简介：AbstractHistorically, breast cancer has been regarded as an immunogenic "cold" tumor. However, the discovery of immune checkpoint inhibitors has made immunotherapy becoming an emerging new treatment modality for breast cancer. This review discusses the immune system, immune features of breast cancer, and the programmed cell death protein-1/programmed cell death protein ligand-1 (PD-1/PD-L1) inhibitors used in the treatment of breast cancer. High T lymphocyte infiltration and mutation burden were observed in triple-negative breast cancer and human epidermal growth factor receptor 2 positive breast cancer. Increasing breast cancer immunogenicity and modulating the tumor microenvironment has been reported to improve the therapeutic efficacy of immunotherapy. Recent clinical trials involving PD-1/PD-L1 inhibitors monotherapy in breast cancer has revealed little efficacy, which highlights the need to develop combinations of PD-1/PD-L1 inhibitors with chemotherapy, molecularly targeted therapies, and other immunotherapies to maximize the clinical efficacy. Collectively, the immunotherapy might be a promising therapeutic strategy for breast cancer and several clinical trials are still on-going.

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简介：AbstractIn recent years, immune checkpoint inhibitors (ICIs) have made breakthroughs in the field of lung cancer and have become a focal point for research. Programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor monotherapy was the first to break the treatment pattern for non-small cell lung cancer (NSCLC). However, owing to the limited benefit of ICI monotherapy at the population level and its hyper-progressive phenomenon, it may not meet clinical needs. To expand the beneficial range of immunotherapy and improve its efficacy, several research strategies have adopted the use of combination immunotherapy. At present, multiple strategies, such as PD-1/PD-L1 inhibitors combined with chemotherapy, anti-angiogenic therapy, cytotoxic T-lymphocyte-associated protein 4 inhibitors, and radiotherapy, as well as combined treatment with new target drugs, have been evaluated for clinical practice. To further understand the current status and future development direction of immunotherapy, herein, we review the recent progress of ICI combination therapies for NSCLC.

简介：Blockadeofimmunecheckpointshasrecentlyemergedasanoveltherapeuticstrategyinvarioustumors.Inparticular,monoclonalantibodiestargetingprogrammedcelldeath1(PD-1)oritsligand(PD-L1)havebeenmoststudiedinlungcancer,andPD-1inhibitorsarenowestablishedagentsinthemanagementofnon-smallcelllungcancer(NSCLC).ThereportsonhighprofileclinicaltrialshaveshowntheassociationofPD-L1expressionbyimmunohistochemistry(IHC)withhigheroverallresponseratestothePD-1/PD-L1axisblockadesuggestingthatPD-L1expressionmayserveasapredictivemarker.Unfortunately,however,eachPD-1orPD-L1inhibitoriscoupledwithaspecificPD-L1antibody,IHCprotocolandscoringsystemforthebiomarkerassessment,makingthehead-to-headcomparisonofthestudiesdifficult.Similarly,multipleclinicalseriesthatcorrelatedPD-L1expressionwithclinicopathologicand/ormolecularvariablesand/orsurvivalhavereportedconflictingresults.Thediscrepancycouldbeexplainedbythedifferencesinethnicityand/orhistologictypesincludedinthestudies,butitappearstobeattributedinparttothedifferencesinPD-L1IHCmethods.Thus,orchestratedeffortstostandardizethePD-L1IHCarewarrantedtoestablishtheIHCasapredictiveand/orprognosticbiomarkerinNSCLC.

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简介：AbstractBackground:PD-1 and PD-L1 inhibitors have emerged as promising treatments for patients with head and neck squamous cell carcinoma (HNSCC).Methods:Systematic review and meta-analysis of PD-1 and PD-L1 inhibitors in HNSCC. Outcomes: median overall survival (mOS), median progression-free survival (mPFS), Response Evaluation Criteria in Solid Tumors (RECIST) and treatment-related adverse events (TRAEs).Results:Eleven trials reported data on 1088 patients (mean age: 59.9 years, range: 18-90). The total mOS was 7.97 months (range: 6.0-16.5). Mean mPFS for all studies was 2.84 months (range: 1.9-6.5). PD-1 inhibitors had a lower rate of RECIST Progressive Disease than PD-L1 inhibitors (42.61%, 95% confidence interval [CI]: 36.29-49.06 vs. 56.79%, 95% CI: 49.18-64.19, P < 0.001). The rate of TRAEs of any grade (62.7%, 95% CI: 59.8-65.6) did not differ.Conclusions:Meta-analysis shows the efficacy of PD-1 and PD-L1 inhibitors in HNSCC and suggests a possible difference in certain RECIST criterion between PD-1 and PD-L1 inhibitors. Future work to investigate the clinical significance of these findings is warranted.

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简介：Oxidativestressiscloselyassociatedwithsecondarycelldeathinmanydisordersofthecentralnervoussystemincludingstroke,Parkinson’sdisease,Alzheimer’sdisease.Amongmanyaberrantoxidativestress-associatedproteins,DJ-1hasbeenassociatedwiththeoxidativestresscelldeathcascadeprimarilyinParkinson’sdisease.Althoughprincipallyexpressedinthecytoplasmandnucleus,DJ-1canbesecretedintotheserumunderpathologicalcondition.Recently,aclosepathologicalassociationbetweenDJ-1andoxidativestressinstrokehasbeenimplicated.Tothisend,weandothershavedemonstratedtheimportantroleofmitochondriainneuroprotectionforstrokebydemonstratingthatthetranslocationofDJ-1inthemitochondriacouldpotentiallymitigatemitochondrialinjury.Here,wediscussourrecentfindingstestingthehypothesisthatDJ-1notonlyfunctionsasaformofintracellularprotectionfromoxidativestress,butthatitalsoutilizesparacrineand/orautocrinecuesinordertoaccomplishextracellularsignalingbetweenneighboringneuronalcells,resultinginneuroprotection.ThisarticlehighlightsrecentevidencesupportingthestatusofDJ-1askeyanti-oxidativestresstherapeutictargetforstroke.

简介：Programmedcelldeathplaysanimportantroleinmaintaininghomeostasisduringanimaldevelopment,andhasbeenconservedinanimalsasdifferentasnematoesandhumans.RecentstudiesofDrosophilahaveprovidedvaluadleinformationtowardourunderstandingofgeneticregulationofdeath.Differentsignalstriggerthenoveldeathregulatorsrpr,hid,andgrim,thatutilizetheevolutionarilyconservediapandarkgenestomodulatecaspasefunction.Subsequentremovalofdyingcellsalsoappearstobeaccomplishedbyconservedmechanisms.ThesimilaritybetweenDrosophilaandhumanincelldeathsignalingpathwaysillustratethepromiseoffruitfliesasamodelsystemtoelucidatekthemechanismsunderlyingregulationofprogrammedcelldeath.

简介：Uponencounteringtheantigen(Ag),theimmunesystemcaneitherdevelopaspecificimmuneresponseofenteraspecificstateofunresponsiveness,tolerance.TheresponseofBcellstotheirspecificAgcanbeactivationandproliferation,leadingtotheimmuneresponse,oranergyandactivation-inducedcelldeath(AICD),leadingtotolerance.AICDinBlymphocytesisahighlyregulatedeventinitiatedbycrosslinkingoftheBcellreceptor(BCR).BCRengagementinitiatesseveralsignalingeventssuchasactivationofPLCγ,Ras,andPI3K,whichgenerallyspeaking,leadtosurvival.However,intheabsenceofsurvivalsignals(CD40orIL-4Rengagement),BCRcrosslinkingcanalsopromoteapoptoticsignaltransductionpathwayssuchasactivationofeffectorcaspases,expressionofpro-apoptoticgenes,andinhibitionofpro-survivalgenes.ThecomplexinterplaybetweensurvivalanddeathsignalsdeterminestheBcellfateand,consequently,theimmuneresponse.

简介：人的免疫不全病毒类型1(HIV-1)Vpr导致房间死亡在哺乳动物并且分裂酵母房间，建议那Vpr可以影响一个保存细胞的过程。然而，导致Vpr的酵母房间死亡是否在哺乳动物的房间模仿调停Vpr的apoptosis，是不清楚的。我们最近识别了很多Vprsuppressors不仅在分裂酵母压制导致Vpr的房间死亡，而且在哺乳动物的房间堵住导致Vpr的apoptosis。这些调查结果建议在酵母的导致Vpr的房间死亡可以类似于一些哺乳动物的房间的apoptotic过程。这研究的目标是为apoptosis的未来研究开发并且验证一个分裂酵母模型系统。类似于在哺乳动物的房间的导致Vpr的apoptosis，我们这里证明在分裂酵母的Vpr支持phosphatidylserine外表表现并且导致线粒体的hyperpolarization，导致mitochondrial膜潜力的变化。而且，反应的氧种类(ROS)的Vpr扳机生产，显示象apoptotic一样细胞死亡可能被ROS调停。有趣地，Vpr在可以为在分裂酵母测量象apoptotic一样过程提供一个简单标记的线粒体导致唯一的词法变化。验证这可能性，我们测试了二Vprsuppressors(EF2和Hsp16)除了最新识别的Vprsuppressor(Skp1)在哺乳动物的房间压制导致Vpr的apoptosis。所有三蛋白质废除了房间死亡由Vpr调停了并且在酵母房间恢复了正常mitochondrial形态学。在结论，在分裂酵母的导致Vpr的房间死亡类似于哺乳动物的apoptotic过程。分裂酵母可以潜在地因此为Vpr和另外的proapoptotic代理人导致的象apoptotic一样过程的未来学习被用作一个简单模型有机体。

简介：Receptor-ligandinteractionsinbloodflowarecrucialtoinitiatesuchbiologicalprocessesasinflammatorycascade,plateletthrombosis,aswellastumormetastasis.Tomediatecelladhesion,theinteractingreceptorsandligandsmustbeanchoredontotwoapposingsurfacesoftwocellsoracellandasubstratum,i.e.,two-dimensional(2D)binding,whichisdifferentfromthebindingofasolubleligandinfluidphasetoareceptor,i.e.,three-dimensional(3D)binding.Whilenumerousworkshavebeenfocusedon3Dkineticsofreceptor-ligandinteractionsintheimmunesystem,2Dkineticsanditsregulationshavebeenlessunderstood,sincenotheoreticalframeworkorexperimentalassayswereestablisheduntil1993.Notonlydoesthemolecularstructuredominate2Dbindingkinetics,buttheshearforceinbloodflowalsoregulatescelladhesionmediatedbyinteractingreceptorsandligands.Here,weprovideanoverviewofcurrentprogressin2Dbindingandregulations,mainlyfromourgroup.Relevantissuesoftheoreticalframeworks,experimentalmeasurements,kineticratesandbindingaffinities,andforceregulationsarediscussed.

简介：Itiswellrecognizedthatcelldeathplaysanimportantroleduringthematurationofthenervoussystemaswellasinmanyneurologicaldiseases.Apoptosishasbeenshowntobeimportantparticularyduringembryogenesisasameanstoeliminatingunwantedneurons.SeveredaxonshavealsobeenshowntodegenerateinanorganizedfashiontermedWalleriandegeneration.Excitotoxicdeathisanotherformofcelldeathinthenervoussystemwhichisinducedbyhighconcentrationsofneurotransmitterssuchasglutamate.Itisnotknownwhetherthesamemolecularmechanismsunderliethesedifferentformsofcelldeathinthenervoussystem.TheBax-/-Bak-/-doubleknock-outmouseprovidesanidealsystemtostudy

简介：Activation-inducedcelldeath(AICD),whichresultsfromtheinteractionbetweenFasandFasligand,isresponsibleformaintainingtolerancetoself-antigen.AdefectinAICDmayleadtodevelopmentofautoimmunity.Duringthelastseveralyears,muchprogresshasbeenmadeinunderstandingthemechanism(s)ofAICDanditspotentialroleinthepathogenesisofautoimmunediseases.Inthisreview,wesummarizethemostrecentprogressontheregulationofthesusceptibilityofTcellstoAICDanditspossibleinvolvementinautoimmunediseases.

简介：Ionizingradiationisoneofthemosteffectivetoolsincancertherapy.Inapreviousstudy,wereportedthatproteintyrosinekinase(PTK)inhibitorsmodulatetheradiationresponsesinthehumanchronicmyelogenousleukemia(CML)celllineK562.Thereceptortyrosinekinaseinhibitor,genistein,delayedradiation-inducedcelldeath,whilenon-receptertyrosinekinaseinhibitor,herbimycinA(HMA)enhancesradiation-inducedapoptosis.Inthisstudy,wefocusedonthemodulationofradiation-inducedcelldeathbygenisteinandperformedPCR-selectsuppressionsubtractivehybridization(SSH)tounderstanditsmolecularmechanism.Weidentifiedhumanthymidinekinase1(TK1),whichiscellcycleregulatorygeneandconfirmedexpressionofTK1mRNAbyNorthernblotanalysis.ExpressionofTK1mRNAandTK1enzymaticactivitywereparallelintheirincreaseanddecrease.TK1isinvolvedinG1-Sphasetransitionofcellcycleprogression.Incellcycleanalysis,weshowedthatradiationinducedG2arrestinK562cellsbutitwasnotabletosustain.However,theadditionofgenisteintoirradiatedcellssustainedaprolongedG2arrestupto120h.Inaddition,theexpressionofcellcycle-relatedproteins,cyclinAandcyclinB1,providedtheevidencesofG1/SprogressionandG2-arrest,andtheirrelationshipwithTK1incellstreatedwithradiationandgenistein.TheseresultssuggestthattheactivationofTK1maybecriticaltomodulatetheradiation-inducedcelldeathandcellcycleprogressioninirradiatedK562cells.

简介：ObjectiveTounderstandthemechanismofnoiseexposureinducedouterhaircells(OHCs)deathpathways.MethodsThirtytwoguineapigswereusedinthisstudy.Theanimalswereeitherexposedfor4h/daytobroadbandnoiseat122dBSPL(A-weighted)for2consecutivedaysorperfusedwithMNNG.Afterauditorytest,thecochleaeofanimalsweredissected.Propidiumiodide(PI),aDNAintercalatingfluorescentprobe,wasusedtotracemorphologicalchangesinOHCnuclei.F-actinstainingwasusedtodeterminemissingOHCs.Caspase-3wasdetectedinlivingorganofCortiwholemountsusingthefluorescentprobe.ThesinglestrandDNA(ssDNA)inapoptoticOHCsinguineapigsandapoptosisinducingfactor(AIF)inhaircellsinguineapigswereexaminedbyimmunohistologymethod.WholemountsoforganofCortiwereprepared.Morphologicalandfluorescentchangeswereexaminedunderaconfocalmicroscope.Results(1)Bothapoptoticandnecrotichaircellsappearedfollowingnoiseexposure.(2)NoiseexposureinducedsinglestrandDNAinapoptoticOHCsbutnotinthenormalOHCs.(3)EitherafternoiseexposureorafterMNNGperfusion,apoptoticOHCswerefeaturedbynuclearcondensationorfragmentationwithcaspase-3activation,whereasnecroticOHCswerecharacterizedbynuclearswellingwithoutcaspase-3activation.(4)InnormalorganofCorti,AIFwaslocatedinthemitochondriaareas.Afternoiseexposure,AIFwastranslocatedfrommitochondriainapoptoticandnecroticOHCs.ConclusionThesefindingsindicatethatnoiseexposuredamagesDNAintheOHC,whichtriggersactionofCaspase-3.Subsequently,AIFistranslocatedtothenucleus,leadingtoDNAdamageandOHCsdeath.

简介：AktandBcl-xLbothpromoteresistancetoapoptosis.AcomparisonofAkt-andBcl-xL-dependentcellsurvivalwasundertaken.ExpressionofconstitutivelyactiveAktallowscellstosurviveforprolongedperiodsintheabsenceofgrowthfactors.ThissurvivalcorrelateswiththeexpressionlevelofactivatedAktandiscomparableinmagnitudetotheprotectionprovidedbytheanti-apoptoticgeneBcl-xL.Althoughbothgenespreventcelldeath,Akt-protectedcellscanbedistinguishedfromBcl-xL-protectedcellsonthebasisofincreasedglucosetransporterexpression,glycolyticactivity,mitochondrialpotential,andcellsize.Inaddition,Akt-expressingcellsrequirehighlevelsofextracellularnutrientstosupportcellsurvival.In

简介：Dickinson’s ,’s ,poets 

简介：在成熟期间，鼠科的myeloid树枝状的房间(DC)upregulatedCD11c，CD25，CD40，CD80，CD86，MHCII和规划死亡的表情1ligands1和2(PD-L1和PD-L2)。当DC被CD40ligand和TNF-触发时，PD-L1和PD-L2的微分表示模式被发现。PD-L1表示被镇压，PD-L2表示在成熟绑扎CD40的DC仍然保持未改变，而TNF-刺激了使PD-L1的表示高并且显著地在DC上提高了PD-L2表示的DC。不成熟的DC刺激的T淋巴细胞的增长被PD-1和PD-1ligand相互作用的封锁提高。但是禁止的效果在淋巴细胞由绑扎CD40的DC刺激了的T被发现。与PD-L1和PD-L2的调整表情，绑扎CD40的DC能支撑一个更长的激活时期并且得到更有效的T淋巴细胞激活。