简介：Activationofthephosphoinositide3kinase(PI3K)/Akt/mammaliantargetofrapamycin(mTOR)pathwayiscommoninbreastcancer.Thereispreclinicaldatatosupportinhibitionofthepathway,andphaseⅠtoⅢtrialsinvolvinginhibitorsofthepathwayhavebeenorarebeingconductedinsolidtumorsandbreastcancer.Everolimus,anmTORinhibitor,iscurrentlyapprovedforthetreatmentofhormonereceptor(HR)-positive,humanepidermalgrowthfactorreceptor2(HER2)-negativebreastcancer.Inthisreview,wesummarisetheefficacyandtoxicityfindingsfromtherandomisedclinicaltrials,withsimplifiedguidelinesonthemanagementofpotentialadverseeffects.Educationofhealthcareprofessionalsandpatientsiscriticalforsafetyandcompliance.WhilethereissomeclinicalevidenceofactivityofmTORinhibitioninHR-positiveandHER2-positivebreastcancers,thebenefitsmaybemorepronouncedinselectedsubsetsratherthanintheoverallpopulation.FurtherdevelopmentofpredictivebiomarkerswillbeusefulintheselectionofpatientswhowillbenefitfrominhibitionofthePI3K/Akt/mTOR(PAM)pathway.

简介：Objective:ToinvestigatetheeffectsofCAL-101,particularlywhencombinedwithbortezomib(BTZ)onmantlecelllymphoma(MCL)cells,andtoexploreitsrelativemechanisms.Methods:MTTassaywasappliedtodetecttheinhibitoryeffectsofdifferentconcentrationsofCAL-101.MCLcellsweredividedintofourgroups:controlgroup,CAL-101group,BTZgroup,andCAL-101/BTZgroup.TheexpressionofPI3K-p110σ,AKT,ERK,p-AKTandp-ERKweredetectedbyWesternblot.TheapoptosisratesofCAL-101group,BTZgroup,andcombinationgroupweredetectedbyflowcytometry.Thelocationchangesofnuclearfactorkappa-B(NF-κB)of4groupswasinvestigatedbyNF-κBKitexploring.Westernblotwasappliedtodetectthelevelsofcaspase-3andthephosphorylationofAKTindifferentgroups.Results:CAL-101dose-andtime-dependentlyinducedreductioninMCLcellviability.CAL-101combinedwithBTZenhancedthereductionincellviabilityandapoptosis.WesternblotanalysisshowedthatCAL-101significantlyblockedthePI3K/AKTandERKsignalingpathwayinMCLcells.ThecombinationtherapycontributedtotheinactivationofNF-κBandAKTinMCLcelllines.However,cleavedcaspase-3wasup-regulatedaftercombinedtreatment.Conclusion:OurstudyshowedthatPI3K/p110σisanoveltherapeutictargetinMCL,andtheunderlyingmechanismcouldbetheblockingofthePI3K/AKTandERKsignalingpathways.ThesefindingsprovidedabasisforclinicalevaluationofCAL-101andarationaleforitsapplicationincombinationtherapy,particularlywithBTZ.

简介：目的探讨苦参碱（Mat）对视网膜母细胞瘤细胞Y79细胞增殖、凋亡及PI3K/Akt信号通路的影响。方法Y79细胞经0.5、1.0、1.5g/LMat处理24h后,采用CCK-8试剂盒检测细胞增殖情况,磷酯酰丝氨酸结合蛋白-异硫氢酸荧光素/碘化丙啶（AnnexinV-FITC/PI）双标记流式细胞术检测细胞凋亡情况,Westernblotting免疫印迹检测各浓度Mat处理后凋亡相关蛋白Bcl-2及Bax、PI3K/Akt信号通路重要蛋白PI3Kp85亚基、Akt及其磷酸化形式p-Akt的蛋白水平。结果不同浓度Mat作用Y79细胞24h后,可呈浓度依赖性方式抑制细胞增殖,增加细胞凋亡率（P〈0.05）。Westernblotting检测发现,Mat可明显增加促凋亡蛋白Bax表达,降低抗凋亡蛋白Bcl-2水平并可降低PI3Kp85α亚基及磷酸化Akt的蛋白水平（P〈0.05）,对总Akt水平无明显影响。结论Mat可抑制人视网膜母细胞瘤增殖并诱导其凋亡,可能与抑制PI3K/Akt信号通路有关。

简介：Objective:Ameta-analysiswasperformedtoaugmenttheinsufficientdataontheimpactofmutativeEGFRdownstreamphosphatidylinositol-3-kinase(PI3K)andmitogen-activatedproteinkinase(MAPK)pathwaysontheclinicalefficiencyofepidermalgrowthfactorreceptortyrosinekinaseinhibitor(EGFR-TKI)treatmentofnon-smallcelllungcancer(NSCLC)patients.Methods:NetworkdatabaseswereexploredinApril,2015.PapersthatinvestigatedtheclinicaloutcomesofNSCLCpatientstreatedwithEGFR-TKIsaccordingtothestatusofK-rasand/orPIK3CAgenemutationwereincluded.Aquantitativemeta-analysiswasconductedusingstandardstatisticalmethods.Oddsratios(ORs)forobjectiveresponserate(ORR)andhazardratios(HRs)forprogression-freesurvival(PFS)andoverallsurvival(OS)werecalculated.Results:MutationinK-rassignificantlypredictedpoorORR[OR=0.22;95%confidenceinterval(CI),0.13-0.35],shorterPFS(HR=1.56;95%CI,1.27-1.92),andshorterOS(HR=1.59;95%CI,1.33-1.91)inNSCLCpatientstreatedwithEGFR-TKIs.MutantPIK3CAsignificantlypredictedshorterOS(HR=1.83;95%CI,1.05-3.20),showedpoorORR(OR=0.70;95%CI,0.22-2.18),andshorterPFS(HR=1.79;95%CI,0.91-3.53)inNSCLCpatientstreatedwithEGFR-TKIs.Conclusion:K-rasmutationadverselyaffectedtheclinicalresponseandsurvivalofNSCLCpatientstreatedwithEGFRTKIs.PIK3CAmutationshowedsimilartrends.InadditiontoEGFR,addingK-rasandPIK3CAasroutinegenebiomarkersinclinicalgeneticanalysisisvaluabletooptimizetheeffectivenessofEGFR-TKIregimensandidentifyoptimalpatientswhowillbenefitfromEGFR-TKItreatment.