.D. from the University
of Pittsburgh. I started mya c a d e m i c  c a r e e r  a s  a nAssistant Professor at theRavindra Khattree,
NorthDakotaStateUniverSenior Scientist
sity. I spent two years at
BFGoodrichChemicalGroupsasaSeniorResearchandDevelopmentStatisticianworkingondevelopmentofseveralprojectsandvariousenvironmental
andsafetyissues.Whilethere,Ialsoservedasan
adjunct faculty member of CaseWestern Reserve
University.ImovedtoOaklandUniversityin1991
whereIservedasanassociateandthenfullprofessor
forthelast19years,withaone-yearleaveinbetween
toworkasaprofessorintheDepartmentofEpidemiology and as Biostatistics Group Leader at theBiomedicalResearchandInformaticsCenter,both
positions in the College of Human Medicine,
Michigan State University. My academic research
interestshavebeeninmultivariateandlongitudinal
dataanalysisandinbioequivalenceproblems,and
my interdisciplinary research mostly focuses on
cancerandmentalhealth-relatedproblems.
IhavealwayswantedtoworkinareaswhereIcancontribute,insomesubstantiveway,tothegood
ofthesocietyatlarge.Thatwasamainmotivation
formetojoinRERFasIconsidertheimplications
oftheresearchdoneheretobefarreachingandvery
relevanttotheeffortsofmakingthisworldabetter
placetolive.Ilookforwardtogettinginvolvedinas
manyprojectsaspossible.IlovechallengesandI
lovestatisticssoIinviteallofyoutodiscusswith
RERF Update Volume 21, Issue 1, 2010

RERF NewsmethestatisticalaspectsofyourresearchprojectsifyouthinkthatIcanbeofhelp.
AlthoughIhavebeenhereonlyafewdays,Iam
alreadybeginningtoloveHiroshima.Withalternatingsunnydaysandrainydaysandthesmellofthesoil,itremindsmeofmychildhooddaysinIndia.
The densha (streetcar) services remind me of my
youth in Kolkata and the clean environment and
organizationalefficiencyofthecityisreminiscentto that in Michigan, USA. I enjoyed going to theFlowerFestival.TherichnessoftheJapanesecultureand the sincere efforts to practice and preserve it,wereveryevidentduringtheFlowerFestival.
Iamlookingforwardtoworkingwithallofyou
during the years to come and learning from you.
Apartfromlearningaboutvariousresearchprojects,
anotherthingwhichIwouldliketolearnmoreabout,
whileinJapan,isBuddhismaspracticedinJapan.Iwould like to visit as many places of Buddhist
heritageaspossible.
Robert D. Abbott
AftergraduatingfromtheUniversityofMichigan
withaPh.D.inbiostatistics,Ijoinedthestaffatthe
U.S. National Heart, Lung, and Blood Institute in
1980. During that time, I became involved in twolong-term follow-up studies (similar to the RERF
AdultHealthStudy).OnestudywastheFramingham
Study,andtheotherwastheHonoluluHeartProgram
(HHP).TheHHPwascreatedaspartoftheNI-HON-

The first Distinguished Lecturer of 2010 wasPeter W. Laird, Ph.D.whodeliveredthekeynote
address to open the International Workshop on
Epigenetics in Radiation Effects amongA-bombSurvivorsandtheirChildren,March17,2010.The
title of his lecture was “The Cancer Epigenome:
OriginsandApplications.”
Dr.LairdisAssociateProfessorofSurgeryandofBiochemistryandMolecularBiologyattheUniversityofSouthernCalifornia(USC),KeckSchool
ofMedicine.HeisDirectoroftheUSCEpigenome
Center,DirectorofBasicResearchfortheDepartment of Surgery, and Program Leader of the EpigeneticsandRegulationProgramattheUSCNorris

Return to Table of Contents

7
SAN study (the HON part)
tohelpexplainthechangingrisk of stroke and heart
diseaseasJapanesemigratedfrom Japan to Hawaii and
California. The NI part
included the RERF Adult
HealthStudy.
AlthoughIlateraccepted
Robert D. Abbott,afacultypositionattheUniSenior Scientist
versityofVirginiain1989,I
continuedmyHHPinvolvement.DuringfrequentvisitstoJapan,Iparticipatedin comparisons between the HHP and cohorts in
Japanthatweregeneticallyhomogeneousbutenvironmentallydifferent.ThosecollaborationscontinuedduringasabbaticalyearatShigaUniversityof
MedicalScience(2006–2007)throughanInvitation
FellowshipfromtheJapanSocietyforthePromotion
ofScience.MyhostscientistwasHirotsuguUeshima.
Attheconclusionofthatrewardingexperience,my
goalwastoreturntoJapanonapermanentbasis.
Withalong-termfamiliaritywiththeRERFandits
proudhistoryinstatisticsandepidemiology,Iknew
thatanappointmentattheRERFwouldbeahighlight
inmycareer.ThetimingwasperfectwhenRERF
openingswereannouncedin2009.Iamnowgratefulandmostfortunatetobeapartofthisprestigious
organization.

Comprehensive Cancer Center. Dr. Laird received
his Ph.D. from the University ofAmsterdam. He
pioneeredtheuseofmousemodelstoinvestigatethe
causalcontributionofDNAmethylationtocancer
andinventedtwoDNAmethylationassays,COBRA
andMethyLight.InhislectureheprovidedanintroductiontotherevolutioninDNAmethylationanalysis technology that has taken place over the past
decadeandsuggestedsomeapproachesthatRERF
scientistsmightconsiderastheyexploreapplicationsof next-generation sequencing (see P. W. Laird,
Principles and challenges of genome-wide DNA
methylation analysis. Nature Reviews/Genetics
11:191–203;2010).

RERF Update Volume 21, Issue 1, 2010

8

Reports on Conferences and Workshops

Kazunori Kodama, Chief Scientist and Chairman of
the Planning Committee for the 52nd JRRS MeetingThe52ndAnnualMeetingoftheJapanRadiation
ResearchSociety(JRRS)washeldwithgreatsuccessat the Hiroshima Minami Ward Community CulturalCenteronNovember11–13,2009.Atotalof
224 presentations including poster presentations
weresubmittedandasmanyas461peopleparticipatedinthemeeting.RERFmadefoundation-wide
effortstoorganizethismeeting,withmanyRERF
staffprovidingsupporteitherattheCenterorfrom
RERF.Iwouldherebyliketotakethisopportunity
to provide a brief description of the 52nd JRRS
meeting.
ThefirstJRRSmeetingwasheldinTokyoin1959.
AtotalofsixmeetingshadbeenheldinHiroshima
(from1962until2005),allofwhichwerehostedbyHiroshima University. RERF has studied health
effectsfromradiationforover60yearssincethedays
ofABCC,anditwasbelievedthathostingtheJRRS
meetingwouldprovideRERFwithanopportunity
toinformJRRSmembersofitsresearchactivitiesand that supporting such meetings was one of
RERF’sduties.Forthosereasons,RERFChairman
Toshiteru OkubodecidedthatRERFwouldpromote
itselfasacandidatefororganizerofthemeeting.In
meetings of the JRRS Board of Councilors and
generalassembly,RERFwasthuschosentobethe
organizerforthe52ndmeeting.
Themeeting’sworkingcommitteeandprogramcommittee, including leading external members,wereestablishedundertheleadershipofChairman
Okubo,whoservedasPresidentofthemeeting.I
wasappointedaschairmanoftheworkingcommittee,andNori Nakamura,RERFChiefScientist,as
chairmanoftheprogramcommittee.
Priortothemeeting,theworkingcommitteemet
11timestomakecarefulplanningandpreparations,
andtheRERFstaffmembersappointedtothemeeting’s secretariat traveled numerous times to theHiroshima Minami Ward Community Cultural
Centertoinspectthevenueanddiscussthemeetingdetailswiththestaffthere.ItwasdecidedthatRERF
would develop an in-house computer system for
managementofthemeeting.Aregistrationsystem
forenrollmentandpresentationsviathewebsiteofthe meeting was developed by the Department ofInformationTechnology(ITD),underthesupervision
ofDepartmentChiefHiroaki Katayama.ITDalsodevelopedanoperationandmanagementsystemfor
themeetingvenue(e.g.,registrationofparticipants
andpresentationofslidesduringthemeeting).
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The scientific program for the meeting was
carefully developed under the leadership of Dr.Nakamura,chairmanoftheprogramcommittee,withafocusonthemaintheme“RadiationHealthEffects
andEpidemiology—FromDNARepairtoEpidemiology.”Manyfreshideaswereincorporatedintothe
scientificprogramdevelopedbyDr.Nakamuraand
others.Theprogramwascomposedofmanyfacets
includingtwospeciallectures,onespecialprogram,
onespecialsession,threeluncheonseminars,three
symposia,eightworkshops,78generalpresentations(oralpresentations),and146posterpresentations.Anumber of RERF research scientists also made
presentations.Thefollowingaresomeofthehighlightsofthemeeting.
AlthoughmanyJRRSmembersarefairlyknowledgeableaboutRERF’sstudyresults,theyseemedtohavelessunderstandingoftheprocessbywhichsuchresultsaregenerated.Itwasthereforedecidedtotakethisopportunitytoprovideabriefdescription
aboutRERF’sepidemiologicalstudies.
In the session “A Quick Lesson on Epidemiological Studies ofA-bomb Radiation Effects,” Dr.Okubo delivered a lecture titled “The Outline of
Epidemiological Studies at the Radiation Effects
ResearchFoundationandChangesintheDosimetry
System.”Yuko Hirai,SeniorScientistoftheGeneticsDepartment,talkedabout“BiodosimetryandIts
Implications for Epidemiological Studies.” Both
presentationsweredesignedtoexplainthemethodology of the epidemiological studies conducted at
RERF.Kotaro Ozasa,ChiefoftheEpidemiology
Department, and Saeko Fujiwara, Chief of theClinical Studies Department, then outlined study
resultsbyprovidinglecturestitled“Epidemiological
Study: Key Points of the Results” and “Clinical
Study: Key Points of the Results,” respectively.
Althoughthissessionstartedafter5:00p.m.,many
JRRS members turned up to listen to the lectureswithgreatinterest.Ibelievethatoneofourinitial
goalswasthusfullyachieved.
On the second day of the meeting, John J.
Mulvihill,RERFScientificCouncilorandProfessor
at the University of Oklahoma Health Sciences
Center,gaveaspeciallecturetitled“GeneticEpidemiology of Offspring of Cancer Survivors: A
WindowonHumanGermCellMutagenesis.”While
providing comparisons with past results from thestudies of the children ofA-bomb survivors, he
reported that a large-scale study of offspring of
RERF Update Volume 21, Issue 1, 2010

Reports on Conferences and Workshops
cancersurvivorsdidnotshowanyhighriskofgenetic
effects.
Itwasdecided,basedonthestrongdesireofDr.
Okubo, to include a session only possible in
Hiroshima. Hence the special program “Message
fromHiroshima”washeld.Inthissession,Sunao
Tsuboi, Chairman of the Hiroshima Prefectural
Confederation ofA-bomb Sufferers Organization,
deliveredamovinglecturetitled“ClosetoDeath,”
inwhichhetalkedaboutthehealthproblemsexperienced byA-bomb survivors based on his ownexperienceasasurvivorandexpressedhisfervent
desirefortheeliminationofnuclearweapons.
The next lecture, titled “Chance to Eliminate
NuclearWeapons—Why President Obama Needs
Japan,”wasgivenbySteven Lloyd Leeper,Chairman of the Board of Directors, Hiroshima Peace
CultureFoundation.Heprovidedhisinsightontheworldsituationpertainingtonuclearweaponsand
thenecessityofnuclearabolition.Hislucidexplanationforsuchacomplexissueresultedintheentire
audiencelisteningattentivelytohislecture.
On the first and second days of the meeting,
luncheon seminars focusing on the theme “PeaceActivities and International Contributions of
Hiroshima”weregiven.Intheseseminars,theaudiencewasabletolistenwhileenjoyinglunch.Hiroo
Dohy,DirectoroftheHiroshimaRedCrossHospital
andAtomic-bombSurvivorsHospital,representingtheHiroshimaInternationalCouncilforHealthCareoftheRadiation-exposed(HICARE),andShizuteru
Usui,PresidentoftheHiroshimaPrefecturalMedicalAssociation,representingtheInternationalPhysiciansforthePreventionofNuclearWar(IPPNW)
JapanOffice,talkedabouttheactivitiesofHICARE
and the IPPNW Japan Office, respectively. In
addition,HICAREandtheHiroshimaPeaceCulture
Foundationbothsetuppanelexhibitions.

9(From left) Takanobu Teramoto, RERF Permanent Director,
Toshiteru Okubo, RERF Chairman, Sunao Tsuboi, Chairmanof the Hiroshima Prefectural Confederation of A-bomb
Sufferers Organization, and Steven Lloyd Leeper, Chairmanof the Hiroshima Peace Culture FoundationOnthelastdayofthemeeting,alectureopento
thepublicwashostedjointlywithHICAREatthe
Hiroshima International Conference Hall. Kenzo
Oshima,VicePresidentoftheJapanInternational
CooperationAgency(JICA)andtheformerPermanentRepresentativeofJapantotheUnitedNations,
deliveredalecturetitled“RecentSituationConcerningSupportforRadiation-exposedbyInternational
Organizations.”AlthoughthisvenueandtheMinami
WardCommunityCulturalCenterareseparatedby
somedistance,therewasagoodturnoutofabout150
people.
Tothebestofmyknowledge,thisisthefourthannualmeetingofanationalacademicsocietyRERF
has organized.Although RERF now has accumulatedsignificantexperienceinorganizingacademic
meetings, this was the first annual meeting of anational academic society for which RERF made
foundation-wideefforts.Iwouldliketoexpressmy
sincereappreciationforthehardworkanddedication
oftheentireRERFstaff.

Evan B. Douple, Associate Chief of Research
The“International Workshop on Epigenetics
in Radiation Effects among A-bomb Survivors
and Their Children”washeldatHiroshimaLaboratoryonMarch17–18,2010.Itincluded13invited
speakers from six Japanese universities (Waseda,
Hiroshima,Kumamoto,Kyushu,TokyoMedicaland
Dental,andSapporoMedical),RIKENKobeInstitute, RERF, and two U.S. universities (Southern
CaliforniaandBrown).Theworkshopwasofficially
opened with words of welcome and appreciation
Return to Table of Contents

from RERF Chairman Toshiteru Okubo. He
explainedthatthegoaloftheworkshopwastohaveexpertsintroduceRERFscientiststotheemerging
frontierofepigenetics,afieldthathasgrownexponentially in recent years, and to enable RERF
speakerstointroduceleadingexpertsinthefieldof
epigeneticstoRERF’sresearchresults,ongoingand
future plans, and unique biosample resources. He
concludedhisopeningremarksbyexplainingthattheworkshopwasdedicatedto Donald G. MacPhee,
RERF Update Volume 21, Issue 1, 2010

Reports on Conferences and Workshops
former RERF ResearchAdvisor and Chief of theDepartmentofRadiobiology, inrecognitionofhis
activeencouragementofRERFscientiststoexplorethefieldofepigenetics.
The workshop was organized into four major
sessionsandthefirstsessionwastitled“Epigenetics:
OverviewandbackgroundofthefieldandofRERF
anditsresources.”Theopeningkeynotelecturewas
deliveredbyPeter W. Laird whoprovidedanintroductory overview of epigenetics—the study of
inheritedchangesinphenotype(appearance)orgene
expressioncausedbymechanismsotherthanchangesintheunderlyingDNAsequence.Theinheritedchangesmayremainthroughseveralcelldivisionsorfortheremainderofthecell’slife,andtheymay
alsobetransmittedtomultiplegenerations.Inotherwords, non-genetic factors cause the organism’s
genestobehaveor“expressthemselves”differently.
Dr.Lairdexplainedthatithasbecomeclearthattheoriginofhealthandsusceptibilitytodiseaseare,in
part,theresultofepigeneticregulationofthegeneticblueprintandsucheffectsmayexplainanumber
ofhumandiseasesincludingcancer.Aformofepigeneticscalledgenomicimprinting(thedifferential
expressionofagenedependingonwhetheritwas
inheritedfromthefatherormother),mayexplaina
numberofhumandiseasesandmaybeinfluenced
byfactorssuchasnutritionandexposuretoenvironmental agents including low doses of ionizingradiation. Dr. Laird summarized his talk with thefollowingpoints:• Epigeneticsdeterminesgeneexpressionpotential,ratherthangeneexpressionstate.
• InmousemodelsystemssuchasApcMinmice,
sufficient levels of DNA methyltransferase
expressionareasessentialfortumorformation
asisthepredisposingmutationintheApcgene.
• Anepigeneticallydefinedsubtypeofcolorectal
cancer, referred to as CpG island methylator
phenotype(CIMP),isverytightlyassociated
withBRAFmutation.IGFBP7isnecessaryand
sufficient for BRAF-induced apoptosis and
senescence.EpigeneticsilencingofIGFBP7by
CIMPislikelyaprerequisitetoacquisitionof
aBRAFmutationincolorectalcancer.
• An epigenetically defined subtype of brain
glioma,referredtoasG-CIMP,isverytightly
associated with IDH1 mutation. G-CIMP
patientsareyounger,andhavebettersurvival,
thannon-G-CIMPpatients.
• Genes occupied by Polycomb repressors in
stemcellsarepredisposedtoacquiringcancerspecificDNAmethylation.
• It is now technically feasible to perform awhole-genome, shotgun-approach bisulfatesequencing to generate DNA methylation
profilesatsingle-basepairresolution.
• Sensitive techniques, such as Digital MethyReturn to Table of Contents

10Light, can be used to detect abnormal DNA
methylation patterns in the bloodstream ofcancerpatients.
RERF’sChiefofResearch,Roy E. Shore,presentedbackgroundaboutRERFinhistalk“RERF:
Auniquelaboratoryforthestudyofhumanradiation
epigeneticeffectsanddisease.”Hepointedoutsix
criteriathattheAdultHealthStudy’scohortmetthat
made RERF a unique and unparalleled laboratory
forthestudyofhumanradiationepigeneticeffects
anddisease:(1)havingawell-definedprospectivecohortwithalargerangeofaccuaratelydetermined
radiation exposure levels; (2) having a substantial
numberofdiseasecases;(3)havingappropriatetypes
ofbiosamplestopermitassaysforvariousepigeneticendpoints;(4)havingbiosamplesthatpredatethedevelopmentofthedisease(s);(5)havingavarietyofexposureagesandbothgenders;and(6)havinginformationonlifestyleandotherexposureto
adjustforthoseconfoundersand/ortoevaluatethemasmodifiersoftheradiationeffect.
Hiroyuki Sasakiclosedthefirstsessionwithareviewofgenomicimprinting—epigeneticprogramming in the germline of mammals that causesparental-origin-specificmonoallelicexpressionofa
small subset of genes through differential DNA
methylation.Hislaboratoryhadpreviouslyshown
thatthede novoDNAmethyltransferaseDnmt3ais
responsibleforestablishmentofthegerm-linespecificmethylationimprints.Heproposedamodelin
which the Piwi-interacting RNA (piRNA) and itstargetRNAplayacriticalroleinmethylationand
imprintingofthemouseRasgrf1locus.
Asecondsessionfocusedon:“Imprinting,development,andfetaloriginsofadultdisease.”Hideoki
Fukuokadescribedthefetaloriginofadultdisease
(FOAD)theoryanditsimportanceforunderstandingthepatho-physiologyofdevelopinglifestyle-related
adultdiseasethathasbeenchangingtobecalledthedevelopmentaloriginsofhealthanddisease(DOHaD).
ThemechanismfortheFOADtheoryisbelievedto
beepigeneticmodificationcausedbyintra-uterinemalnutrition.Theonecarbonmetabolismregulates

Chairman Toshiteru Okubo (right) opens the International
Epigenetics Workshop.

RERF Update Volume 21, Issue 1, 2010

Reports on Conferences and Workshops
theepigeneticmodificationwithDNAmethylation
andfolatevitaminsB6andB12arekeynutrientsfor
the metabolism. Jun-ichi Nakayama described aroleofchromodomain(CD)proteinsintheepigenetic gene regulation and DNA damage response.
He and his colleagues have shown that the CD,anevolutionarilyconservedproteinmodule,binds
tomethylatedhistonesandthusplaysdiverseroles
inepigeneticgeneregulationandchromatindynamics. MRG15 is one example that binds to Lys36methylated histone H3 and is linked to cellularsenescence in human cells. The author’s recent
results suggest that MRG15 is a key molecule in
epigeneticgeneregulationandregulateshomologydirectedrepairofchromosomalbreaks,andpossibly
isamolecularlinkerbetweenBRCA1andBRCA2.
A third session focused on “Epigenetics and
carcinogenesis.”AlthoughafamilyemergencyprohibitedOlga Kovalchukfromattendingtheworkshop,sheprovidedherrecentpublication(Environmental and Molecular Mutagenesis49:16–25,2008)
in which she hypothesized that changes in global
and regional DNA methylation and regulatory
microRNAsplaypivotalrolesinradiationresponses
andradiation-inducedgenomicinstability.Toshiya
Inabapointedoutthatepigeneticdysregulationcan
abolish the expression of anti-oncogenes allowingthe development and/or promotion of malignanttransformation.Heposedthequestion“Isepigenetic
suppression of the anti-oncogenes equivalent to
geneticdeletioninoncogenesis?”Monosomy7,or
deletionofthelongarmofchromosome7(-7/7q-)
isthemostfrequentlyobservedchromosomeanomalyinmyeloidleukemiaamongirradiatedpersons,
aswellasinthegeneralpopulation.Inaba’sgrouphasrecentlyidentifiedSamd9Lgeneonchromosomeband7q21asapromisingcandidatefortheresponsiblegenefor-7/7q-.Hedescribedrecentstudiesin
whichresultssuggestthatgeneticdeletionofgenesandtranscriptional/epigeneticdownregulationplaydifferentbiologicalrolesinoncogenesis.
Mitsuyoshi Nakao reportedhisfindingthatthehighmobilitygroupA(HMGA)proteinsareoverexpressed,directlyinhibitRB,andmaintainmalignant features in cancers. He concluded that DNA
methylationandchromatinfactorsareimportantfor
cellregulationandderegulation.
Karl T. Kelsey describedtheworkinhislaboratoryusingarrayplatformstodelineatetheextentofvariationinnormaltissues,includingvariationassociatedwithageandwithenvironmentalexposures.
They have shown that reduction in the extent of
methylationoftherepetitiveLINE1region,detectable in peripheral blood, is associated with an
increasedriskofsporadicheadandneckcancerand
bladdercancer.Theyhaveproposedthatriskmaybe
modifiedbyexposuresordiet.
DNAmethylationplays acriticalroleinsilencing
Return to Table of Contents

11
cancer-related genes and Minoru Toyota and hiscolleagues have shown that subsets of colorectal
cancers(CRCs)resultingenome-widemethylation
defectsthattheycallCIMP.Newmethodsfordetecting DNA methylation have enabled his group to
create epigenetic profiles of CRCs and to classifythemintothreedistinctsubgroupsbasedongenetic
and epigenetic alterations: CIMP1, CIMP2, and
CIMPnegative.Theyhavehypothesizedthatgenes
inactivatedbyDNAmethylationareinvolvedinthe
BRAFandp53signalingpathways.Methylationof
IGFBP7wascorrelatedwithBRAFmutations,an
absenceofp53mutations,andthepresenceofCIMP.
Thus,epigenetic inactivationofIGFBP7appearstoplayakeyroleinthecarcinogenesisofCRCswith
CIMPbyenablingescapefromp53-inducedsenescence.
ToclarifytheroleofmiRNAingastriccarcinogenesis, Yasuhito Yuasa and his colleagues performed miRNA microarray analyses and investigated expression changes of miRNAs in a gastric
cancercellline.ThemiR-181cexhibitedCpGislands
intheirupstreamsequences,andtheirup-regulation
was verified by reverse transcription-polymerasechain reaction (RT-PCR) analysis. Their results
indicated that miR-181c may be silenced throughmethylationandplayimportantrolesingastriccarcinogenesisthroughitstargetgenessuchasNOTCH4
and KRAS. They also examined the methylation
statusofsixtumor-relatedgenesinprimarygastric
carcinomasbymethylation-specificPCRandcompared them to the past lifestyles of the patients.
Significant association was found between adecreased intake of green tea and methylation of
CDX2andBMP-2,andmorephysicalactivitywas
correlated with a lower methylation frequency of
CACNA2D3.Theyareexaminingfurtherwhether
themethylationstatesofbloodleukocyteDNAcan
beasurrogatemarkerforliabilitytocancer.
The final session, “Brainstorming:A role for
RERFinepigeneticresearch,”includedpresentationsby four RERF scientists who described their preliminaryresultsandfutureresearchplans:• Norio Takahashi asked the question: “How
canwebestutilizethetrio-samplesinfuture
epigeneticstudies?”Asbackgroundinformation,hesummarizedthestudiesoftrans-generationaleffectsofA-bombirradiationthathave
beenconductedbytheGeneticsDepartment,
andhedescribedthearchivalspecimensstoredinthedepartment.
• Reiko Ito described results of a pilot study:
“Epigenetic alterations in colorectal cancer
among atomic-bomb survivors.” The study
focused on microsatellite instability (MSI)relatedCRC,andanalyzedbothepigeneticand
geneticalterationsofMLH1andselectedRassignaling related genes, as well as CIMP.
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Reports on Conferences and Workshops
AlthoughCIMPstatussignificantlycorrelated
withMLH1methylation,nosignificantassociation was found with MSI-H and radiation
exposure.
• Yasuharu Niwa discussed the establishmentandvalidationofassaysystemsforevaluation
of radiation- and aging-related epigenetic alterationsinbloodcells,includingchangesin
gene-specificmethylationandH3K9acetylationfrequencies.Combinedbisulfiterestriction
analysis(COBRA)andenzyme-linkedimmunosorbentassay(ELISA)methodswerecombined for detection of DNA methylation and
histoneacetylation,respectively.GlobalDNA
methylation was evaluated with methylationfrequencyinthelonginterspreadnucleareleinterspersed
ment1(LINE1),andgene-specificmethylation
was assessed for several aging-related genes
includingTUSC3.HistoneH3lysine9(H3K9)
acetylationwasalsoexamined.
• Kazuo Neriishi presented results of annualexamsthatincludedmeasuringsystolicbloodpressure and systolic hypertension in 1,014
adolescentA-bomb survivors (at ages 9–19)
whowereexposedinutero.Forthemeasurementsofsystolicbloodpressure,thedoseeffectwasanincreaseof2.09mmHgperGyandwas
significant(p=0.017).Asignificantradiationdoseeffectwasfoundforthesecondtrimester(p=0.001)withanestimated4.17mmHgper
Gy.Fortheprevalenceofsystolichypertension,

theradiationdoseeffectwassignificant(p=0.009);theoddsratioat1Gywas2.23(95%
confidenceinterval:1.23,4.04).
RERF scientists received valuable information,
encouragement,andadviceonhowbesttodetermine
whetherepigeneticsmighthaveanimportantrolein
theincreasedhealtheffectsobservedintheA-bomb
survivors and how best to use RERF’s valuable
databasesandbiosamplestoaddressthisquestion.
Theparticipantsactivelyandfranklyexchangedtheir
views,andsomeoftheinvitedexpertsexpressedaninterestinexploringfutureresearchcollaborationswith RERF scientists.A summary of their major
observationsincludesthefollowingpoints:• Epigeneticsislikelytomediatesomeaspects
ofsusceptibilitytoradiation-associatedeffects,
includingthecancers,butalsothecardiovascular and other non-cancer health effects
recordedintheA-bombsurvivors.
• Array-basedplatformsarewellsuitedtobiomarker discovery in cancer and non-cancer
healtheffects.
• TheRERFcohortsandthebiosampleresources represent an extraordinary opportunity for
explorationofepigenetichypotheses.
• Additionaleffortstoobtaintumorspecimensarewarranted.
• The in utero-exposed cohort is particularly
importantforexplorationofepigenetichypotheses.

Participants of the International Epigenetics Workshop held at the Hiroshima Laboratory

Return to Table of Contents

RERF Update Volume 21, Issue 1, 2010

13

Science Articles

A Special Opportunity for RERF to Expand
Studies of Immunosenescence and Other
Late Effects of Acute Ionizing Radiation
Exposure in A-bomb Survivors
YoichiroKusunoki,1TomonoriHayashi,1EvanB.Douple,2andKeiNakachi3
DepartmentofRadiobiology/MolecularEpidemiology,2AssociateChiefofResearch,ConsultantandProjectPrincipalScientist,RERF

1
3

AbstractAnewprojecthasbegunatRERFthatisbasedon the results of RERF’s studies of the effects ofradiationontheimmunesystemofA-bombsurvivors
conductedovertwodecades.Fundingprovidedby
theU.S.NationalInstituteofAllergyandInfectious
Diseases(NIAID)willenableRERFresearchersto
strengthentheireffortstodefineeffectsofionizingradiation on aging of the human immune system(immunosenescence) and elucidate underlying
responsible mechanisms. The proposed approach
rests on three critical and unique advantages: (i)utilization of the large, unique database and biosamplesfroma63-yearfollow-upofA-bombsurvivorsbyRERF;(ii)integrationofcomplementaryinvitro and in vivo mechanistic studies (including ahumanizedmousemodel)tohelpguidethestudiesinhumans;and(iii)synergisticeffortsofco-investigatorsfromfiveU.S.andfourJapaneseinstitutionswhobringkeyexpertiseandmethodologiestoassist
RERFinanalysesandattainingstudyobjectives.The
researchprogramconsistsoffourfocusedprojects
with explicit goals of assessing mechanisms and
effectsofradiationonimmuneaginganddysfunction:(1)theroleofhematopoieticstemcellsandtheir
microenvironmentinT-celldevelopment;(2)dendriticcellnumbers,responsiveness,andfunction;(3)
immuneresponsivenesstoinfluenzavaccination;and(4)amultivariableassessmentofimmunepatterns
to create an integrated scoring system of immune
competence. Project 4 will incorporate RERF’s
previouslyandnewlystudiedparameterswithnovelfindingsfromprojects1–3,inordertoprovidenew
analytical tools for radiation effects, aging, and
diseaseoutcomes.Theresultsoftheproposedstudieswillnotonlyprovideawealthoffundamental
biologicalinformationontheprocessof—andthe
impactofradiationon—agingoftheimmunesystem,butmayalsoprovideinsightsthatleadtoameliorationofimmunedysfunctionandotheradversehealth
outcomesinA-bombsurvivorsandradiation-exposed
olderadultsingeneral.
Return to Table of Contents

A. Background Relative to Immunosenescenceand Radiation
RERF’s mission is to “conduct research, for
peacefulpurposes,onthemedicaleffectsofradiation
onman,withaviewtocontributingtothehealthand
welfare of the atomic-bomb survivors and to theenhancement of the health of mankind.” RERF
scientistsandthescientistsofitspredecessorinstitution,theABCC,havebeenevaluating,documenting,
andpublishingforthepast63yearsthelong-term
healtheffectsassociatedwiththeionizingradiations
emittedbytheA-bombsinHiroshimaandNagasaki(see for example mortality studies summarized in
refs.1–6).MuchoftheresearchofABCC,andnowRERF, has focused upon characterization of theeffects of theA-bomb radiation exposure on theimmunologicalparametersinthesurvivors.Those
studiesarebeingconductedinanagingpopulation
inoneofthelongest-livingandmosthomogeneous
populationsintheworld.SowhenNIAIDidentifiedanimportantneedformoreinformationontheeffects
ofradiationontheimmunesystemandimmunosenescence,RERFwasinauniquepositiontoaddress
basicsciencequestionsthatareofdirectrelevance
tounderstandingeffectsofradiationexposureonthe
immunesystemacrossthelifespan.
Immunosenescence is the gradual deterioration
oftheimmunesystemwithagingasillustratedinthe
Figureonthenextpage.Asanaturalphysiological
process,immunosenescenceisinvolvedinarange
ofvitalactivities,including:(i)degradationofhostcapacity to respond to infections; (ii) diminished
development and retention of long-term immune
memory,includingtheonegeneratedbyvaccination;
(iii)alterationofimmunecellturnover;and(iv)an
imbalancebetweeninnateandadaptiveimmunity,
potentiallycausingenhancedandpersistentinflammatory responses. Immunosenescence is a major
contributory factor to the increased frequency of
morbidity and mortality among the elderly from
variousaging-relateddiseasesasalsoillustratedintheFigure.
RERF Update Volume 21, Issue 1, 2010

14

Science Articles

Figure. Immunosenescence as a natural aging process

Understandingtheeffectsofradiationonimmunosenescenceshouldlayafoundationtomechanisticallyexplainsomeofthelong-termhealtheffects
thathavebeenpreviouslydocumentedintheA-bomb
survivors.Thatknowledgewillhelpdevelopamore
robust database for radiation hygienic purposes,
especially in terms of protecting exposed populations.
NIAIDandRERFheldaworkshop27–29November2007inHiroshimathatwasorganizedwiththe
guidanceofRERF’sAssociateChiefofResearch,
ThomasSeed.Theworkshopgoalwastoreviewthe
RERF’s extensive information regarding immunologicaleffectsintheA-bombsurvivorsandtoexplore
areas where additional scientific information was
needed (see workshop report byY. Kusunoki in
Update Volume19,Issue1,2008).In2008,NIAID
issuedarequestforproposals(RFP)thatsolicited
researchproposalsthatwouldexploretheeffectsofradiation exposure on immunosenescence. RERF
respondedtotheNIAIDRFPandthescientificwork
outlinedintheresultantproposalclearlyisconsistent
withtheresearchmissionofRERF.
Severalmajorstudygroups(cohorts)havebeen
establishedandtrackedbyABCC-RERFscientists
overseveraldecadesrelativetothelong-termhealth
effectsassociatedwiththeA-bombirradiations.The
“LifeSpanStudy”(LSS)cohortisthemajorcohortand includes some 120,000 individuals. Based on
intensivefollow-upstudiesofthosecohorts,dosedependentrelationshipsbetweenradiationexposureandsubsequentmortalityandmorbidityresponses
havebeendefinedanddocumented.Thevolumeofdata collected is enormous, especially from the“AdultHealthStudy”(AHS)cohort,whosemembers
haveundergonebiennialhealthexaminationswithahigh participation rate and have donated bloodsamplesoveraperiodoffivedecades.Thestrength
of the studies has been based on the fact that thecohorts are quite large, the radiation doses for
individualscoverawiderange,andthedoseshave
beenreconstructedusingasophisticatedandrecently
upgradeddosimetrysystem,calledDS02.7,8
Return to Table of Contents

TheRERFbiosamplerepositoryincludesalarge
numberofautopsyspecimens,frozenbloodfractions(plasmaandsera),andfrozen,immortalized,viable
lymphocytes.While some of the biosamples have
beenusedinanumberofstudies,RERFhasbeenverycautiousinutilizingthisvaluableresourcesince
scientific technologies for analyses of such biosampleshavebeendevelopingrapidlyandimproving
theircapabilities,speed,sensitivities,accuracy,and
efficiency.WhileinthepastRERFhasprobablybeenjudgedtobeprudentinnotconsumingtheprecious
andfiniteresource,especiallygiventheiruniqueness
andpotentialvalue,tworecentreports(bytheRERF
SeniorReviewPanelandtheRERFScientificCouncil) have encouraged RERF scientists to begin to
applythenewestandmostappropriatetechnologies
to address some important scientific questions. In
order to make the optimum and most efficacious
analyses,thescientistswereencouragedtocollaborate with the best scientists from Japan and othercountriesandtoconducttheexperimentsinorderto
take advantage of the expertise and the expensiveequipmentandspecialfacilitiesrequiredforimplementing the latest scientific methodologies. In
summary,RERF’sscientistswereuniquelypoisedtorespondtotheNIAIDRFPandhavedevelopeda
workplanincollaborationwithacarefullyselected
team composed of scientific collaborators from
institutions in the U.S. and Japan to rigorously
answerthemostcriticalquestionsrelatedtoradiation
andimmunologicalaging.
B. Summary of ABCC-RERF Immunological
Findings
ThemajorcausesofdeathwithintheLSScohort
havebeenanalyzedbyproducingestimatesoftheexcessrelativerisk(ERR)expressedperradiationdose(Gy)fortheyearsfrom1950to2002.Earlyrisk
estimateswerefoundtobeelevatedforleukemiaand
laterforsolidcancers,butinrecentyearsanumberofnon-cancerdiseasesalsoappeartobeelevatedintheradiation-exposedA-bombsurvivors.Oneplausible premise to interpret those findings is that a
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betterunderstandingofthedefectsinanindividual’s
immunological system over time and with prior
radiationexposureiscriticaltohumanhealthfromatleasttwostandpoints:first,itwillprovideasolid,
scientifically-grounded basis for risk assessment,
regardless of the disease outcome of interest; and
second,itwillopenopportunitiesforprophylaxis,
prevention,andtreatmentoftheresultingdisorders.
Morethan60yearsaftertheA-bombings,significantradiation-relatedalterationsintheimmunesystem
havebeenobservedinthesurvivors.ToaddressthequestionofhowexposuretoA-bombradiationhas
affected the human immune system and caused
diseases,wehavehypothesizedthatA-bombradiationhasacceleratedimmunologicalaging.
ImmunologicalagingfoundinA-bombsurvivorsismainlycharacterizedby(i)adecreaseinthymic
T-cellproduction;(ii)frequentclonalexpansionofmemorycellpopulations;(iii)dysregulatedautoimmune responses; and (iv) enhanced inflammatory
responses.Itshouldbepossibletoapplythenewly
available biomedical technologies (i.e., so-called“omics,” such as immunogenomics, immunomics,
proteomics, metabolomics, etc.) to probe RERF’suniquedatabasesandstoredbiosamplestoexaminethe nature and degree of age/radiation exposureassociated decrements in the immune system.We
alsohypothesizethatindividualimmunogeneticfactors may be involved in determining individualsusceptibilitytoradiation-associateddiseases.Therefore, RERF’s testing of various immunological
parameters inA-bomb survivors with long-termfollow-upcouldbeusedtoinvestigatelinksbetween
immunologicalphenotypes,genotypes,anddisease
outcomes.Suchanimmunogeneticapproachshould
providenewcluesforidentifyinggroupsathighrisk
ofradiation-associateddiseasesandassessthegeneradiation interaction in disease development. Past
andongoingstudiesatABCC-RERFhaveprovided
severaltypesofassessmentsthatareexpectedtohave
relevancetoimmunosenescence.
1. Assessments of blood lymphocytes of A-bomb
survivors
Studieshaveshownsignificantradiationeffects

onT-cellfunctions(Table1). By contrast,no significantlong-termeffectsofA-bombirradiationon
bloodNKcells,monocytes,orgranulocytes,interms
ofspecificfunctionalendpoints(e.g.,K562celllysis,
phagocytosis, in vitro migration, etc.), have been
noted.14 However,acautionarynoteiswarranted,in
thatanintegratedandsystematicexaminationofthesurvivor’s innate immune system (as well as itsinteraction with adaptive immunity) has yet to be
conducted.
2. Assessments of lymphocyte subsets of A-bomb
survivors
Studieshaveindicated:(i)significanteffectsofA-bomb irradiation on T- and B-lymphocyte subpopulations(Table2);(ii)radiationdose-dependent
decreases in the proportion of CD4T cells, especiallythenaïveCD4Tcells,aswellasdose-dependentincreasesintheproportionofmemoryCD8T
cells;(iii)dose-dependentincreasesintheproportion
ofBcells;(iv)significantlyhigherpercentagesof
CD4–CD8–TCRα/βTcellsinsurvivorswhohad
beenexposedtoradiationdosesgreaterthan1.5Gy15;
and(v)nosignificantradiationeffectonCD3+TCR
γ/δTcells,CD3+CD56+Tcells,CD4+/CD28–Tcells,
CD8+/CD28–Tcells,theTh1/Th2cellratio,orCD16+
NKcells.Adose-dependentincreaseintheproportionofCD4+/CD25+/CD127–regulatoryTcellshas
recentlybeenobserved.16
3. Radiation-associated persistent inflammationand infection-related factors in the survivors
Previous findings include: (i) increased plasmalevels of selected immunoglobulins such as IgM,
IgG, and IgA with increasing radiation dose17;(ii) increased prevalence of high-titered antibody
responsestotheearlyantigenofEpstein-Barr(EB)
virusamongA-bombsurvivors,comparedwithnonexposedindividuals18;(iii)dose-dependentdecreasesinplasmalevelsofantibodytoChlamydia pneumonia amongA-bomb survivors, compared with
non-exposed individuals 19; (iv) radiation dosedependent elevations of plasma inflammatory
cytokinelevelsfortheTh2-relatedcytokines,interleukin-6(IL-6)andIL-10,aswellastheTh1-related

Table 1. Radiation-related alterations in cellular immune functions among A-bomb survivors
Cell type

Function

Radiation-related
alteration

Study period andnumber of study
subjects (N)Reference

T cells

PHA response
MLR
IL-2 production
Sag response

Decrease
Decrease
Decrease
Decrease

1974–77 (683)
1984–85 (139)
1988–92 (410)
1992–95 (723)

9
10
11
12

NK cells

K562 cell lysisNS

1983–86 (1,316)

13

PHA = Phytohemagglutinin; MLR = Mixed lymphocyte reaction; Sag = Super antigen;
NK = Natural killer; NS = No significant alteration
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Table 2. A-bomb radiation-associated alterations of lymphocyte subsets
Lymphocyte subset

Effects

Study period (d)RefDecrease (2%)

1992–95 (723)12

Decrease (8%)
Decrease (25%)

Decrease (5%)
Decrease (9%)

1992–95 (723)
2000–03 (533)1224F>M (8%)
F>M (10%)
F>M (7%)NS
Decrease (11%)
Increase (8%)

NS
NS
NS

1992–95 (723)
2000–03 (533)
2000–03 (533)

12
24
24

NS

NS

NS

1992–95 (723)

12

Naïve
CD45RO–/CD62L+

F>M (19%)

Decrease (35%)

Decrease (8%)

2000–03 (533)24

MemoryCD45RO+/CD62L+
CD45RO+/CD62L–

NS
M>F (12%)NS
Increase (6%)sug

Increase (12%)
Increase (8%)

2000–03 (533)
2000–03 (533)2426

B cells

F>M (5%)Decrease (7%)

Increase (8%)

1988–92 (411)2526

NK cells

M>F (20%)

Increase (21%)

NS

1988–92 (411)2625Gender (a)Age (b)Radiation (c)F>M (5%)Decrease (5%)

Naïve
CD45RA+
CD45RO–/CD62L+

F>M (3%)
NS

MemoryCD45RA–
CD45RO+/CD62L+
CD45RO+/CD62L–

T cells
CD4 Total

CD8 Total(a) Percents in parentheses represent change between genders(b) Percents in parentheses represent change per 10-year period of aging(c) Percents in parentheses represent change estimated per Gray (Gy)(d) Numbers in parentheses represent number of subjects
Note: All percent changes are significant (p < 0.05) unless designated as NS = Non-significant (p > 0.1) or
sug = Suggestive significance (0.05 < p < 0.1)

cytokines,interferon-γ(IFN-γ)andtumornecrosis
factor-α(TNF-α)17,20;and(v)radiationdose-dependentelevationofinflammatorymarkers,i.e.,plasmaC-reactiveprotein(CRP)levels20,21anderythrocyte
sedimentationrate(ESR).22Theresultsareconsistentfindingsthroughoutseveralsurveysconductedoverthepastdecade,andgaverisetothe“bottomline”
conclusionthat“pastradiationexposureaccelerated
age-dependentincreaseoftheknowninflammatorymarkers.”20,23
4. Assessments of the T-cell receptor (TCR) repertoire
Results have shown: (i) no radiation-specific
alteration in the TCRVβ family profile of eithernaïveormemoryCD4Tcells24;(ii)decreasedT-cell
proliferativeresponsestosuperantigenstaphylococcal enterotoxins almost regardless of TCR Vβ
usages12;(iii)memoryCD4T-cellTCRVβfamily
expression levels significantly diverged from thepopulationaverageforcontrolsubjects,especiallyin individuals who had been exposed to higherradiationdosesandwere20yearsofageandolderat the time of the bombing 24; and (iv) largerdifferencesintheTCRVβrepertoiresbetweennaïveandmemoryCD4T-cellpoolsinheavilyexposedsurvivorsthaninunexposedcontrols.24

Return to Table of Contents

5. Studies on memory T cells
Resultsrevealed:(i)co-stimulatoryfunctionsofCD43inhumanmemoryCD4Tcells26;(ii)identification of functionally distinct CD4+/CD45RO+humanmemoryT-cellsubsetsbyusingamonoclonal
antibodytoCD43withnovellineagespecificityfor
theanalyses27;(iii)dose-dependentincreasesinthe
proportionsofhypofunctional(CD43intermediate)
andanergic(CD43low)memoryCD4T-cellsubsets
intheperipheralbloodofA-bombsurvivors28;(iv)
identificationofclonalchromosomeaberrationsof
memory T-cell origin, indicating frequent clonal
expansionofasubsetofmemoryT-cellpopulationsinA-bomb survivors29; and (v) markedly uneven
distributionsofnaïveandmemoryTcellsintheCD4
andCD8T-cellpopulationsderivedfromsinglestem
cellsinA-bombsurvivors,suggestinganinfrequent
entryofnaïveTcellsintomemoryT-cellpoolsin
adulthoodamongtheradiation-exposed.30
6. Immunogenome studies
Experimental results demonstrated: (i) an
increasedprevalenceoftype-2diabetesinheavily
exposed individuals with particular class II MHC
DQA1andDRB1alleles,comparedtonon-exposed
individuals31;and(ii)NKG2Dhaplotypeassociationswith natural cytotoxic activity of peripheral-blood
lymphocytesandcancerincidenceinanon-exposed
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population.32
7. TCR mutation studies
Studiesservedtoestablishnovelassaysystems
todetectmutantCD4Tcellsthatlackexpressionof
TCR/CD3 complexes in humans 33 and mice. 34
Withthoseassays,thefollowingobservationswereobtained: (i) significant increase in the mutation
fractions (MF) of TCR-mutant cells with age in
healthy donors,35 despite no significant radiation
dose-dependenteffectontheTCRMFinA-bomb
survivors; (ii) significant increase of TCR MF in
patients who had been treated with Thorotrast,36
patientswiththyroiddiseasewhohadbeentreated
withtheiodineradioisotope,I131,35andpatientswith
ataxiatelangiectasia33;(iii)two-foldhigherTCRMF
inthep53null andp53hemizygous micethanthosein similarly irradiated p53 wild-type mice37; (iv)
significant strain difference in the sensitivity to
radiation-inducedTCRMFamongnormalmice,and
the dose response for BALB/c mice was significantlyhigherthanthatforC57BLl6orC3H/Hemice/
twoweeksafterX-irradiation34;and(v)TCRmutationsmightbeusedasamarkerofin vivoresting
CD4Tcells,sinceitwassuggestedthatthemutantcells exhibit blunted proliferation in response to
antigenstimulationduetotheirlackofTCR/CD3
signaling (Note: a long-term kinetics study on
survivalofradiation-inducedTCRmutantsamongCD4+CD45RA–memoryandCD4+CD45RA+naïveT-cellfractionsinradiotherapypatientsshowedthatthelifespanofmatureCD4Tcellswastwotothree
yearsintheabsenceofTCR/CD3expression,i.e.,in
therestingstage,regardlessofitsmemoryornaïve
phenotype38).
8. Studies on hematopoietic stem cells (HSC)
Experimentalresultssuggested:(i)adose-dependentincreaseintheabsolutenumberofcirculatingCD34+cellsinfemalesurvivors(unpublishedobservation),butthispilotstudyrequiresamorethoroughfollow-up using a refined assay; (ii) decades-long
persistenceofradiation-inducedsomaticmutationsinHSC,asindicatedbythedose-dependentincreaseinglycophorinA(GPA)mutantfractionsofcirculating erythrocytes39; (iii) the presence of an HPRT
mutationthathadpossiblyoriginatedfromamutationinasinglestemcellofonemalesurvivor40;(iv)
thepresenceofaclonalchromosomeaberrationthat
hadoriginatedfromasinglestemcellaberrationof
onefemalesurvivor41;(v)adevelopmentalarrestofhumandendriticcellsattheCD34–/CD4+/HLA-DR+
stage in the bone marrow of NOD/SCID-humanchimericmice42;and(vi)anincreasedradiosensitivityofCD34+/CD38–cellstoinducedapoptosis,alongwith increased production of intracellular O2- and
decreased intracellular pH, compared to CD34+/
CD38+ andCD34–/CD38+ cells.43
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17
9. Evaluations of processes related to NK-mediatedcancer immunosurveillance
Resultsofexperimentssuggested:(i)aninverserelationship between individual natural cytotoxic
activityofperipheralbloodlymphocytesandcancer
incidence among a non-exposed population44; and(ii)anNK-mediatedeliminationofmutantlymphocytesthathavelostexpressionofmajorhistocompabilitycomplex(MHC)classImolecules.45,46HaplotypesofNKG2D receptorgenewereidentifiedasa
potentgeneticfactorofindividualnaturalcytotoxic
activity.47 Current studies include examining therelationship between NKG2D haplotypes and theconsequence (persistent infection or clearance) ofviralhepatitisinA-bombsurvivors.
10. Evaluations of T-cell homeostasis and immunological aging
Studiesareongoingthatinclude:(i)enumeration
ofCD4andCD8TlymphocytesthatcontainT-cell
receptor-rearrangementexcisioncircles(TREC),in
ordertoaddressthequestionastowhetherornot
priorA-bomb irradiation impaired thymic T-cell
production; (ii) determining lengths of telomere
repeatsinnaïveandmemoryCD4Tcells,CD8T
cells,andgranulocytesinordertotestthehypothesisthatTcells,especiallymemoryTcells,haddivided
more frequently during the initial recovery phase
followingA-bombirradiation;and(iii)analyzingthe
agingprofilesinlymphocytesubsets(e.g.,decreased
proportionofnaïveTcells,increasedproportionof
particular types of T cells, etc.) in longitudinal
samples by flow cytometry in order to provide
evidence for the concept thatA-bomb irradiation
acceleratedT-cellimmunologicalagingassuggestedbyRERF’slongitudinalfollow-updataofindividuals.
11. Characterization of persistent inflammation interms of disease outcome
Ongoingexperimentsinclude:(i)assaysofserum
inflammatorycytokinelevelsinrelationtoageand
radiationdose;and(ii)estimationsofnetoxidative
stressinthesurvivorsbytestingproductionofreactiveoxygenspecies(ROS)inbloodcellsandplasma.
SerumlevelsofROSmetabolitesrevealedasignificantradiation-dosedependence(unpublisheddata).
12. Attempts to characterize the immunogenetic
background of the survivors
Wearecontinuingtoexaminethewideandvaried
responseoftheimmunesystemofA-bombsurvivorsand the equally-varied disease outcomes. Studies
involve:(i)identifyinggenepolymorphismsresponsible for the individually-differing immune and
somatic-mutability responses to prior radiation
exposureamongthesurvivors(suchgenepolymorphismsmayfurtherrelatetoindividualsusceptibilRERF Update Volume 21, Issue 1, 2010

Science Articles
itytoradiation-associateddiseases);and(ii)genome
association studies relative to specific radiogenic
diseaseoutcomes,e.g.,differingrisksofradiationassociated stomach cancer by IL-10 haplotypes
(unpublished data) and radiation-associated lung
cancerrisksbyEGFRgenotypes.48
13. Radiation-induced genomic instability andlong-term responses of the lymphohematopoietic
system of the survivors
In collaboration with the Cytogenetics LaboratoryintheDepartmentofGeneticsatRERF,weare
investigatingthechangeinchromosomeaberrationfrequenciesasaconsequenceofclonalpropagation
ofTcellsin vivo orin vitro.Sofarnoclearevidencehasindicatedthatgenomicinstabilitypersistsforalong period in peripheral T-cell populations in
A-bomb survivors. 49 The following studies are
underway:(i)determiningthefrequenciesofmicronucleated reticulocytes within blood ofA-bomb
survivors;(ii)conductingcomparativein vitroand
in vivoanalysesofgeneticdamageandinflammatorybiomarkers,includingmeasuresofnetoxidative
stress,inbloodcellsofsurvivors(thelatterisbasedon the hypothesis that radiation-induced genomic
instability may partly be involved in long-lasting
inflammation);andfinally(iii)examiningassociated
measuresofradiation-associatedgenomicinstabilityandcancer.
Resultsofthepreviouslycompletedandongoing
studiesindicatethatRERF’sscientistshaveconsiderabledataandinformationrelativetotheimmunological status of the radiation-exposedA-bomb
survivors.Theobservationshaveprovidedinputtothe development of the hypotheses that will be
tested in RERF’s proposed work plan and experimental designs that were submitted to NIAID in
February, 2009.After extensive NIAID review,
includingreviewsbyexternalscientists,theRERF
proposalwasacceptedandacontracttoperformtheexperimental work for a period of five years was
signedbyRERFandNIAIDeffectiveSeptember30,
2009.
C. Studies to be Conducted by RERF and by
Collaborating Subcontractors
Four major statements of work or projects are
identifiedintheNIAIDcontracttoaddresskeyquestionsrelatedtocriticalelementsofimmunosenescence.
1. Project 1: Effects of ionizing radiation exposureand aging on hematopoietic stem cells (HSC)Thisstudywillexaminetheeffectsofionizingradiationexposureandagingonblood-derivedHSC
includingthedeterminationofnumericalandfunctionalchangesinthecirculatingHSCpoolinrelationto age and radiation dose. HSC provide the reguReturn to Table of Contents

18
latedlifelongsupplyofleukocyteprogenitorsabletodifferentiateintoanarrayofspecializedimmune
cells.HSCarespeculatedtodiminishinnumberand
declineincapacitytoself-renewwithphysiological
aging.TheprimaryquestionaddressedbythisprojectiswhetherthepriorA-bombirradiationaccelerated
thisprocess,andifso,towhatextent,andbywhat
process(es) (e.g., increasing the accumulation of
oxidativedamagetoDNAorbyshorteningtelomeric
terminalsofchromosomes).
Self-renewalanddifferentiationpotentialswillbe
evaluatedalongwithmeasurementsofcell-cycleand
redox status and genomic damage in HSC, and
otherparameterssuchasmicronucleifrequenciesin
reticulocytes, the GPA mutant fraction in erythrocytes, and telomere length in granulocytes. The
projectwillalsoincludeexperimentsthatwillassessthehumanHSCabilitytoreconstitutetheimmune
system using a humanized mouse model. ExperimentswillanalyzeHSCfrommicefollowingnaturalagingand/orradiationexposureandwilldetermine
effects of irradiation and aging on hematopoietic
microenvironments.
2. Project 2: Effects of ionizing radiation exposureand aging on dendritic cells (DC) and their precursors
 In a similar manner to the first project that
focusesonHSC,thisstudywillexamineeffectsofionizing radiation exposure and aging on DC and
their precursors. DC are crucial in triggering primaryimmuneresponsesagainstpathogens,butalsointhecontrolofadaptiveimmunity,andmaythereforebeinvolvedinimpairedT-cellresponsivenessandimpairedhomeostasiswithaginginirradiated
individuals.TheprojectwilladdressthequestionastowhetherornotpriorA-bombirradiationaffects
cell-mediated immunity and interferes with theability of effector T lymphocytes to modulate an
adaptiveimmuneresponsebyimpactingDC.
Experiments will determine numerical changes
in circulating (cDC) and plasmacytoid (pDC)
populations,aswellasthoseinbloodT-helperand
regulatory-T (Treg) subsets in relation to age and
radiation dose. Changes in the functional and
differentiation status of circulating cDC and pDCpopulationswillalsobeascertainedrelativetoage
andradiationdose,alongwiththeiractivationstatus
(Toll-likereceptor[TLR]expression,HLA-DR,costimulatory molecules, etc.), and production of
cytokinesbeforeandafterTLRtriggering.RadiobiologicalanalysesofhumanDCdifferentiationand
functionwillalsobeinvestigatedin vitro followingin vitro irradiation.Finally,toexploremechanisms
morethoroughly,radiobiologicalanalysesofmouseDCdifferentiationandfunctionin vitro andin vivo
willbeconducted.

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3. Project 3: Effects of ionizing radiation exposureand aging on vaccination responses and investigation of methods to augment immune responses
Vaccinationisperhapsthemostimportantmeasureforpreventionofinfections,particularlyinthe
elderly.AprimaryquestioniswhetherornotpriorA-bombirradiationincombinationwithphysiological aging significantly alters the effectiveness of
vaccination. Project 3 will evaluate the effects of
ionizingradiationexposureandagingonvaccinationeffectivenessintermsofhostimmuneresponsesto
influenzavaccinationinA-bombsurvivorswhohaveelectedtobeimmunizedinresponsetoannualpublic health guidelines.Antibody titers and in vitro
re-stimulation of cytokine responses will be measured along with plasma levels of cytokines and
inflammation-related proteins. T-cell responses to
influenza vaccination, lymphocyte subsets, and
intracellularactivationmarkers(cytokineproduction,transcription factors, etc.) will be measured alongwith cytokines in culture supernatant of T-cell
stimulation. Mechanistic studies will also be conductedin vivo inmousemodels.
4. Project 4: Development of an integrated scoring
system for human immune competence as it relates
to age and ionizing radiation
The goal of this project is to develop an integrated scoring system for human immune competenceasitrelatestoageandpastionizingradiation
exposureusingcross-sectionaldata(singlemeasurementsonindividualsubjects).Developmentofsuchan integrated scoring system for immunological
capacityandcompetencewouldprovideavaluable
clinical tool for evaluating the health status of
A-bombsurvivorsandpeoplewhowereexposedto
radiationingeneral.Theprimaryquestioniswhetheraclinically-relevant,statistically-basedmodelcanbedevelopedusingthevariousparametersandbiomarkers of radiation exposure and immunosenescence.Acomputationalscoringsystempredictiveof
exposurelevelswillbedevelopedandvalidatedalongwith the identification and validation of new biomarkers and measurements.Approximately 500different immune biomarkers will be incorporatedtopredictimmunologicalimpactsofirradiationinanagingpopulation.TheconstructionofacomprehensiveimmunescoringsystemwillmakeuseoftheuniqueRERFlongitudinaldatabase(repeatedmeasurementsonindividualsubjects).RERFscientists
willattempttocompletethelongitudinaldatabaseofstudysubjects,includingthegeneticfactors,and
incorporatethedataofnewly-developedbiomarkers
withuseofproteinchiparraysand/ormultipleximmunoassays.Associatedmeasurementsoftelomere
lengthsinbloodcellswillalsobeincorporated.By
linkingwiththeRERFfollow-updata,theprediction
modelwillbeexpandedtoincludediseaseoutcomes.
Return to Table of Contents

19Inordertosuccessfullyaccomplishthestudiesinthe four areas summarized above, RERF has
assembledateamofcollaboratorsinlaboratoriesinJapan and the U.S. Those scientific collaborators
haveessentialexpertiseand/ormethodologicalsystemsinplacetocomplementtheresearchcapabilities
ofRERFandcriticallycontributetothesuccessful
performanceofthefourprojectsdescribedabove.
TheprimecontractorfortheprojectisRERFand
theFoundation’sscientistswillconductresearchon
immunosenescenceandionizingradiationasspecified in the four tasks/projects. Experiments are
designedtodeterminethecontributionoftheimmune
systemtodiseasedevelopmentinthoseexposedto
A-bomb radiation.The research will focus on thenatureofthecombinedactionsofpriorirradiation
and aging and its impact on immunosenescence.
Research proposed will examine the relationships
betweenimmunedysfunctionandapersistentinflammatorystate,andtheresultingdiseasesandinfectionsthatmayoccurasaconsequenceofimmunosenescenceintheA-bombsurvivors.RERFscientistswill
relyheavilyontheappropriateuseoftheexistingcohortsandawide-rangeofreconstructedradiationdose estimates for individual cohort members,
includingappropriatecontrol(nosignificantA-bomb
radiationexposure)populations.Theywillalsorelyon the appropriate use of the unique and valuable
resource of biological specimens that have been
contributedbyA-bombsurvivorsatbiennialclinical
examinations, beginning in 1969.Animal modelswillalsobeusedinordertosupplement,detail,and
refineproposeddescriptiveandmechanisticstudieson radiation/age-related immunosenescence usingbiospecimensfromtheA-bombsurvivorcohorts.
AmajorcomponentofRERFscientistswillbe
from the Department of Radiobiology/MolecularEpidemiology (RME) in Hiroshima, but scientistsfromotherRERFdepartmentswillbeinvolvedintheprojects.TheformerChiefofRME,KeiNakachi,istheresponsiblePrincipalInvestigator(PI)forthe
overallcontract.YoichiroKusunoki,thecurrentActingChiefofRME,alongwithTomonoriHayashi,
currentChiefoftheImmunologyLaboratory,will
serveastheco-PIsonthestudy.Dr.Kusunokiwill
serveasthe‘responsiblescientist’forProjects1and
2,whileDr.Hayashiwillserveasthe‘responsible
scientist’forProjects3and4.TheAssociateChief
ofResearch(EvanDouple)andtheAssociateChief
of Secretariat (Douglas Solvie) will serve as theadministrativeandfinancialmanagers,respectively,
oftheoverallstudy.
BeforesigningacontractwithNIAIDandbefore
beginningtheproject,RERFseniorleadershipmade
presentationsatmeetingsoftheLocalLiaisonCouncilsinHiroshimaandinNagasakitoinformthose
stakeholdersandtoaddressthequestionstheyhadin order to create a climate of transparency and
RERF Update Volume 21, Issue 1, 2010

Science Articles
understanding, especially amongst theA-bomb
survivors,cooperatingphysicians,andcommunity
members.Althoughasmanyexperimentsaspossible
willbeperformedbyRERFscientistswithinRERF’slaboratories,ateamoffivekeyscientistsfromthe
U.S. and four key scientists from Japan has been
selectedontherationalethatthemembers’expertiseandexperiencearecomplementarytothatofRERF
scientists and/or they have special equipment and
establishedmethodologiesthatarenotavailableintheRERFlaboratories.Inaddition,threeU.S.and
twoJapanesescientistshavebeenrecruitedtoserveaskey‘subjectmatterexperts’orconsultantsonthe
project. The following list indicates the key coinvestigatorsandtheirinstitutions.
Susan M. Geyer, Ph.D.,SeniorBiostatisticalScientist,CenterforBiostatistics,OhioStateUniversity
Yoko Hirabayashi, M.D.,SectionChiefandSenior
Scientist, Division of Cellular and MolecularToxicology, National Center for Biological
SafetyandResearch,JapanNationalInstituteof
HealthSciences
Kayo Inaba, Ph.D., Professor, Laboratory of Immunobiology,DepartmentofAnimalDevelopment and Physiology, Graduate School of
Biostudies,KyotoUniversity
Tohru Inoue, M.D., Ph.D.,Consultant,ToxSafety
Consultations(ToxSCO),andVisitingScientist,
National Center for Biological Safety and Research,JapanNationalInstituteofHealthSciences
Atsushi Iwama, M.D., Professor, Department of
Cellular and Molecular Medicine, Graduate
SchoolofMedicine,ChibaUniversity
Shigeo Koyasu, Ph.D., Professor and Chairman,
DepartmentofMicrobiologyandImmunology,KeioUniversitySchoolofMedicine
Nancy R. Manley, Ph.D.,ChairofDevelopmental
Biology,andProfessor,DepartmentofGenetics,
UniversityofGeorgia
Donna Murasko, Ph.D., Professor of BioscienceandDean,CollegeofArtsandSciences,Drexel
University

20
Janko Nikolich-Zugich, M.D., Ph.D., Chairman,
Department of Immunology, and Co-Director,
Arizona Center onAging,Arizona University
CollegeofMedicine
Thomas M. Seed, Ph.D.,PrincipalConsultant,TechMicroServices
Gregory D. Sempowski, Ph.D.,DukeHumanVaccineInstitute,AssociateProfessor,Department
ofMedicineandPathology,DukeUniversity
Marcel R. M. van den Brink, M.D., Ph.D., Professor of Immunology and Head, Division of
Hematologic Oncology, Memorial SloanKetteringCancerCenter
Nan-ping Weng, M.D., Ph.D.,SeniorInvestigatorandChief,LymphocyteDifferentiationSection,
Laboratory of Immunology, U.S. National
InstituteonAging
Koji Yasutomo, M.D., Ph.D.,ProfessorandChairman,DepartmentofImmunologyandParasitology,InstituteofHealthBiosciences,University
ofTokushimaAsaresultofthefundingprovidedbyNIAID,
andtheassembledteamofcollaboratorswhowillbe
providing special analyses and complementaryexperimentation with carefully-monitored use of
biosamplesandprotectionofpersonalinformation,
itisanticipatedthatRERFscientistswillbeableto
take its research to a new level of excellence and
honortheirpledgetoapplythelatestandbestscientificmethodologiestothedataandbiosamplesthat
theA-bombsurvivorshaveentrustedtoRERF.Itis
expectedthattheeffortsofthecollaboratingscientistswillbesynergisticandtheprojectisexpected
tocontributeimportantinformationtobasicscience,
theA-bombsurvivors,andmankindastowhetherradiationexposurehasanimportantroleinmodifyingtheprocessofimmunosenescenceandwhether
thatroleexplainsinpartthehealtheffectsthathave
beenobservedinthestudiesofABCCandRERF.
(This new study is supported by Contract No. HHSN272200900059CwiththeU.S.NationalInstituteofAllergy
andInfectiousDiseases.)

References 1. ShimizuY,KatoH,SchullWJ,PrestonDL,FujitaS,PierceDA.LifeSpanStudyReport11.Part1.Comparison
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RERF Update Volume 21, Issue 1, 2010

Science Articles

21

Report12,PartI.Cancer:1950–1990.Radiat Res 146:1-27,1996.
 5. Pierce DA, Preston DL. Studies of the mortality of atomic bomb survivors. Report 12, Part II. Noncancermortality:1950–1990.Radiat Res 152:374-89,1999.
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alterationofin vitromixedlymphocytecultureresponseofbloodlymphocytesfromA-bombsurvivors.RadiatRes117:26-34,1989.
11. KusunokiY,HayashiT,MorishitaY,YamaokaM,MakiM,BeanMA,KyoizumiS,HakodaM,KodamaK.
T-cell responses to mitogens in atomic bomb survivors:A decreased capacity to produce interleukin 2
characterizestheTcellsofheavilyirradiatedindividuals.Radiat Res155:81-8,2001.
12. KusunokiY,YamaokaM,KasagiF,HayashiT,KoyamaK,KodamaK,MacPheeDG,KyoizumiS.Tcellsof
atomicbombsurvivorsrespondpoorlytostimulationbyStaphylococcusaureustoxinsin vitro:Doesthisstemfrom their peripheral lymphocyte populations having a diminished naïve CD4 T-cell content? Radiat Res
158:715-24,2002.
13. BloomET,AkiyamaM,KornEL,KusunokiY,MakinodanT.ImmunologicalresponsesofagingJapanese
A-bombsurvivors.Radiat Res116:343-55,1988.
14. KusunokiY,KyoizumiS,HiraiY,FujitaS,AkiyamaM.IncreasedfrequencyofCD4–8–TcellsbearingT-cell
receptoralphabetachainsinperipheralbloodofatomicbombsurvivorsexposedtohighdoses.Radiat Res
139:67-72,1994.
15. HayashiT,MorishitaY,KuboY,KusunokiY,HayashiI,KasagiF,HakodaM,KyoizumiS,NakachiK.Longtermeffectsofradiationdoseoninflammatorymarkersinatomicbombsurvivors.Am J Med118:83-6,2005.
16. KusunokiY,YamaokaM,KuboY,HayashiT,KasagiF,DoupleEB,NakachiK.T-cellimmunosenescenceand
inflammatoryresponseinatomic-bombsurvivors.Radiat Res2010.(Inpress)
17. AkiyamaM,KusunokiY,KyoizumiS,OzakiK,MizunoS,CologneJB.Studyofthetitersofanti-Epstein-Barrvirusantibodiesintheseraofatomicbombsurvivors.Radiat Res133:297-302,1993.
18. HakodaM,KasagiF,KusunokiY,MatsuuraS,HayashiT,KyoizumiS,AkahoshiM,SuzukiG,KodamaK,
FujiwaraS.LevelsofantibodiestomicroorganismsimplicatedinatherosclerosisandofC-reactiveproteinamongatomicbombsurvivors.Radiat Res166:360-6,2006.
19. HayashiT,KusunokiY,HakodaM,MorishitaY,KuboY,MakiM,KasagiF,KodamaK,MacPheeDG,Kyoizumi
S.Radiationdose-dependentincreasesininflammatoryresponsemarkersinA-bombsurvivors.Int J Radiat
Biol79:129-36,2003.
20. SuzukiG,IzumiS,HakodaM,TakahashiN.LTA252GallelecontaininghaplotypeblockisassociatedwithhighserumC-reactiveproteinlevels.Atherosclerosis176:91-4,2004.
21. NeriishiK,NakashimaE,DelongchampRR.PersistentsubclinicalinflammationamongA-bombsurvivors.Int
J Radiat Biol77:475-82,2001.
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receptorVbetarepertoiresofCD4memoryT-cellpopulationsintheperipheralbloodofradiation-exposed
people.Br J Haematol122:975-84,2003.
23. NakachiK,HayashiT,ImaiK,KusunokiY.Perspectivesoncancerimmuno-epidemiology.Cancer Sci95:9219,2004.
24. YamaokaM,KusunokiY,KasagiF,HayashiT,NakachiK,KyoizumiS.DecreasesinpercentagesofnaïveCD4
andCD8TcellsandincreasesinpercentagesofmemoryCD8T-cellsubsetsintheperipheralbloodlymphocyte
populationsofA-bombsurvivors.Radiat Res161:290-8,2004.

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RERF Update Volume 21, Issue 1, 2010

Science Articles

2225. KusunokiY,KyoizumiS,HiraiY,SuzukiT,NakashimaE,KodamaK,SeyamaT.Flowcytometrymeasurements
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26. KyoizumiS,OharaT,KusunokiY,HayashiT,KoyamaK,TsuyamaN.ExpressioncharacteristicsandstimulatoryfunctionsofCD43inhumanCD4+memoryTcells:AnalysisusingamonoclonalantibodytoCD43thathasa
novellineagespecificity.J Immunol172:7246-53,2004.
27. OharaT,KoyamaK,KusunokiY,HayashiT,TsuyamaN,KuboY,KyoizumiS.Memoryfunctionsanddeath
pronenessinthreeCD4+CD45RO+humanTcellsubsets.J Immunol169:39-48,2002.
28. KyoizumiS,YamaokaM,KuboY,HamasakiK,HayashiT,NakachiK,KasagiF,KusunokiY.MemoryCD4
T-cellsubsetsdiscriminatedbyCD43expressionlevelinA-bombsurvivors.Int J Radiat Biol86:56-62,2010.
29. NakanoM,KodamaY,OhtakiK,ItohM,AwaAA,CologneJB,KusunokiY,NakamuraN.Estimatingthe
number of hematopoietic or lymphoid stem cells giving rise to clonal chromosome aberrations in bloodT
lymphocytes.Radiat Res161:273-81,2004.
30. KusunokiY,HiraiY,HakodaM,KyoizumiS.UnevendistributionsofnaïveandmemoryTcellsintheCD4
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31. HayashiT,FujiwaraS,MorishitaY,KusunokiY,NakashimaE,NakanishiS,SuzukiG,NakachiK,Kyoizumi
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32. HayashiT,ImaiK,MorishitaY,HayashiI,KusunokiY,NakachiK.IdentificationoftheNKG2Dhaplotypes
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33. KyoizumiS,AkiyamaM,HiraiY,KusunokiY,TanabeK,UmekiS.Spontaneouslossandalterationofantigen
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36. UmekiS,KyoizumiS,KusunokiY,NakamuraN,SasakiM,MoriT,IshikawaY,CologneJB,AkiyamaM.FlowcytometricmeasurementsofsomaticcellmutationsinThorotrastpatients.Jpn J Cancer Res82:1349-53,1991.
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39. KyoizumiS,AkiyamaM,CologneJB,TanabeK,NakamuraN,AwaAA,HiraiY,KusunokiY,UmekiS.Somatic
cellmutationsattheglycophorinAlocusinerythrocytesofatomicbombsurvivors:Implicationsforradiation
carcinogenesis.Radiat Res146:43-52,1996.
40. HakodaM,HiraiY,ShimbaH,KusunokiY,KyoizumiS,KodamaY,AkiyamaM.Cloningofphenotypically
differenthumanlymphocytesoriginatingfromasinglestemcell.J Exp Med169:1265-76,1989.
41. KusunokiY, KodamaY, HiraiY, Kyoizumi S, Nakamura N,Akiyama M. Cytogenetic and immunologic
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86:2106-12,1995.
42. NobuyoshiM,KusunokiY,SeyamaT,KodamaK,KimuraA,KyoizumiS.Arrestofhumandendriticcellsat
theCD34–/CD4+/HLA-DR+stageinthebonemarrowofNOD/SCID-humanchimericmice.Blood97:3655-7,
2001.
43. HayashiT,HayashiI,ShinoharaT,MorishitaY,NagamuraH,KusunokiY,KyoizumiS,SeyamaT,NakachiK.
Radiation-inducedapoptosisofstem/progenitorcellsinhumanumbilicalcordbloodisassociatedwithalterationsinreactiveoxygenandintracellularpH.Mutat Res556:83-91,2004.
44. ImaiK,MatsuyamaS,MiyakeS,SugaK,NakachiK.Naturalcytotoxicactivityofperipheralbloodlymphocytes
andcancerincidence:An11-yearfollow-upstudyofageneralpopulation.Lancet356:1795-99,2000.

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RERF Update Volume 21, Issue 1, 2010

Science Articles

2345. KusunokiY,KyoizumiS,HonmaM,KuboY,OhnishiH,HayashiT,SeyamaT.NK-mediatedeliminationofmutantlymphocytesthathavelostexpressionofMHCclassImolecules.J Immunol165:3555-63,2000.
46. KusunokiY,KyoizumiS,KuboY,HayashiT,MacPheeDG.Possibleroleofnaturalkillercellsinnegativeselectionofmutantlymphocytesthatfailtoexpressthehumanleukocyteantigen-A2allele.Mutat Res476:12332,2001.
47. HayashiT,ImaiK,MorishitaY,HayashiI,KusunokiY,NakachiK.IdentificationoftheNKG2Dhaplotypes
associatedwithnaturalcytotoxicactivityofperipheral-bloodlymphocytesandcancerimmunosurveillance.
Cancer Res66:563-70,2006.[Correctionin:Cancer Res66:5976,2006]
48. YoshidaK,NakachiK,ImaiK,CologneJB,NiwaY,KusunokiY,HayashiT.Lungcancersusceptibilityamong
atomic-bombsurvivorsinrelationtoCArepeatnumberpolymorphismofepidermal growth factor receptor
geneandradiationdose.Carcinogenesis30:2037-41,2009.
49. HamasakiK,KusunokiY,NakashimaE,TakahashiN,NakachiK,NakamuraN,KodamaY.ClonallyexpandedTlymphocytesfromatomicbombsurvivorsin vitro shownoevidenceofcytogeneticinstability.Radiat Res
172:234-43,2009.

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RERF Update Volume 21, Issue 1, 2010

24

Science Articles

Highlights of RERF Departments: Radiation
Research Activities in the Department ofClinical Studies
SaekoFujiwara1andMasazumiAkahoshi2
Departmentsof1ClinicalStudies(Hiroshima)and2ClinicalStudies(Nagasaki),RERF
Abstract
TheDepartmentsofClinicalStudiesinHiroshima
andNagasakiarethekeydepartmentsforexaminingA-bomb survivors in a clinical setting. Those
examinations,basedontheRERFplatformprotocolcalled theAdult Health Study (AHS), have been
conductedoveraperiodofmorethan50years.They
enableRERFscientiststodetermineradiationrisks
fordiseasesthatcannotbedocumentedadequately
through the larger mortality study called the Life
SpanStudy(LSS).Forexample,theclinicalstudies
includetheeffectsofradiationontheriskofnonfatal heart disease or stroke, high blood pressure,
various benign tumors, and other adverse health
effects. Since it is well known that both lifestylefactorsandgeneticfactors,inadditiontoradiation
exposure,contributetothedevelopmentofdisease,itisnecessarytofurtheranalyzethelifestyle-related
factors,includingsmokinganddietaryhabits,biological characteristics, psychological factors, and
geneticbackground.Studiesusingstoredbiological
sampleshelpclarifythejointeffectsofradiationand
otherenvironmentalandgeneticfactors.AHSsubjects have provided biological samples at biennial
examinations,repeatedsamplesthatarerarelyavailable elsewhere in the world and that allow us to
observechangesovertime.
AnotherimportantcohortistheF1ClinicalStudy
(FOCS)inwhichapproximately12,000offspringofA-bomb survivors, have participated in a health
examination to evaluate the possible association
between parental radiation exposure dose and theprevalenceofvariouscommondiseasesintheoffspring(suchasheartdisease,stroke,hypertension,
anddiabetes).Thatgroupisstillyoung—theiraverageageisonlyabout50years—andthusrelatively
littlediseasehasdeveloped.Wearemakingplansforacontinuedclinicalfollow-upoftheoffspringoftheA-bombsurvivors.
Additional studies of the department are summarized in this article including special clinical
studies,specialcancerstudies,immunologicalstudies,seracollection,cataractstudies,andstudiesofseniledementia.Wewillconcludewithadiscussion
ofourdepartment’sfutureplans.
Return to Table of Contents

Adult Health Study (AHS)
TheAHSwasinitiatedtoprovidethefirstscientific information on the long-term clinical health
consequencesofA-bombradiation.Biennialcomprehensivemedicalexaminationsbeganin1958withatargetedpopulationofabout20,000survivorsand
controls in the contact areas of Hiroshima and
Nagasaki. In 1978, theAHS sample was enriched
withabout2,400additionalhigher-dosesubjectsand
allavailable(~1,000)personswhowereexposedinutero.Thoseexamsareintheir26thcycle.Duringthe25thcycle(July2006–June2008),atotalof3,609
individuals were examined, representing approximately 70% of theAHS cohort still living in thecontactareasofinterest.
Thepurposeofthestudieshasbeentodetermine(a)thetypesofdiseases,and(b)thephysiological
orbiochemicalabnormalitiesthatmayhaveoccurred,asaconsequenceofpreviousexposuretoionizingradiation, and to correlate this information with
other life experiences and modes and patterns of
death.TheAHSclinicalexaminationfunctionsasa
principalsourceofbiologicalmaterialsforawide
varietyofotherspecialstudies.TheAHShasgreatly
increasedinimportanceinrecentyearsasaresultofthe accumulation of an enormous body of datafrom the serial medical examinations. Particularly
noteworthy is the accumulating evidence of theradiationdose-relatedincreaseinnon-cancerdisease
morbidity,suchascardiovasculardisease,hyperparathyroidism, thyroid diseases, uterine myoma,chronicliverdisease,andcataracts.Thoseimportant,
largely unexpected relationships could never be
properlystudiedusingdeathcertificatedataalone.
Anotherunexpectedfindingmadelargelyretrospectivelyisthatradiationisassociatedwithpremature
menopause,andthis,inturn,mayresultintheearlieronsetofotherconditions,suchasanincreaseincholesterollevelsandcardiovasculardisease.Giventheadvancingageofthesurvivors,thetimeforsuchstudiesislimited,makingitimperativethatresearch
opportunitiesinvolvingtheindividualsbeconsideredinatimelymanner.
TheDepartmentsofClinicalStudiesinHiroshima
andNagasakifollowexactlythesameproceduresfor
RERF Update Volume 21, Issue 1, 2010

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25

clinicalexaminationandlaboratorytesting(history
taking, physical examination, electrocardiography,
chestXray,abdominalultrasonography,andhematologicalandbiochemicalexamination)aswellas
computerdataentryforAHSparticipantsbasedontheAHSplatformresearchprotocol(RP),allowing
analysis of combinedAHS cohort data in the twocities.Thereare6researchscientists,6nurses,and
26clinicalstaffinHiroshima,andthecorresponding
numbersinNagasakiare4,4,and18,respectively.
PreviousRERFstudiesdemonstratedthatyoungersurvivors showed higher radiation risk for cancer
and certain non-cancer diseases (benign thyroid
tumors, hyperparathyroidism, hepatitis B virus
(HBV)infection,andmyocardialinfarction)compared with those exposed in adulthood or whenelderly.Consequently,weareadding1,900survivors
whowereexposedbeforetheageof10yearstothe
AHSpopulationtoinvestigatetheirradiationriskof
non-cancer diseases, which will substantially
improve the precision of risk estimates for thisyoungeragegroup.InOctober2007westartedto
examine as a pilot study an augmented sample of
younger cohort subjects and, in November 2008,
RERFbeganafull-scalestudythatwillincludebiennialexaminationsoftheyoungercohortfromJuly
2010.
Otherrecentlyinitiatedradiation-relatedstudies
include studies of liver stiffness, chronic kidney
dysfunction/disease and the risk of cardiovasculardisease, and pre-clinical measurements of atherosclerosis. Recent reports of new findings include
radiationandlifetimeriskofstroke,radiationand
dementia,metaboliccardiovascularriskfactorsand
subclinical hypothyroidism, genotypes associated
with diffuse-type noncardia gastric cancer, and
associationsofbiologicalageandmortality.

F1 Clinical Study (FOCS)
The FOCS is intended to assess the possible
geneticeffectsandassociatedlong-termhealthconsequencesamongchildrenofJapaneseparentswho
wereacutelyexposedtoionizingradiationfromtheA-bombdetonationsoverHiroshimaandNagasaki.
The hypothesis behind the FOCS is that ionizingradiationmayinducegeneticmutationsingermcells
that cause heritable diseases, in particular, adultonset multi-factorial diseases including diabetes,essential hypertension, coronary heart disease,
stroke,etc.Thestudyhasthreemajorobjectives:(1)
to investigate the effects of parental exposure to
A-bomb radiation on the development of multifactorial diseases among the children ofA-bomb
survivors,(2)topreservebloodsamplesforfuture
molecularbiologicalstudies,and(3)tocontributeto
thehealthandwelfareoftheF1populationviahealth
examinations,andhealthguidance,basedonmeasurementsreflectingclinicalorpreclinicalchanges
relatedtomulti-factorialdiseases.
TheFOCSexaminationsbeganinJanuary2002
and were completed in September 2006. RERF
conductedseveraltrans-generationalstudiesinthe
past,andisconductingthemortalityfollow-upstudy
ofA-bomb survivors’ children and the genetic
analysesof1,000familytrios(father,mother,and
child).However,owingtotheyoungageoftheF1
group(meanageof48years),mostofthedisease
experienceisyettooccur,soweareconvertingthe
sampletoacohortforaprospectivefollow-up,and
plansfortheF1clinicalfollow-upstudyhavealmostbeencompleted.
A total of 11,951 participated in the health
examinationsduringthestudyperiodfrom2002to
2006. The clinical assessment of nearly 12,000
offspringofA-bombsurvivorsprovidednoevidencefor an increased prevalence of adult-onset multi-

Research Scientists of Hiroshima Clinical Studies (first row
from left) Michiko Yamada, Saeko Fujiwara (Department
Chief), Kazuo Neriishi, (second row from left) Ikuno
Takahashi, Waka Ohishi, Yoshimi Tatsukawa

Research Scientists of Nagasaki Clinical Studies (first row
from left) Ayumi Hida, Nobuko Sera, (second row from left)
Misa Imaizumi, Masazumi Akahoshi (Department Chief)

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RERF Update Volume 21, Issue 1, 2010

26

Science Articles
Table 1. Adjusted prevalence odds ratios for multifactorial disease among
offspring in relation to parental radiation dose
Odds ratio at 1 Gy (95% confidence interval)*
All participants

Male offspring

Female offspring

Father’s dose
Mother’s dose

0.91 (0.81–1.01)
0.98 (0.86–1.10)

0.76 (0.65–0.89)
0.97 (0.81–1.17)

1.04 (0.90–1.21)
0.98 (0.83–1.16)

Sum of both doses

0.94 (0.86–1.02)

0.85 (0.75–0.96)

1.02 (0.91–1.13)* Odds ratios were adjusted for categories of age, sex, city, body mass index,
parental history of multi-factorial disease, female menopause, smoking,alcohol intake, and occupation.

factorial diseases in relation to parental radiation
exposure(seeTable1).1
Analysesofgeneticeffectsonindividualmultifactorial diseases such as hypertension, hypercholesterolemia, and diabetes are ongoing with thecollaborationoftheDepartmentsofStatistics,Epidemiology,andGenetics.RERFhasanF1Clinical
Follow-up Study Research Group that has been
discussingtheresearchplandetailsforalong-term
healthstudyofF1.
Special Clinical StudiesIn addition to collaborating on the main “platform” research protocols, the two clinical departments in Hiroshima and Nagasaki also actively
collaborate,withdepartmentalstaffmembersservingas primary investigators, on 9 additional Special
ClinicalStudies.Further,NagasakiClinicalStudiesis working independently on five Special Clinical
StudieswhiletheHiroshimadepartmentisworking
independently on three additional clinical studies.
Someexamplesareillustratedasfollows.
Cardiovascular diseases
1. Astudyofarteriosclerosisasoneofthepotential
mechanisms by which radiation may promote
cardiovasculardiseaseisunderway.Paststudies
havereportedasignificantassociationbetween
radiation exposure and atherosclerotic diseasemortality/morbidity amongA-bomb survivors.
Atherosclerosis conceptually has two aspects:
atherosis(fattydegeneration)andsclerosis(arterialstiffness).Inthiscross-sectionalstudy,we
areevaluatingtheassociationsofradiationand
arterialstiffnesstakingintoaccountcorrelations
among stiffness indices (brachial-ankle pulsewave velocity [baPWV], augmentation index[AI]),atheromatousdiseaseindices/riskfactors
(ankle-brachial blood pressure index [ABI],
carotidarteryintima-mediawallthickness[IMT],
aorticcalcification,andleftventricularhypertrophy),andatherosclerosisriskfactors(Framingham
riskscores),bothinHiroshimaandinNagasaki.
Theprotocolwasapprovedattheendof2009,
and we started to measure the indices among
Return to Table of Contents

AHSsubjectsinApril2010.
2. AstudyisevaluatingasetofunderlyinggeneticfactorsassociatedwithsurvivalamongA-bomb
survivorswhoprobablysufferedfromradiation
injuries,burns,andearlyinfections,inorderto
determineifthesefactorsalsoincreasedtherisk
ofchronicinflammationandmyocardialinfarction.Subjectsareallthe1,100individualswho
participatedinthefirstcycleoftheAHSclinical
examinationsandwhowereexposedwhenyoung(<30yearsofageatthetimeofthebombings)
toatleast1Gyofradiation,and1,100oftheir
sex-, age-, and city-matched <5 mGy exposed
controls.Wearetestingknowngeneticpolymorphismswithinanarrayofgenesrecognizedto
be responsive to external stress based on thehypothesesthat(a)geneticpolymorphismscontrolthemagnitudeofinflammatoryresponsesto
manylifestyle-associatedstresses;andthat(b)
thesesamepolymorphismsserveasriskfactors
forcardiovasculardisease.Suchaneffectcould
haveledtoa“populationbias”incardiovasculardiseaserisk,especiallyintheearlydecadesaftertheA-bombexposure.Specificgeneticpolymorphiclociwillbeexamined,includingLTAsingle
nucleotidepolymorphisms(SNP),representative
ofthehaplotype-blockencompassingtheLTA,NFKBIL1, and BAT1 genes, and a TLR2 deletionalpolymorphisminexon1.Atotalof2,274
studysubjectswereselectedforthisstudy,and
stored blood samples of 1,928 subjects fromwhomwehaveobtainedaninformedconsentfor
geneticstudiesarebeingused.
3. AstudystartedinFebruary2010isexaminingtheassociationbetweenchronickidneydisease
(CKD) and cardiovascular disease (CVD) in
A-bombsurvivorssinceCKDhasrecentlybeen
recognizedasariskfactorforCVD.CKDand
CVDsharemanycommonriskfactorssuchas
obesity, insulin resistance, impaired glucosetolerance, hypertension, dyslipidemia, and
nephritis.ThisstudywillexaminewhetherCKD
isrelatedtoradiationdose,andwhetherCKD
mightserveasamediatingvariableintheassociationofradiationwithCVD.TheprevalenceRERF Update Volume 21, Issue 1, 2010

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Science Articles
ofcasesofCKDdiagnosedduringthefour-yearbaselineperiod(1988–1991)andincidentcases
ofCKDdiagnosedduringthe15-yearfollow-up
periodof1992–2006willbeascertainedinthe
AHScohort.InvestigatorswillalsoidentifybothprevalentandincidentcasesofCVDduringthe
above-mentionedperiods,respectively.CVDwill
includecoronaryheartdisease(CHD)andstroke.
Basedonthedata,theinvestigatorswilldetermine whether the effects ofA-bomb radiation
exposurecanbeobservedforseveralendpoints,
withadjustmentforotherriskfactors.
Liver stiffnessInordertodeterminewhetherA-bombradiation
exposure has increased liver stiffness, which is amarkerofliverfibrosisseverity,astudymeasured
liverstiffnessusinganelastometerinexaminations
ofHiroshimaA-bombsurvivors.Thepurposeofthe
studyistoexaminetherelationshipbetweenliver
stiffness and radiation dose in order to determine
whetherradiationexposureisinvolvedinincreases
ofchronichepatitisandlivercirrhosis.Additionally,
wewillexaminewhetherincreasedliverfibrosisis
involved,throughinsulinresistance,inthedevelopmentofatheroscleroticdiseases,inordertoelucidatemechanisms of radiation effects underlying thesediseases.Duringtwoexaminationcycles(fouryears),
wewillmeasureliverstiffnessasamarkerofliver
fibrosis severity with an elastometer and measure
bloodcytokinesrelatedtochronicinflammationand
insulinresistanceforabout3,800AHSparticipants
(includingtheexpandedgroupofyoungersurvivors)
inHiroshima.Theresearchprotocolwasapproved
inOctober,2008,andmeasurementsofliverstiffnessandbloodcytokinesforyoungerA-bombsurvivors
havebeenconductedsinceNovember2008.Duringthe period of November 2008 to March 2010, we
measured liver stiffness with the elastometer for
1,579survivors.Wealsomeasuredbloodcytokine
levelsrelatedtochronicinflammationand/orinsulin
resistancesuchasTNF-α,IL-6,IP-10,MCP-1,PAI1, leptin, resistin, IGF-I,
1 and IGFBP-3 for 1,451
survivors.
Thyroid diseasesTheobjectiveofthecurrentstudyistoinvestigate
whether there are positive associations between
radiationdoseandthyroiddisease.RERFscientists

foundthatmalignantthyroidtumor,benignnodules,andcystswereincreasedwithradiationdoseandthe
relationships were significantly higher in those
exposedatyoungerages.Ontheotherhand,autoimmunehypothyroidismandGraves’diseasewerenot
associatedwithradiationdose.2Nosignificantdose
responsesforthyroiddiseaseswereobservedamongthoseexposedin utero,althoughtheriskestimates
weresimilartothosewithjuvenileexposureandthenullresultsmayreflectlimitedstatisticalpower(seeTable2).3Cancersweremorefrequentlydetectedin
subjectswithsolidthyroidnodulesthaninnodulefreecontrols4suggestingthatathyroidnoduleisa
riskfactorforsubsequentthyroidcancer.Wearenow
conducting thyroid examinations in the newly
expandedcohortofAHSsubjectstostudytheeffects
oflow-doseradiationonthyroiddiseasesexposedat
youngerages.
Special Cancer Studies
Inflammation
1. Theobjectiveofonestudyistoinvestigatethe
relationship between inflammatory biomarkersandcancerincidenceinAHSparticipants.Laboratoryandepidemiologicalstudieshavereportedarelationshipbetweeninflammationandcancer.
BecauseA-bombsurvivorshaveradiationdosedependentincreasesofinflammatorybiomarkers,weareinvestigatingtherelationshipbetweenthe
biomarkersandcancerincidenceamong12,870
AHSparticipantsfollowedfrom1965to1999.
We examine white blood cell (WBC) counts(measuredsince1958),erythrocytesedimentation rate (since 1958), alpha 1 and alpha 2
globulin (since 1985), and sialic acid (1988–
1992)asparametersinrelationtocancerincidencedatafor1965–1999fromtheHiroshima
andNagasakitumorregistries.Amanuscripton
longitudinal trends in leukocyte counts is in
press.5Ajointmodeltoestimatecausalassociationsamongradiation,inflammation,andsolid
cancer incidence was specified and analyzed.
Threepotentialtypesofintermediatevariablesare being considered: (1) average leukocyte
count,(2)longitudinaltrendsofleukocytecount,
and (3) a latent inflammatory factor estimated
usingmultipleindicators.Apreliminaryresultof a joint model using persons’ averageWBC
countsasamediatingfactorshowsthatthereis

Table 2. Odds ratios of all solid thyroid nodules by mode of exposure

In utero exposureChildhood exposure
Combined*

No. (%)

Odds ratio at 1 Gy
(95% confidence interval)

P

35/319 (11.0)
63/437 (14.4)
98/756 (13.0)

2.91 (0.53, 12.18)
2.65 (1.96, 3.65)
2.66 (1.97, 3.63)

0.20<0.001<0.001*Combined analysis of in utero exposure and childhood exposure.
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RERF Update Volume 21, Issue 1, 2010

28

Science Articles
asignificantcausalassociationofradiation,averageWBCcount,andsolidcancerincidence.The
proportionofthemediatingeffectisabout8%
ofthetotalradiationeffectoncancer.
2. The primary goal of a case-control study of
atrophicgastritisandgastriccancerusingfrozenseraandgenomicDNAistodeterminewhetherthe radiation-exposure dependence of gastric
cancersseenintheA-bombsurvivorsisrelated
tochronictissueinflammationassociatedwith
H. pyloriinfection.Specificaimsincludeestablishing (1) new biomarkers for pathogenic H.
pyloriandrelatedchronicgastritis;and(2)thegeneticfactorscontrollingthehost’sinflammatoryresponsetobacterialinfections.Resultshave
indicatedthatH. pyloriinfection,chronicgastritis,andsmokingareallindependentpredictors
of gastric cancer. In terms of radiation-dosedependency,higherrelativeriskswerenotedwiththediffusetypeofgastriccancers,whereasmuch
lowerriskswerenotedwiththeintestinaltypeofgastriccancers,afteradjustingfortheriskfactors.6TheLTA 252 genotypeisassociatedwith
noncardia gastric cancer of the diffuse type in
Japan,andthegenotypewasaneffectmodifierforradiationdose7(Table3).Wearealsoanalyzingtherelationshipbetweengastriccancerand
chronicgastritisinrelationtoradiationexposure.
Radiation risk was significant only for people
without chronic gastritis in developing diffuse
typenon-cardiacgastriccancers.Toconfirmtheresults,aresearchprotocolonmodelbuildingfor
joint effects of radiation and radiation relatedintermediateriskfactorsinnestedcase-control
studieshasbeenpreparedbycolleaguesinthe
DepartmentofStatistics.

measurements, including total estradiol (E2), freeE2, testosterone, sex hormone binding globulin(SHBG),progesterone,insulin-likegrowthfactor-1
(IGF-1),insulin-likegrowthfactorbindingprotein-3
(IGFBP-3),andprolactin.Thestudyalsoincluded
genistein measurements to index phytoestrogen
consumption, and biomarkers indicative of antioxidant availability and iron-mediated oxidative
stress,D-Romandferritin,respectively.Thisisone
ofthefirststudiestosimultaneouslyanalyzesuchawidevarietyofbloodserumcomponentsinrelationtobreastorendometrialcancer,andisoneofthefew
to utilize blood samples collected up to 30 years
beforecancerdiagnosis.Controlswereselectedbycounter-matchingonradiationdosesoastoincreasethestatisticalpowertodetectradiationeffects.Allthelaboratorymeasurementshavebeencompletedon the 243 breast cancer cases and 486 matched
controls.Preliminaryresultsrevealedasignificantradiation dose-dependent increase in estrogen and
testosteronelevelsamongpostmenopausalwomen.
Appropriateanalyticalmethodsforthejointrelationshipofradiationandhormonesuponcancerriskwill
bedeveloped,withwhichthedatawillbeanalyzed.
Liver cancer
1. Theprimaryobjectiveofonestudyistoinvestigatetherelationshipbetweenradiationexposureandtheriskofhepatocellularcarcinoma(HCC)
among A-bomb survivors after taking into
account hepatitis virus infection. Our working
hypothesisisthatradiationexposureaccelerated
HCCoccurrenceintheearlystageofliverfibrosisafterhepatitisCvirus(HCV)infection.The
study includes evaluations of the interactionsbetween(a)theinitialdoseofradiation;(b)the
status of hepatitis virus infection; and (c) theseverityofliverfibrosis,alongwithotherpotentialriskfactorstobeevaluatedintermsofthe
etiologyofHCC.Forthispurpose,amongcasesand controls, selected biomarkers of evolving
liverdiseasearebeingassayed,includinghepatitis virus markers, and fibrosis markers. Currently,therearestoredserafromsome224HCC

Breast and endometrial cancerThepurposeofthisnestedcase-controlstudyofbreastandendometrialcanceretiologyistocharacterizethejointeffectsofradiationandserum-based
indicatorsofhormonalstatus,oxidativestress,and
phytoestrogenconsumption.Theresearchprotocol
had examined a series of hormone-related serum

Table 3. Interaction among three risk factors: radiation risk for non-cardia gastriccancer is restricted to subjects with LTA 252G-carriage and smoking status
Risk categories

Relative risk

95% confidence interval

P

Radiation dose (1 Gy)

0.8

0.5–1.2

0.3

Radiation dose (1 Gy) for current
smoker with LTA 252G-carriage

1.3

0.6–1.9

0.4

Radiation dose (1 Gy) for noncurrent
smoker with LTA 252AA

2.0

0.6–3.4

0.2

Radiation dose (1 Gy) for noncurrent
smoker with LTA 252G-carriage

3.8

1.7–5.9

0.009(Helicobacter 2009; 14:571–9)
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RERF Update Volume 21, Issue 1, 2010

Science Articles
casesandthreecontrolspercasematchedonage,
sex,city,andtimeofserastorage,andcountermatchedonradiationexposure.HBVandHCV
infection,alcoholconsumption,andbodymassindex (BMI) of >25 kg/m2 (Obesity) 10 years
before HCC diagnosis were independent risk
factorsthatcontributedtoincreasedHCCrisk.
HBVandHCVinfectionandobesityremained
independentriskfactorsafteradjustingforseverityofliverfibrosis.8Weestimatedrelativerisks
(RR) of HCC for HBV or HCV infection and
excessrelativerisk(ERR)ofHCCforliverdoseofradiation.Afteradjustingforalcoholconsumption and BMI, the ERR per Gy (ERR/Gy) ofradiation exposure for HCC, was 0.55 (P =
0.003),whiletheRRsforHBVorHCVinfection
were61(P<0.001)and80(P<0.001),respectively. Those estimates changed little whenradiationandviraleffectswerefitjointly.TheERR/Gyofradiationexposurefornon-B,non-C
HCCwas1.15(P=0.026)withadjustmentfor
alcohol consumption or BMI. The results
indicated that HBV and HCV infection and
radiationexposureareassociatedindependently
withincreasedriskofHCC,andthatradiation
exposureisasignificantriskfactorfornon-B,
non-C HCC with no apparent confounding by
alcoholconsumptionorBMI.
2. The hypothesis behind a nested case-control
studyisthatchronicinflammationduetoradiationexposuremaybeinvolvedinthedevelopment of HCC through insulin resistance. The
objectiveofthestudyistoexaminethecontributionofinsulinresistancetoHCCrisk,takinginto
accountradiationexposure,hepatitisvirusinfection, lifestyle-related factors, and severity of
liver fibrosis. This research protocol is an
addendumtoastudyoftheeffectsofradiation
exposure,hepatitisvirusinfection,andlifestylerelated factors on the risk for development of
HCC.Furthermore,theongoinganalysessuggest
that radiation exposure, alcohol consumption,
andBMIareallindependentlyassociatedwith
increased risk of non-B, non-C HCC. This
researchprotocolwasapprovedinApril,2009
and we have started measurements of blood
cytokinesusingstoredseraobtainedfromHCC
cases and controls of this nested case-control
study.Of1,372samples,wehavemeasuredblood
cytokine levels such as TNF-α, IL-6, MCP-1,
leptin, and resistin, with the enzyme-linked
immunosorbent assay (ELISA) method or themultiplexLuminexmethod,for1,146samples.
3. A third study of liver disease is studying therelationshipbetweenradiationdoseandinfection
byHBVandHCV.Thehypothesisbehindthisstudyisthationizingradiationmayincreasethe
incidenceofHCCeitherbyincreasingtherates
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29
ofHBVorHCVinfectionorbyfacilitatingdiseaseprogressionafterhepatitisvirusinfection.
Thepurposesofthisstudyaretoinvestigatethe
associationsofradiationwith(a)ratesofHCV
infection,(b)HBVactivity(hepatitisBe-antigen:
HBeAg)inHBVcarriers,and(c)HBeAgand
hepatitisBsurfaceantigen(HBsAg)seroconversionratesamongHBVcarriers.Wehaveassessedtheeffectsofimmunogeneticbackground(HLADRB1 and/or NKG2D polymorphisms) and
radiation dose on the course following HCV
infectionincollaborationwiththeDepartment
ofRadiobiology/MolecularEpidemiology.PreliminaryanalysessuggestedthatHLA-DRB1and/orNKG2Dpolymorphismsaffecttheclearance
and/orpersistencefollowingHCVinfection,and
that an NKG2D-mediated immune response is
involved in the mechanisms underlying HCVclearance.
Immunological Studies
MembersoftheDepartmentofClinicalStudies
have a long-standing collaboration with RERF
scientistswhohavebeenmeasuringimmunological
markersandfactorsinthebloodsamplesprovided
bytheAHSparticipants.Theresultsofthestudies
suggest that radiation in many ways mimics thenatural immunosenescence associated with aging
populations.Asaresultofthesestudies,RERFwas
able to obtain significant funding to conduct fourmajorprojectsthataredescribedinpage13ofthisissueofUpdate.TheRPsassociatedwiththenew
projects include a study of the response ofAHS
participantstoinfluenzavaccinationwhichwillbe
conducted in collaboration with members of theDepartmentofClinicalStudies.
Cataract and Other Opthalmologic Studies
1. ThereareseveralophthalmologicstudiesoftheA-bombsurvivors.Theprevalenceofradiation
cataracts is being evaluated within two study
subject groups, namely (a) a select group of
survivorswhowererelativelyyoung(13years
oldoryounger)atthetimeoftheatomicbombing,buthadnotbeenpreviouslygivenophthalmic
examinations; and (b) a larger group that had
beenevaluatedpreviously,butbyoldermethods.
For both groups, dose-response analyses wereconductedforposteriorsubcapsularaxialopacities(Figure)andpolychromaticchangesandfor
peripheral opacities using a standard gradingsystem,whileadjustingforavarietyofpotential
confounding factors.A total of 883 personsunderwent ophthalmologic examinations in
Hiroshima and Nagasaki, from which three
papers were published.9–11An analysis of theprevalenceofseverecataractcaseswithsurgical
lens removal was also published (see the FigRERF Update Volume 21, Issue 1, 2010

Science Articles

Figure. The main-effect model dose-response curve in regression analysis after adjusting for city, sex, age at
the time of the bombings, and diabetes mellitus in
A-bomb survivors who had undergone lens removal surgery (odds ratio at 1 Gy, 1.39; confidence
interval, 1.24–1.55).

ure). 12 Stored lens images collected during
2000–2002wereusedtoconductare-evaluation
withtheMerriam-Fochtcataractscoringmethod.
Thepreliminaryresultsofanopacityre-evaluation
withtheMerriam-Fochtmethodindicatethatthedose responses for the two major research
cohorts,A-bombsurvivorsandChernobylcleanupworkers,arealmostidentical.
2. AsecondprojectisinvestigatingstorageconditionsforcataracttissueofA-bombsurvivorsandacollectionandstorageprogram.Thegoalofthe
projectistoconfirmtheadequacyofastorage
methodforcataracttissuesofAHSparticipants
whoundergoacataractoperation,andtocollectandstorethetissueforfutureanalyses.Thestored
cataract tissues are expected to contribute significantlytofutureresearchonradiation-induced
cataract.When enough numbers of tissues are
collected,anewresearchprotocolforbiological
studieswillbeprepared.Basedontheestablished
method, an actual program of collection and
storageoflenstissuestartedonJanuary2009in
Hiroshimaand20sampleshavebeencollected
andstoredasofMarch2010.ThesameprogramwasmorerecentlybeguninNagasaki.
3. Astudywasdesignedtoinvestigateonaquantitativebasistheopacityofeyelensesandretinal
arteriolosclerosis of the offspring ofA-bomb
survivors,andtolookintotherelationshipofthisvaluewithseveralriskfactors.Wewillalsostudy
whetherornottheincidenceofage-relatedcataracts and congenital cataracts increases due to
A-bomb exposure in the parents. The digital
imageswerecomputerizedandstored.Cataractis a multi-factorial disease that stems from a
combination of environmental and geneticfactors.Animalexperimentshavesuggestedthe
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30
possibility of an increase in the incidence ofcongenital cataracts in relation to radiation
exposure.However,sincetheexpectednumber
ofcasesissmall,wewillstudyitqualitatively
ratherthanquantitatively.ThestudyisquantitativelyinvestigatinglensopacityandretinalarteriolosclerosisintheoffspringofA-bombsurvivorswhoareatleast50yearsofageatthetimeofexamination.Itisexaminingtheassociation
oflensopacitywithbothmulti-factorialdiseasesandparentalradiationdoses.Theexaminations
were completed in September 2006. We will
conductfurtheranalysestolookintotherelationshipofthecataractswithseveralriskfactors.
4. An association between ataxia telangiectasia
mutated(ATM)geneandlensradiosensitivityhas
been well documented in experimental animals.13,14SinceA-bombsurvivorsdemonstrateda significant dose-response relationship in
prevalence of cataract surgery withA-bomb
radiation,andsincegenotypingdataonATMand
othergenesareavailablefromanotherstudyat
RERF,aprotocolaimstoinvestigateanassociationbetweenpolymorphismsofATMandothergenes and the dose-dependent prevalence of
cataract surgery inA-bomb survivors.Among
5,126AHSparticipantswhounderwentmedical
examinationduring2000–2001,thosewhohave
information on polymorphisms of ATM and
othergenesinthestudyandwhoagreedtouse
theinformationforthestudywereselected.In
5,126AHSparticipants,therewere645personswithcataractsurgery.ThedatasetofpolymorphismsofATMandothergeneswillbeobtained
fromtheDepartmentofRadiobiology/MolecularEpidemiology and merged with the cataract
surgerydata.Theprevalenceofcataractsurgery
willbecomparedbyradiationdoseandpolymorphismsofATMandothergenes.Twotypesof
analysisareenvisioned.Onewouldbebasedon
individual candidate SNPs and the other on
haplotypes.
5. Afinalophthalmologicstudyproposestoinvestigate additional questions, specifically (a)whetherornotradiation-inducedcataractsprogresswithtimeand(b)whetherornotthereisadoseresponsewhencataractsareassessedbya
radiation-specific classification system (theMerriam-Focht method). Ten years will have
passedsincetheconductofthepreviousstudy;
storeddigitallensimagesobtainedinthatstudy
will be compared with those obtained in theproposedstudy.Ophthalmologicalexaminationson AHS participants will be conducted by
ophthalmologists. The methods will be essentially identical to those of the previous study.
Morethan700AHSsubjectsunderage13who
participatedinthepreviousstudy,andanaddiRERF Update Volume 21, Issue 1, 2010

31

Science Articles
tional300ormoreeligiblenewparticipantsnot
previouslyexamined,areexpectedtovisitRERF
during2010–2012.Thestatisticalpowerofthat
study is calculated as more than 90% for theradiation-associatedprevalenceofcataractcases.
6. A Radiation Cataractogenesis Workshop was
heldinMarch2009atRERF.Theresultsfrom
RERF,togetherwithotherdatapresentedattheworkshop, have provided strong evidence of alowerthresholdfortheradiationdoseresponse
thanhadbeenassumedpreviously.Theworkshop
summary, including our current results, and
another review of the RERF and other epidemiologic cataract findings have been published.15,16

HiroshimaAHSsubjectsaged60yearsorolderat
baseline examination (1992–1996). Dementia
prevalencewasobserved,and2,286dementia-freesubjectswerefolloweduptoassessdementiaincidence.Manuscriptsregardingradiationeffectsand
otherriskfactorsondementiaincidencehavebeen
published17,18(Table4).Althoughnoassociationwas
found between previous radiation exposure and
cognitive impairment and/or development of
dementiaamongsurvivorsexposedat≥13yearsofage,survivorsexposed<13yearsofagemaywellbe more vulnerable.We are considering potential
instruments for assessing cognitive and other
psychoneurologicalfunctionamongtheyoungerand
in uterosurvivors.

Age-related Disease Study (Senile Dementia)
RERF scientists are examining the effects ofradiationexposureoncognitivefunction,theprevalence and incidence of dementia, and other agerelatedphysiologicvariablessuchasreactiontimeatolderagesamongadultsurvivorsintheAHS.A
wide spectrum of radiation effects on the central
nervoussystemhavebeenwelldocumentedinRERF
studies,especiallyforindividualswhowereexposed
prenatallyorduringchildhood.Thisstudyinvestigates the hypothesis that the effects of ionizingradiationonthematurecentralnervoussystemmaybe manifested as accelerated neurological aging.
Studysubjectsweresurvivorsexposedat≥13years
ofage.Weevaluatedcognitiveperformanceforabout
3,113subjectsinHiroshimaandNagasakiwiththe
CognitiveAbilities Screening Instrument (CASI)
during the period 1992–1998. The prevalence of
dementiaanditssubtypeswasassessedamong2,648

Biological Sample Collection
TheAHS and its biennial examinations have
providedextensivebiologicalspecimensandinformation concerning lifestyle or other potential risk
factorsformanyfieldsofstudy,includingcytology,
genetics, immunology, radiobiology, and medical
biodosimetry. The biological specimens collected
areusedforclinicaldeterminationsandstoredfor
future studies. Research protocols using stored
specimensarebeingconductedtoevaluatepossible
interactionsbetweenradiationandinfectiousagents
or hormones and cancer risk, and phenotypic and
genetic factors associated with inflammation and
myocardialinfarction.Tissuecollectionandstorage
ofsurgically-removedcataracttissuewasbegunin
2009.Serahavebeencollectedandstoredfromthe
AHSparticipantsduringexaminationssince1969.
AMicrosoftAccessTM-baseduser-friendlyinventory
ofstoredserahasbeenestablishedincollaboration
withtheDepartmentofInformationTechnology.Adigital recording and alarm system for biological
samplesindeepfreezerswasinstalledtosafeguard
theprecioussamples.Examplesofclinicalstudies
usingstoredseraincludetheevaluationofinteractions between radiation and infectious agents or
hormonesinthedevelopmentofHCC,gastric,and
breastcancer.

Table 4. Radiation effects on dementia incidence(Results of Poisson regression analysis)

All dementia
dose 1
dose 2
Probable AD
dose 1
dose 2
Possible AD
dose 1
dose 2
Probable VaD
dose 1
dose 2

Hazard ratio

95% CI

p-value

0.82
0.94

0.59–1.14
0.65–1.33

0.238
>0.5

0.64
0.94

0.37–1.09
0.54–1.62

0.105
>0.5

0.88
0.87

0.45–1.09
0.40–1.81

>0.5
>0.5

0.84
0.77

0.37–1.84
0.32–1.77

>0.5
>0.5

Dose 1: 5–499 mGy group vs <5 mGy group
Dose 2: ≥500 mGy group vs <5 mGy group
CI: confidence interval
AD: Alzheimer’s disease, VaD: Vascular dementia
Model is adjusted for age, (age)2, education, BMI,
smoking, drinking, menopausal age, and history of
hypertension, diabetes, and stroke.
Return to Table of Contents

Summary of Recent FindingsIn summary, highlights of the Clinical Studies
Department’smorerecentfindingsinclude:• The prevalence of cataract increased with
radiationdosewithadose-effectthresholdthatwasmuchlowerthanthatpreviouslybelieved,• Asignificantlinearradiationdoseresponsefor
thyroidnodulesexistsinA-bombsurvivors,but
thereisnosignificantradiationdoseresponseforautoimmunethyroiddiseasenorforthyroid
antibodies,• The dose response to radiation for thyroid
nodulesorautoimmunethyroiddiseasesamongthose exposed in utero was not statistically
RERF Update Volume 21, Issue 1, 2010

Science Articles
significant, but the risk estimate for solidthyroidnoduleswassimilarforthoseexposedin uteroandthoseexposedinchildhood,• The dose-response relationship for the incidenceofhypertension,hypercholesterolemia,or cardiovascular disease among survivors
exposedin uterowasnotstatisticallysignificant,19and• Nosignificantdose-responserelationshipwas
observedforSjögren’ssyndrome20prevalenceorfordementiaincidence.
Future Studies
AHS
During the next year or two, RERF’s Clinical
Studies scientists plan to publish several papers
pertaining to radiation effects on: sub-types and
long-termriskofstroke,incidenceofcataractextractions, and prevalence of glaucoma. Modifiers ofradiation risk are also being analyzed: radiation,
serum sex hormones and breast cancer; radiation,
chronic atrophic gastritis, and gastric cancer; and
radiation,hepatitisvirusinfection,andlivercancer.
Asafollow-uptosomeoftherecentfindings,new
studieshavejustbegunorwillsoonbeginbasedonthehighlightsfromrecentfindingsinthestudyoftheAHS.Someexamplesincludetwonewstudies
relatedtocardiovasculardiseaseentitled“Associationbetweenchronickidneydiseaseandcardiovascular disease among atomic bomb survivors” and
“StudyofarteriosclerosisintheAdultHealthStudy
population(Part1.Physiologicalindicesofarteriosclerosis).”ThreenewRPsonradiationoculareffects,afollow-upofearly-to-moderatecataractsto
documentcataractprogression,astudytoevaluate
retinalarteriolosclerosisasanearlymarkerforcardiovasculardiseaseriskandglaucoma,andastudy
onATMandcataract,haverecentlybeenapproved
byRERF.
Non-cancerdiseasesandconditionsthathavesofarshownapositiverelationshiptoradiationexposurearethyroiddisease,hyperparathyroidism,uterinemyoma,cataracts,chronicliverdiseases,HBV
carrier status, and cardiovasculoar diseases. The
scientistsintheDepartmentofClinicalStudiesplantocontinuetoclarifytheetiologicalnatureofthosediseasesandconditionsandtoestimatetheradiation
componentamongotherriskfactors.Someexamplesofprojectedstudiesinclude: 1. Mechanisms of radiation effects at low/moderate doses on CVD: various mechanistic or
pathwaystudiesareproposedthatwillbeprioritized after discussion in the RERF CVDWorkingGroup.
 2. Effect modification or mediating variables forradiation effects on stroke incidence:analyses
of a number of potential risk factors such as
bodymassindex,cholesterol,bloodpressure,Return to Table of Contents

32
smoking,etc.,foroverallstrokeandsubtypes
ofstrokeinrelationtoradiationdose.
 3. Radiation and arteriosclerosis: study of thephysiological indices of atherosclerosis and
accelerationofarterialstiffnessassub-clinical
measuresofarteriosclerosis,aswellasstudies
ofthecytokinenetworkrelatedtoarteriosclerosisandtherelationshipbetweenmarkersoffactorsrelatedtoinflammationanddifferentiationindevelopmentofarteriosclerosisinrelationtoradiationdose.
 4. Chronic kidney disease:examinationofwhetherCKDincidenceisrelatedtoradiationdoseand whether CKD radiation damage is amediatorofCVDriskinA-bombsurvivors.
 5. Valvular disease among A-bomb survivors:
examinationofradiationdoseonincidenceof
valvularheartdiseaseintheAHScohort.
 6. Reanalysis of stored digital photos of cataract:
using the classic Merriam-Focht radiationspecific scoring system to compare risk of
cataract in theAHS with other populations
exposedtoradiation.
 7. Radiosensitivity differences for cataract surgery:investigationoftheassociationbetweenpolymorphisms ofATM and other genes onthe dose-dependent prevalence of cataract
surgery.
 8. Additional ophthalmologic follow-up: to
answer questions as to whether radiationinduced cataracts progress with time and
whetherthereisadoseresponsewhenassessed
byaradiation-specificclassificationsystem(theMerriam-Fochtmethod).
 9. Neurocognitive function among in uteroexposed or in early childhood:useofcurrentdiagnostic medical technologies to evaluate
neurocognitive function in those exposed in
uteroor<13yearsofage.
10. Radiation and liver disease: to investigate
whether radiation affected the progression of
liver fibrosis and/or development of HCC by
analyzingtherelationshipbetweenliverstiffness and blood cytokines and to analyze
whetherbloodcytokinesarerelatedtochronic
inflammationandinsulinresistance.
11. Radiation and diabetes mellitus:usingastandardizedcriteriafordiabetesinbothHiroshima
andNagasakiandmeasuringseveralbiomarkers
ofinsulinresistanceamongyoungersurvivors.
12. Rheumatoid arthritis and Sjögren’s syndrome
among A-bomb survivors: a comprehensive
autoimmune disease study in Hiroshima and
Nagasaki using a highly specific measure of
rheumatoidarthritisandSjögren’ssyndrometo
examine the possible association between
autoimmunediseaseandA-bombradiation.

RERF Update Volume 21, Issue 1, 2010

Science Articles
Wehaveaddedsurvivorswhowereexposedatages0–9yearsatthetimeofthebombtotheAHS
population in order to evaluate risk better amongthosewhowereexposedtoradiationwhenyoung,agroupbelievedtobeespeciallyradiosensitive.FullscaleclinicalexaminationswerebeguninNovember
2008,andweexpecttoexamineapproximately1,900
subjects as of June 30, 2010. Repeated biennial
examinationsofthosesubjects,inthesamemanner
astheoriginalAHSsubjects,willbeginin2010.
F1 Clinical Study
RERF scientists are continuing to analyze theeffectsofparentalexposuretoA-bombradiationonthe development of individual multi-factorial
diseases,suchashypertension,diabetes,hypercho-

33
lesterolemia,cataract,andphysiologicalconditions.
TheinitialclinicalF1studyofabout12,000wason
subjectswhoseaverageagewasonly48years,far
tooyoungforustodrawdefinitiveconclusionsasto
whethertheradiationexposureoftheirparentsmay
have impacted the development of multi-factorial
diseasesamongthem.Sincethehereditaryriskofradiationexposureuponadult-onsetcancerormultifactorialdiseasesissoimportantanissueandtherearevirtuallynootherhumandatatoaddressit,itis
essentialthattheF1cohortfollow-upbecontinued
foranother30–40yearstoevaluatelifetimerisk.Wehavecompletedresearchplansofacontinuedclinical follow-up. The early assessments that wereconductedalreadyprovideausefulbaselineforassessingfuturediseaseincidence.

References 1. 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adultonsetmultifactorialdiseaseamongoffspringofatomicbombsurvivors.Radiat Res170(4):451-7,2008.
 2. ImaizumiM,UsaT,TominagaT,NeriishiK,AkahoshiM,NakashimaE,AshizawaK,HidaA,SodaM,Fujiwara
S,YamadaM,EjimaE,YokoyamaN,OkuboM,SuginoK,SuzukiG,MaedaR,NagatakiS,EguchiK.Radiation
dose-responserelationshipsforthyroidnodulesandautoimmunethyroiddiseasesinHiroshimaandNagasaki
atomicbombsurvivors55–58yearsafterradiationexposure.JAMA295(9):1011-22,2006.
 3. 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.J Clin Endocr Metab93(5):1641-8,2008.
 4. ImaizumiM,UsaT,TominagaT,AkahoshiM,AshizawaK,IchimaruS,NakashimaE,IshiiR,EjimaE,Hida
A,SodaM,MaedaR,NagatakiS,EguchiK.Long-termprognosisofthyroidnodulecasescomparedwith
nodule-freecontrolsinatomicbombsurvivors.J Clin Endocr Metab90(9):5009-14,2005.
 5. HsuWL,TatsukawaY,NeriishiK,YamadaM,CologneJB,FujiwaraS.Longitudinaltrendsoftotalwhitebloodcellanddifferentialwhitebloodcellcountsofatomicbombsurvivors.J Radiat Res2010.(Inpress)
 6. SuzukiG,CullingsHM,FujiwaraS,HattoriN,MatsuuraS,HakodaM,AkahoshiM,KodamaK,TaharaE.
Low-positiveantibodytiteragainstHelicobacter pyloricytotoxin-associatedgeneA(cagA)maypredictfuture
gastriccancerbetterthansimpleseropositivityagainstH. pyloricagAoragainstH. pylori. Cancer Epidem
Biomar16(6):1224-8,2007.
 7. SuzukiG,CullingsHM,FujiwaraS,MatsuuraS,KishiT,OhishiW,AkahoshiM,HayashiT,TaharaE.LTA
252GG and GA genotypes are associated with diffuse-type noncardia gastric cancer risk in the Japanese
population.Helicobacter14(6):571-9,2009.
 8. 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 Epidem Biomar
17(4):846-54,2008.
 9. MinamotoA,TaniguchiH,YoshitaniN,MukaiS,YokoyamaT,KumagamiT,TsudaY,MishimaHK,Amemiya
T,NakashimaE,NeriishiK,HidaA,FujiwaraS,SuzukiG,AkahoshiM.Cataractinatomicbombsurvivors.
Int J Radiat Biol80(5):339-45,2004.
10. NakashimaE,NeriishiK,MinamotoA.Areanalysisofatomic-bombcataractdata,2000–2002:Athreshold
analysis.Health Phys90(2):154-60,2006.
11. NakashimaE,NeriishiK,MinamotoA.Comparisonofmethodsforordinallensopacitydatafromatomic-bomb
survivors:Univariateworse-eyemethodandbivariateGEEmethodusingglobaloddsratio.Ann I Stat Math60(3):465-82,2008.
12. Neriishi K, Nakashima E, MinamotoA, Fujiwara S,Akahoshi M, Mishima HK, Kitaoka T, Shore RE.Return to Table of Contents

RERF Update Volume 21, Issue 1, 2010

Science Articles

34

Postoperativecataractcasesamongatomicbombsurvivors:Radiationdoseresponseandthreshold.Radiat Res
168(4):404-8,2007.
13. WorgulBV,SmilenovL,BrennerDJ,JunkA,ZhouW,HallEJ.ATMheterozygousmicearemoresensitiveto
radiation-inducedcataractsthanaretheirwild-typecounterparts.Proc Natl Acad Sci USA99(15):9836-9,2002.
14. KleimanNJ,DavidJ,EllistonCD,HopkinsKM,SmilenovLB,BrennerDJ,WorgulBV,HallEJ.Lieberman
HB.Mrad9andATMhaploinsufficiencyenhancespontaneousandX-ray-inducedcataractogenesisinmice.
Radiat Res 168(5):567-73,2007.
15. Blakely EA, Kleiman NJ, Neriishi K, Chodick G, Chylack LT, Cucinotta FA, MinamotoA, Nakashima E,
Kumagami T, Kitaoka T, Kanamoto T, KiuchiY, Chang P, Fujii N, Shore RE. Meeting report “Radiation
cataractognesis:Epidemiologyandbiology.”Radiat Res173:709-17,2010.
16. ShoreRE,NeriishiK,NakashimaE.Epidemiologicstudiesofcataractriskatlow-to-moderateradiationdoses:
(Not)seeingisbelieving.Radiat Res2009.(Inpress)
17. YamadaM,KasagiF,MimoriY,MiyachiT,OhshitaT,SasakiH.Incidenceofdementiaamongatomic-bomb
survivors—RadiationEffectsResearchFoundationAdultHealthStudy.J Neurol Sci281(1-2):11-4,2009.
18. YamadaM,MimoriY,KasagiF,MiyachiT,OhshitaT,SasakiH.IncidenceandrisksofdementiainJapanese
women:RadiationEffectsResearchFoundationAdultHealthStudy.J Neurol Sci283(1-2):57-61,2009.
19. TatsukawaY, Nakashima E,Yamada M, Funamoto S, HidaA,Akahoshi M, Sakata R, Ross NP, Kasagi F,
FujiwaraS,ShoreRE.Cardiovasculardiseaseriskamongatomicbombsurvivorsexposedin utero,1978–2003.
Radiat Res170(3):269-74,2008.
20. HidaA,AkahoshiM,TakagiY,AshizawaK,ImaizumiM,SodaM,MaedaR,NakashimaE,IdaH,Kawakami
A,NakamuraT,EguchiK.PrevalenceofSjögren’ssyndromeamongNagasakiatomicbombsurvivors.Ann
Rheum Dis67:689-95,2008.

Return to Table of Contents

RERF Update Volume 21, Issue 1, 2010

35

Human Interest Notes

An Intriguing Story of Mystery and
Humanitarian Service
Evan B. Douple, Associate Chief of ResearchAninterestingemailwasforwardedtomebyan
earlyABCC scientist and long-time supporter of
ABCC-RERF,AaronBertrand“Randy”Brill(ABCC
1957–1959)whoiscurrentlyaResearchProfessor
ofRadiologyandRadiologicalSciencesatVanderbilt
UniversityMedicalCenterinNashville,Tennessee.
Randy had been contacted by a cancer researcherandprofessorinaBelgiummedicaluniversity,Jan
Bernheim, who, along with his daughter who is afilmmaker,wasinterestedinwritingabiographyofaphysiciannamedAlphonseVanSchoote(AVS).Dr.
VanSchoote(orAVS)wasanM.D.andLieutenantintheMedicalCorpsoftheBelgiumUnitedNationsCommand during the KoreanWar in 1953–1954.
Afterhisdischargefromthemilitaryin1954,thereisagapintheknowledgeaboutAVS’slife,buthe
eventuallycontinuedhismedicaltraininginpathologyintheU.S.universitiesatColumbia,Duke,and
M.D.Anderson(UniversityofTexas).AVS’medical
colleaguesindicatedthathedevelopedaninterestinthe human health consequences of exposure to
atomicexplosionsandthattheinteresttookhimto
Micronesia where from 1961 until 1969 he was apublic-healthphysicianintheTrukArchipelago,not
farfromBikiniandEniwetokatollsthatwerenear
nucleartestingsitesintheMarshallIslands.Hewas
respectedforhisdedicatedassistancetothehealth
needsofthenativeswhomhevisitedbysailinglarge

The “Atoll Doctor ” Alphonse Van Schoote inhis boat (courtesy of Jan Bernheim)
Return to Table of Contents

distancesinhissmallboat.Hebecamewidelyknown
for his humanitarian services and was called the“atolldoctor.”In1969,ashewasapparentlysailingtoreplenishhismedicalsupplies,AVSwascaughtinastormanddisappearedatsea.AttachedisoneofthelastphotosthatapparentlyareavailableofAVS
kindlyprovidedbyprofessorBernheim.
SoprofessorBernheimwasinterestedintryingtofillinthegapsafterAVSleftKorea.Heknewthat
AVS’s family had received anAVS letter from
Nagasakiin1953.CouldAVS’sinterestinthehealth
effectsofvictimsofnuclearbombingshavedevelopedfromavisittoABCC?RERF’sAssociateChief
ofSecretariat,DouglasSolvie,wenttotheABCC
personnel files and sure enough—11 documents,
includinghandwrittenlettersfromAVS—confirmed
thatAVS had visitedABCC. Frank H. Connell,ABCC Director, Nagasaki, introduced him to the
ABCC Director in Hiroshima, Robert H. Holmes.
AVS asked whether he could study withABCC
doctors in Hiroshima after his discharge from thearmyinKoreainOctober,1954,andheindicatedhe
wouldbewillingtoworkforonlymealsandaroom.
DirectorHolmesacceptedAVS’srequestandindicated he would be “working in hematology and
parasitology” and “Dr. Dobos [Emeric I. Dobos,
M.D.;ABCCChief,LaboratoriesandChief,MicrobiologyDepartment,1954–1956]hasrecommendedyouhighly,andyouwillbeworkingwithhim.”
AVS’sABCCterminationclearanceformshowshewasatABCCforonlyafewmonths,buthisletters
indicatethathewas“highlyimpressedbythehighleveloftheABCC.”Iwouldliketothinkthathis
favorableimpressionsoftheworkofABCCandhis
shortexposuretoABCCcontributedtohisdedicatedinterestinhelpingvictimsexposedtoradiationand
influenced his humanitarian service to the island
peoples in theTrustTerritories. If anyone readingthishasmemoriesofAVSoradditionalinformation,his only surviving heir, a brother, and professor
Bernheim,wouldappreciatehearingfromyou.
JanBernheim,M.D.,Ph.D.
Louisastraat24/32
8400Oostende,Belgium
Mobile:+32-(0)477-726516
Jan.bernheim@vub.ac.be

RERF Update Volume 21, Issue 1, 2010

36

Human Interest Notes

In Memoriam
Donald G. MacPhee, Ph.D.
(9 April 1942–16 September 2009)

RERF employees were saddened to learn that
Donald G. MacPhee, a former RERF Chief ofRadiobiology(21September1999–30June2002),
diedattheageof67inAustralia,16September2009,
with his wife (Valerie) and children (Cait and
Murdoch)byhisside.Dr.MacPheehaddecidedto
stoptreatmentforlymphomaandhewillalwaysbe
admiredforhispositiveoutlookonlifeandhisvaliant
struggleswithanumberofhealthchallenges.Born
inInverness,ScotlandandacitizenoftheUKand
Australia,Dr.MacPheewasrecruitedtoRERFbythe NationalAcademy of Sciences. He will be
rememberedasakindmanandapopulardepartment
chiefwhosethighprofessionalstandardsandencouraged scientists to work hard and to excel.After
steppingdownasdepartmentchiefon30June2002,
he continued to serve RERF as ResearchAdvisor
until 30 September 2004. Dr. MacPhee’s research
interestsincludedtheheritabilityofinducedepigeneticeventsandheencouragedRERF’sscientiststo
explore the field of epigenetics that is currently
receivingconsiderableattention.Hewasespecially
remembered in March when RERF hosted anInternational EpigeneticsWorkshop following theScientificCouncilMeeting.

Return to Table of Contents

Dr. Donald G. MacPhee in summer of 2001

RERF Update Volume 21, Issue 1, 2010

Research Protocols

Research Protocols Approved in
October 2009–March 2010
RP 6-09 Evaluation of the Nonmelanoma Skin
Cancer Risk among Heterozygotes Bearing aFounder Mutation Allele Unique to a Japanese
Population at Xeroderma Pigmentosum GroupA (XPA) Gene
HiraiY,NakamuraN,NodaA,CullingsHM,Ozasa
K,TokuokaS,YoneharaS,FujiharaM,MoriwakiS,
Nishigori C, Mabuchi K, Kraemer KH, Land CE,KodamaY
The frequency of patients (homozygotes) withcancer-pronerecessivehereditarydisorders,suchas
xeroderma pigmentosum (XP), is usually low, at
severalcasesper100,000people,butcarriers(heterozygotes)arenotrare,withafrequencycloseto
theorderofonepercent.However,thereislittledataregardingcancerriskinthecarriersoftheseheterozygotes, as they are generally difficult to identify.
But,theexaminationofcarriersofaninactivemutantalleleismostappropriateasamodelinestablishinga cancer risk of mutation heterozygotes, on theassumptionthatthecellularfunctionsdecreasedto
about50%amongtherelevantcarriers.Theaimofthisresearchprotocolistoevaluatethecancerrisk
of heterozygotes by comparing the frequency of
carriersbearingafoundermutationintheXPAgenein nonmelanoma skin cancer patients to control
population, by taking advantage of the fact that afoundermutationattheXPAgene(inactivemutation)
exists at a relatively high frequency among theJapanesepopulationandcanbefoundeasilyusingthepolymerasechainreaction-restrictionfragment
lengthpolymorphism(PCR-RFLP)method.Based
onthefrequencyfromthepilotstudy,weproposeto
conduct screening of 1,000 nonmelanoma skin
cancercasesandcomparethefrequencyinacontrol
population(estimatedfromourpreviousresultsplus
500newcasesinHiroshimatobestudiedinthisRP).
This research protocol is suitable for a model in
establishingacancerriskofheterozygouscarriers
ofmutationsatgenesrelatedtocancer-pronerecessivehereditarydisorders.
RP 7-09 Study of Arteriosclerosis in the Adult
Health Study Population (Part 1. Physiological
Indices of Arteriosclerosis)
TakahashiI,HidaA,AkahoshiM,KohataM,YamadaM, Hsu WL, Misumi M, Takahashi T, KiharaY,
MatsumotoM,FujiwaraS
Paststudieshavereportedsignificantassociation
between radiation exposure and atherosclerotic
diseasemortality/morbidityamongA-bombsurvivors.Atherosclerosiscomprisestwoaspects:atherosis (fatty degeneration) and sclerosis (acceleration
ofarterialstiffness),bothofwhicharesemi-indeReturn to Table of Contents

37
pendentlyrelatedtoatheroscleroticdisease.Inthisstudy,measurespertainingtoatheromaincludethe
ankle-brachialindex(ABI),toe-brachialindex(TBI),
andintima-mediathickness(IMT),whilethoseused
forarterialstiffnessincludetheaugmentationindex(AI) and brachial-ankle pulse wave velocity
(baPWV).Althoughaccelerationofarterialstiffness
might be caused by structural changes in arterial
walls, the association of radiation and radiationinducedinjuryandrepairofarterialwallshasnot
beenfullyinvestigated.
Inthisstudy,wehypothesizethatradiationexposureisasignificantriskfactorforarterialstiffing.
We propose to conduct a cross-sectional study to
obtainmeasurementsofatherosclerosisandarterial
stiffness.Thestudycohortwillcompriseabout4,000
AdultHealthStudy(AHS)subjects,includingthe
expandedAHS group of younger subjects. Theassociations of radiation and the aforementioned
arteriosclerosis indices will be analyzed using thegeneralized estimating equations (GEE) model to
accountforcorrelationamongtheindices,withdue
considerationpaidtoatheromatousdiseaseindices(ABI/TBI,IMT,etc.)andarteriosclerosisriskfactors
(Framinghamriskscores;FRS).

RP 1-10 Estimation of Genetic Effects of Radiation in Male Germ Cells of Mice: Study for
Assessment of High-density Microarray CGH
Platform
AsakawaJ,KodairaM,CullingsHM,ShimadaY,
NakamuraN
Planningafull-scalegeneticstudyintheoffspringofA-bomb survivors is a difficult task because,
comparedwithanimalstudiesthatusedlargeradiationdoses,A-bombsurvivorsreceivedmuchsmaller
doses on the average, and radiation sensitivity of
human germ cells is not well understood. On theotherhand,animaldataarenotfreefromproblems
either;theyaremostlylimitedtoRussell’s7lociand
practically no information exists on the whole
genome.
Recently, high-density (HD) microarray slides
havebecomecommerciallyavailable,whichenables
ustoconducthigh-resolutioncomparativegenomic
hybridization(CGH)studies.ThisHD-arrayallowsustoexaminecopynumberchanges(deletionsand/oramplifications)atevery1kbthroughoutthewhole
genomesbetweentwoDNAsamplesfromthesame
species(examinationofatotalof2.1millionDNAloci).
In the proposed study, we will first conduct amodelexperimenttoestimatethedetectionrateand
thesizeofthesmallestcopynumbervariation(CNV)
byexaminingthepolymerasechainreaction(PCR)confirmed CNVs existing in two different mouse
genomes. Following the characterization of themethods,wewillundertakeasmall-scalescreening
RERF Update Volume 21, Issue 1, 2010

Research Protocols
studyof30DNAsamplesfromF1micederivedfrom
irradiatedspermatogonialcellsand30samplesfrom
controlF1micetoobtaincrudeinformationonthe
spontaneousaswellasradiation-inducedmutation
rates that are essential for planning a larger scale
studyfordeterminingthedoseresponse.Finally,it
iscruciallyimportanttoknowifradiationexposure
mayinducenotonlydeletionsbutalsoamplificationsinthisanimalmodelstudy.

RP 2-10 Evaluation of Retinal Arteriolosclerosis and Age-related Macular Degeneration
Using Stored Retinal Images with Standardized
Measurements in Relation to Glaucoma Development in Atomic Bomb Survivors and to
Association with Aortic Arteriosclerosis(Addendum to RP 1-05)
Neriishi K,Yanagi M, Kawasaki R, Takahashi I,
NakashimaE,HsuWL,YokoyamaT,TakamatsuM,KinoshitaH,TsuikiE,UematsuM,KumagamiT,
KiuchiY,KitaokaT,FujiwaraS,HidaA,Akahoshi
MThepreliminaryanalysisofglaucomastudy(RP1-05) indicated that normal tension glaucoma
prevalenceissignificantlyassociatedwithA-bomb
radiationandretinalarteriolosclerosisisreportedly
associated with normal tension glaucoma as acausalfactor.Weplananevaluationbasedonstandardized retinal measurements of stored retina
images.Wewillinvestigateifretinalarteriolosclerosis is involved as an intermediate risk factor in
radiation-associated glaucoma. This study should
provide evidence regarding a possible mechanism
forradiation-associatedglaucoma.
Asecondendpointthatmayberelatedtoretinal
arteriolosclerosisandage-relatedmaculardegeneration is aortic arteriosclerosis. Using stored retina
imagesandstandardizedmeasurements,wealsoplantoevaluateretinalarteriolosclerosisandage-related
macular degeneration in order to investigate theirassociationswithaorticarteriosclerosis.

38
unanswered.Thisaddendumproposestoinvestigate
thosequestions.
Ophthalmological examinations on theAdult
Health Study participants will be conducted by
ophthalmologists.Themethodswillbeessentially
identicaltothoseofthepreviousstudyinorderto
investigate whether there are changes from theprevious findings after nine years. In particular,
(1)subjectswillbethosewhowereage13orlessatthetimeofthebombs,(2)theLensOpacityClassification System II will be used for grading, (3) a
variety of potentially confounding factors will be
incorporated in the analysis, and (4) digital computerimagesoflensandretinawillbestored.Fora
population-based cross-sectional study, more than
1,000participants,includingmorethan700subjects
whoparticipatedinthepreviouslongitudinalstudy,areexpectedtovisitRERFforexaminationduring
2009–2011.The power of this study is calculatedas more than 90% for the radiation-associated
prevalenceofcataractcases.

RP 3-10 Ophthalmologic Follow-up Study in
Atomic Bomb Survivors (Addendum to RP
3-00)
NeriishiK,YokoyamaT,TakamatsuM,Kumagami
T, Uematsu M, Tsuiki E, MinamotoA, KiuchiY,
Kitaoka T, Nakashima E, Hida A, Fujiwara S,
AkahoshiM
This addendum proposes to investigate severalunansweredquestionsinapreviousophthalmologic
study conducted from 2000 to 2002 based on RP
3-00. The ophthalmologic study of 837A-bomb
survivorsbasedonRP3-00hadrevealedastatisticallysignificantdoseresponsewithposteriorsubcapsular and cortical cataracts, and suggested alowerthresholdalthoughnotsignificant.However,
several important research questions still remain
Return to Table of Contents

RERF Update Volume 21, Issue 1, 2010

39

Recent Publications

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

AkahoshiM.Ischemicheartdiseaseamongatomic
bomb survivors: Possible mechanism(s) linkingischemic heart disease and radiation exposure.
NakashimaM,etal.,eds.RadiationHealthRisk
Sciences. Proceedings of the First International
Symposium of the Nagasaki University Global
COE Program “Global Strategic Center for
Radiation Health Risk Control.” NewYork:
Springer;2009,pp63-8.
AsakawaJ,NakamuraN,ShiroishiT.Detectionof
hyper-mutableAT-rich sequences among mice:
Fingerprints of micro-evolution. Hoshasen
Seibutsu Kenkyu [Radiation Biology Research
Communications]2009;44(4):407-18.(Japanese)
Darby SC, Cutter DJ, Boerma M, Constine LS,FajardoLF,KodamaK,MabuchiK,MarksLB,
MettlerFA,PierceLJ,TrottKR,YehETH,ShoreRE. Radiation-related heart disease: Current
knowledge and future prospects. International
JournalofRadiationOncology,Biology,Physics
2010(March);76(3):656-65.
Fujiwara S. Exercises and evaluation of physical
activity among the elderly. Kurosawa A, ed.Therapeutic Exercise for Chronic LocomotiveDiseases. Tokyo: Kanehara-Shuppan; 2009, pp
268-73.(Japanese)
Fujiwara S. Development of WHO FRAX and
significance. Seikei Saigai Geka [Orthopaedic
SurgeryandTraumatology]2009;52(11):1285-92.
(Japanese)
FujiwaraS.PathtraveledbytheRadiationEffects
ResearchFoundation’sresearch.HiroshimaIgaku[Journal of the Hiroshima MedicalAssociation]
2010 (April); 63(4):244-7. (Proceedings of the50th LateA-bomb Effects Research Meeting,
2009)(Japanese)
FujiwaraS,YamadaM,TakahashiI.Currentstatus
of large-scale epidemiological study—Adult
HealthStudyinHiroshimaandNagasaki.Nosocchu[JapaneseJournalofStroke]2009(November);31(6):439-42.(Japanese)
HamasakiK,KusunokiY,NakashimaE,Takahashi
N,NakachiK,NakamuraN,KodamaY.Genomic
instability in clonally expanded T-lymphocytes
from A-bomb survivors in vitro. Hoshasen
Seibutsu Kenkyu [Radiation Biology Research
Communications] 2009 (December); 44(4):396Return to Table of Contents

406.(Japanese)
HamataniK,EguchiH,MukaiM,KoyamaK,Taga
M,ItoR,HayashiY,NakachiK.ImprovedmethodforanalysisofRNApresentinlong-termpreserved
thyroidcancertissueofatomicbombsurvivors.
Thyroid 2010 (January); 20(1):43-9. (RERF
Report7-08)
HamataniK,TakahashiK,MukaiM.Mechanisms
of development of human adult-onset radiationassociatedpapillarythyroidcancer—Characteristics in early events. Hoshasen Seibutsu Kenkyu
[Radiation Biology Research Communications]
2009(December);44(4):379-95.(Japanese)
HayashiY,LagardeF,TsudaN,FunamotoS,Preston
DL,KoyamaK,MabuchiK,RonE,KodamaK,
Tokuoka S. Papillary microcarcinoma of thethyroid among atomic bomb survivors. Cancer
2010(April);116(7):1646-55.(RERFReport1108)
HiraiY.HowtoobtainenoughDNAfromalimited
amountofclinicalmaterials.HiyamaE,Hiyama
K,eds.ClinicalApplicationofMolecularDiagnosis—Cancer, Radiation Effects, and HumanDiseases. Kerala, India: Transworld Research
Network;2009,pp9-20.
HiraiY. Effective screening of heterozygotes for
ATM mutations. Hiyama E, Hiyama K, eds.
ClinicalApplication of Molecular Diagnosis—
Cancer,RadiationEffects,andHumanDiseases.
Kerala, India: Transworld Research Network;
2009,pp53-63.
HiraiY,InoueT,NakanoM,OhtakiK,KodamaY,
NakamuraN.ComparisonofESR-estimateddosein tooth enamel with chromosomally-estimated
doseinbloodlymphocytesamongatomicbomb
survivors. Hiroshima Igaku [Journal of theHiroshima MedicalAssociation] 2010 (April);
63(4):267-9.(Proceedingsofthe50thLateA-bomb
EffectsResearchMeeting,2009)(Japanese)
HsuWL,SodaM,NishiN,PrestonDL,FunamotoS,TomonagaM,IwanagaM,SuyamaA,Kasagi
F.Leukemia,lymphoma,andmultiplemyeloma
incidence in the LSS cohort: 1950–2001.
NakashimaM,etal.,eds.RadiationHealthRisk
Sciences. Proceedings of the First International
Symposium of the Nagasaki University Global
COE Program “Global Strategic Center for
Radiation Health Risk Control.” NewYork:
Springer;2009,pp69-73.
IshidaN,IchimaruS,HidaA,SodaM,Nakamura
RERF Update Volume 21, Issue 1, 2010

Recent Publications
T,Akahoshi M. Risk assessment of metabolic
syndromeusingtransportedestimatesinretrospectivecohortstudy.KeiryoSeibutsugaku[JapaneseJournalofBiometrics]2009(December);30(2):93104.(Japanese)
KodairaM.Theuseofhumanminisatellitemarkers
for the evaluation of genetic risk. Hiyama E,
HiyamaK,eds.ClinicalApplicationofMolecularDiagnosis—Cancer,RadiationEffects,andHumanDiseases. Kerala, India: Transworld Research
Network;2009,pp35-51.
Kodaira M, Ryo H, Kamada N, Furukawa K,
TakahashiN,NakajimaH,NomuraT,NakamuraN. No evidence of increased mutation rates at
microsatellitelociinoffspringofA-bombsurvivors. Radiation Research 2010 (February);
173(2):205-13.(RERFReport9-09)
KondoH,NakashimaM,SodaM,MineM,Yokota
K, ShibataY, Sekine I.Association of exposure
distancewithmultiplicityofcolorectaladenomas
in Nagasaki atomic bomb survivors. Hiroshima
Igaku [Journal of the Hiroshima MedicalAssociation]2010(April);63(4):304-6.(Proceedings
ofthe50thLateA-bombEffectsResearchMeeting,2009)(Japanese)
Kyoizumi S,Yamaoka M, KuboY, Hamasaki K,
Hayashi T, Nakachi K, Kasagi F, KusunokiY.
Memory CD4 T-cell subsets discriminated by
CD43 expression level inA-bomb survivors.
InternationalJournalofRadiationBiology2010
(January);86(1):56-62.(RERFReport11-07)
MasunariN,FujiwaraS.Impactfactorsofosteoporosisonhealth-relatedqualityoflife.HoffmanEC,
ed. Health-Related Quality of Life. NewYork:
NovaSciencePublishers;2009,pp1-29.
Mikamoto T, Toyoshima M, XiY, Honda H,
HamasakiK,KusunokiY,KamiyaK.Theeffects
ofoverexpressedtranslesionDNAsynthesispolymeraseRev1onmutagenesisinducedbyionizingradiation. Hiroshima Igaku [Journal of theHiroshima MedicalAssociation] 2010 (April);
63(4):345-7.(Proceedingsofthe50thLateA-bomb
EffectsResearchMeeting,2009)(Japanese)
MiuraS,NakashimaM,KondoH,ItoM,Meirmanov
S,HayashiT,SodaM,SekineI.Significanceof
oncogene amplifications in breast cancer in
atomicbombsurvivors:Associationswithradiationexposureandhistologicalgrade.NakashimaM, et al., eds. Radiation Health Risk Sciences.
ProceedingsoftheFirstInternationalSymposium
oftheNagasakiUniversityGlobalCOEProgram
Return to Table of Contents

40“GlobalStrategicCenterforRadiationHealthRisk
Control.”NewYork:Springer;2009,pp285-93.
NakamuraN.Ageneralizedviewofradiationcarcinogenesis. Hiroshima Igaku [Journal of theHiroshima MedicalAssociation] 2010 (April);
63(4):218-21.(Proceedingsofthe50thLateA-bomb
EffectsResearchMeeting,2009)(Japanese)
OhishiW,ChayamaK.CurrenttreatmentforchronichepatitisBinJapan.ClinicalJournalofGastroenterology2009(October);2(5):325-30.
OkuboT.Researchresourcesanditsfutureroleofthe Radiation Effects Research Foundation.
Hiroshima-ken Naikakai Kaishi [Journal of
Hiroshima Naika MedicalAssociation] 2009
(October);No.10:58-9.(Japanese)
Okubo T. Future plans of the Radiation Effects
ResearchFoundation.HiroshimaIgaku[Journal
of the Hiroshima MedicalAssociation] 2010
(April); 63(4):206-9. (Proceedings of the 50th
LateA-bomb Effects Research Meeting, 2009)
(Japanese)
SatoY,HoshiM,OhtakiM,MaruyamaH,Cullings
HM,KawakamiH.Usinggeographicinformation
system(GIS)forimprovementofHibakushalocation accuracy. Hiroshima Igaku [Journal of theHiroshima MedicalAssociation] 2010 (April);
63(4):261-4. (Proceedings of the 50th LateAbombEffectsResearchMeeting,2009)(Japanese)
ShimizuY,KodamaK,NishiN,KasagiF,Suyama
A, Soda M, Grant EJ, Sugiyama H, Sakata R,
Moriwaki H, Hayashi M, Konda M, Shore RE.Radiationexposureandcirculatorydiseaserisk:
Hiroshima and Nagasaki atomic bomb survivor
data,1950–2003.BritishMedicalJournal2010;
340:193 (Full article online: doi10.1136/bmj.
b5349).
SugiyamaH,NishiN,ItoK,NaraharaH,YasuiW,
KajiharaH,KamadaN,AritaK,OzasaK.Achievements of follow-back survey of the HiroshimaPrefecture cancer registry. Hiroshima Igaku[Journal of the Hiroshima MedicalAssociation]
2009(November);62(11):528-32.(Japanese)
SugiyamaH,NishiN,KuwabaraM,NinomiyaM,
AritaK,YasuiW,KasagiF,KodamaK.Incidenceandsurvivalofchildhoodcancercasesdiagnosed
between1998and2000inHiroshimaCity,Japan.
AsianPacificJournalofCancerPrevention2009
(October);10(4):675-80.(RERFReport6-09)
Suzuki G, Cullings HM, Fujiwara S, Matsuura S,
RERF Update Volume 21, Issue 1, 2010

Recent Publications

41

Kishi T, Ohishi W, Akahoshi M, Hayashi T,
Tahara E. LTA 252GG and GA genotypes are
associated with diffuse-type noncardia gastric
cancer risk in the Japanese population. Helicobacter 2009 (December); 14(6):571-9. (RERF
Report1-09)
TakahashiN.Phosphoglucomutase(PGM).Nippon
Rinsho [Japanese Journal of Clinical Medicine]
2010(January);68(Suppl1):864-7.(Japanese)
Tasaki M,YamashitaY,WatanabeY, Mitsuoka T,
Fukui M,YamasakiA, HidaA,Akahoshi M,
KawakamiA,EguchiK.Effectsofexamination
techniquesandroomconditionsonSchirmerand
Saxontests.KangoGijutsu[TheJapaneseJournal
ofNursingArts]2010(May);56(6):82-6.(Japanese)
Toyoshima M, XiY, Mikamoto T, Watanabe H,
MasudaY,HondaH,HamasakiK,KusunokiY,
Kamiya K. Role of Rev1 in radiation-induced
tumorigenesis. Hiroshima Igaku [Journal of theHiroshima MedicalAssociation] 2010 (April);
63(4):348-50.(Proceedingsofthe50thLateA-bomb
EffectsResearchMeeting,2009)(Japanese)
YamadaM,KasagiF,MimoriY,MiyachiT,Ohshita
T,SasakiH.Incidenceofdementiaamongatomicbomb survivors—Radiation Effects Research
FoundationAdult Health Study. Journal of theNeurologicalSciences2009(June),281(1-2):11-4.
(RERFReport12-08)
YoshidaK,NakachiK,ImaiK,CologneJB,Niwa
Y,KusunokiY,HayashiT.Lungcancersusceptibility among atomic bomb survivors in relation toCA repeat number polymorphism of epidermal
growth factor receptor geneandradiationdose.
Carcinogenesis 2009 (December); 30(12):203741.(RERFReport10-09)

Return to Table of Contents

RERF Update Volume 21, Issue 1, 2010