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简介：Objective:ToexaminetheeffectofpSer9-GSK-3βonbreastcancerandtodeterminewhethertheunderlyingmetabolicandimmunologicalmechanismisassociatedwithROS/eIF2Bandnaturalkiller(NK)cells.Methods:WeemployedTWS119toinactivateGSK-3βbyphosphorylatingSer9andexploreditseffectonbreastcancerandNKcells.TheexpressionofGSK-3β,naturalkillergroup2memberD(NKG2D)ligands,eIF2BwasquantifiedbyPCRandWesternblot.Wemeasuredintracellularreactiveoxygenspecies(ROS)andmitochondrialROSusingDCFH-DAandMitoSOXTMprobe,respectively,andconductedquantitativeanalysisofcellularrespirationon4T1cellswithmitochondrialrespiratorychaincomplexⅠ/Ⅲkits.Results:OurinvestigationrevealedthatTWS119downregulatedNKG2Dligands(H60aandRae1),suppressedthecytotoxicityofNKcells,andpromotedthemigrationof4T1murinebreastcancercells.Nevertheless,LY290042,whichattenuatesp-GSK-3βformationbyinhibitingthePI3K/Aktpathway,reversedtheseeffects.WealsofoundthathigherexpressionofpSer9-GSK-3βinducedhigherlevelsofROS,andobservedthatabnormalityofmitochondrialrespiratorychaincomplexⅠ/ⅢfunctioninducedthedysfunctionofGSK-3β-inducedelectrontransportchain,naturallydisturbingtheROSlevel.Inaddition,theexpressionofNOX3andNOX4wassignificantlyup-regulated,whichaffectedthegenerationofROSandassociatedwiththemetastasisofbreastcancer.Furthermore,wefoundthattheexpressionofpSer535-eIF2BpromotedtheexpressionofNKG2Dligands(Mult-1andRae1)followingbyexpressionofpSer9-GSK-3βandgenerationofROS.Conclusions:ThePI3K/Akt/GSK-3β/ROS/eIF2BpathwaycouldregulateNKcellactivityandsensitivityoftumorcellstoNKcells,whichresultedinbreastcancergrowthandlungmetastasis.Thus,GSK-3βisapromisingtargetofanti-tumortherapy.

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简介：Non-small-celllungcancer(NSCLC)accountforapproximately80%ofalllungcancer.Onlyalowpercentageofpatientspresentdiseasesusceptibletosurgicalresection.30%to40%ofpatientswithNSCLCpresentwithlocallyorregionallyadvancedunresectabletumors.lllChestirradiationp...

简介：Objective:Toevaluatetherelationbetweenargyrophilicnucleolarorganizerregion(AgNOR)-associatedproteinsandclinicopathologicalparametersandsurvivalinnon-small-celllungcancer(NSCLC).Methods:Atotalof207surgicalspecimensdiagnosedasNSCLCwereincludedinthisstudy.Double-stainingprocedureswereperformedusingantigenKi-67(cloneMIB-1)andsilvernitratebyimmunohistochemicalandAgNOR-stainingmethods.Results:TheAgNORareainMIB-1-positivecellsofNSCLCisrelatedtoclinicopathologicalparametersundertheTNM(tumor,node,andmetastasis)system.ThesurvivalofpatientswithsmallAgNORareainMIB-1-positivecellsisbetterthanthatofpatientswithlargeAgNORarea.Molecular,biological(AgNORareainMIB-1-positivecells),andclinicopathological(greatesttumordimension,metastasestoregionallymphnodes,histology,anddifferentiation)parametersareindependentprognosticfactorsofNSCLC.Conclusion:TheAgNORareainMIB-1-positivecellsisrelatedtoclinicopathologicalparametersandsurvivalinNSCLC.

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简介：Duringthelastdecade,wehaveseentremendousprogressinthetherapyoflungcancer.DiscoveryofactionablemutationsinEGFRandtranslocationsinALKandROS1haveidentifiedsubsetsofpatientswithexcellenttumorresponsetooraltargetedagentswithmanageablesideeffects.Inthisreview,wehighlighttreatmentoptionsincludingcorrespondingclinicaltrialsforoncogenicalterationsaffectingthereceptortyrosinekinasesMET,FGFR,NTRK,RET,HER2,HER3,andHER4aswellascomponentsoftheRAS-RAF-MEKsignalingpathway.

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简介：Objective:Toexplorethereversaleffectofmifepristoneonmultidrugresistance(MDR)indrug-resistanthumanbreastcancercelllineMCF7/ADRanditsmechanisms.Methods:ExpressionofMDR1andMDR-associatedprotein(MRP)mRNAinMCF7/ADRcellswasdetectedusingreversetranscription-polymerasechainreaction(RT-PCR).WesternblottingwasusedtoassaytheproteinlevelsofP-glycoprotein(P-gp)andMRP.Intracellularrhodamine123retentionand[3H]vincristine(VCR)accumulationweremeasuredbyflowcytometryandliquidscintillationcounter,respectively.MTTreductionassaywasusedtodeterminethesensitivityofcellstotheanticanceragent,adriamycin(ADR).Additionally,aMCF7/ADRcellxenograftmodelwasestablishedtoassessthereversaleffectofmifeprisoneonMDRinMCF7/ADRcellsinvivo.Results:Miferpristonedose-dependentlydown-regulatedtheexpressionofMDR1andMRPmRNAinMCF7/ADRcells,accompaniedbyasignificantdecreaseintheproteinlevelsofP-gpandMRP.Afterexposureto5,10,and20μmol/Lmifepristone,MCF7/ADRcellsshoweda3.87-,5.81-,and7.40-foldincreaseintheaccumulationofintracellularVCR(aknownsubstrateofMRP),anda2.14-,4.39-,and5.53-foldincreaseintheretentionofintracellularrhodamine123(anindicatorofP-gpfunction),respectively.MTTanalysisshowedthatthesensitivityofMCF7/ADRcellstoADRwasenhancedby7.23-,13.62-,and20.96-foldafterincubationwithmifepristoneasabove-mentioneddosesfor96h.Invivo,mifepristoneeffectivelyrestoredthechemosensitivityofMCF7/ADRcellstoADR.After8weeksofadministrationwithADR(2mg·kg-1·d-1)aloneorincombinationwithmifepristone(50mg·kg-1·d-1),thegrowthinhibitoryrateofxenograftedtumorsinnudemicewas8.08%and37.25%,respectively.Conclusion:MifepristoneexertspotentreversaleffectsonMDRinMCF7/ADRcellsinvitroandinvivothroughdown-regulationofMDR1/P-gpandMRPexpressionandinhibitionofP-gp-andMRP-dependentdrugefflux,thusincreasing

简介：Objective:Non-smallcelllungcancer(NSCLC)patientswithepidermalgrowthfactorreceptor(EGFR)-activatingmutationshavehigherresponserateandmoreprolongedsurvivalfollowingtreatmentwithsingle-agentEGFRtyrosinekinaseinhibitor(EGFR-TKI)comparedwithpatientswithwild-typeEGFR.However,allpatientstreatedwithreversibleinhibitorsdevelopacquiredresistanceovertime.Themechanismsofresistancearecomplicated.ThelackofestablishedtherapeuticoptionsforpatientsafterafailedEGFR-TKItreatmentposesagreatchallengetophysiciansinmanagingthisgroupoflungcancerpatients.ThisstudyevaluatestheinfluenceofEGFR-TKIretreatmentfollowingchemotherapyafterfailureofinitialEGFR-TKIwithinatleast6monthsonNSCLCpatients.Methods:Thedataof27patientswhoexperiencedtreatmentfailurefromtheirinitialuseofEGFR-TKIwithinatleast6monthswereanalyzed.Afterchemotherapy,thepatientswereretreatedwithEGFR-TKI(gefitinib250mgqdorerlotinib150mgqd),andthetumorprogressionwasobserved.Thepatientswereassessedforadverseeventsandresponsetotherapy.TargetedtumorlesionswereassessedwithCTscan.Results:Ofthe27patientswhoreceivedEGFR-TKIretreatment,1(3.7%)patientwasobservedincompleteresponse(CR),8(29.6%)patientsinpartialresponse(PR),14(51.9%)patientsinstabledisease(SD),and4(14.8%)patientsinprogressivedisease(PD).Thediseasecontrolrate(DCR)was85.2%(95%CI:62%-94%).Themedianprogression-freesurvival(mPFS)was6months(95%CI:1-29).Ofthe13patientswhoreceivedthesameEGFR-TKI,1patientinCR,3patientsinPR,8patientsinSD,and2patientsinPDwereobserved.TheDCRwas84.6%,andthemPFSwas5months.Ofthe14patientswhoreceivedanotherEGFR-TKI,nopatientinCR,6patientsinPR,6patientsinSD,and2patientsinPDwereobserved.TheDCRwas85.7%,andthemPFSwas9.5months.SignificantdifferencewasfoundbetweenthetwogroupsinPFSbutnotinresponserateorDCR.Conclusion:RetreatmentofEGFR-TKIscanbeconsideredano

简介：Objective:ActivatingKRASmutationsarethemostcommondriversinthedevelopmentofnon-smallcelllungcancer(NSCLC).However,unsuccessoftreatmentbydirectinhibitionofKRAShasbeenproven.DeregulationofPI3KsignalingplaysanimportantroleintumorigenesisanddrugresistanceinNSCLC.TheactivityofPI3Kα-selectiveinhibitionagainstKRAS-mutatedNSCLCremainslargelyunknown.Methods:CellproliferationwasdetectedbysulforhodamineBassay.Cellcycledistributionandapoptosisweremeasuredbyflowcytometry.CellsignalingwasassessedbyWesternblotandimmunohistochemistry.RNAinterferencewasusedtodown-regulatetheexpressionofcyclinD1.HumanNSCLCxenograftswereemployedtodetecttherapeuticefficacyinvivo.Results:CYH33possessedvariableactivityagainstapanelofKRAS-mutatedNSCLCcelllines.AlthoughCYH33blockedAKTphosphorylationinalltestedcells,RbphosphorylationdecreasedinCYH33-sensitive,butnotinCYH33-resistantcells,whichwasconsistentwithG1phasearrestinsensitivecells.CombinedtreatmentwiththeCDK4/6inhibitor,PD0332991,andCYH33displayedsynergisticactivityagainsttheproliferationofbothCYH33-sensitiveandCYH33-resistantcells,whichwasaccompaniedbyenhancedG1-phasearrest.Moreover,down-regulationofcyclinD1sensitizedNSCLCcellstoCYH33.Reciprocally,CYH33abrogatedthePD0332991-inducedup-regulationofcyclinD1andphosphorylationofAKTinA549cells.Co-treatmentwiththesetwodrugsdemonstratedsynergisticactivityagainstA549andH23xenografts,withenhancedinhibitionofRbphosphorylation.Conclusions:SimultaneousinhibitionofPI3KαandCDK4/6displayedsynergisticactivityagainstKRAS-mutatedNSCLC.ThesedataprovideamechanisticrationaleforthecombinationofaPI3KαinhibitorandaCDK4/6inhibitorforthetreatmentofKRASmutatedNSCLC.

简介：Somaticstemcells(SSCs),beingessentialinmaintaininghomeostasisofnormaltissue,replenishdyingcellsandregeneratedamagedtissuesfororganism.Ontheotherhand,withtheself-renewedability,SSCsareidealcellulartargetstobeacquiredinmultiplemutationstransformingSSCstocancerstemcells(CSCs)whichcausemalignanciesandevenrecurrenceaftercancertreatmentifCSCsfailtobeeradicated(1).OneyearafterDrs.JohnB.GurdonandShinyaYamanakasharedthe2012NobelPrizeinPhysiologyorMedicinefortheirdiscoverythatmaturecellscanbereprogrammedtobecome

简介：客观：为了调查抵抗和颠倒的机制，在导致cisplatin的multidrug抵抗ligustrazine和cyclosporinA完成卵巢的癌症房间线3Ao/cDDP。方法：用每周期在30mgcisplatin从临床的化疗计算的相应剂量，我们建立了3Ao/cDDP，3Ao每次在10渭g/ml在常规间隔并且反复暴露了到cisplatin的高级集中24个小时。LRP，MRP，P-gp，GST蟺和TopoII的表情是与FCM检测的份量上。为药抵抗颠倒，没有cytotoxicity，cyclosporinA和ligustrazine在最大的剂量单身地或在联合被管理。抑制率被MTT试金决定。结果：3Ao/cDDP在4.5个月以后被建立，与抵抗因素1.6它类似于临床的抵抗度。MRP和P-gp的低表示层次在3Ao和3Ao/cDDP被发现(P>0.05)，并且在3Ao/cDDP的LRP和GST蟺表示层次比在3Ao的那些显著地高(P<0.005andP<0.05，分别地)，并且在3Ao/cDDP的TopoII显著地更低对3Ao(P<0.05)。cDDP的抑制率是20.807卤0.015%，加ligustrazine的cDDP27.421卤0.07%(P>0.05对cDDP)，加cyclosporinA的cDDP49.635卤0.021%(P<0.01对cDDP)，并且加ligustrazine和cyclosporinA的cDDP58.861卤0.014%(P<0.01对cDDP)。结论：3Ao/cDDP，由cisplatin导致了并且由为上皮的卵巢的癌症模仿临床的化疗的特征建立了，是为cisplatinresistanceinvitro的调查的一个理想的模型。在3Ao/cDDP的Cisplatin抵抗能被说明为由更高的LRP，GST蟺和更低的TopoII表示并且没与MRP或P-gp被联系。Ligustrazine没在A能颠倒的cisplatin抵抗，而是cyclosporin上有重要颠倒效果抵抗有效地。

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简介：Cancertreatmentfailure,drugresistance,ormetastaticrecurrencearethoughttobecausedmainlybytheexistenceofaverysmallnumberofcancerstemcells(CSCs).Thecharacteristicsofthissubgroupofcellsincludeself-renewal,tumorigenesis,multipledifferentiationandhighinvasiveness,metastasis,anddrugresistancepotential.ManystudieshavedemonstratedthatCSCsplayimportantrolesintumorgrowth,spreadandmetastaticrelapseaftertreatment,andarecloselyrelatedtotheprognosisofpatients.Fromatherapeuticviewpoint,deepinsightsintotheCSCsbiology,developmentofspecifictherapeuticstrategiesfortargetingCSCs,andcharacterizationoftheirmicroenvironmentcouldbeanidealwaytocombatcancer.

简介：Cancergenomicsisarapidlygrowingdisciplineinwhichthegeneticmolecularbasisofmalignancyisstudiedatthescaleofwholegenomes.Whilethedisciplinehasbeensuccessfulwithrespecttoidentifyingspecificoncogenesandtumorsuppressorsinvolvedinoncogenesis,itisalsochallengingourapproachtomanagingpatientssufferingfromthisdeadlydisease.Specificallycancergenomicsisdrivingclinicaloncologytotakeamoremolecularapproachtodiagnosis,prognostication,andtreatmentselection.Wereviewhererecentworkundertakenincancergenomicswithanemphasisontranslationofgenomicfindings.Finally,wediscussscientificchallengesandresearchopportunitiesemergingfromfindingsderivedthroughanalysisoftumorswithhigh-depthsequencing.

简介：Non-smallcelllungcancer(NSCLC)ranksastheleadingcauseofcancer-relateddeathintheworld.Brainmetastasis(BM)isacommoncomplicationofNSCLC,with25%–40%ofpatientsdevelopingBMduringthecourseofthedisease.Asignificantstrategyoflocaldiseasecontrolinthecentralnervoussystemisradiationtherapy.Withthedevelopmentofprecisionmedicine,theconceptoftreatinglungcancerBMhasgraduallychanged.Inthiscase,weperformedasurgicalproceduretoobtainenoughtumortissueforthedetectionofthetargetgeneandotherrelatedexperimentsafterthepatientwasinformed.Finally,wefoundthatthepatienthadbothhepatocytegrowthfactorreceptor(MET)geneamplificationandkinesinlightchain1-anaplasticlymphomakinasefusion(KLC1-ALK)throughnext-generationsequencingandshowedsensitivitytothetargetedtherapyofcrizotinib.Thepatientexhibitedgoodresponse.Ourcasewassuccessfulandunderwenttargetedtherapywiththeguidanceofprecisediagnosis.