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：规划death-1(PD-1)，CD28家庭的一个成员，能否定地调整TCR由与它的血缘的ligands(PD-L1或PD-L2)交往的开始建筑群的发信号。PD-1/PD-L1小径起一个重要作用在下面调整适应有免疫力的回答的有效阶段和这条小径的封锁被证明提高抗病毒并且antitumoral免疫，建议让治疗的发展与病毒感染或恶意在病人改进T房间回答可能是一个潜在的目标。在现在的学习，有一个carboxyl终端他的标签的人的PD-1的细胞外的域(指定了为sPD-1)在Escherichiacoli被表示为包括身体。产品是在列上refolded，由使不能调动的金属亲密关系层析净化了，并且由西方的弄污描绘了。而且，有高纯净的可溶的PD-1与它的血缘的ligandPD-L1拥有了特定的有约束力的活动，并且分离常数是由Scatchard情节分析决定了的0.43nmol/L。这些结果建议从原核生物的房间的refoldedsPD-1可能具有对提高抗病毒和antitumoral免疫者回答的治疗学的兴趣。

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

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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：Sphingolipids被建议了在植物房间为一连串的细胞的发信号活动充当第二个送信人，包括压力回答并且规划了房间死亡(PCD)。然而，这些过程不是的机制underpinning很好理解。这里，我们报导那Arabidopsis异种，fumonisinB1抵抗11-1(fbr11-1)没能产生反应的氧中介(ROI)，不能当异种被fumonisinB(1)(FB(1))质问时，开始PCD，ceramidesynthase的一个特定的禁止者。显示的分子的分析FBR11编码一个长链的底1(LCB1)丝氨酸palmitoyltransferase(SPT)的子单元，它催化denovosphingolipid的第一限制率的步合成。sphingolipid集中的集体度谱的分析表明而fbr11-1变化没影响sphingoid底的基础层次，异种响应FB(1)显示出sphingoid底的稀释形成。由一个直接的喂实验，我们证明免费sphingoid底dihydrosphingosine，phytosphingosine和鞘氨醇高效地导致产生由房间死亡跟随了的ROI。相反地，dihydrosphingosine导致的ROI产生和房间死亡被它的phosphorylated形式dihydrosphingosine-1-phosphate明确地以一种剂量依赖者方式堵住，建议在一个免费sphingoid底和它的phosphorylated衍生物之间的动态平衡的维护对决定房间命运批评。因为sphingolipid水平的改变发生在ROI生产以前，我们建议免费sphingoid库在Arabidopsis涉及PCD的控制，大概在收到不同发展或环境的暗示之上通过ROI的规定铺平。

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：Objective:ToinvestigatetheantitumoractivityandthemechanismofBRM-SJSonbreastcancercells.Methods:Flowcytometry,DNAagarosegelelectrophoresisandothertechniqueswereusedtostudytheinvitroandinvivoinhibitoryeffectonBcaP-37cellsbyBRM-SJS.Results:BRM-SJSshowedaninhibitoryrateof33.8%oninvivotransplantedtumor(P<0.05,comparedwithcontrol).TheflowcytometryanalysisofBRM-SJStreatedBcaP-37(2.5μmol/L,5μmol/L,10μmol/Lfor48hand72h)revealedtypicalsub-G1peak.ThespecificDNALadderswereexhibitedwithBRM-SJSBcaP-37cellstreated.Conclusion:BRM-SJShasmarkedantitumoractivityonBcaP-37anditsinhibitoryeffectsontumorwererealizedbybothinductionofapoptosisandnecrosisofthetumorcells.

简介：我们以前报导了那ONO-AE-248，选择EP3受体收缩筋，没有apoptosis和坏死的典型特征，被显示了引起嗜中性的死亡。然而，嗜中性的死亡的机制是不清楚的。由使用西方的弄污，流动cytometry(FACS)和扫描显微镜学(CLSM)的共焦的激光，我们调查了嗜中性的死亡的细胞的信号transduction小径。研究结果证明ONO-AE-248导致的嗜中性的死亡没显示出apoptosis的词法变化并且没与p38-MAPK的caspase-3，caspase-8，和phosphorylation的活动被联系。然而，线粒体transmembrane潜力的缺陷在房间死亡的过程期间被发现了。这些调查结果建议ONO-AE-248导致了non-apoptoticneutrophils通过的规划房间死亡部分线粒体发信号transduction小径。

简介：AbstractGamete production is essential for mammalian reproduction. In the ovaries, the primordial follicle, which is the basic reproductive unit, is formed either perinatally or during the second pregnancy stage in humans. However, some oocytes die before the establishment of the primordial follicle pool. Consequently, it is essential to uncover how the size of the primordial follicle pool is determined and how the programmed cell death of oocytes is performed under potential surveillance. According to recent studies, the fate of oocytes in the fetal ovary seems to be determined by different protective strategies through the timely control of apoptosis or autophagy. In this review, we discuss at least three oocyte-derived protective biomarkers, glycogen synthase kinase 3 beta, X-linked inhibitor of apoptosis, and Lysine-specific demethylase 1 (also known as KDM1A), responsible for surveilling the developmental quality of fetal oocytes to coordinate primordial follicle formation in the fetal ovary. This review contributes to a better understanding of the secrets of the female reproductive reserve under physiological conditions.

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