Predicting Outcomes of Prostate Cancer Immunotherapy by Personalized Mathematical Models 英文参考文献.docVIP

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Predicting Outcomes of Prostate Cancer Immunotherapy by Personalized Mathematical Models 英文参考文献.doc

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Predicting Outcomes of Prostate Cancer Immunotherapy by Personalized Mathematical Models 英文参考文献

PredictingOutcomesofProstateCancerImmunotherapy byPersonalizedMathematicalModels NatalieKronik1¤,YuriKogan1,MoranElishmereni1,KarinHalevi-Tobias1,StanimirVuk-Pavlovic′2., ZviaAgur1*. 1InstituteforMedicalBioMathematics,BeneAtaroth,Israel,2CollegeofMedicine,MayoClinic,Rochester,Minnesota,UnitedStatesofAmerica Abstract Background:Therapeuticvaccinationagainstdisseminatedprostatecancer(PCa)ispartiallyeffectiveinsomePCapatients. Wehypothesizedthattheefficacyoftreatmentwillbeenhancedbyindividualizedvaccinationregimenstailoredbysimple mathematicalmodels. Methodology/PrincipalFindings:Wedevelopedageneralmathematicalmodelencompassingthebasicinteractionsofa vaccine,immunesystemandPCacells,andvalidateditbytheresultsofaclinicaltrialtestinganallogeneicPCawhole-cell vaccine. Formodel validationintheabsenceof anyotherpertinent marker, weusedtheclinically measured changesin prostate-specificantigen(PSA)levelsasacorrelateoftumorburden.Upto26PSAlevelsmeasuredperpatientweredivided into each patient’s training set and his validation set. The training set, used for model personalization, contained the patient’sinitialsequenceofPSAlevels;thevalidationsetcontainedhissubsequentPSAdatapoints.Personalizedmodels weresimulatedtopredictchangesintumorburdenandPSAlevelsandpredictionswerecomparedtothevalidationset. ThemodelaccuratelypredictedPSAlevelsovertheentiremeasuredperiodin12ofthe15vaccination-responsivepatients (the coefficient of determination between the predicted and observed PSA values was R2=0.972). The model could not accountfortheinconsistentchangesinPSAlevelsin3ofthe15responsivepatientsattheendoftreatment.Eachvalidated personalizedmodelwassimulatedundermanyhypotheticalimmunotherapyprotocolstosuggestalternativevaccination regimens.Personalizedregimenspredictedtoenhancetheeffectsoftherapydifferedamongthepatients. Conclusions/Significance: Using a few initial measurements, we constructed robust patient-specific models of PCa immunotherapy,whichwereretrospectivelyvalidatedbyclinica