中山大学循证医学3TranslationalMedicine-ZSU-FS

TranslationalMedicine

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PersonalizedMedicine转化医学和个体化医学杨学宁XueningYang,MD广东省人民医院GuangdongGeneralHospital广东省肺癌研究所GuangdongLungCancerResearchInstitute《循证医学》杂志JournalofEvidence-basedMedicine1h第1页EBPModelsTraditionalpracticeModel(×)Model1:UsethehighestqualityinformationtoguideclinicaldecisionsModel2:Search,evaluate,andmakeavailablespecialtyspecificLevel1informationModel3:CreateoriginalresearchorsystematicreviewsModel4:Translationalresearch……2h第2页BackgroundInthepast30years，NCI$200BillionsResults：1.56millionarticles80％onmice,fruitflyandroundworm。Nochangeoncancerrelatedmortalityrate3h第3页Background4h第4页BackgroundNewbiotechnologyGenomics(基因组),Proteomics(蛋白质组)Bioinformatics(生物信息学)Increasingcomplexityofclinicalresearch5h第5页DefinitionTranslationalresearch,“transformsscientificdiscoveriesarisingfromthelaboratory,clinical,orpopulationstudiesintoclinicalapplications…”Include：benchtobedside(基础研究到临床应用)bedsidetobench(临床治疗成果促进基础研究)Source:NationalCancerInstitute,NationalInstitutesofHealth6h第6页Definition

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

T2:totesthowcanefficientlyuseclinicalresultstooptimizehealthpracticesandimproveguidelinesandhealthpolicy(from-bedside-to-population)9h第9页Settings/knowledgebackgroundT1:requiresmasteryofmolecularbiology,genetics,andotherbasicsciences;clinicalscientistsworkinginstronglaboratoriesandwithcutting-edgetechnology;asupportiveinfrastructurewithintheinstitution.T2:the“laboratory”forT2researchisthecommunityandambulatorycaresettingsmasteryofthe“implementationscience”offieldingandevaluatinginterventionsinrealworldsettingsmasteryofthedisciplinessuchasclinicalepidemiologyandevidencesynthesis,communicationtheory,behavioralscience,publicpolicy,financing,organizationaltheory,informatics,andmixedmethods/qualitativeresearch.10h第10页ChallengesT1:strugglesmorewithbiologicalandtechnologicalmysteries,trialrecruitment,andregulatoryconcernsT2:strugglesmorewithhumanbehaviorandorganizationalinertia,infrastructureandresourceconstraints,andthemessinessofprovingtheeffectivenessof“movingtargets”underconditionsthatinvestigatorscannotfullycontrol11h第11页InvestigatorsT1:BasicscientistscooperatewithclinicaldoctorsT2:Population-basedinvestigatorsandepidemiologistsandhealthpolicymakers,etc...Moreeffectivecollaborationbetweenlabscientistsandclinicaldoctors12h第12页TranslationalMedicineDisseminationoftheinnovationAdoptionoftheinnovationMaintainingtheinnovationRefiningandevolvingasbodyofknowledgeexpands13h第13页TheTranslationContinuumBasicScientificDiscoveryEarlyTranslationLateTranslationDisseminationAdoptionPromisinggeneBasicepidemiologicalfindingPartnershipsInterventiondevelopmentPhaseIIItrialsRegulatoryapprovalPartnershipsHealthservicesresearchtosupportdisseminationandadoptionTocommunityprovidersTopatientsandpublicAdoptionofadvancebyproviders,patients,andpublicPaymentmechanismstoenableadoptionSource:NationalCancerInstitute14h第14页TranslationalMedicineTranslatethesuccessingenomicmedicineintoclinicalapplicationsEvidence-basedmedicinedeveloprationaleandtheoryfordrugdesignandtherapeuticinterventionDeveloppersonalmedicineandpreventivemedicine15h第15页TranslationalMedicineTranslationalResearch-hotspotGenomicandgenediagnosisandtreatment基因组研究及基因诊断治疗PhaseItrialfordrugs药品一期临床试验GenomicPharmocologyandpersonalizedmedicine基因组药理学与个体化医学Biomarks生物标识物Signaltransductingpathwayandclinicalapplications信号传导通路研究及其临床应用Stemcell干细胞16h第16页TranslationalMedicineTheheartoftranslationalresearchresidesinPhaseItrialswherenoveltreatmentsare：testedforfeasibilityandtoxicitypreparationforaPhaseIItrialinwhichtherapeuticeffectivenessistestedMarincola,FMTranslationalMedicine:Atwo-wayroad,JTM,202317h第17页ClinicalResearchTrainingProgramComputerSkillsClinicalResearchMethodsBiostatistics:StatisticalApproachinClinicalResearchMeasurementsinClinicalResearchEthicsandRegulationsofClinicalResearchResearchDesignandDevelopmentCost-effectivenessAnalysisRegressionandANOVALogisticRegressionClinicalTrials18h第18页TheprocessofTranslationChoosearesearchtopicrelatedtoyourclinicalpractice19h第19页EarlystudyonnitricoxideSynthase20h第20页UsesforaclonedgeneHomologycomparisonQuantitategeneexpressionChromosomalmappingDeterminetranscriptionalregulationPreparerecombinantproteinAntibodydevelopmentTissuelocalizationDeveloptransgenic/knockoutanimalsGenetransfer/genetherapystudiesIntellectualproperty/technologytransfer21h第21页22h第22页ExploreGeneandDiseases23h第23页24h第24页PhysiopathologicalStudyBench:VasoprotectivePropertiesofNitricOxideInhibitsplateletaggregationInhibitsleukocytechemotaxisInhibitsVSMCproliferationInhibitsVSMCmigrationPromotesECgrowthInhibitsECapoptosisPotentvasodilator25h第25页CellandAnimalAdenoviralVector(type5,E1-,E3-)腺病毒载体26h第26页SmallAnimals27h第27页BiggerAnimals28h第28页AnimalExperiment2023年29h第29页30h第30页PhaseⅠClinicalTrialClinicalTrial:AdiNOSgenetherapytoblockAVfistulaneointimalhyperplasiainhemodialysispatients202331h第31页CurrentStateofTranslationalMedicine17yearinnovationadoptioncurvefromdiscoveryintoacceptedstandardsofpracticeEvenifastandardisaccepted,patientshavea50:50chanceofreceivingappropriatecare,a5-10%probabilityofincurringapreventable,anticipatableadverseeventThemarketisbalkingathealthcareinflation,newdiagnosticsandtherapeuticswillfindincreasingresistanceforreimbursement32h第32页PersonalizedMedicine

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

genesisKeyprocess：c-kitmutation---KITTKactivationPDGFRmutation86%

GIST

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

phaseIIstudy(B2222)

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