CD28 and 4-1BB costimulatory endodomains included in chimeric antigen receptor(CAR)molecules play a critical role in promoting sustained antitumor activity of CAR-T cells.However,the molecular events associated with t...CD28 and 4-1BB costimulatory endodomains included in chimeric antigen receptor(CAR)molecules play a critical role in promoting sustained antitumor activity of CAR-T cells.However,the molecular events associated with the ectopic and constitutive display of either CD28 or 4-1BB in CAR-T cells have been only partially explored.In the current study,we demonstrated that 4-1BB incorporated within the CAR leads to cell cluster formation and cell death in the forms of both apoptosis and necroptosis in the absence of CAR tonic signaling.Mechanistic studies illustrate that 4-1BB sequesters A20 to the cell membrane in a TRAF-dependent manner causing A20 functional deficiency that in turn leads to NF-κB hyperactivity,cell aggregation via ICAM-1 overexpression,and cell death including necroptosis via RIPK1/RIPK3/MLKL pathway.Genetic modulations obtained by either overexpressing A20 or releasing A20 from 4-1BB by deleting the TRAF-binding motifs of 4-1BB rescue cell cluster formation and cell death and enhance the antitumor ability of 4-1BB-costimulated CAR-T cells.展开更多
目的系统评价糖尿病与下丘脑．垂体．肾上腺（HPA）轴功能的关系，为临床筛查糖尿病患者HPA轴功能提供一定的客观依据。方法检索PubMed、Ovid、Embase、Web of Science文献数据库，筛选糖尿病与HPA轴功能关系的观察性研究。以标准化均...目的系统评价糖尿病与下丘脑．垂体．肾上腺（HPA）轴功能的关系，为临床筛查糖尿病患者HPA轴功能提供一定的客观依据。方法检索PubMed、Ovid、Embase、Web of Science文献数据库，筛选糖尿病与HPA轴功能关系的观察性研究。以标准化均数差（SMD）作为合并效应量，采用Stata12．0软件进行met0分析。结果Meta分析结果显示：与对照组相比，糖尿病组、T1DM组、T2DM组、糖尿病伴或不伴慢性并发症组及糖尿病合并高血压组血基础皮质醇水平均较高；糖尿病组地塞米松抑制后血皮质醇显著高于对照组：糖尿病组24hUFC、血ACTH水平较对照组均无显著差异。定性评价发现，糖尿病组与对照组之间清晨唾液皮质醇及皮质醇觉醒反应（CAR）各研究结果存在不一致，多数研究显示糖尿病患者存在CAR水平降低。结论糖尿病患者存在HPA轴功能异常，且存在合并症可能加重HPA轴功能异常。展开更多
基金Supported by NSFC(11201235)Program of Natural Science Research of Jiangsu Higher Education Institution of China(12KJB110010)+2 种基金Philosophy and Social Science Fund of Jiangsu Higher Education Institution of China(2013SJD790031)China Postdoctoral Science Foundation(2013M541697)Postdoctoral Foundation of Jiangsu Province(1302044C)
基金P30CA016086NIH S10 Shared Instrumentation Grant,S10OD026951,for supporting this work.
文摘CD28 and 4-1BB costimulatory endodomains included in chimeric antigen receptor(CAR)molecules play a critical role in promoting sustained antitumor activity of CAR-T cells.However,the molecular events associated with the ectopic and constitutive display of either CD28 or 4-1BB in CAR-T cells have been only partially explored.In the current study,we demonstrated that 4-1BB incorporated within the CAR leads to cell cluster formation and cell death in the forms of both apoptosis and necroptosis in the absence of CAR tonic signaling.Mechanistic studies illustrate that 4-1BB sequesters A20 to the cell membrane in a TRAF-dependent manner causing A20 functional deficiency that in turn leads to NF-κB hyperactivity,cell aggregation via ICAM-1 overexpression,and cell death including necroptosis via RIPK1/RIPK3/MLKL pathway.Genetic modulations obtained by either overexpressing A20 or releasing A20 from 4-1BB by deleting the TRAF-binding motifs of 4-1BB rescue cell cluster formation and cell death and enhance the antitumor ability of 4-1BB-costimulated CAR-T cells.
文摘目的系统评价糖尿病与下丘脑．垂体．肾上腺（HPA）轴功能的关系，为临床筛查糖尿病患者HPA轴功能提供一定的客观依据。方法检索PubMed、Ovid、Embase、Web of Science文献数据库，筛选糖尿病与HPA轴功能关系的观察性研究。以标准化均数差（SMD）作为合并效应量，采用Stata12．0软件进行met0分析。结果Meta分析结果显示：与对照组相比，糖尿病组、T1DM组、T2DM组、糖尿病伴或不伴慢性并发症组及糖尿病合并高血压组血基础皮质醇水平均较高；糖尿病组地塞米松抑制后血皮质醇显著高于对照组：糖尿病组24hUFC、血ACTH水平较对照组均无显著差异。定性评价发现，糖尿病组与对照组之间清晨唾液皮质醇及皮质醇觉醒反应（CAR）各研究结果存在不一致，多数研究显示糖尿病患者存在CAR水平降低。结论糖尿病患者存在HPA轴功能异常，且存在合并症可能加重HPA轴功能异常。
