简介：Qidong(Jiangsu,China)hasbeenofinteresttocancerepidemiologistsandbiologistsbecause,untilrecently,itwasanendemicareaforlivercancer,havingamongstthehighestincidenceratesintheworld.TheestablishmentoftheQidongCancerRegistrytogetherwiththeQidongLiverCancerInstitutein1972haschartedthepatternsoflivercancerincidenceandmortalityinastablepopulationthroughoutaperiodofenormouseconomic,social,andenvironmentalchangesaswellasofimprovementsinhealthcaredelivery.UpdatedincidencetrendsinQidongaredescribed.Notably,theChinaage-standardizedincidencerateforlivercancerhasdroppedbyover50%inthepastseveraldecades.MolecularepidemiologicandgenomicdeepsequencingstudieshaveaffirmedthatinfectionwithhepatitisBvirusaswellasdietaryexposuretoaflatoxinsthroughcontaminationofdietarystaplessuchascorn,andtomicrocystins–blue-greenalgaltoxinsfoundinditchandpondwater–werelikelyimportantetiologicfactorsthataccountforthehighincidenceoflivercancerinthisregion.PublichealthinitiativestofacilitateuniversalvaccinationofnewbornsagainstHBVandtoimprovedrinkingwatersourcesinthisruralarea,aswellaseconomicandsocialmandatesserendipitouslyfacilitatingdietarydiversity,haveledtoprecipitousdeclinesinexposurestotheseetiologicfactors,concomitantlydrivingsubstantivedeclinesinthelivercancerincidenceseennowinQidong.Inthisregard,Qidongservesasatemplatefortheglobalimpactthatapackageofinterventionstrategiesmayexertoncancerburden.

简介：Overthepastdecades,cellsurfacecharge,althoughexperimentallyobserved,hasnotbeenwellunderstoodparticularlyfromtheviewpointofbiophysics.Ourrecentstudieshaveshownthatallcancercellsexhib让negativesurfacechargesthataredirectlyproportionaltothesecretedlacticacid,auniquecancermetaboliccharacteristic:highrateofglycolysis.Wehavethereforedesignedanddevelopedasetofelectrically-charged,fluorescent,andsuper-paramagneticnanoprobes,capableofsensitivedetectionofcancercellsbasedonthesurfacecharges.Theseprobesareutilizedtobindontocellsviaelectrostaticreactionforcaptureandmagneticseparation.Inthisfashion,weareabletocharacterizecellsurfacechargesthatareregulatedbydifferentmetabolicpatterns,thereforeeffectivelydistinguishingthecancercellsfromthenormalcells.All22cancercellsofdifferentorgansarefoundtobenegativelychargedthereforeboundstronglybythepositively-chargednanoprobes,whereasthenormalcellsshowinsignificantbindingtothenanoprobesofeitherchargesigns(positiveornegative).Thisfindingsuggeststhatalltestedcancercellsarenegatively-chargedandnormalcellsareeithercharge-neutralorslightlypositive.Fordiagnosis,cancercellscanbedetected,electrostaticallybound,andmagneticallyseparatedinbloodbychargedandsuper-paramagneticnanoprobes.Intherapeutics,circulatingcancercells(CTCs)canbefilteredandremovedinacontinuousfashiontoreducetheriskofcancermetastasis.Ifsuccessful,thisnewnanotechnologywillrevolutionizeearlycancerdiagnosisandpotentiallyenablenewtherapeuticsinclinicalsettings.

简介：Objective:Despiteevidencethatestrogensandinsulinareinvolvedinthedevelopmentandprogressionofmanycancers,theirsynergisticroleinendometrialcarcinoma(EC)hasnotbeenanalyzedyet.Methods:Here,weinvestigatedhowestrogensactsynergisticallywithinsulintopromoteECprogression.Cellgrowthinvitroandinvivo,effectsofestradiolandinsulinonapoptosisandcellcycledistribution,andexpressionandactivationofestrogenreceptor(ER),insulinreceptor(InsR),andkeyproteinsinthePI3KandMAPKpathwayswereexaminedaftercombinedstimulationwithestradiolandinsulin.Results:ComparedtoECcellstreatedwithestradiolorinsulinalone,thosetreatedwithbothestradiolandinsulinexhibitedstrongerstimulation.EstradiolsignificantlyinducedphosphorylationofInsR-βandIRS-1,whereasinsulinsignificantlyinducedphosphorylationofER-α.Inaddition,treatmentwithbothinsulinandestradioltogethersignificantlyincreasedtheexpressionandphosphorylationofAkt,MAPK,andERK.Notably,InsR-βinhibitionhadalimitedeffectonestradiol-dependentproliferation,cellcycle,andapoptosis,whereasER-αinhibitionhadalimitedinsulin-dependenteffect,inECcelllines.InsulinandestradiolindividuallyandsynergisticallypromotedECxenograftgrowthinmice.Conclusions:EstrogenandinsulinplaysynergisticrolesinECcarcinogenesisandprogressionbyactivatingInsR-βandER-α,promotingacrosstalkbetweenthem,andtherebyresultingintheactivationofdownstreamPI3K/AktandMAPK/ERKsignalingpathways.

简介：Wepresentherethedevelopmentofcholesterol(Chol)-modifieddendrimersystemfortargetedchemotherapyoffolate(FA)receptor-expressingcancercells.Inourstudy,poly(amidoamine)(PAMAM)dendrimersofgeneration5(G5)werefunctionalizedstepby-stepwithChol,fluoresceinisothiocyanate(FI),andFAviaapoly(ethyleneglycol)(PEG)spacer(PEG-FA),andthenacetamidetoshieldtheirremainingsurfaceamines.ThesynthesizedG5.NHAc-Chol-FI-PEG-FA(forshort,G5-CFPF)dendrimerswereutilizedtoencapsulate10-hydroxycamptothecin(HCP),ahydrophobicanticancerdrug.WefindthateachG5-CFPFdendrimercanencapsulate13.8HCPmolecules.ThecomplexesshowaslowerreleaseprofilesofHCPinapH-dependentmannerthanthecontrolcomplexesformedusingthesamedendrimerswithoutCholunderthesameconditions.ThankstothetargetingroleplayedbyFA,thecomplexesdisplayaspecificinhibitionefficacytoFAreceptor-expressingcervicalcancercells.ThedesignedChol-modifieddendrimersmaybeadoptedasapromisingcarrierforapplicationintargetedcancertherapy.

简介：Theadaptivetreatmenttolerance(ATT)ofcancercellsisthemainencumbrancetocancerchemotherapy.Apotentialsolutiontothisproblemistotreatcancercellswithmultipledrugsusingnanoparticles(NPs).Inthisstudy,wetestedtheco-administrationofcurcumin(Cur)anddoxorubicin(Dox)toMCF-7resistantbreastcancercellstoblocktheATTandelicitefficientcellkilling.Drugswereco-administeredtocellsbothsequentiallyandsimultaneously.Sequentialdrugco-administrationwascarriedoutbypre-treatingthecellswithalbuminnanoparticles(ANPs)loadedw让hCur(Cur@ANPs)followedbytreatmentwithDox-loadedANPs(Dox@ANPs).Simultaneousdrugco-administrationwascarriedoutbytreatingthecellswithANPsloadedwithboththedrugs(Cur/Dox@ANPs).Wefoundthatthesimultaneousdrugco-administrationledtoagreaterintra-cellularaccumulationofDoxandcellkillingwithrespecttothesequentialdrugco-administration.However;thesimultaneousdrugco-administrationledtoalowerintracellularaccumulationofCurwithrespecttothesequentialdrugco-administration.WeshowedthatthisresultwasduetotheaggregationandentrapmentofCurinthelysosomesassoonasitwasreleasedfromCur@ANPs,aphenomenoncalledlysosomotropism.Incontrast,thesimultaneousreleaseofDoxandCurfromCur/Dox@ANPsintothelysosomesledtolysosomalpHelevation,which,inturn,avoidedCuraggregation,ledtolysosomeswellinganddrugreleaseinthecytosol,andfinallyprovokedefficientcellkilling.Ourstudyshedthelightonthemolecularprocessesdrivingthetherapeuticeffectsofanti-cancerdrugsco-administeredtocancercellsindifferentmanners.

简介：TherootbarkofMorusalbaL.orwhitemulberryiswidelyusedastraditionalmedicineinChina,JapanandKorea.Majorclassesandtypesofphenoliccompoundsisolatedfromtherootbarkareflavonoids(kuwanons,morusin,cyclomorusinandsanggenons),benzofurans(moracinsandmulberrofurans),andstilbenoids(mulberrosides).SomeoftheflavonoidsandbenzofuransareproductsofDiel-Aldertypeadducts.Otherclassesofcompoundsincludetriterpenes,phenolicacidsandcoumarins.Morusin,aprenylatedflavonoid,wasfirstisolatedfromtherootbarkofM.alba,andlaterfromtheleaf,stembarkandtwigoftheplant.Thepotentanti-cancerpropertiesofmorusinhaveattractedmuchattentionwithresearchon-goingandnewfindingsbeingpublished.Thecompoundinhibitsangiogenesis,tumourprogressionandtumourmigration,andtriggersapoptosis,cellcyclearrestandautophagyincolorectal,cervical,prostate,breast,hepatoma,pancreatic,glioblastoma,gastric,ovarianandlungcancercelllines.Theanti-canceractivitiesofmorusinareexecutedviavariousmoleculartargetsandsignallingpathways.Itisanticipatedthaton-goinginvitrostudieswillprogressgraduallytoinvivostudiesusinganimalmodelsbeforeeffortstowardsdrugdevelopmentcanbeinitiatedforclinicaltrials.

简介：Objective:Europeanlungcancerscreeningstudiesusingcomputedtomography(CT)haveshownthatamanagementprotocolbasedonmeasuringlungnodulevolumeandvolumedoublingtime(VDT)ismorespecificforearlylungcancerdetectionthanadiameter-basedprotocol.However,whetherthisalsoappliestoaChinesepopulationisunclear.Theaimofthisstudyistocomparethediagnosticperformanceofavolume-basedprotocolwithadiameter-basedprotocolforlungcancerdetectionandoptimizethenodulemanagementcriteriaforaChinesepopulation.Methods:Thisstudyhasapopulation-based,prospectivecohortdesignandincludes4000participantsfromtheHexidistrictofTianjin,China.Participantswillundergolow-dosechestCTatbaselineandafter1year.Initially,detectedlungnoduleswillbeevaluatedfordiameterandmanagedaccordingtoaroutinediameter-basedprotocol(ClinicalPracticeGuidelineinOncologyforLungCancerScreening,Version2.2018).Subsequently,lungnoduleswillbeevaluatedforvolumeandmanagementwillbesimulatedaccordingtoavolume-basedprotocolandVDT(aEuropeanlungnodulemanagementprotocol).Participantswillbefollowedupfor4yearstoevaluatelungcancerincidenceandmortality.TheprimaryoutcomeisthediagnosticperformanceoftheEuropeanvolume-basedprotocolcomparedtodiameter-basedmanagementregardinglungnodulesdetectedusinglow-doseCT.Results:Thediagnosticperformanceofvolume-anddiameter-basedmanagementforlungnodulesinaChinesepopulationwillbeestimatedandcompared.Conclusions:Throughthestudy,weexpecttoimprovethemanagementoflungnodulesandearlydetectionoflungcancerinChinesepopulations.

简介：Resistancetocisplatin(DDP)-basedchemotherapyisamajorcauseoftreatmentfailureinhumangastriccancer(GC).Itisnecessarytoidentifythedrugstore-sensitizeGCcellstoDDP.Inourpreviousresearch,ZuoJinWanFormula(ZJW)hasbeenprovedcouldincreasethemitochondrialapoptosisviacofilin-1inaimmortalizedcellline,SGC-7901/DDP.Duetotheimmortalizedcellsmaystilldifficulthighlyrecapitulatetheimportantmoleculareventsinvivo,primaryGCcellsmodelderivedfromclinicalpatientwasconstructedinthepresentstudytofurtherevaluatetheeffectofZJWandtheunderlyingmolecularmechanism.ImmunofluorescentstainingwasusedtoindentifyprimaryculturedhumanGCcells.Westernblottingwascarriedouttodetecttheproteinexpression.CellCountingKit-8(CCK-8)wasusedtoevaluatecellproliferation.Flowcytometryanalysiswasperformedtoassesscellapoptosis.ZJWinhibitedproliferationandinducedapoptosisinprimaryDDP-resistantGCcells.Notably,theapoptosisinGCcellswasmediatedbyinducingcofilin-1mitochondrialtranslocation,down-regulatingBcl-2andup-regulatingBaxexpression.Surprisingly,thelevelofp-AKTproteinwashigherinDDP-resistantGCcellsthanthatoftheDDP-sensitiveGCcells,andtheactivationofAKTcouldattenuateZJW-inducedsensitivitytoDDP.ThesedatarevealedthatZJWcanincreasethechemosensitivityinDDP-resistantprimaryGCcellsbyinducingmitochondrialapoptosisandAKTinactivation.ThecombiningchemotherapywithZJWmaybeaneffectivetherapeuticstrategyforGCchemoresistancepatients.

简介：Next-generationsequencing(NGS)technologyiscapableofsequencingmillionsorbillionsofDNAmoleculessimultaneously.Therefore,itrepresentsapromisingtoolfortheanalysisofmoleculartargetsfortheinitialdiagnosisofdisease,monitoringofdiseaseprogression,andidentifyingthemechanismofdrugresistance.OnbehalfoftheTumorBiomarkerCommitteeoftheChineseSocietyofClinicalOncology(CSCO)andtheChinaActionableGenomeConsortium(CAGC),thepresentexpertgroupherebyproposesadvisoryguidelinesonclinicalapplicationsofNGStechnologyfortheanalysisofcancerdrivergenesforprecisioncancertherapy.Thisgroupcomprisesanassemblyoflaboratorycancergeneticists,clinicaloncologists,bioinformaticians,pathologists,andotherprofessionals.Aftermultipleroundsofdiscussionsandrevisions,theexpertgrouphasreachedapreliminaryconsensusontheneedofNGSinclinicaldiagnosis,itsregulation,andcompliancestandardsinclinicalsamplecollection.Moreover,ithaspreparedNGScriteria,thesequencingstandardoperationprocedure(SOP),dataanalysis,report,andNGSplatformcertificationandvalidation.

简介：Objective:Prostatecancers(PCa)inAsianindividualsaremolecularlydistinctfromthosefoundintheirCaucasiancounterparts.ThereisnoriskstratificationtoolforAsianmenwithrapidbiochemicalrecurrence(BCR)followingradicalprostatectomy(RadP).Thisstudyaimstoassessthedetectionrateof^68Ga-prostate-specificmembraneantigen-positronemissiontomography/computedtomography(PSMA-PET/CT)fordiagnosisofclinicalrecurrenceandasatreatmentdecisionmakingtoolinAsianpatientswithBCRpost-RadP.Methods:^68GaPSMA-PETandCTbodywith/withoutbonescan[conventionalworkup(CWU)]wereperformedin55AsianpatientswithBCRwithin36monthspost-RadP.Twoblindedreviewersassessedtheimages.Detectionratesof^68GaPSMAPET/CTwereevaluated,andimpactonmanagementwasreviewedbycomparisonwithCWU.Results:MediantimetoBCRpost-RadPwas8.1months.Detectionratefor^68GaPSMA-PET/CTwas80%(44/55).Apositivescanwassignificantlyassociatedwithincreasingprostate-specificantigen(PSA)level[oddsratio(OR)=1.13(95%CI1.05–1.30),P=0.017],butnotwithhigherGleasongradeorshorterPSAdoublingtime.ComparedtoCWU,68GaPSMA-PET/CTdetectedanadditional106lesionsin33/44patientswithapositivescan,resultinginachangeinmanagementin25/44(56.8%)patients:10tohormonaltherapy(HT)andwholepelvisradiotherapy(RT)inadditiontobedRT,and15topalliativeHTalone.Conclusions:Inthepresentreport,wedemonstratedthediagnosticandtreatmentdecisionutilityof^68GaPSMA-PET/CTinAsianmenwithrapidBCR.DetectionofsmallvolumenodalandsystemicrecurrencesatlowPSAlevels(<1.0ng/mL)highlightstheroleofthetoolinassigningpatientstotreatmentintensificationwithHT-RTorpalliativeHTinpolymetastaticdisease.

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：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.