简介：

简介：AbstractIncreasing numbers of targeted drugs are used in hormone receptor (HR)-positive metastatic breast cancer (MBC) to overcome or delay resistance to endocrine therapy. This study will systemically review the progress made in endocrine therapy combined with targeted therapy in the treatment of HR-positive MBC. From the "AI (aromatase inhibitor) era" represented by aromatase inhibitors, we have gradually entered the "post-AI era" represented by fulvestrant. Under the guidance of research on the molecular mechanism of endocrine therapy resistance, the "combination of endocrine therapy and targeted therapy" era is approaching. The development of drugs that target endocrine therapy resistance has concentrated on cyclin-dependent kinase 4/6 inhibitors, histone deacetylase inhibitors, and inhibitors of drug targets in the phosphatidylinositol 3 kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway, providing new strategies for HR-positive MBC. Exploring biomarkers to guide the more precise use of targeted drugs in endocrine therapy for MBC is the focus of current and future research.

简介：

简介：无

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.

简介：AbstractBackground:Atrial natriuretic peptide (ANP) and its natriuretic peptide receptors A (NPR-A) and C (NPR-C) are involved in the regulation of physiological and pathophysiological process of blood pressure. The present study aimed to determine the role of NPR-C in the development of salt-sensitive hypertension.Methods:The Dahl salt-sensitive (DS) and salt-resistant (DR) rats were used in this study. Animals were matched according to their age and weight, and then placed on either a high-salt (HS, 8%) or a normal-salt (NS, 0.4%) diet for 6 weeks randomly using random number table. The systolic blood pressure (SBP), plasmatic sodium concentration (PLNa), urinary sodium excretion (UVNa), and serum creatinine concentration (Scr) were measured. The concentration of ANP in blood and tissues (heart and kidney) was detected by enzyme-linked immunosorbent assay. The expression of ANP, NPR-A, and NPR-C in kidney was evaluated with western blot analysis. Regarding renal redox state, the concentration changes in malondialdehyde (MDA), lipofuscin, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox), and nitric oxide synthase (NOS) in kidney were detected by a spectrophotometric method. The kidney damage was evaluated using pathological techniques and the succinodehydrogenase (SDHase) examination. Furthermore, after an intra-peritoneal injection of C-atrial natriuretic peptide (ANP)4-23 (C-ANP4-23), an NPR-C receptor agonist, the SBP, biochemical values in blood and urine, and renal redox state were evaluated. The paired Student’s t test and analysis of variance followed by the Bonferroni test were performed for statistical analyses of the comparisons between two groups and multiple groups, respectively.Results:The baseline SBP in all groups was within the normal range. At the end of the 6-week experiment, HS diet significantly increased the SBP in DS rats from 116.63 ± 2.90 mmHg to 162.25 ± 2.15 mmHg (t = -10.213, P < 0.001). The changes of SBP were not significant in DS rats on an NS diet and DR rats on an NS diet or on an HS diet (all P > 0.05). The significant increase of PLNa, UVNa, and Scr related to an HS diet was found in both DS and DR rats (all P < 0.05). However, significant changes in the concentration (t= -21.915, P < 0.001) and expression of renal ANP (t= -3.566, P = 0.016) and the expression of renal NPR-C (t = 5.864, P = 0.002) were only observed in DS hypertensive rats. The significantly higher desmin immunochemical staining score (t = -5.715, P = 0.005) and mitochondrial injury score (t = -6.325, P = 0.003) accompanied by the lower SDHase concentration (t= 3.972, P = 0.017) revealed mitochondrial pathologic abnormalities in podocytes in DS rats with an HS diet. The distinct increases of MDA (t= -4.685, P= 0.009), lipofuscin (t= -8.195, P= 0.001), and Nox (t= -12.733, P < 0.001) but not NOS (t = -0.328, P = 0.764) in kidneys were also found in DS hypertensive rats. C-ANP4-23 treatment significantly decreased the SBP induced by HS in DS rats (P < 0.05), which was still higher than NS groups with the vehicle or C-ANP4-23 treatment (P < 0.05). Moreover, the HS-induced increase of MDA, lipofuscin, Nox concentrations, and Nox4 expression in DS rats was significantly attenuated by C-ANP4-23 treatment as compared with those with HS diet and vehicle injection (all P < 0.05).Conclusions:The results indicated that the renal NPR-C might be involved in the salt-sensitive hypertension through the damage of mitochondria in podocytes and the reduction of the anti-oxidative function. Hence, C-ANP4-23 might serve as a therapeutic agent in treating salt-sensitive hypertension.

简介：Analysisofthefrequencyofantigen-specificcytotoxicTlymphocytes(CTLs)exvivoislargelydependentontheuseofMHC/peptidetetramers.However,thelatterreagentshavenotbeenwidelyavailable,mostlikelybecauseoftheircostlyandtime-consumingproduction.InthisreportweutilizedaneconomicstrategytoconstructHLA/peptidetetramerswithrecombinantpeptide-linkedβ2microglobulin(β2m).TheHLA-A2-restricted,melanomaantigenMARTl-derivedpeptideMARTI27-35(AAGIGILTV)wasfusedtotheNterminusofhumanβ2mthrougha15-aminoacid(aa)-longlinkerbeforebeingrefoldedwiththerecombinantbiotinylatedHLA-A2heavychainectodomain.Theresulted2-component(2C)monomerwasthentetramerizedwithphycoerythin-labeledstreptavidin.Theexperimentalresultshowedthatthe2CHLA-A2/MARTI27-35monomerwasshowntobindtotheHLAclassⅠcomplex-specificmonoclonalantibodyW6/32andtheHLA-A2/MARTI27-35complex-specificsinglechainantibodyfragment(scFv)8.3,suggestingthecorrectnessofitsspecificity.Furthermore,the2CHLA-A2/MARTI27-35tetramerdetectedaspecificCD8^+TcellpopulationinHLA-A2-restrictedmelanomainfiltratinglymphocytesastheconventional3CHLA-A2/MARTI27-35tetramer.Theyieldof2CHLA-A2/MARTI27-35monomerwas2.5timesmorethanthatoftheconventional3Cmonomer.Takentogether,thesedataindicatethattheHLA-A2/MARTI27-35tetramercanbegeneratedconvenientlythroughtheuseofMARTI27-35peptide-β2mfusionproteins,whichcanfacilitatethemonitoringofHLA-A2-restricted,MARTl-specificCTLresponsesinpatientswithmelanoma.

简介：AbstractNearly 70% of breast cancer (BC) is hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, and endocrine therapy is the mainstay of treatment for this subtype. However, intrinsic or acquired endocrine resistance can occur during the endocrine treatment. Based on insights of endocrine resistance mechanisms, a number of targeted therapies have been and continue to be developed. With regard to HR-positive, HER2-negative advanced BC, aromatase inhibitor (AI) is superior to tamoxifen, and fulvestrant is a better option for patients previously exposed to endocrine therapy. Targeted drugs, such as cyclindependent kinases (CDK) 4/6 inhibitors, mammalian target of rapamycin (mTOR) inhibitors, phosphoinositide-3-kinase (PI3K) inhibitors, and histone deacetylase (HDAC) inhibitors, play a significant role in the present and show a promising future. With the application of CDK4/6 inhibitors becoming common, mechanisms of acquired resistance to them should also be taken into consideration.

简介：BackgroundComparedtoclopidogrel,Ticagrelorsignificantlyreducestheriskofcardiovasculareventsinpatientswithacutemyocardialinfarction(AMI)howeverincreasestheincidenceofbleedingandtheriskoffatalintracranialhemorrhage.Inthisstudy,wescreenedtheAMIpatientswithclopidogrelresistence,anddeterminedwhetherticagrelorsequentialtherapycouldreducetheriskofcardiovasculareventsandbleedingrisk.MethodsAtotalof319AMIpatientswereenrolledinthisprospectiveclinicalstudy.Theplateletinhibitionratesinadenosine5'-diphosphate(ADP)pathwaysweremeasuredbyathrombelastography(TEG)system.ThepatientswithclopidogrelresistanceweredividedintoTicagrelorsequentialtherapygroup(ticagrelorfor3monthsandclopidogrelfor9months,n=143)andClopidogrelgroup(clopidogrelfor12months,n=176).Theriskofmajoradversecardiacevents(MACE)andthesafetyendpointsat1-yearfollow-upwereanalyzed.ResultsTheratesofstentthrombosis(ST)(2.1%vs.8.0%,P=0.017)orMI(2.8%vs.10.2%,P=0.009)werelowerintheticagrelorsequentialtherapygroupthanintheclopidogrelgroup.Dyspneawasmoreoftenintheticagrelorsequentialtherapygroupthanintheclopidogrelgroup(17.5%vs.4.5%,P<0.001).Nosignificantdifferenceintherateofmajorbleedingwasfoundbetweenthegroups(3.4%vs.3.9%,P=0.528).ConclusionsInAMIpatientswithhyporesponsivenesstoclobidogrelticagrelorsequentialtherapygroupsignificantlydecreasedtheratesofSTandMIwithoutincreasedriskofmajorbleedingascomparedwithclopidolgrel.

简介：Themonoclonalantibodyagainstbovinerotavirus(BRV)receptor(BRV-R-mAb)wasusedtoexplorethesimilaritybetweenthereceptorsofBRVandhumanrotavirus(HRV).ELISA,dotimmunobindingassay,cellprotectionassay,solid-phaseassayandimmunohistochemistrymethodwereapplied.BRV-R-mAbboundbothanti-BRVIgGandanti-HRVIgGrespectivelyandcouldprotectMA104cellsagainstBRVandHRVchallenges.Immunohistochemistrytestshowedthattherewererotavirusreceptorsonthesurfacesoffoetalintestinal,trachealmucosaandMA104cellsmembrane.WepurifiedtherotavirusreceptorsonMA104ceils,whichcouldbindbothBRVandHRVinvitro.ItisconcludedthatBRVreceptorandHRVreceptorarehomogenousproteinsandcanberecognizedbybothBRVandHRV.

简介：Unsaturatedradionuclidemigrationexperimentswereconductedinapitinsidethetestinghall.Severaltypesofradionuclideswereusedintheexperiments.Tritiumwasusedasatracerforwatermovementinunsaturatedloess.Otherkindsofradionuclideswerealsousedinordertoobtainfundamentalparametersforradionuclidemigrationsothatfurtherenvironmentalassessmentoflow—levelradioactivewastedisposalcanbecar-riedout.Mechanismsgoverningunsaturatedflowinloess,thatis,principlesofone—waylateralflow,arepresentedqualitativelyinthispaper.Andacontinuumone—dimensionalmodelforradionuclidemigrationtestingisdevelopedbasedontheex-perimentsconductedundertheparticularconditionsatthetestsite.Thedatameasuredfromthetestswerecomparedwithsolutionsofthisone—dimensionalmodel.Resultsshowthatthismodelisfeasibleformodelingradionuclidemigrationinunsaturatedloess.

简介：Sedimentationfromsoilerosionisacriticalreservoirwatershedmanagementissue.Duetothedifficultyoffieldinvestigations,empiricalformulasarecommonlyusedtoestimatethesoilerosionrate.However,theseestimationsareoftenfarfromaccurate.Aneffectivealternativetoestimatingsoilerosionistoanalyzethespatialvariationof137Csinventoryinthesoil.137Cscanbeadsorbedbythesoilandiswidelyassumedtochangeitsdistributiononlywhendisturbedbyrainfallandhumanactivities.Thus,137Csdistributedinsoilscanbeausefulenvironmentaltracertoestimatesoilerosion.Inthisstudy,thenetsoillossestimateis108,346t/yrandthegrosserosionandneterosionratesare10.1and9t/hayrrespectively.Thesedimentdeliveryratioisthereforeestimatedtobe0.9basedonthetwoerosionrates.Becauseofthesteephillsidesinthewatershed,only10%ofthesedimentyieldstayedinthedepositionsitesand90%wastransportedtotheriverasthesedimentoutput.Soilerosionestimatesfromspatialvariationsofthe137CsactivityintheBaishiriverwatershedshowedsatisfactoryaccuracywhencomparedtosedimentyielddata.Usingsoil137CsconcentrationsisthereforeafeasiblemethodforestimatingsoillossordepositioninTaiwan.Datasampling,analysisandresultofthisapproacharegiveninthispaper.

简介：ToselecttheimmunogenicshortpeptidemimicsofmalewormoriginofSchistosomajaponicum(Sj)andtoexploretheirprotectioneffectagainstschistosomiasisinmice,therandomphagedisplaypeptidehbraryof12-merwasscreenedwithIgGtosolublemalewormantigenofSj,andthespecificpositiveclonesselectedthroughthreeroundsofscreeningsweredetectedbyDot-ELISA,andtheninjectedsubcutaneouslyintomiceforvaccinationandprotectionassessmentagainstSj.Itwasfoundthat18randomlypickedphagedisplayedclonesallshoweddefiniteantigenicitywithvariousintensities.Thepooledphagesdisplayedclonescouldinduceproductionofspecificantibodiesandcause31.72%ofwormreductionrateand51.54%ofeggreductionrateinmice,revealingasignificantdifference(P<0.001)incomparisonwiththoseofthecontrols.ItconcludesthattheshortpeptidemimicsofmalewormoriginofSjobtainedbyaffinityscreeningphagedisplayptidelibrarycanelicitpartialprotectionagainstthispathogen.

简介：ThelaserphotolysisofN-diisopropylphosphoryltryptophyltyrosinedipeptidemethylester(N-DiPP-TrpH-TyrOH)hasbeencarriedoututilizingaKrF(248nm)laser.ThedirectintramolecularETbetweenTrpH+residueandTyrOHresiduewasdetectedfirstandtheETbetweenTrpandTyrOHbecameslow.Itwassuggestedthatphosphorylgroupstabilizeneighbourradicalofaromaticringbyhyperconjugation.IncombinationwithcomputermodelingweobtainedthekineticparametersoftheETandprovedthatphosphorylgroupstookpartintheprocessofET.Theresultsshouldbesignificantforbiologicalsystemsinceeverybiologicalprocessinvolvesthephosphorylationornonphosphorylation.

简介：基因治疗为癌症的治疗提供一条新途径。编码immunostimulatorycytokines的基因的转移与显著成功被使用了在动物消除癌症。然而，在有这策略的病人的临床的试用限制了功效。因此，基因转移向量系统的改进是必要的。混合病毒的向量，与鼠科的IL-12或记者LacZ基因由SFVreplicon组成，被构造。这混合向量在vitro并且在vivo在HCC显示出表示的特性和高水平。在一个老鼠orthotropic肝肿瘤模型，没有伴随毒性，由有mIL-12基因的混合向量的确定的肿瘤的治疗导致了一项强壮的反肿瘤活动。随后，助手依赖者侵入人体气管粘膜的病菌包含mifepristone(RU486)的向量可诱导的系统被构造为控制并且人的interleukin的肝特定的表示12(hIL-12)(HD-Ad/RUhIL-12)并且鼠标IL-12(mIL-12)(HD-Ad/RUmIL-12)。数据证明hIL-12的高、支撑的浆液层次能被继续RU486的管理达到每12或24h。hIL-12的重复正式就职能被获得在上，至少在HD-Ad/RUhIL-12的单个注射以后的48个星期的一个时期。肝转移与的处理HD-Ad/RUmIL-12，正RU846在所有动物导致了完全的肿瘤回归。然后，不同cytokine基因被插入到有条件的replicative侵入人体气管粘膜的病菌向量(也叫的oncolytic侵入人体气管粘膜的病菌)。在肿瘤房间的侵入人体气管粘膜的病菌的复制将杀死肿瘤房间和版本病毒，它感染包围肿瘤房间。由oncolytic侵入人体气管粘膜的病菌的cytopathic效果和transgene的生物效果的联合将施加强壮的反肿瘤活动。向量的这些新类型可以为癌症基因治疗提供一个有势力和安全工具。

简介：考生进入高三后，紧张的情绪会逐渐加深，每天可以听20-30分钟音乐舒缓一下情绪。

简介：许多病毒的epitope在匹配MHC的个人的特定的T房间受体(TCR)被表明了在链包含保存氨基酸主题决定补充的区域3(CDR3)。然而，保存主题是否能也在TCR链被发现，不肯定。在以前的研究，我们开发了一个修改方法扩大cytomegalovirus(CMV)的百分比pp65在由在vitro的连续的肽刺激的PBMC的肽特定的CD8+T房间，它为察觉提供特定的T房间的足够的数字。在这研究，我们进一步分析了TCRV和V基因家庭的限制用法并且调查了pp65的CDR3基因顺序肽特定的CD8+T房间。CDR3spectratypes的分析建议了TCR链AV8，AV12，AV21，AV31家庭和TCR的一个限制用法链BV3，BV14，BV21，BV23，在施主CD8+T房间的BV11家庭由pp65肽刺激了。这些T房间的序列包含了类似的顺序(TX)在TCR链和L(XT)的CDR3区域的G(X)A在TCR的G(X)A链。

简介：AIMTo调查vasoactive的角色在形式剥夺的肠的肽(贵宾)近视(频分多路复用).METHODSFDM被放在三组八只小鸡创造一半透明在他们的右眼睛上更弥漫。Intravitreal注射盐并且贵宾一天被使用一次进组的堵塞眼睛2和3分别地。视网膜镜检法和轴的长度(AL)大小在第一和8th天更弥漫穿。在三个组的右眼睛和白天8上的第一个组的左眼睛的VIP受体和ZENK蛋白质的视网膜mRNA层次用在权利的中部的最后的折射(D)看的.RESULTSThe是的实时聚合酶链反应(PCR)被决定-13.75(-16.00,-12.00),-11.50(-12.50,-7.50),和-1.50(在组的-4.75,-0.75)1，2，和3，分别地(P<0.001)。在右眼睛的中部的AL(公里)是10.65(10.00，11.10)，9.90(9.70，10.00)，并且9.20(9.15，9.25)在组1，2，和3，分别地(P<0.001)。为VIP2受体的中部的三角洲三角洲周期阀值(CT)价值是1.07(0.82，1.43)，1.22(0.98，1.65)，0.29(0.22，0.45)在组的右眼睛1，2，和3，和1.18(0.90，1.37)在组1的左眼睛，分别地(P=0.001)。为ZENK蛋白质的中部的三角洲三角洲CT价值是1.07(0.63，5.03)，3.55(2.20，5.55)，在组的右眼睛无法发现1，2，和3和1.89(0.21，4.73)在组1的左眼睛，(P=0.001)分别地，.CONCLUSIONVIP在频分多路复用的发展有潜在的禁止的效果。

简介：2013年10月12—13日中国生理学会张锡钧基金会第十二届全国青年优秀生理学学术论文交流会在湖南长沙顺利召开。由各省生理学会推荐的37名参赛选手的论文参与评选，会议展示了选手们近3年来在生理学研究方面所取得的最新研究成果。经过专家对参评者论文和现场报告的综合评判，评出一等奖、二等奖、三等奖、特别奖、最佳表达奖、最佳答辩奖和最佳图标奖共11名。从2013年第6期开始，《生理通讯》将陆续转载获奖者的参评论文各一篇，以飨读者。

简介：Inthepastdecade,anincreasedamountofclinically-orientedresearchinvolvingimmunotoxinshasbeenpublished.Immunotoxinsareagroupofartificially-madecytotoxicmoleculestargetingcancercells.Thesemoleculescomposedofatargetingmoiety,suchasaligandoranantibody,linkedtotoxinmoiety,whichisatoxinwitheithertruncatedordeletedcell-bindingdomainthatpreventsitfrombindingtonormalcells.Immunotoxinscanbedividedintotwocategories:chemicallyconjugatedimmunotoxinsandrecombinantones.Theimmunotoxinsofthefirstcategoryhaveshownlimitedefficacyinclinicaltrialsinpatientswithhematologicmalignanciesandsolidtumors.Withinthelastfewyears,single-chainimmunotoxinsprovideenhancedtherapeuticefficacyoverconjugatedformsandresultinimprovedantitumoractivity.Inthisreview,webrieflyillustratethedesignoftheimmunotoxinsandtheirapplicationsinclinicaltrials.Cellular&MolecularImmunology.2005;2(2):106-112.