简介：Modulationbybalancingactivatingandinhibitoryreceptorsconstitutesanimportantmechanismforregulatingimmuneresponses.Cellsthatareactivatedfollowingligationofreceptorsbearingimmunoreceptortyrosine-basedactivationmotifs(ITAMs)canbenegativelyregulatedbyotherreceptorsbearingimmunoreceptortyrosine-basedinhibitionmotifs(ITIMs).Humanmastcells(MCs)arethemajoreffectorcellsoftypeIhypersensitivityandimportantparticipantsinanumberofdiseaseprocesses.Antigen-mediatedaggregationofIgEboundtoitshigh-affinityreceptoronMCsinitiatesacomplexseriesofbiochemicaleventsleadingtoMCactivation.WithgreatdetaileddescriptionandanalysisofseveralinhibitoryreceptorsonhumanMCs,acentralparadigmofnegativeregulationofhumanMCactivationbythesereceptorshasemerged.Cellular&MolecularImmunology.2004;1(6):408-415.

简介：MicroRNAs(miRNAs)aresmall,non-codingsingle-strandedRNAsthatcanmodulatetargetgeneexpressionatposttranscriptionallevelandparticipateincellproliferation,differentiation,andapoptosis.Tcellshaveimportantfunctionsinacquiredimmuneresponse;miRNAsregulatethisimmuneresponsebytargetingthemRNAsofgenesinvolvedinTcelldevelopment,proliferation,differentiation,andfunction.Forinstance,miR-181familymembersfunctioninprogressionbytargetingBcl2andCD69,amongothers.MiR-17tomiR-92clustersfunctionbybindingtoCREB1,PTEN,andBim.ConsideringthatthesuppressionofTcell-mediatedimmuneresponsesagainsttumorcellsisinvolvedincancerprogression,weshouldinvestigatethemechanismbywhichmiRNAregulatesTcellstodevelopnewapproachesforcancertreatment.

简介：肺上皮是在各种各样的肺疾病的肺损坏的主要地点。上皮的房间apoptosis被认为是在各种各样的肺疾病的起始的事件。发信号的Apoptosis古典主义地由二条原则小径组成。一个人是从死亡受体结扎的一条直接小径到caspase串联激活和房间死亡。象药，放射，传染代理人和反应的氧种类那样的压力触发的另外的小径被线粒体调停。Endoplasmic蜂窝胃也被显示了是细胞器调停apoptosis.Epithelial房间死亡被改变过程跟随，它由组成上皮并且成纤维细胞激活，cytokine生产，凝结小径的激活，neoangiogenesis，re-epithelialization和fibrosis.Epithelial和间充质的相互作用在这些过程起重要作用。apoptosis由新奇策略发信号和它的规定的进一步的理解可以对各种各样的肺疾病导致有效治疗。我们在apoptosis发信号的理解考察最近的进展并且在肺改变讨论apoptosis的参与。

简介：Inordertounderstandthedevelopmentofstemcellsintospecializedmaturecellsitisnecessarytostudythegrowthofcellsinculture.Forthispurposeitisveryusefultohaveanefficientcomputerizedcelltrackingsystem.Inthispaperaprototypesystemfortrackingneuralstemcellsinasequenceofimagesisdescribed.Inordertogetreliabletrackingresultsitisimportanttohavegoodandrobustsegmentationofthecells.Toachievethiswehaveimplementedthreelevelsofsegmentation.Theprimarylevel,appliedtoallframes,isbasedonfuzzythresholdandwatershedsegmentationofafuzzygrayweighteddistancetransformedimage.Thesecondlevel,appliedtodifficultframeswherethefirstalgorithmseemstohavefailed,isbasedonafastgeometricactivecontourmodelbasedonthelevelsetalgorithm.Finally,theautomaticsegmentationresultonthecrucialfirstframecanbeinteractivelyinspectedandcorrected.Visualinspectionandcorrectioncanalsobeappliedtootherframesbutthisisgenerallynotneeded.Forthetrackingallcellsareclassifiedintoinactive,active,dividingandclusteredcells.Differentalgorithmsareusedtodealwiththedifferentcellcategories.Aspecialbacktrackingstepisusedtoautomaticallycorrectforsomecommonerrorsthatappearintheinitialforwardtrackingprocess.

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简介：Objective:Chroniclymphocyticleukemia(CLL)andmantlecelllymphoma(MCL)cellsover-expressaguanineexchangefactor(GEF),Rasgrf-1.ThisGEFincreasesactiveRasasitcatalyzestheremovalofGDPfromRassothatGTPcanbindandactivateRas.ThisstudyaimstostudythemechanismofactionofRasgrf-1inB-cellmalignancies.Methods:N-terminustruncatedRasgrf-1variantshaveahigherGEFactivityascomparedtothefull-lengthtranscriptthereforeaMCLcelllinewithstableover-expressionoftruncatedRasgrf-1wasestablished.TheB-cellreceptor(BCR)andchemokinesignalingpathwayswerecomparedintheRasgrf-1over-expressingandacontroltransfectedcellline.Results:Cellsover-expressingtruncatedformofRasgrf-1haveahigherproliferativerateascomparedtocontroltransfectedcells.BCRwasactivatedbylowerconcentrationsofanti-IgMantibodyinRasgrf-1over-expressingcellsascomparedtocontrolcellsindicatingthatthesecellsaremoresensitivetoBCRsignaling.BCRsignalingalsophosphorylatesRasgrf-1thatfurtherincreasesitsGEFfunctionandamplifiesBCRsignaling.ThisactivationofRasgrf-1inover-expressingcellsresultedinahigherexpressionofphospho-ERK,AKT,BTKandPKC-alphaascomparedtocontrolcells.BesidesBCR,Rasgrf-1over-expressingcellswerealsomoresensitivetomicroenvironmentstimuliasdeterminedbyresistancetoapoptosis,chemotaxisandERKpathwayactivation.Conclusions:ThisGEFproteinsensitizesB-cellstoBCRandchemokinemediatedsignalingandalsoupregulatesanumberofothersignalingpathwayswhichpromotesgrowthandsurvivalofthesecells.

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简介：CD8+细胞毒素的T淋巴细胞(CTL)疲劳是为在长期的传染疾病的无效病毒消除的一个主要问题。我们产生了新奇ovalbumin(卵)特定的OVA-Texo和导致治疗学的免疫的HIV特定的Gag-Texo疫苗。在长期的感染估计他们的治疗学的效果，我们由与表示卵的侵入人体气管粘膜的病菌AdVova感染C57BL/6老鼠的i.v开发了一个新长期的感染模型。在长期的AdVova感染期间，老鼠CTL被发现房间死亡protein-1(PD-1)和淋巴细胞激活gene-3(LAG-3)到禁止的分子规划了的快车，证明在T房间增长，IFN-生产和cytolytic的重要缺乏完成机能上地精疲力尽并且。天真的CD8+T房间upregulated禁止的PD-ligand1(PD-L1)，B淋巴细胞和T淋巴细胞衰减器和T房间联系变应力缺乏的分子(圣盘和痒)当时下面调整在在有长期的感染的老鼠的刺激之上的proliferative反应。显著地，OVA-Texo疫苗抵抗了T房间变应力缺乏并且变换了CTL疲劳。后者与(i)被联系为CTL功能的一个标记的upregulation，diacetylatedhistone-H3(diAcH3)，(ii)CTL，宿主DC的发生独立人士或CD4+T细胞的四折的增加，并且(iii)CTLIFN-生产和cytotoxicity的恢复。在vivoOVA-Texo-stimulatedCTLupregulatedmTORC1的活动小径相关的分子Akt，S6，eIF4E和T赌注，和有一个mTORC1禁止者的CTL的处理，rapamycin，显著地在CTL减少了OVA-Texo-induced增加。有趣地，发信号的OVA-Texo-mediatedCD40L在观察免疫学的效果起了一个关键作用。重要地，Gag-Texo疫苗在长期的感染导致了作呕特定的治疗学的免疫。因此，这研究应该为人的免疫不全在新治疗学的疫苗的发展有严肃的影响病毒(HIV-1)感染。

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简介：AthalfpasteightonthemorningofMarch28,inabasementnearYabaoRoadinChaoyangDistrictofBeijing,Chen,65yearsold,wasgoingtocooksomecongeewiththecookertoeatwithhiswife.Thelandlinephonerangsuddenly.'Shifu,akidwasgoneintheemergencyroom.Pleasecome.''Howoldwasthekid?''Onlytwodaysago.Intestinalnecrosis.''Alas,toobad.I'llberightthere.'Chenwalkedoutofthebedroom,unpluggedthecooker,tookdownthewhitecoatfromthehangerandreturnedto

简介：backgroundIn-hospital(IH)mortalityforpatientsunderwentpercutaneouscoronaryintervention(PCI)inourcenterfrom1994to2004was1.01%(33/3252).ThePCIvolumeinourstateincreasedquicklyduringthelastfewyears,sodiditinourcenter.MethodsandResultsWeretrospectivelyscreenedatotalof3274caseswhounderwentPCIin2009,amongwhich24(0.73%,P=0.22vs.1994-2004)IHdeathoccurred.Analysisofthese24casesrevealedthatallofthemwerediagnosedasacutecoronarysyndrome(ACS),andhadtheindicationofPCI.Fifteen(63%)carriedachanceof≥10%todieinhospitalaccordingtoGRACEmodel.Significantleft-main(LM)and/ortriple-vesseldisease(TVD)weredefinedin21(88%)cases.SYNTAXscoreswere≥23in15(63%)and≥33in12(50%)cases.CompleterevascularizationwithPCIwasfulfilledinonly5(21%)cases.Myocardialischemiaorheartfunctioncouldn'timprovebyPCIwasthemostfrequentcauseofdeath,whichcontributedtothatof11(46%)cases.Cardiacruptureoccurredinallofthe4patientswithSTelevatedacutemyocardialinfarction(STE-AMI)involvinginferiorventricularwallbut'reserved'anteriorwall,andcontributedmainlytotheirmortality.ConclusionsPost-PCIIHmortalityhasmaintainedlowinourcenter.ItmostlikelyoccursinpatientswithACS.Themajorcauseofdeathisthatmyocardialischemiacouldn'timprovebyPCI,exceptforpatientswithinferiorbutnoanteriormyocardialinfarction,whosufferfromcardiacruptureinstead.

简介：在一个二维的方形的数组的螺线波浪的开发由于部分离子隧道块(钾，钠)被调查，节点的动力学被HodgkinHuxley神经原描述，这些神经原最近被结合邻居连接。参数比率xNa(并且xK)，它定义钠(钾)的工作离子隧道数字的比率到钠的全部的离子隧道数字(并且钾)，被用来测量隧道块导致的移动传导力。在二参数的阶段空间(参数比率对毒害的区域)的统计可变R的分发广泛地被计算为部分离子隧道块导致的螺线波浪的转变标记参数区域，有同步R的更小的因素的区域被联系那个螺线波浪使明白毒害的隧道、柔韧的参数区域。当毒害的区域(钾或钠)和沉醉的度是小的时，螺线波浪保持活着，不同转变(死亡，几个螺线波浪共存或多手臂螺线波浪出现)发生在中等比率xNa下面(并且xK)当堵住的区域的尺寸超过某些阀值时。螺线波浪的决裂发生，螺线的多手臂飘动当隧道噪音被考虑时，被观察。

简介：

简介：Ⅰ.RestrictionandAnalysisofDeathPenaltyinExistingSubstantiveLawinChinaInthenormativecriminallaw,thepersonaldangerousnessisthepossibilityoftheactortocommitacrimeagain.Beforethepersonaldangerousnessastheunaccomplishedcrimedoesnotbecomeaconsensusconcepttoentertheviewofthepublicscholars,howdoesitfitwiththecontrolofdeathpenaltyinourexistingsubstantivelaw?

简介：AbstractBackground:Allogeneic natural killer (NK) cell immunotherapy is recognized as a promising anti-tumor strategy, but whether it plays a role in poor CD4 recovery among human immunodeficiency virus type 1 (HIV-1) infected patients is unknown. This study aimed to investigate the safety and effectiveness of allogeneic NK cells immunotherapy on HIV-1 immunological non-responders (INRs) receiving antiretroviral therapy (ART).Methods:From February to April 2018, a prospective, randomized, controlled, open-label clinical trial, which enrolled 20 HIV-1 INRs following specific inclusion criteria, was conducted at Nankai University Second People’s Hospital. Participants were randomly allocated (simple randomization 1:1) to either the combined treatment (NK + ART) group (n = 10) or the control (ART) group (n = 10). The allogenic highly activated NK cells from killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen (HLA)-Cw mismatched healthy donor were prepared (108 cells in each injection) and intravenously infused to each recruited patient of NK+ART group in three courses. Key immune parameters (CD4 count, CD8 count, CD4/CD8 ratio), laboratory tests (count of blood cells, biochemistry panel) and symptoms at baseline and at month 1, 3, 6, 9, 12, and 24 were measured/collected to analyze the safety and efficacy of the therapy. Comparisons were between the seven time-points of both groups using repeated measurement analysis of variance (ANOVA) test. Generalized estimating equations (GEE) model was performed to evaluate the overall effect of the NK+ART group vs. the ART group.Results:From baseline to 24 months, we noted a mean CD4 count augmentation (139 to 243 cells/μL) in the NK + ART group and (144 to 176 cells/μL) in the ART group (difference, 67; 95% CI, 10 to 124; P = 0.024). Our estimations revealed that NK+ART group could improve CD4 level (β = 54.59, P= 0.006) and CD8 level (β = 322.47, P= 0.010) on average among the six measurements compared with the ART group. Only two (2/10, 20%) participants in the NK+ART group developed a transient mild fever after the first course.Conclusions:This preliminary study informs that HIV-1 INRs, allogenic NK cells immunotherapy is safe and could significantly improve CD4 recovery but not CD4/CD8 ratio. The practical effects, however, need long-term follow-up observations. Further study on the potential underlying mechanism is warranted.Registration info:www.chictr.org.cn/showproj.aspx?proj=34912 (No. ChiCTR1900020634).

简介：Thenon-classicalHLAclassIantigenHLA-GisanimmunemodulatorwhichinhibitsthefunctionsofTcells,NKcells,andtheDendriticcells(DC).Asaresult,HLA-Gexpressioninmalignantcellsmayprovidethemwithamechanismtoescapetheimmunesurveillance.Inmelanoma,HLA-Gantigenexpressionhasbeenfoundin30%ofsurgicallyremovedlesionsbutinlessthan1%ofestablishedcelllines.OnepossiblemechanismunderlyingthedifferentialHLAGexpressioninvivoandinvitroisthattheHLA-Ggeneisepigeneticallyrepressedinmelanomacellsinvitro.Totestthishypothesis,wetreatedtheHLA-GnegativemelanomacelllineOCM-1AwiththeDNAmethyltransferaseinhibitor5-aza-2'-deoxycytidine(5-AC)andanalyzedwhetherHLA-Gexpressioncanberestored.OurdatastronglysuggestthatHLA-GissilencedasaresultofCpGhypermethylationwithina5'regulatoryregionencompassing220bpupstreamofthestartcodon.Aftertreatment,HLA-GmRNAexpressionwasdramaticallyincreased.WesternblotandflowcytometryshowedthatHLA-Gproteinwasinduced.Interestingly,HLA-Gcellsurfaceexpressiononthe5-ACtreatedOCM-1AcellsismuchlessthanthatontheHLA-GpositiveJEG-3cellswhileasimilaramountoftotalHLA-Gwasobserved.Possiblemechanismsforthedifferencewereanalyzedinthestudysuchascellcold-treatment,peptideloadingandantigenprocessingmachinerycomponents(APM)aswellasβ2microglobulin(β2-m)expression.DatarevealedthattheAPMcomponentcalreticulinmightbeinvolvedinthelowerHLA-GsurfaceexpressiononOCM-1Acells.Takentogether,ourresultsindicatedthatDNAmethylationisanimportantepigeneticmechanismbywhichHLA-Gantigenexpressionismodulatedinmelanomacellsinvitro.Furthermore,tothefirsttime,wehypothesizedthatthedeficiencyofcalreticulinmightbeinvolvedinthelowHLA-Gsurfaceexpressiononthe5-ACtreatedOCM-lAcells.

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.

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

简介：ObjectiveTodetectthecellviabilityandtheexpressionsofstemcellsurfacemarkersafterchemotherapeuticdrugtreatment.MethodsWeobservedthecytotoxiceffectsofthreechemotherapeuticagents[epirubicin(Epi),fluorouracil(5-FU)andcyclophosphamide(Cyc)]inthreecelllines,andthecellviabilitiesafterremovedthesechemotherapeuticagents.ExpressionsofstemcellsurfacemarkersCD44,CD24,CD90,CD14andaldehydedehydrogenase1(ALDH1)inbreastcancercellswereanalyzedbyreal-timePCR.Theposthocanalysis(Tukey’stests)inconjunctionwithone-wayANOVAwasusedforstatisticalanalysis.ResultsTheinitialcytotoxicefficacywasmostnotable.Afterthetreatmentofthesametherapeuticagents,cellviabilitywasdecreasedby64.8%35.14%,32.25%inBT-483cells,66.4%,22.94%and45.88%inMDA-MB-231cells,97.1%,99.5%and76.4%inMCFcells.Thedifferencewassignificantcomparedwiththatbeforetreatment(P=0.000).However,theinhibitoryeffectswerediminishedafterchemotherapeuticagentwithdrawal.Cellviabilitieswereincreasedto167.9%,212.04%and188.66%inMDA-MB-231cellsat48hafterwithdrawal.At72hafterwithdrawal,cellviabilitywasincreasedwithasignificantdifferenceinthreecelllines(allPvalues=0.000).ExpressionsofCD44andALDH1weremostprevalentforMDA-MB-231,BT-483andMCF-7cells.ALDH1mRNAlevelwassignificanthigherinBT-483(HER-2overexpressioncellline)thanMDA-MB-231(triplenegativecellline)(P=0.012).CD14mRNAlevelinMCF-7cellsweresignificantlylowerthanthatinMDA-MB-231andBT-483(P=0.003,0.001).BT-483showedsignificantlyhigherlevelofCD44thanMDA-MB-231andMCF-7cellline(P=0.013,0.020),andnosignificantdifferencewasdetectedbetweenMDA-MB-231andMCF-7breastcancercells(P=0.955).CD90mRNAexpressionsweredetectedinMDA-MB-231cellsandMCF-7cells,butnotinBT-483cells.ConclusionSomemalignantcellscouldsurviveinvitroandbegintoproliferateagainbetweencyclesofchemotherapy.

简介：AbstractCD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy is effective in refractory/relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL). This review focuses on achievements, current obstacles, and future directions in CAR-T research. A high complete remission rate of 68% to 93% could be achieved after anti-CD19 CAR-T treatment for B-ALL. Cytokine release syndrome and CAR-T-related neurotoxicity could be managed. In view of difficulties collecting autologous lymphocytes, universal CAR-T is a direction to explore. Regarding the high relapse rate after anti-CD19 CAR-T therapy, the main solutions have been developing new targets including CD22 CAR-T, or CD19/CD22 dual CAR-T. Additionally, some studies showed that bridging into transplant post-CAR-T could improve leukemia-free survival. Some patients who did not respond to CAR-T therapy were found to have an abnormal conformation of the CD19 exon or trogocytosis. Anti-CD19 CAR-T therapy for R/R B-ALL is effective. From individual to universal CAR-T, from one target to multi-targets, CAR-T-cell has a chance to be off the shelf in the future.