Background: The programmed cell death-1(PD-1)/programmed cell death-ligand 1(PD-L1) pathway inhibits the activation of T cells and plays a crucial role in the negative regulation of cellular and humoral immune respons...Background: The programmed cell death-1(PD-1)/programmed cell death-ligand 1(PD-L1) pathway inhibits the activation of T cells and plays a crucial role in the negative regulation of cellular and humoral immune responses.Diffuse large B-cell lymphoma(DLBCL) is the most common lymphoid malignancy in adults. In the present study, we aimed to detect the expression of PD-L1 in DLBCL and to analyze its relationship with prognosis.Methods: We reviewed medical records of 204 newly diagnosed DLBCL patients in Sun Yat-sen University Cancer Center between October 2005 and August 2012. The expression of PD-L1 in tumor tissues from these 204 patients was detected using immunohistochemical(IHC) assay. The expression of anaplastic lymphoma kinase(ALK), CD5,CD30, and C-Myc in tumor specimens from 109 patients was detected using IHC, and Epstein-Barr virus(EBV)-encoded RNAs(EBERs) were detected using fluorescence in situ hybridization. The Spearman method was used for correlation analysis. The Kaplan-Meier method with log-rank test was used for univariate analysis. Cox proportional hazards model was used for multivariate analysis.Results: Of the 204 patients, 100(49.0%) were PD-L1-positive in tumor cells and 44(21.6%) were PD-L1-positive in tumor microenvironment. PD-L1 expression in tumor cells and tumor microenvironment were more common in the non-germinal center B-cell-like(GCB) subtype than in the GCB subtype(P = 0.02 and P= 0.04). Patients with PD-L1 expression in tumor microenvironment were more likely to be resistant to first-line chemotherapy when compared with the patients without PD-L1 expression in tumor microenvironment(P = 0.03). PD-L1 expression in tumor microenvironment was negatively correlated with C-Myc expression(r =-0.20, P = 0.04). No correlations were detected between PD-L1 expression and the expression of ALK, CD5, and CD30 as well as EBERs. The 5-year overall survival(OS)rates were 50.0% and 67.3% in patients with and without PD-L1 expression in tumor cells(P = 0.02). PD-L1 expression in tumor cells was an independent risk predictor for OS(P < 0.01).Conclusions: PD-L1 expression is more common in the non-GCB subtype than in the GCB subtype. PD-L1 expression in tumor microenvironment has a negative correlation with C-Myc. PD-L1 positivity predicts short survival in DLBCL patients. For patients with PD-L1 expression, more strategy such as anti-PD-L1 antibody treatment should be recommended.展开更多
目的通过癌症基因组图谱(The Cancer Genome Atlas,TCGA)数据库分析弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)中铁死亡相关基因的表达及其与程序性死亡受体配体-1(programmed death ligand-1,PD-L1)和免疫细胞的关系,为D...目的通过癌症基因组图谱(The Cancer Genome Atlas,TCGA)数据库分析弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)中铁死亡相关基因的表达及其与程序性死亡受体配体-1(programmed death ligand-1,PD-L1)和免疫细胞的关系,为DLBCL的治疗提供新的靶标。方法通过TCGA数据库查找获得22个铁死亡相关基因。从TCGA数据库获取48例DLBCL(DLBCL组)及54例反应性淋巴结增生患者(对照组)淋巴结标本的铁死亡相关基因以及PD-L1的表达数据。使用Wilcoxon秩和检验进行组间差异性表达分析。基因表达相关性分析采用Spearman相关性分析。采用R软件包pheatmap分析DLBCL中铁死亡相关基因表达与免疫细胞的相关性。采用R软件GSVA包分析铁死亡相关基因表达与磷脂酰肌醇-3-激酶-蛋白激酶B-哺乳动物雷帕霉素靶蛋白(phosphatidylinositol 3 kinase-protein kinase B-mammalian target of rapamycin,PI3K-Akt-mTOR)信号通路的相关性。结果DLBCL中周期素依赖性激酶抑制因子1A(cyclin dependent kinase inhibitor 1A,CDKN1A)、70 kDa热休克蛋白5(heat shock 70 kDa protein 5,HSPA5)、内质膜蛋白复合体亚基2(endoplasmic membrane protein complex subunit 2,EMC2)、溶质载体家族7成员11(solute carrier family 7,member 11,SLC7A11)、金属硫蛋白1G(metallothionein 1G,MT1G)、热休克蛋白B1(heat shock protein B1,HSPB1)、谷胱甘肽过氧化酶4(glutathione peroxidase4,GPX4)、范可尼贫血互补群D2(Fanconi anemia complementary group D2,FANCD2)、柠檬酸合成酶(citrate synthase,CS)、CDGSH铁硫结构域1(CDGSH iron sulfur domain 1,CISD1)、法尼基二磷酸法尼基转移酶1(farnesyl diphosphate farnesyltransferase 1,FDFT1)、SLC1A5、转铁蛋白受体(transferrin receptor,TFRC)、核糖体蛋白L8(ribosomal protein L8,RPL8)、核受体共激活因子4(nuclear receptor coativator 4,NCOA4)、二肽基肽酶Ⅳ(dipeptidyl peptidaseⅣ,DPP4)和花生四烯酸15脂氧合酶(arachidonate-15-lipoxygenase,ALOX15)基因表达均上调(均P<0.05)。免疫细胞相关分析显示,铁死亡相关基因可激活体内巨噬细胞M1(P<0.05)。DLBCL中长链脂酰辅酶A合成酶4(acyl-CoA synthetase long chain family member 4,ACSL4)、CDKN1A、DPP4、EMC2、谷氨酰胺酶2(glutaminase 2,GLS2)、HSPA5、溶血卵磷脂酰基转移酶3(lysophosphatidylcholine acyltransferase 3,LPCAT3)、MT1G、NCOA4、红细胞衍生核因子2样蛋白2(nuclear factor erythroid 2-like-2,NFE2L2)、精脒/精胺N1-乙酰基转移酶1(spermidine/spermine N1-acetyltransferase 1,SAT1)、SLC7A11和TFRC这些铁死亡相关基因的表达均与PD-L1表达呈正相关(均r>0.4,均P<0.05)。铁死亡相关基因LPCAT3、NCOA4和TFRC的表达均与PI3K-AktmTOR通路呈正相关(均r>0.4,均P<0.05)。结论多数铁死亡相关基因在DLBCL组织中高表达,且与PD-L1、免疫浸润及PI3K-Akt-mTOR通路有关。展开更多
Cannabidiol (CBD), one of the most studied phytocannabinoids, is non-psychotropic and can induce protective effects on the central nervous system against acute and chronic brain injury. Interestingly, CBD inhibits pro...Cannabidiol (CBD), one of the most studied phytocannabinoids, is non-psychotropic and can induce protective effects on the central nervous system against acute and chronic brain injury. Interestingly, CBD inhibits processes relating to amyloid beta (Aβ)-induced neurotoxicity in mouse models of Alzheimer’s disease, though the detailed molecular mechanism underlying the CBD neurotoxicity modulation is not fully understood. In this study, using atomic force microscopy, we find that CBD promotes the aggregation of Aβ peptides, enhancing the formation of Aβ oligomers, also known as Aβ-derived diffusible ligands (ADDLs). The CBD-mediated sequestration of Aβ monomers in soluble ADDLs could reduce neurotoxicity. This study highlights a possible role of CBD in modulating the formation of ADDL aggregates and provides insight into potentially neuroprotective properties of CBD in Alzheimer’s disease.展开更多
目的探讨程序性死亡蛋白受体-1配体(programmed death ligand-1, PD-L1)和TNF家族的B细胞活化因子(B cell-activating factor belonging to the TNF family, BAFF-R)在胃弥漫性大B细胞淋巴瘤(gastric diffuse large B-cell lymphoma, GD...目的探讨程序性死亡蛋白受体-1配体(programmed death ligand-1, PD-L1)和TNF家族的B细胞活化因子(B cell-activating factor belonging to the TNF family, BAFF-R)在胃弥漫性大B细胞淋巴瘤(gastric diffuse large B-cell lymphoma, GDLBCL)的瘤组织和瘤旁组织中的表达及其临床意义。方法采用免疫组织化学法和定量逆转录-聚合酶链反应法(quantitative real time polymerase chain reaction, qRT-PCR)检测26例GDLBCL瘤组织和瘤旁组织中的PD-L1和BAFF-R的表达,分析PD-L1和BAFF-R的表达与GDLBCL临床分期和病理分型之间的关系和PD-L1与BAFF-R表达的相关性。结果 PD-L1和BAFF-R在GDLBCL中的表达显著高于瘤旁组织(P<0.01)。PD-L1和BAFF-R表达与GDLBCL分期及病理分型均有明显相关性(P<0.01),PD-L1与BAFF-R有相关性(P<0.01)。结论 PDL-1和BAFF-R表达上调与GDLBCL分期及病理分型密切相关,联合检测PD-L1和BAFF-R可能成为GDLBCL有价值的预后指标。以PD-L1和BAFF-R信号通路为靶点的治疗有望成为GDLBLC免疫治疗的潜在方案。展开更多
基金supported by National Natural Science Foundation of China(Nos.81672686,81372883,and 81001052)Natural Science Foundation of Guangdong Province,China(No.2015A030313020)+2 种基金Science and Technology Planning Project of Guangdong Province,China(No.2011B031800222)Young Talents Key Project of Sun Yat-sen University(No.2015ykzd13)the Sister Institution Network Fund of MD Anderson Cancer Center
文摘Background: The programmed cell death-1(PD-1)/programmed cell death-ligand 1(PD-L1) pathway inhibits the activation of T cells and plays a crucial role in the negative regulation of cellular and humoral immune responses.Diffuse large B-cell lymphoma(DLBCL) is the most common lymphoid malignancy in adults. In the present study, we aimed to detect the expression of PD-L1 in DLBCL and to analyze its relationship with prognosis.Methods: We reviewed medical records of 204 newly diagnosed DLBCL patients in Sun Yat-sen University Cancer Center between October 2005 and August 2012. The expression of PD-L1 in tumor tissues from these 204 patients was detected using immunohistochemical(IHC) assay. The expression of anaplastic lymphoma kinase(ALK), CD5,CD30, and C-Myc in tumor specimens from 109 patients was detected using IHC, and Epstein-Barr virus(EBV)-encoded RNAs(EBERs) were detected using fluorescence in situ hybridization. The Spearman method was used for correlation analysis. The Kaplan-Meier method with log-rank test was used for univariate analysis. Cox proportional hazards model was used for multivariate analysis.Results: Of the 204 patients, 100(49.0%) were PD-L1-positive in tumor cells and 44(21.6%) were PD-L1-positive in tumor microenvironment. PD-L1 expression in tumor cells and tumor microenvironment were more common in the non-germinal center B-cell-like(GCB) subtype than in the GCB subtype(P = 0.02 and P= 0.04). Patients with PD-L1 expression in tumor microenvironment were more likely to be resistant to first-line chemotherapy when compared with the patients without PD-L1 expression in tumor microenvironment(P = 0.03). PD-L1 expression in tumor microenvironment was negatively correlated with C-Myc expression(r =-0.20, P = 0.04). No correlations were detected between PD-L1 expression and the expression of ALK, CD5, and CD30 as well as EBERs. The 5-year overall survival(OS)rates were 50.0% and 67.3% in patients with and without PD-L1 expression in tumor cells(P = 0.02). PD-L1 expression in tumor cells was an independent risk predictor for OS(P < 0.01).Conclusions: PD-L1 expression is more common in the non-GCB subtype than in the GCB subtype. PD-L1 expression in tumor microenvironment has a negative correlation with C-Myc. PD-L1 positivity predicts short survival in DLBCL patients. For patients with PD-L1 expression, more strategy such as anti-PD-L1 antibody treatment should be recommended.
文摘Cannabidiol (CBD), one of the most studied phytocannabinoids, is non-psychotropic and can induce protective effects on the central nervous system against acute and chronic brain injury. Interestingly, CBD inhibits processes relating to amyloid beta (Aβ)-induced neurotoxicity in mouse models of Alzheimer’s disease, though the detailed molecular mechanism underlying the CBD neurotoxicity modulation is not fully understood. In this study, using atomic force microscopy, we find that CBD promotes the aggregation of Aβ peptides, enhancing the formation of Aβ oligomers, also known as Aβ-derived diffusible ligands (ADDLs). The CBD-mediated sequestration of Aβ monomers in soluble ADDLs could reduce neurotoxicity. This study highlights a possible role of CBD in modulating the formation of ADDL aggregates and provides insight into potentially neuroprotective properties of CBD in Alzheimer’s disease.
文摘目的探讨程序性死亡蛋白受体-1配体(programmed death ligand-1, PD-L1)和TNF家族的B细胞活化因子(B cell-activating factor belonging to the TNF family, BAFF-R)在胃弥漫性大B细胞淋巴瘤(gastric diffuse large B-cell lymphoma, GDLBCL)的瘤组织和瘤旁组织中的表达及其临床意义。方法采用免疫组织化学法和定量逆转录-聚合酶链反应法(quantitative real time polymerase chain reaction, qRT-PCR)检测26例GDLBCL瘤组织和瘤旁组织中的PD-L1和BAFF-R的表达,分析PD-L1和BAFF-R的表达与GDLBCL临床分期和病理分型之间的关系和PD-L1与BAFF-R表达的相关性。结果 PD-L1和BAFF-R在GDLBCL中的表达显著高于瘤旁组织(P<0.01)。PD-L1和BAFF-R表达与GDLBCL分期及病理分型均有明显相关性(P<0.01),PD-L1与BAFF-R有相关性(P<0.01)。结论 PDL-1和BAFF-R表达上调与GDLBCL分期及病理分型密切相关,联合检测PD-L1和BAFF-R可能成为GDLBCL有价值的预后指标。以PD-L1和BAFF-R信号通路为靶点的治疗有望成为GDLBLC免疫治疗的潜在方案。
