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TranslationalMedicine&PrecisionMedicine转化医学和精准医学广东省肺癌研究所GuangdongLungCancerInstitute《循证医学》杂志JournalofEvidence-basedMedicineClinicalResearch:NIHDe

finition•Epidemiologicandbehavioralstudies•Outcomesresearchandhealthservicesresearch•Patient-orientedresearch-Researchconductedwith

humansubjects,tissues,specimens,orcognitivephenomenaforwhichaninvestigatordirectlyinteractswithhumansubjects•Healthyvolunte

er:personwithnoknownsignificanthealthproblemwhoparticipatesinclinicalresearchtotestadrug,device,orinterventionClinicalTrials•Aprospec

tivestudyinvolvinghumansubjectsthatisdesignedtoanswerspecificquestionsabouttheeffectsorimpactofparticularbiomedic

alorbehavioralinterventions•NOThealthyvolunteerstudies,whicharedesignedtodevelopnewknowledge,butprovidenodirectbenefitstothesubjectsTranslationalRese

arch:NIHDefinition•Theprocessofapplyingdiscoveriesgeneratedduringresearchinthelaboratory,andinpreclin

icalstudies,todevelopmentoftrialsandstudiesinhumans•Leveragingtheobservationsmadeinclinicalpracticetodrivenewmechanisticinvestigationsat

thebench•EnhancingtheadoptionofbestpracticesinthecommunityBackground•Inthepast30years，NCI$200Billions•Results：1.56millionarticles–80

％onmice,fruitflyandroundworm。–NochangeoncancerrelatedmortalityrateBackgroundBackground•Newbiotechnology•Genomics(基因组),Proteomics(蛋白质组)•Bioi

nformatics(生物信息学)•IncreasingcomplexityofclinicalresearchDefinition•Translationalresearch,“transformsscientificdiscov

eriesarisingfromthelaboratory,clinical,orpopulationstudiesintoclinicalapplications…”•Include：–benchtobeds

ide(基础研究到临床应用)–bedsidetobench(临床治疗结果促进基础研究)•Source:NationalCancerInstitute,NationalInstitutesofHealthBasicandClinica

lResearchareInterdependentTranslationfrombasicsciencetohumanstudiesTranslationofnewknowledgeintoclinicalpracticeBasicResearchClinicalResearchImprov

edHealthAdaptedfromSungetal.(2003)JAMA,289,1278-89.Copyright©(2003)AmericanMedicalAssociation.AllRightsreserved.“T1”“T2”T

heproductionofapromisingnewtreatment/methodthatcanbeusedclinicallyorcommercialized.Ensurethatnewtreatmentsand

researchknowledgeactuallyreachthepatientsorpopulationsforwhomtheyareintendedandareimplementedcorrectly

TranslationalMedicine•Translatethesuccessingenomicmedicineintoclinicalapplications•Evidence-basedmedicinedevel

oprationaleandtheoryfordrugdesignandtherapeuticintervention•DeveloppersonalmedicineandpreventivemedicineTransla

tionalMedicine•TranslationalResearch-hotspot–Genomicandgenediagnosisandtreatment基因组研究及基因诊断治疗–PhaseItrialfordrugs药物一期临床试验–Genom

icPharmocologyandpersonalizedmedicine基因组药理学与个体化医学–Biomarks生物标记物–Signaltransductingpathwayandclinicalapp

lications信号传导通路的研究及其临床应用–Stemcell干细胞TranslationalMedicine•TheheartoftranslationalresearchresidesinPhaseItrialswherenoveltreatmentsare：–t

estedforfeasibilityandtoxicity–preparationforaPhaseIItrialinwhichtherapeuticeffectivenessistested»Marincola,FM»TranslationalMed

icine:Atwo-wayroad,JTM,2006ClinicalResearchTrainingProgram•ComputerSkills•ClinicalResearchMethods•Biostatistics

:StatisticalApproachin•ClinicalResearch•MeasurementsinClinicalResearch•EthicsandRegulationsofClinical•Research•ResearchDes

ignandDevelopment•Cost-effectivenessAnalysis•RegressionandANOVA•LogisticRegression•ClinicalTrialsEarlystudyonnitric

oxideSynthaseUsesforaclonedgene•Homologycomparison•Quantitategeneexpression•Chromosomalmapping•Determinetranscriptionalregulation•P

reparerecombinantprotein•Antibodydevelopment•Tissuelocalization•Developtransgenic/knockoutanimals•Genetra

nsfer/genetherapystudies•Intellectualproperty/technologytransferExploreGeneandDiseasesPhysiopathologicalStudy•Bench:Vaso

protectivePropertiesofNitricOxide–Inhibitsplateletaggregation–Inhibitsleukocytechemotaxis–InhibitsVSMCproliferation–InhibitsVSMCmigration–Promo

tesECgrowth–InhibitsECapoptosis–PotentvasodilatorCellandAnimal•AdenoviralVector(type5,E1-,E3-)腺病毒载体SmallAnimalsBiggerAnimalsAnimalExpe

riment•2005年PhaseⅠClinicalTrial•ClinicalTrial:AdiNOSgenetherapytoblockAVfistulaneointimalhyperplasiainhemodialysispat

ients–2006CurrentStateofTranslationalMedicine•17yearinnovationadoptioncurvefromdiscoveryintoacceptedstandardsofpractice•Eve

nifastandardisaccepted,patientshavea50:50chanceofreceivingappropriatecare,a5-10%probabilityofincurringapreventable,anti

cipatableadverseevent•Themarketisbalkingathealthcareinflation,newdiagnosticsandtherapeuticswillfindincreasingresistanceforreimbursementP

recisionmedicine2015-1-20PrecisionMedicine⚫PrecisionMedicine(personalizedmedicine):aformofmedicinethatusesinformationaboutaper

son’sgenes,proteins,andenvironmenttopreventdiagnose,andtreatdisease.(NCI)⚫Specificmarkers⚫diagnose&treatmentdecisions⚫Pre

cisionCancerMedicine(PCM)RightDrugRightPatientRightTimeRightDoseMoleculareventKnowledgedecisionClinicalTrialImatinibforGIST•GISTgenesis–K

eyprocess：c-kitmutation---KITTKactivation–PDGFRmutation–86%GISTkitmutation，prognosisfactor•Imatinib–OralsmallmoleculeTKI–InhibitTKactivation抑制酪氨

酸激酶活化–Designforchronicmyeloidleukemia(CML)ImatinibforGISTImatinibforGIST•JoensuuH，etal.2001PretreatmentOnem

onthoftherapyH&E(atdiagnosis)H&EKi67CD117JoensuuHetal.NEnglJMed.2001;344:1052-1056.TheFirstGISTPatient:Histo

logyImatinibforGISTImatinibforGIST•JoensuuH，etal.2001–Theory：ImatinibcouldtargetGIST–EasyDetectedtumormarker：CD117

–Tissuefromthepatient•Responseconfirmedbypathology•Dynamicmonitoredbytumormarker–Ethics：•IRBImatinib治疗GIST

•2000.3：JoensuuH.firstcase•2000.7：phaseIIstudy(B2222)•2001autumn：phaseIIstudy(S0033,EORTC)•2002.2：FDAImatinibforGIST•5-yea

rsurvival–KitmutationpredictImatinibresponseImatinibforGISTImatinibforGIST•Imatinibresistanceclinic→lab•OvercomeImat

inibresistancelab→clinic•MechanismofImatinibresistanceclinic→labImatinibforGIST•SurgeryinadvanceGIST•Whentos

top?Choi’sImatinibforGISTChoietal,JClinOncology,2007;25:1753-1759ImatinibforGIST•C-kitactivationnormallyassociatedwithKITmutations•C-kitactivati

onsometimeswithoutKITmutations•Somec-kitnegativetumorshaveKITmutations•Somec-kitnegativeGISTshaveactivatingmutationsi

nadifferentTK(tyrosinekinase),PDGFRa•……BasketTrial2014AACRprogressionreportBaskettrialsaimtotestonedrugoronepartic

ulargeneticmutationacrossmultipleorgansUmbrellaTrial2014AACRprogressionreportUmbrellatrials:seektotestadru

gordrugsacrossmultiplegeneticmutationswithinaparticulartypeofcancer.Summary•Clinicalexpertiseisimportant

•EBM:improveclinicalpracticeandresearch•TranslationalMedicine&PersonalizedMedicine:newtrend•IntegrationofEB

MandTranslationalMedicine