TranslationalMedicine

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PersonalizedMedicine轉化醫(yī)學和個體化醫(yī)學楊學寧XueningYang,MD廣東省人民醫(yī)院GuangdongGeneralHospital廣東省肺癌研究所GuangdongLungCancerResearchInstitute《循證醫(yī)學》雜志JournalofEvidence-basedMedicine1h第1頁EBPModelsTraditionalpracticeModel(×)Model1:UsethehighestqualityinformationtoguideclinicaldecisionsModel2:Search,evaluate,andmakeavailablespecialtyspecificLevel1informationModel3:CreateoriginalresearchorsystematicreviewsModel4:Translationalresearch……2h第2頁BackgroundInthepast30years，NCI$200BillionsResults：1.56millionarticles80％onmice,fruitflyandroundworm。Nochangeoncancerrelatedmortalityrate3h第3頁Background4h第4頁BackgroundNewbiotechnologyGenomics(基因組),Proteomics(蛋白質組)Bioinformatics(生物信息學)Increasingcomplexityofclinicalresearch5h第5頁DefinitionTranslationalresearch,“transformsscientificdiscoveriesarisingfromthelaboratory,clinical,orpopulationstudiesintoclinicalapplications…”Include：benchtobedside(基礎研究到臨床應用)bedsidetobench(臨床治療成果促進基礎研究)Source:NationalCancerInstitute,NationalInstitutesofHealth6h第6頁Definition

ClinicLabPopulationT1T2T1:applyingbasicsciencefindingsfromlabresearchinclinicalstudiesofpatientsT2:applyingthefindingsofclinicalstudiestoalterhealthpracticesinthecommunityEBMTranaslationalMedicinePersonalizedMedicine7h第7頁Goals/PurposeT1:Theproductionofapromisingnewtreatment/methodthatcanbeusedclinicallyorcommercialized.T2:Ensurethatnewtreatmentsandresearchknowledgeactuallyreachthepatientsorpopulationsforwhomtheyareintendedandareimplementedcorrectly8h第8頁ResearchcontentT1:totest,inhumans,thenoveltherapeuticstrategiesdevelopedthroughexperimentation(exvivoorfrom-bench-to-bedside)

T2:totesthowcanefficientlyuseclinicalresultstooptimizehealthpracticesandimproveguidelinesandhealthpolicy(from-bedside-to-population)9h第9頁Settings/knowledgebackgroundT1:requiresmasteryofmolecularbiology,genetics,andotherbasicsciences;clinicalscientistsworkinginstronglaboratoriesandwithcutting-edgetechnology;asupportiveinfrastructurewithintheinstitution.T2:the“l(fā)aboratory”forT2researchisthecommunityandambulatorycaresettingsmasteryofthe“implementationscience”offieldingandevaluatinginterventionsinrealworldsettingsmasteryofthedisciplinessuchasclinicalepidemiologyandevidencesynthesis,communicationtheory,behavioralscience,publicpolicy,financing,organizationaltheory,informatics,andmixedmethods/qualitativeresearch.10h第10頁ChallengesT1:strugglesmorewithbiologicalandtechnologicalmysteries,trialrecruitment,andregulatoryconcernsT2:strugglesmorewithhumanbehaviorandorganizationalinertia,infrastructureandresourceconstraints,andthemessinessofprovingtheeffectivenessof“movingtargets”underconditionsthatinvestigatorscannotfullycontrol11h第11頁InvestigatorsT1:BasicscientistscooperatewithclinicaldoctorsT2:Population-basedinvestigatorsandepidemiologistsandhealthpolicymakers,etc...Moreeffectivecollaborationbetweenlabscientistsandclinicaldoctors12h第12頁TranslationalMedicineDisseminationoftheinnovationAdoptionoftheinnovationMaintainingtheinnovationRefiningandevolvingasbodyofknowledgeexpands13h第13頁TheTranslationContinuumBasicScientificDiscoveryEarlyTranslationLateTranslationDisseminationAdoptionPromisinggeneBasicepidemiologicalfindingPartnershipsInterventiondevelopmentPhaseIIItrialsRegulatoryapprovalPartnershipsHealthservicesresearchtosupportdisseminationandadoptionTocommunityprovidersTopatientsandpublicAdoptionofadvancebyproviders,patients,andpublicPaymentmechanismstoenableadoptionSource:NationalCancerInstitute14h第14頁TranslationalMedicineTranslatethesuccessingenomicmedicineintoclinicalapplicationsEvidence-basedmedicinedeveloprationaleandtheoryfordrugdesignandtherapeuticinterventionDeveloppersonalmedicineandpreventivemedicine15h第15頁TranslationalMedicineTranslationalResearch-hotspotGenomicandgenediagnosisandtreatment基因組研究及基因診斷治療PhaseItrialfordrugs藥品一期臨床試驗GenomicPharmocologyandpersonalizedmedicine基因組藥理學與個體化醫(yī)學Biomarks生物標識物Signaltransductingpathwayandclinicalapplications信號傳導通路研究及其臨床應用Stemcell干細胞16h第16頁TranslationalMedicineTheheartoftranslationalresearchresidesinPhaseItrialswherenoveltreatmentsare：testedforfeasibilityandtoxicitypreparationforaPhaseIItrialinwhichtherapeuticeffectivenessistestedMarincola,FMTranslationalMedicine:Atwo-wayroad,JTM,202317h第17頁ClinicalResearchTrainingProgramComputerSkillsClinicalResearchMethodsBiostatistics:StatisticalApproachinClinicalResearchMeasurementsinClinicalResearchEthicsandRegulationsofClinicalResearchResearchDesignandDevelopmentCost-effectivenessAnalysisRegressionandANOVALogisticRegressionClinicalTrials18h第18頁TheprocessofTranslationChoosearesearchtopicrelatedtoyourclinicalpractice19h第19頁EarlystudyonnitricoxideSynthase20h第20頁UsesforaclonedgeneHomologycomparisonQuantitategeneexpressionChromosomalmappingDeterminetranscriptionalregulationPreparerecombinantproteinAntibodydevelopmentTissuelocalizationDeveloptransgenic/knockoutanimalsGenetransfer/genetherapystudiesIntellectualproperty/technologytransfer21h第21頁22h第22頁ExploreGeneandDiseases23h第23頁24h第24頁PhysiopathologicalStudyBench:VasoprotectivePropertiesofNitricOxideInhibitsplateletaggregationInhibitsleukocytechemotaxisInhibitsVSMCproliferationInhibitsVSMCmigrationPromotesECgrowthInhibitsECapoptosisPotentvasodilator25h第25頁CellandAnimalAdenoviralVector(type5,E1-,E3-)腺病毒載體26h第26頁SmallAnimals27h第27頁BiggerAnimals28h第28頁AnimalExperiment2023年29h第29頁30h第30頁PhaseⅠClinicalTrialClinicalTrial:AdiNOSgenetherapytoblockAVfistulaneointimalhyperplasiainhemodialysispatients202331h第31頁CurrentStateofTranslationalMedicine17yearinnovationadoptioncurvefromdiscoveryintoacceptedstandardsofpracticeEvenifastandardisaccepted,patientshavea50:50chanceofreceivingappropriatecare,a5-10%probabilityofincurringapreventable,anticipatableadverseeventThemarketisbalkingathealthcareinflation,newdiagnosticsandtherapeuticswillfindincreasingresistanceforreimbursement32h第32頁PersonalizedMedicine

ClinicLabPopulationT1T2T1:applyingbasicsciencefindingsfromlabresearchinclinicalstudiesofpatientsT2:applyingthefindingsofclinicalstudiestoalterhealthpracticesinthecommunityEBMTranaslationalMedicinePersonalizedMedicine33h第33頁Personalizedmedicinetheapplicationofgenomicandmoleculardatatobettertargetthedeliveryofhealthcare,facilitatethediscoveryandclinicaltestingofnewproducts,andhelpdetermineaperson'spredispositiontoaparticulardiseaseorconditionapatient'sprotein,geneormetaboliteprofilecouldbeusedtotailormedicalcaretothatindividual'sneeds34h第34頁ImatinibforGISTGIST

genesisKeyprocess：c-kitmutation---KITTKactivationPDGFRmutation86%

GIST

kitmutation，prognosisfactorImatinibOralsmallmoleculeTKIInhibitTKactivation抑制酪氨酸激酶活化Designforchronicmyeloidleukemia(CML)35h第35頁ImatinibforGIST36h第36頁ImatinibforGISTJoensuuH，etal.202337h第37頁PretreatmentOnemonthoftherapyH&E(atdiagnosis)H&EKi67CD117JoensuuHetal.NEnglJMed.2023;344:1052-1056.TheFirstGISTPatient:HistologyImatinibforGIST38h第38頁ImatinibforGISTJoensuuH，etal.2023Theory：ImatinibcouldtargetGISTEasyDetectedtumormarker：CD117TissuefromthepatientResponseconfirmedbypathologyDynamicmonitoredbytumormarkerEthics：IRB39h第39頁Imatinib治療GIST2023.3：JoensuuH.firstcase2023.7：

phaseIIstudy(B2222)

2023autumn：phaseIIstudy(S0033,EORTC)2023.2：FDA40h第40頁41h第41頁ImatinibforGIST5-year