平成25年度大阪大学医学部医学科学士編入学試験問題【英語】 1／10 ページ Ⅰ 次の文章を読んで、間1∼間6に答えなさい。 Thecancerstemcell（CSC）Conceptwasinitiallyproposedseveraldecadesagotoexplain （Å）tWOreCurringObservations．ThefirstisthatmostcancersconsistofphenotypICally heterogeneoustumorcellsthatmayresembledistinctstagesofnormaltissue development．TheotheristhatonlyaffactionofcellsfrombothhematologlCandsolid malignanciesaretumorigenic．Studies（a）theearly1990sofhumanchronic（CML）and acutemyeloidleukemias（AML）usinginvitrolong−termCulturesorseverecombined immunodeficient（SCID）micedemonstratedthatphenotypicallydistinctcellsresembling Primitivehematopoieticcellswerecapable（b）givingrise（C）leukemia．Importantly， these studiesestablishedthattumorlgenicpotentialwasnotequallysharedbyallce11s Withinanindividualtumorbutinherentlylinkedandrestricted（d）phenotypically distinct subsets．Sincethencellswithenhancedtumor−initiatingpotentialhavebeen PrOSPeCtivelyidentifiedinawidevariety（e）humanmalignanciesbased（f）specific CellsurfaceantlgeneXPreSSionaswellasfunctionalcharacteristics，SuChasaldehyde dehydrogenase（ALDH）activityandincreaseddrugeffluxpotential．Moreover，thesecell POPulationscangiverise（g）thefu11spectrum（h）celltypesthatrecapitulatesthe Orlglnaltumoraswellasmaintaintumorlgenicpotentialduringserialtransplantation． Therefbre，thedefinitionfbrCSCshasbeenexpandedtoincludethecapacltyfbr differentiation and self−reneWal． Giventheirunlquefunctionalproperties，theCSChypothesishasprovidedapotential explanationfbr severalphenomenainclinicaloncology．Onesuchphenomenonisthe noteddiscordancebetweenearlymeasuresofclinicalresponseandlong−termOutCOmeS formanycancers．Forexample，theefficacyofantitumortherapylSuSuallydetermined byseriallyevaluatlngtumOrburden，anditisgenera11yassumedthatimprovementsin theseparametersresult（i）clinicalbenefit．AlthoughdiseasecontroIcanalleviate SymPtOmSinindividualpatients，theachievementofobjectiveresponses（i．e．，tumOr reduction）acrossapopulationmaynotbeassociated（j）improvementsinlong−term OutCOmeS，SuChasthedurationofoverallsurvival・In（B）tWOlargerandomizedclinical 吐出ComparlnglnitialtherapleSfbrnewlydiagnosedpatientswithAML，the administrationofincreaseddosesofchemotherapyslgnificantlylmPrOVedtheproportion Ofpatientsachievingcompleteremissions．However，desplteimproveddiseasecontrol， nodifferenceswereobservedinoverallsurvivalbetweentreatmentgroupsineithertrial． Intheplasmace11malignancymultiplemyeloma，therelationshipbetweenthedepthof responseandoverallsurvivalhasbeenexaminedinavarietyoflargerandomizedtrials usinghigh−dosechemotherapyandautologousstemcelltransplantation．Inmanyofthese Studies，theachievementofacompleteresponseandtotaleradicationofallmacroscopIC diseaseshasnotbeenassociatedwithincreasedoverallsurvivalascomparedtopatients achievingonlypartialremissions・Thesefindingsarealsonotedin（C）SOlidtumors・For 平成25年度大阪大学医学部医学科学士編入学試験問題【英語】 2／10 ページ example，anumberoflargerandomizedstudiesusingcombinationchemotherapyln PanCreaticadenocarcinomahavedemonstratedimprovedratesoftumorresponseor PrOgreSSion−freesurvival，butthesedemonstratedonlynegligibleornoimprovementsin OVerallsurvival・Overall，thesestudiesdemonstratethatresponseandsurvivalratesmay beindependententitiesinmanydiseasesandsuggestthateachreflectstreatmenteffects agalnStdistinctcancercelltypes． ItispossiblethattherarltyOfCSCsmayexplainthe（D）discrepancybetweenclinical responseandsurvivalinmanymalignanciesasdiseaseresponseprlmarilyreflects Short−termChangesinbulktumorcells，Whereaslong−termOutCOmeS，SuChasdisease relapseandprogression，aredictatedbyrareCSCs・InitialstudiesuslngSyngeneic transplantsofmurinecancercellsdemonstratedthatthe丘equencyoftumorinitiating Cellsarerareinmultiplemyelomaandlymphoma，andsimilarfindingshavebeen Observedthroughxenograftingstudiesofprlmaryhumantumorsinawidevarietyof diseases・However，areCentStudyinmelanomaquestionedtherarltyOfCSCsby demonstratlngthatmodificationstothexenotransplantationprotocol，includingtheuse Ofmoreimmunodeficientnonobesediabetic／SCID／IL2†Cnullmice，COlnJeCtionoftumor Cellswithmatrlgel，andwaitingatleast20weekstoassesstumorfbrmation，dramatically increasedthefrequencyoftumorinitiatingcellsandeliminatedtheirrestrictiontoany SPeCificphenotype・Theseresultsmaybespecifictomelanoma，aStheseexperimental modificationshavefailedtoslgnificantlylnCreaSethefrequencyofclonogenictumor Cellsinpancreatic，lung，andovariancarcinomas・Therefbre，therelationshipbetween diseaseresponseandsurvivalmaydependonthefrequencyofCSCswithinaspecific disease．（出典：STEMCELLS29；883−887，2011より抜粋・改変）間1．本文の（a）∼（j）に適切な前置詞を記入しなさい。間2．下線（A）tworecurringobservations とはどのような二つのことを示すのか、それぞれ日本語で説明しなさい。間3．下線（B）の臨床試験では、どのような結論が得られたか、句読点を含めて、 80字以内で簡潔に説明しなさい。間4．下線（C）の例として、本文で記載されている腫瘍の由来臓器を述べなさい。間5．下線（D）は本文では何によって説明できると述べられているか、句読点を含めて、20字以内で記述しなさい。間6．下線（D）を説明できる現象が成立しないと本文で述べられている腫瘍を英語で答えなさい。平成25年度大阪大学医学部医学科学士編入学試験問題【英語】 3／10 ページ Ⅰ 次の文章を読んで、間1∼間5に答えなさい。 Oxygeniscentraltobiologybecauseofitsutilizationintheprocessofresplration・02 SerVeSaSthefinalelectronacceptorinoxidativephosphorylation，Whichcarrieswithit theriskofgeneratingreactiveoxygenspecies（ROS）thatreactwithcellular macromoleculesandaltertheirbiochemicalorphysICalproperties，reSultinglnCe11 dysfunctionordeath．Asaconsequence，metaZOanOrganismshaveevoIvedelaborate Cellularmetabolic andsystemicphysiologlCalsystemsthataredesignedtomaintain OXygenhomeostasis．Thehypoxia−induciblefactors（HIFs）aretranscriptionalactivators thatfunctionasmasterregulatorsofoxygenhomeostasisinallmetazoanspecies・ Hypoxia−induciblefactorl（HIF−1）isexpressedbyallextantmetazoanspeciesanalyzed・ HIF−1consistsofHIF−1αandHIF−1βsubunits，eaChofwhichcontainsbasic helix−loop−helix−PAS（bHLH−PAS）domainsthatmediateheterodimerizationandDNA binding．HIF−1βheterodimerizeswithotherbHLH−PASproteinsandispresentinexcess， SuChthatHIF−1αPrOteinlevelsdetermineHIF−1transcrlPtlOnalactivlty・ TheregulationofmetabolismisaprlnCIPalandprlmOrdialfunctionofHIF−1・Under hypoxicconditions，HIF−1mediatesatransitionfromoxidativeto glycolyticmetabolism throughitsregulationofthefbllowing：PDKl，enCOdingpyruvatedehydrogenase（PDH） kinasel，WhichphosphorylatesandinactivatesPDH，therebyinhibitingtheconversion OfpyruvatetoacetylcoenzymeA（AcetylCoA）fbrentryintothetricarboxylicacidcycle （TCACycle）；LDHA，enCOdinglactatedehydrogenaseA，Whichconvertspyruvateto lactate；andBNIP3，Whichmediates selectivemitochondrialautophagy．HIF−l also mediatesasubunit switchincytochromecoxidasethatimprovestheefficiencyof electrontransferunderhypoxicconditions．Ananalogoussubunitswitchisalsoobserved inSaccharomycescerevisiae，althoughitismediatedbyacompletelydifferent mechanism（yeastlackHIF−1），SuggeStingthatitmayrepresentafundamentalresponse Ofeukaryoticce11stohypoxia． ItisconventionalwisdomthatcellsswitchtoglycolysISWhenO2becomeslimitingfbr mitochondrialATPproduction．Yet，HIF−1α−nullmouseembryo fibroblasts，Whichdonot down−regulateresplrationunderhypoxicconditions，havehigherATPlevelsat1％02 thanwild−tyPeCellsat20％02，demonstratingthatundertheseconditionsO2isnot limitingfbrATPproduction．However，theHIF−1α−nullcellsdieunderprolonged hypoxicconditionsduetoROStoxiclty．Thesestudieshaveledtoaparadigmshiftwith regardtoourunderstandingoftheregulationofcellularmetabolism：（1）theDur130SeOf thisswitchistopreventexcessmltOChondrialgeneratlOnOfROSthatwouldotherwISe OCCurduetothereducedefficiencyofelectrontransferunderhypoxICCOnditions・This mavbeparticularlvimportantinstemcells．inwhichavoidanceofDNAdamaEeis critical．平成25年度大阪大学医学部医学科学士編入学試験問題【英語】 4／10 ページ Cancerscontainhypoxicreg10nSaSareSultofhighratesofcellproliferationcoupled withthefbrmationofvasculaturethatisstructurallyandfunctionallyabnormal． IncreasedHIF−1αand／orHIF−2αlevelsindiagnostictumorbiopsleSareaSSOCiatedwith increasedriskofmortalitylnCanCerSOfthebladder，brain，breast，COlon，CerVix， endometrium，head／neck，lung，OVary，PanCreaS，PrOState，reCtum，andstomach；these resultsarecomplementedbyexperimentalstudies，Whichdemonstratethatgenetic manlPulationsthatincreaseHIF−1αeXPreSSionresultinincreasedtumorgrowth，Whereas lossofHIFactivltyreSultsindecreasedtumorgrowth．HIFsarealsoactivatedbygenetic alterations，mOStnOtably，VHLlossoffunctioninclearcellrenalcarcinoma・HIFs activatetranscrlPtlOnOfgenesthatplaykeyrolesincriticalaspectsofcancerbiology， including（1）cellmaintenance，Cellimmortalization，ePithelia1−meSenChymaltransition，（2）instability，VaSCularization，（3）metabolism，PHregulation，immuneevasion， lnVaSionand（4），andradiation（5）．GiventheextensivevalidationofHIF−1asa potentialtherapeutictarget，drugsthatinhibitHIF−1havebeenidentifiedandshownto hal▼eanti−CanCereffectsinxenograftmodels． 01一erlOOwomendieeverydayofbreastcancerintheU．S．ThemeanPO2islOmmHg lnbreastcancerascomparedto＞60mmHglnnOrmalbreasttissue，andcancerswith PO二く10mmHgareassociatedwithincreasedriskofmetastasisandpatientmortality・ IncreasedHIF−1αPrOteinlevels，aSidentifiedbylmmunOhistochemicalanalysISOftumor blOpSleS．areaSSOCiatedwithincreasedriskofmetastasisand／orpatientmortalityln unselectedbreastcancerpatientsandinlymphnode−POSitive，lymphnode−negative， HER2二orestrogenreceptor＋subpopulations・Metastasisisresponsiblefbr＞90％of breastcancermortality．TherequirementfbrHIF−1inbreastcancermetastasishasbeen demonstratedforbothautochthonoustumorsintransgenicmiceandorthotopIC transplantsinimmunodeficientmice．Primarytumorsdirecttherecruitmentofbone marrow−derivedcellstothelungsandothersitesofmetastasis・Inbreastcancer，hypoxia inducestheexpressionoflysyloxidase（LOX），aSeCretedproteinthatremodelscollagen at sitesofmetastatic niche fbrmation．Inadditionto LOX，breastcancers also express LOX−likeproteins2and4．LOXLOXL2，andLOXL4areallHIF−1−regulatedgenesand （2）HIF−1inhibitionblocksmetastatlCnicheformatlOnregardlessofwhichLOX／LOXL PrOtelnlSeXPreSSed，WhereasavailableLOXinhibitorsarenoteffectlVeagalnStall LOXLprotelnS，agalnillustratlngtheroleofHIF−lasamasterregulatorthatcontroIsthe express10nOfmultiplegeneslnVOIvedinaslnglephysiologlCalprocess・（出典：CeJH4針jタクー40β，20ノ2より抜粋・改変）平成25年度大阪大学医学部医学科学士編入学試験問題【英語】 5／10 ページ間1．HIF−1の生体内における主な働き2つをそれぞれ10字以内で記入しなさい。間2．下線（1）を句読点を含めて、150字以内で和訳しなさい。間3．本文の（1），（2），（3），（4），（5）に入れるのに適当であると考えられる単語（それぞれ一語）を記入しなさい。間4．下線（2）を句読点を含めて、150字以内で和訳しなさい。