Objective： Sepsis remains a leading cause of death in many Intensive Care Units worldwide, lmmunosuppression has been a primary locus of sepsis research as a key pathophysiological mechanism. Given the important role...Objective： Sepsis remains a leading cause of death in many Intensive Care Units worldwide, lmmunosuppression has been a primary locus of sepsis research as a key pathophysiological mechanism. Given the important role of the negative costimulatory molecules programmed cell death-1 （PD-1） and programmed death-ligand 1 （PD-LI） in the occurrence of immunosuppression during sepsis, we reviewed literatures related to the PD-1/PD-L 1 pathway to examine its potential as a new target for sepsis treatment. Data Sources： Studies of the association between PD-I/PD-LI and sepsis published tip to January 31, 2017, were obtained by searching tile PubMed database. Study Selection： English language studies, including those based on animal models, clinical research, and reviews, with data related to PD- 1/PD-L I and sepsis, were evaluated. Results： lmmunomodulatory therapeutics could reverse the deactivation of immune cells caused by sepsis and restore immune cell activation and function. Blockade of＇the PD-1/PD-LI pathway could reduce the exhaustion ofT-cells and enhance the proliferation and activation ofT-cells. Conclusions： The anti-PD- I/PD-L 1 pathway shows promise as a new target for sepsis treatment. This review provides a basis for clinical trials and Iiiture studies aimed at revaluating the efficacy and safety of this targeted approach.展开更多
Background: Anti-programmed death-1/programmed death-ligand 1(PD-1/PD-L1) immunotherapy has been proved to be effective on gastric cancer in ongoing clinical trials. However, the value of PD-L1 in predicting responses...Background: Anti-programmed death-1/programmed death-ligand 1(PD-1/PD-L1) immunotherapy has been proved to be effective on gastric cancer in ongoing clinical trials. However, the value of PD-L1 in predicting responses of patients with gastric cancer to anti-PD-1/PD-L1 immunotherapy is controversial. Some studies suggested that intra-and inter-tumoral heterogeneity of PD-L1 expression might explain the controversy.This study aimed to analyze the expression of PD-L1, PD-L2, and PD-1 as well as CD8(+) T-cell density in primary tumors and lymph nodes from patients with stage T1-4 N+M0 gastric adenocarcinoma to explore the heterogeneity of PD-1 signaling pathway molecules.Methods: In primary tumors and metastatic as well as non-metastatic lymph nodes from patients with stage T1-4 N+M0 gastric adenocarcinoma, we detected PD-L1 and PD-L2 expression with immunohistochemistry. CD8(+)T-cell density in primary tumors and PD-1 expression on CD8(+)T cells were detected with immunofluorescence. Univariate analysis was used to determine the prognostic values of them. Cox proportional hazard regression model was used to identify independent risk factors that affect patients' overall survival and disease-free survival.Results: Among 119 eligible patients who had undergone surgical resection, the positive rate of PD-L1 was higher in metastatic lymph nodes than in primary tumors(45.4% vs. 38.7%, P = 0.005); the positive rate of PD-1 on CD8(+)T cells was significantly higher in primary tumors and metastatic lymph nodes than in tumor-free lymph nodes(both P < 0.001). The intensity of PD-1 expression on CD8(+) T cells in primary tumors and in metastatic lymph nodes were stronger than that in tumor-free lymph nodes from the same patient. Beside, the positive rate of PD-L2 did not show any differences between primary tumors and metastatic lymph nodes. In multivariate analysis, PD-L1 expression,PD-L2 expression, a low density of CD8(+) T cells in primary tumors, and PD-1 expression on CD8(+) T cells in primary tumors were associated with展开更多
Blockade of the programmed death ligand 1(PD-L1) and programmed cell death 1(PD-1) receptor axis represents an effective form of cancer immunotherapy. Preclinical evidence initially suggested that gastric and gastroes...Blockade of the programmed death ligand 1(PD-L1) and programmed cell death 1(PD-1) receptor axis represents an effective form of cancer immunotherapy. Preclinical evidence initially suggested that gastric and gastroesophageal junction(GEJ) cancers are potentially immunotherapy-sensitive tumors. Early phase clinical trials have demonstrated promising antitumor activity with PD-1/PD-L1 blockade in advanced or metastatic gastric/GEJ cancer. Microsatellite instability(MSI) and PD-L1 expression have been shown to predict higher response to PD-1 inhibitors as highlighted by the recent approvals of pembrolizumab in treatmentrefractory solid tumors with MSI status and the thirdline or greater treatment of PD-L1 positive advanced gastric/GEJ cancers. However, predictive and prognostic biomarkers remain an ongoing need. In this review, we detail the preclinical evidence and early tissue biomarker analyses illustrating potential predictive biomarkers to PD-1/PD-L1 blockade in gastric/GEJ cancer. We also review the clinical development of PD-1/PD-L1 inhibitors in gastric/GEJ cancer and highlight several areas in need of future investigation in order to optimize the efficacy of PD-1/PD-L1 blockade in gastric/GEJ cancer.展开更多
目的综述近年来靶向程序性细胞死亡受体1(programmed cell death 1,PD-1)和程序性细胞死亡配体1(programmed cell death ligand 1,PD-L1)的单克隆抗体、多肽抑制剂、小分子抑制剂,以及癌症疫苗等方面的研究进展。方法以“PD-1”、“PD-L...目的综述近年来靶向程序性细胞死亡受体1(programmed cell death 1,PD-1)和程序性细胞死亡配体1(programmed cell death ligand 1,PD-L1)的单克隆抗体、多肽抑制剂、小分子抑制剂,以及癌症疫苗等方面的研究进展。方法以“PD-1”、“PD-L1”、“抑制剂”等为检索词对国内外文献进行查阅,总结了PD-1/PD-L1靶向抑制剂的研究进展。结果目前,PD-1/PD-L1靶向抑制剂包括单克隆抗体、多肽类抑制剂、小分子抑制剂、抗癌疫苗等,它们旨在阻断PD-1/PD-L1相互作用,恢复T细胞活性。结论在靶向PD-1/PD-L1相互作用的抑制剂中,单克隆抗体的发展最快并获得了成功的应用,但其有免疫原性高等不足;多肽类抑制剂、小分子抑制剂和抗癌疫苗虽未得到广泛应用,但其有着免疫原性低,渗透性好等优点,是未来PD-1/PD-L1靶向药物研发的重点。展开更多
目的检测妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)孕妇血清程序性细胞死亡因子4(programmed cell death factor 4,PDCD4)和葡萄糖转运蛋白1(glucose transporter 1,GLUT1)的表达水平,分析二者与孕妇妊娠结局...目的检测妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)孕妇血清程序性细胞死亡因子4(programmed cell death factor 4,PDCD4)和葡萄糖转运蛋白1(glucose transporter 1,GLUT1)的表达水平,分析二者与孕妇妊娠结局的相关性。方法收集巴中市巴州区妇幼保健院产科2018年7月~2020年7月收治的ICP孕妇126例作为研究组,其中轻度ICP组46例,重度ICP组80例,选择同期该院120例健康产检孕妇作为对照组。采用实时荧光定量PCR(qRT-PCR)法测定ICP孕妇血清PDCD4和GLUT1水平,多因素Logistic回归分析影响ICP孕妇妊娠结局的因素,Pearson相关性分析ICP孕妇血清PDCD4和GLUT1水平的相关性。结果与对照组比较,研究组PDCD4(1.36±0.23 vs 1.02±0.21),GLUT1(1.40±0.22 vs 0.99±0.18)水平升高,差异具有统计学意义(t=15.935,12.090,均P=0.000)。重度ICP组PDCD4(1.41±0.25),GLUT1(1.45±0.22)水平显著高于轻度ICP组(1.27±0.20,1.31±0.21),差异具有统计学意义(t=3.246,3.496,均P<0.05)。研究组羊水胎粪污染(20.63%)、自发性早产(7.14%)、产后出血(8.73%)、宫内窘迫(11.90%)等不良妊娠结局的发生率均高于对照组(0.00%,0.83%,0.83%,1.67%),差异均具有统计学意义(χ^(2)=1.049~29.159,均P<0.05);妊娠结局良好组和妊娠结局不良组患者的发病程度(OR=1.109,95%CI=1.035~1.188)、PDCD4(OR=1.428,95%CI=1.013~2.012)以及GLUT1(OR=1.453,95%CI=1.066~1.980)水平差异具有统计学意义(均P<0.05);多因素Logistic回归分析显示,发病程度、PDCD4,GLUT1为ICP孕妇妊娠结局不良的影响因素(Waldχ^(2)==8.738,1.428,1.453;P=0.003,0.041,0.018);Pearson相关性分析显示,ICP孕妇血清PDCD4与GLUT1水平呈正相关(r=0.460,P<0.05)。结论PDCD4,GLUT1在ICP孕妇血清中表达均上调,二者呈正相关,是ICP孕妇妊娠结局不良的影响因素。展开更多
目的:观察程序性细胞死亡因子1(programmed cell death 1,PD-1)免疫治疗联合贝伐单抗进行抗血管生成双靶治疗Ⅳ期肺腺癌的疗效,并分析其对细胞免疫功能、短期预后和不良反应的影响。方法:选取成都大学附属医院2018年12月至2020年8月收...目的:观察程序性细胞死亡因子1(programmed cell death 1,PD-1)免疫治疗联合贝伐单抗进行抗血管生成双靶治疗Ⅳ期肺腺癌的疗效,并分析其对细胞免疫功能、短期预后和不良反应的影响。方法:选取成都大学附属医院2018年12月至2020年8月收治的Ⅳ期肺腺癌患者67例,按照治疗方式不同分为对照组(n=33)和联合组(n=34),对照组予以化疗+PD-1抑制剂治疗,联合组予以化疗+PD-1抑制剂+贝伐单抗治疗,比较2组患者近期治疗疗效、治疗前后细胞免疫功能、卡氏功能状态(Karnofsky performance status,KPS)评分变化情况、不良反应及无进展生存期。结果:联合组患者治疗总有效率和疾病控制率分别为29.41%和79.41%,显著高于对照组的9.09%和54.55%(P<0.05);治疗后,联合组患者CD3^(+)、CD4^(+)、CD4^(+)/CD8^(+)显著高于对照组(P<0.05),CD8^(+)与对照组患者比较无统计学差异(P>0.05);联合组患者KPS评分增加稳定率为73.53%,显著高于对照组患者的45.45%(P<0.05);联合组患者骨髓抑制、消化道反应、血液毒性、肝肾功能损害及周围神经毒性不良反应发生率与对照组患者比较,差异无统计学意义(P>0.05);联合组患者中位无进展生存期为9.73个月,对照组患者中位无进展生存期为6.05个月,差异有统计学意义(P<0.05)。结论:PD-1免疫治疗联合贝伐单抗进行抗血管生成双靶治疗Ⅳ期肺腺癌,可明显提高近期治疗疗效,改善患者免疫功能,提高其生存质量,延长其无进展生存时间。展开更多
文摘Objective： Sepsis remains a leading cause of death in many Intensive Care Units worldwide, lmmunosuppression has been a primary locus of sepsis research as a key pathophysiological mechanism. Given the important role of the negative costimulatory molecules programmed cell death-1 （PD-1） and programmed death-ligand 1 （PD-LI） in the occurrence of immunosuppression during sepsis, we reviewed literatures related to the PD-1/PD-L 1 pathway to examine its potential as a new target for sepsis treatment. Data Sources： Studies of the association between PD-I/PD-LI and sepsis published tip to January 31, 2017, were obtained by searching tile PubMed database. Study Selection： English language studies, including those based on animal models, clinical research, and reviews, with data related to PD- 1/PD-L I and sepsis, were evaluated. Results： lmmunomodulatory therapeutics could reverse the deactivation of immune cells caused by sepsis and restore immune cell activation and function. Blockade of＇the PD-1/PD-LI pathway could reduce the exhaustion ofT-cells and enhance the proliferation and activation ofT-cells. Conclusions： The anti-PD- I/PD-L 1 pathway shows promise as a new target for sepsis treatment. This review provides a basis for clinical trials and Iiiture studies aimed at revaluating the efficacy and safety of this targeted approach.
文摘Background: Anti-programmed death-1/programmed death-ligand 1(PD-1/PD-L1) immunotherapy has been proved to be effective on gastric cancer in ongoing clinical trials. However, the value of PD-L1 in predicting responses of patients with gastric cancer to anti-PD-1/PD-L1 immunotherapy is controversial. Some studies suggested that intra-and inter-tumoral heterogeneity of PD-L1 expression might explain the controversy.This study aimed to analyze the expression of PD-L1, PD-L2, and PD-1 as well as CD8(+) T-cell density in primary tumors and lymph nodes from patients with stage T1-4 N+M0 gastric adenocarcinoma to explore the heterogeneity of PD-1 signaling pathway molecules.Methods: In primary tumors and metastatic as well as non-metastatic lymph nodes from patients with stage T1-4 N+M0 gastric adenocarcinoma, we detected PD-L1 and PD-L2 expression with immunohistochemistry. CD8(+)T-cell density in primary tumors and PD-1 expression on CD8(+)T cells were detected with immunofluorescence. Univariate analysis was used to determine the prognostic values of them. Cox proportional hazard regression model was used to identify independent risk factors that affect patients' overall survival and disease-free survival.Results: Among 119 eligible patients who had undergone surgical resection, the positive rate of PD-L1 was higher in metastatic lymph nodes than in primary tumors(45.4% vs. 38.7%, P = 0.005); the positive rate of PD-1 on CD8(+)T cells was significantly higher in primary tumors and metastatic lymph nodes than in tumor-free lymph nodes(both P < 0.001). The intensity of PD-1 expression on CD8(+) T cells in primary tumors and in metastatic lymph nodes were stronger than that in tumor-free lymph nodes from the same patient. Beside, the positive rate of PD-L2 did not show any differences between primary tumors and metastatic lymph nodes. In multivariate analysis, PD-L1 expression,PD-L2 expression, a low density of CD8(+) T cells in primary tumors, and PD-1 expression on CD8(+) T cells in primary tumors were associated with
文摘Blockade of the programmed death ligand 1(PD-L1) and programmed cell death 1(PD-1) receptor axis represents an effective form of cancer immunotherapy. Preclinical evidence initially suggested that gastric and gastroesophageal junction(GEJ) cancers are potentially immunotherapy-sensitive tumors. Early phase clinical trials have demonstrated promising antitumor activity with PD-1/PD-L1 blockade in advanced or metastatic gastric/GEJ cancer. Microsatellite instability(MSI) and PD-L1 expression have been shown to predict higher response to PD-1 inhibitors as highlighted by the recent approvals of pembrolizumab in treatmentrefractory solid tumors with MSI status and the thirdline or greater treatment of PD-L1 positive advanced gastric/GEJ cancers. However, predictive and prognostic biomarkers remain an ongoing need. In this review, we detail the preclinical evidence and early tissue biomarker analyses illustrating potential predictive biomarkers to PD-1/PD-L1 blockade in gastric/GEJ cancer. We also review the clinical development of PD-1/PD-L1 inhibitors in gastric/GEJ cancer and highlight several areas in need of future investigation in order to optimize the efficacy of PD-1/PD-L1 blockade in gastric/GEJ cancer.
文摘目的综述近年来靶向程序性细胞死亡受体1(programmed cell death 1,PD-1)和程序性细胞死亡配体1(programmed cell death ligand 1,PD-L1)的单克隆抗体、多肽抑制剂、小分子抑制剂,以及癌症疫苗等方面的研究进展。方法以“PD-1”、“PD-L1”、“抑制剂”等为检索词对国内外文献进行查阅,总结了PD-1/PD-L1靶向抑制剂的研究进展。结果目前,PD-1/PD-L1靶向抑制剂包括单克隆抗体、多肽类抑制剂、小分子抑制剂、抗癌疫苗等,它们旨在阻断PD-1/PD-L1相互作用,恢复T细胞活性。结论在靶向PD-1/PD-L1相互作用的抑制剂中,单克隆抗体的发展最快并获得了成功的应用,但其有免疫原性高等不足;多肽类抑制剂、小分子抑制剂和抗癌疫苗虽未得到广泛应用,但其有着免疫原性低,渗透性好等优点,是未来PD-1/PD-L1靶向药物研发的重点。
基金国家自然科学基金(8147228481672699)+3 种基金Supported by National Natural Science Foundation of China(8147228481672699)上海市浦江人才项目(16PJD004)Shanghai Pujiang Talent Program(16PJD004)
文摘目的检测妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)孕妇血清程序性细胞死亡因子4(programmed cell death factor 4,PDCD4)和葡萄糖转运蛋白1(glucose transporter 1,GLUT1)的表达水平,分析二者与孕妇妊娠结局的相关性。方法收集巴中市巴州区妇幼保健院产科2018年7月~2020年7月收治的ICP孕妇126例作为研究组,其中轻度ICP组46例,重度ICP组80例,选择同期该院120例健康产检孕妇作为对照组。采用实时荧光定量PCR(qRT-PCR)法测定ICP孕妇血清PDCD4和GLUT1水平,多因素Logistic回归分析影响ICP孕妇妊娠结局的因素,Pearson相关性分析ICP孕妇血清PDCD4和GLUT1水平的相关性。结果与对照组比较,研究组PDCD4(1.36±0.23 vs 1.02±0.21),GLUT1(1.40±0.22 vs 0.99±0.18)水平升高,差异具有统计学意义(t=15.935,12.090,均P=0.000)。重度ICP组PDCD4(1.41±0.25),GLUT1(1.45±0.22)水平显著高于轻度ICP组(1.27±0.20,1.31±0.21),差异具有统计学意义(t=3.246,3.496,均P<0.05)。研究组羊水胎粪污染(20.63%)、自发性早产(7.14%)、产后出血(8.73%)、宫内窘迫(11.90%)等不良妊娠结局的发生率均高于对照组(0.00%,0.83%,0.83%,1.67%),差异均具有统计学意义(χ^(2)=1.049~29.159,均P<0.05);妊娠结局良好组和妊娠结局不良组患者的发病程度(OR=1.109,95%CI=1.035~1.188)、PDCD4(OR=1.428,95%CI=1.013~2.012)以及GLUT1(OR=1.453,95%CI=1.066~1.980)水平差异具有统计学意义(均P<0.05);多因素Logistic回归分析显示,发病程度、PDCD4,GLUT1为ICP孕妇妊娠结局不良的影响因素(Waldχ^(2)==8.738,1.428,1.453;P=0.003,0.041,0.018);Pearson相关性分析显示,ICP孕妇血清PDCD4与GLUT1水平呈正相关(r=0.460,P<0.05)。结论PDCD4,GLUT1在ICP孕妇血清中表达均上调,二者呈正相关,是ICP孕妇妊娠结局不良的影响因素。
