A Computer Simulation of Progesterone and Cox2 Inhibitor Treatment for Preterm Labor 英文参考文献.docVIP

A Computer Simulation of Progesterone and Cox2 Inhibitor Treatment for Preterm Labor 英文参考文献.doc

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A Computer Simulation of Progesterone and Cox2 Inhibitor Treatment for Preterm Labor 英文参考文献

AComputerSimulationofProgesteroneandCox2 InhibitorTreatmentforPretermLabor OzlemEquils1,2*,PriyaNambiar3,CalvinJ.Hobel4,RogerSmith5,CharlesF.Simmons1,2,ShireenVali3 1DepartmentofPediatrics,StevenSpielbergPediatricResearchCenter,BurnsandAllenResearchInstitute,Cedars-SinaiMedicalCenter,DavidGeffenSchoolofMedicine atUniversityofCaliforniaLosAngeles,LosAngeles,California,UnitedStatesofAmerica,2MedicalDivision,PfizerInc.,NewYork,NewYork,UnitedStatesofAmerica, 3Cellworks Group Inc., Saratoga, California, United States of America, 4Obstetrics and Gynecology, Cedars-Sinai Medical Center, David Geffen School of Medicine at UniversityofCaliforniaLosAngeles,LosAngeles,California,UnitedStatesofAmerica,5EndocrineUnit,MothersandBabiesResearchCentre,JohnHunterHospital,Hunter MedicalResearchInstitute,Newcastle,NewSouthWales,Australia Abstract Background:Sufficientinformationfrominvitroandinvivostudieshasbecomeavailabletopermitcomputermodelingof theprocessesthatoccurinthemyometriumduringlabor.Thisdevelopmentallowstheinsilicoinvestigationofpathological mechanismsandthetrialingofpotentialtreatments. Methods/Results:Basedonthehumanliterature,wedevelopedacomputermodeloftheimmune-endocrineenvironment ofthemyometrialcell.Theinteractionsbetweenmoleculesarerepresentedbydifferentialequations.Themodelisdesigned to simulate the estrogen and progesterone receptor changes during pregnancy and particularly the changes in the progesteronereceptor(PR)isoformsAandBthatarethoughttomediatefunctionalprogesteronewithdrawalinthehuman atlabor.ParturitionisrepresentedbyanincreaseinthePRAtoPRBratiotolevelsseeninwomeninlabor.Infectionisshown by inducing inflammation in the system by increasing phospho-IkB kinase concentration (IKK) levels; which lead to increasedNF-kBactivation,causinganincreaseinthePRA/PRBratio.Weexaminedtheeffectsofprogesteroneorcyclo- oxygenase2(Cox2)inhibitortreatmentsonthePRA/PRBratioinsilico.Themodelpredictedthathighdosesofprogesterone andCox2inhibitionwouldbeeffectiveinpreventinganNF-

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