Expression of programmed cell death 1/programmed cell death ligand 1 in the tumor microenvironments of primary gastrointestinal diffuse large B cell lymphomas

Background

Gastrointestinal diffuse large B cell lymphoma (GI DLBCL) is the most common gastrointestinal lymphoma. However, there has not been a comprehensive investigation into the expression patterns of programmed cell death 1 (PD-1) and programmed cell death ligand 1(PD-L1) in GI DLBCL tissues.

Effects of the programmed cell death 1 (PDCD1) polymorphisms in susceptibility to systemic lupus erythematosus

The failure of immunological tolerance to self‐antigens plays a fundamental role in the pathogenesis of systemic lupus erythematosus (SLE). PD‐1 is an inhibitory receptor for regulating the immune system and preventing development of autoimmune disorders. This study aimed to determine the role of four single‐nucleotide polymorphisms (SNPs) within programmed cell death 1 (PDCD1 or PD‐1) gene and haplotypes defined by these SNPs in susceptibility to SLE in the Iranian population. Blood samples were obtained from 253 SLE and 564 healthy subjects. Red blood cells were lysed and genomic DNAs were extracted using salting‐out method. Genotype determinations of PD1.1, PD1.3, PD1.5 and PD1.9 SNPs were performed by polymerase chain reaction–restriction fragment length polymorphism (PCR‐RFLP), and 12 haplotypes were constructed by PDCD1 SNPs. Our results showed significant differences in PD1.5 genotype frequencies between patient and control groups (p < .001). The frequencies of PD1.5 C/C, C/T and T/T genotypes versus other genotypes in SLE patients significantly differed from healthy subjects (p < .001, p = .001 and p = .002, respectively). Allelic analysis indicated a significant association between the frequency of PD1.5C allele and development of SLE in our population (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.51–2.42, p < .001). At the haplotype level, GGCC, GACT and GGCT haplotypes were significantly different between SLE and control groups (OR = 2.14, 95% CI = 1.73–2.66, p < .001; OR = 9.76, 95% CI = 4.47–21.3, p < .001; and OR = 0.32, 95% CI = 0.24–0.42, p < .001, respectively). Based on these findings, PD1.5 SNP and some haplotypes of PDCD1 contribute to SLE risk in the Iranian population.     

细胞自噬的调控与自噬程序性死亡的研究进展

自噬(autophagy)是一种溶酶体依赖性降解途径,涉及细胞内长寿蛋白和受损伤细胞器的降解,其既是细胞保守的自我防御机制,又是一种程序性细胞死亡机制(PCD),与机体的多种疾病有密切关系.自噬具有独特的形态改变和特有的调控通路,自噬的调控涉及到多种机制、如翻译后修饰等.凋亡是研究最清楚的程序性细胞死亡机制,凋亡与细胞自噬程序性死亡之间存在着复杂的关系.对哺乳动物细胞自噬的分子调控机制,自噬程序性细胞死亡过程及其与凋亡的关系等方面进行探讨很有意义.     

中性粒细胞非凋亡性程序化细胞死亡的研究概况

中性粒细胞是机体固有免疫应答的主要效应细胞，也是机体内重要的炎症细胞。中性粒细胞除了凋亡和坏死外，还存在一种非凋亡性程序化细胞死亡形式。该形式具有空泡化，线粒体通透性增大等形态学特征，具有caspase-3、caspase-8非依赖性以及无DNA片段化的生物化学特征。目前尚不知其确切的生物学意义，但它与发育和许多生理／病理现象有关。这些研究成果对于重新认识和定位中性粒细胞程丰化细胞死亡的多样性和复杂性提出了新的思路。     

程序性细胞凋亡1基因单倍型及紫外线暴露与系统性红斑狼疮的相关性研究

目的 探讨中国长江以南汉族人群中程序性细胞凋亡1基因(programmed celll death 1,PDCD1)多态性与紫外线暴露在系统性红斑狼疮(systemic lupus erythematosus,SLE)发病中的关系.方法 采用病例对照研究设计,收集159例病例和159名对照,应用聚合酶链反应-限制性片段长度多态技术检测PDCD1基因多态;分别在隐性、显性、相加及共显性遗传模式下,应用Logistic回归模型估计基因、环境及基因-环境交互效应.结果 根据赤池信息量准则(Akaike's Information Criteria,AIC)值最小原则,筛出3个相加遗传模式下的最优模型和1个显性遗传模式下的最优模型.控制年龄与性别因素后,4个模型均存在SLE患病人群既往紫外线暴露率高于对照组,差异有统计学意义(P值均＜0.05).在由PDCD1基因PD1.2、PD1.5及PD1.6多态位点等位基因组成的单倍型方面,在相加遗传模式下,SLE患者人群的G-T-A单倍型频率高于对照组(0.1196 vs 0.0363),差异有统计学意义(P＜0.05,OR=4.319);而A-C-A单倍型频率病例组低于对照组(0.4746 vs 0.5399),差异亦有统计学意义(P＜0.05,OR=0.571);此遗传模式下,还发现A-C-G单倍型与紫外线暴露存在交互作用,(β5=1.182,Z=2.2898,P＜0.05,OR=3.261).此外,在显性遗传模式下,SLE患者人群的G-C-G单倍型频率高于对照组(0.1287 vs 0.0361),差异有统计学意义(P＜0.05,OR=4.332).结论 特定遗传模式下,紫外线暴露、PDCD1基因G-C-G或G-T-A单倍型以及A-C-G单倍型与紫外线暴露的交互作用可能与中国长江以南汉族人群系统性红斑狼疮的遗传易感性相关.     

Expression and prognostic significance of programmed death protein 1 and programmed death ligand‐1, and cytotoxic T lymphocyte‐associated molecule‐4 in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignancies and causes of death worldwide. In this study, we assessed the correlation between clinicopathologic factors with programmed cell death protein 1 (PD‐1) and programmed cell death ligand‐1 (PD‐L1), and cytotoxic T lymphocyte‐associated molecule‐4 (CTLA‐4) expressions. Furthermore, we analyzed the prognostic significance of these proteins in a subgroup of patients. We retrospectively evaluated the PD‐1, PD‐L1, and CTLA‐4 expressions in 294 HCC tissue microarray samples using immunohistochemistry. PD‐1 and PD‐L1 expressions were significant related to high CD8+ tumor‐infiltrating lymphocytes (TILs) (r = 0.664, p < 0.001 and r = 0.149, p = 0.012). Only high Edmondson–Steiner grade was statistically related to high PD‐1 expression. High PD‐L1 expression was demonstrated as an independent poor prognostic factor for disease‐free survival in addition to previous known factors, size >5 cm and serum albumin ≤3.5 g/dL in high CD8+ TILs group. We have demonstrated that the combined high expression of PD‐L1 and CD8+ TIL is an important prognostic factor related to the immune checkpoint pathway in HCC and furthermore, there is a possibility that it could be used as a predictor of therapeutic response. Also, this result would be helpful in evaluating the applicable group of PD‐1/PD‐L1 blocking agent for HCC patients.     

Association of programmed death‐1 gene polymorphisms with the risk of basal cell carcinoma

Environmental and genetic factors play a fundamental role in the pathogenesis of basal cell carcinoma (BCC) defined as the most common cancer of skin. Programmed death‐1 (PD‐1), encoded by programmed cell death‐1 (PDCD1) gene, serves as an inhibitory molecule in the suppression of immune responses and a risk factor in the development of different cancers. In this study, we investigated the role of two single nucleotide polymorphisms (SNPs) within PDCD1 gene, and haplotypes defined by these SNPs, in the development of BCC in an Iranian population. Whole blood samples were obtained from 210 BCC and 320 healthy subjects. Genomic DNA was extracted from whole blood samples, polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) was used to genotype determinations of PD1.3 (rs11568821) and PD1.5 (rs2227981) SNPs, and 4 haplotypes were constructed by PDCD1 SNPs. The frequency of G allele of PD1.3 was significantly higher in BCC patients than healthy subjects (p < 0.02), while these significant differences were not observed in the frequencies of PD1.5 alleles between BCC and healthy subjects. Moreover, we found that there were no statistically significant differences in PD1.3 and PD1.5 genotypes between BCC and control groups. Of all estimated haplotypes for PDCD1, only AC haplotype was associated with BCC (OR = 0.22, 95% CI = 0.06–0.79, p < 0.01). These findings suggest that PD1.3G allele and AC haplotype of PDCD1 contribute to BCC in the Iranian population. However, further studies in different populations with larger sample size are required to confirm this study.     

骨关节炎软骨细胞的新型程序性死亡

背景：骨关节炎是一种常见的关节退行性疾病,其发生机制复杂,目前尚未阐明。但已有的研究表明,骨关节炎的发生发展与软骨细胞程序性死亡有关。目的：总结骨关节炎软骨细胞新型程序性死亡的研究进展。方法：“Osteoarthritis,Pyroptosis,Necroptosis,Ferroptosis,ROS,L-ROS,Iron-overload”为英文检索词,以“骨关节炎、细胞焦亡、坏死性凋亡、铁死亡、铁超载、脂质活性氧”为中文检索词,使用计算机在CNKI、万方数据库、PubMed、维普数据库检索2012年7月至2022年7月有关于程序性细胞死亡的相关文章,并进行系统地归纳、总结和分析。结果与结论：焦亡与骨关节炎的关系近年来备受关注,目前的研究重点仍是NLRP3炎性小体和脂多糖。有关坏死性凋亡的研究中,骨关节炎的发展也已被证明与受体相互作用蛋白激酶1密切相关,受体相互作用蛋白激酶1有可能是治疗骨关节炎的潜在靶点。铁死亡是一种最新发现的细胞死亡方式,研究发现其通过铁超载和脂质过氧化介导了软骨细胞的死亡,但铁死亡的发生涉及多个基因的表达和调控,具有复杂的信号通路和机制,目前尚未完全阐明。细胞焦亡...     

Activated inducible co-stimulator-positive programmed cell death 1-positive follicular helper T cells indicate disease activity and severity in ulcerative colitis patients

Inducible co-stimulator-positive (ICOS) and programmed cell death 1-positive (PD-1) are important markers for follicular helper T cells (Tfh); however, their roles and clinical values in ulcerative colitis (UC) remain unknown. In this study, we recruited 68 UC patients and 34 healthy controls. Circulating ICOS⁺, PD-1⁺ and ICOS⁺PD-1⁺ Tfh subsets were analyzed by flow cytometry. Twelve active UC patients achieving remission after treatment with 5-aminosalicylic acid were followed-up and Tfh subset changes were analyzed. Serum immunoglobulin (Ig)G, C-reactive protein (CRP), interleukin (IL)-4 and IL-21 levels and B cell subsets were analyzed and Mayo scores were calculated. Correlation analyses were performed between Tfh subsets and the clinical indicators. Receiver operating characteristic (ROC) curves were generated to evaluate the efficiency of Tfh subsets for disease monitoring. We found that levels of ICOS⁺, PD-1⁺ and ICOS⁺PD-1⁺ Tfh cells were significantly increased in active UC and significantly decreased when achieving clinical remission. Activated ICOS⁺PD-1⁺Tfh cells were positively correlated with serum CRP and Mayo scores. Furthermore, ICOS⁺PD-1⁺ Tfh cells were significantly correlated with circulating new memory B cells and plasmablasts, as well as serum IgG, IL-4 and IL-21. ROC analyses showed that when ICOS⁺PD-1⁺ Tfh cells were used in combination with PD-1⁺ Tfh cells, the diagnostic efficacy in distinguishing active UC from stable remission patients was higher than that of any one used alone, with area under curve (AUC) value 0·931. Our findings suggest that increased ICOS⁺PD-1⁺ Tfh cells are associated with the activation of B cells in the pathogenesis of UC, and may be a potential biomarker for UC disease monitoring.     

Non-small cell lung carcinomas with a minor sarcomatoid component and pleomorphic carcinomas are associated with high expression of programmed death ligand 1

Pleomorphic carcinomas are known to be highly programmed death ligand 1 (PD-L1) positive non-small cell lung cancer (NSCLC) types. However, the level of PD-L1 expression in lung carcinomas with a minor sarcomatoid component, comprising less than 10 % of the tumor mass, has not been determined yet. We hypothesized that NSCLC with a minor sarcomatoid component is more closely related to pleomorphic carcinomas in terms of PD-L1 expression than to NSCLC types without sarcomatoid features. The surgical resections from 690 lung carcinoma patients were retrospectively analyzed for the presence of PD-L1 by means of immunohistochemistry using the 22C3 PharmDx assay. The tumor proportion score system was applied to quantify the level of PD-L1 expression. Membranous staining present in ≥ 1 % of tumor cells was chosen as the cut-off to define a positive result for PD-L1 expression. Tumors were allocated into one of four subgroups: “adenocarcinoma”, “squamous cell carcinoma”, “pleomorphic carcinoma”, or “NSCLC with a minor sarcomatoid component”. PD-L1 expression in pleomorphic carcinomas (26/32, 81.3 %) and in the subgroup of NSCLC with a minor sarcomatoid component (35/46, 76.1 %) was identified in a comparable proportion of cases. Pleomorphic carcinomas were significantly more often PD-L1 positive than adenocarcinomas (p < 0.001) or squamous cell carcinomas (p = 0.0015). Accordingly, the proportion of PD-L1 expressing NSCLC with a minor sarcomatoid component was significantly higher than that of the adenocarcinoma (p < 0.001) or squamous cell carcinoma (p = 0.002) subgroup. In summary, we identified a presumable new subgroup of highly PD-L1 positive neoplasms within the NSCLC spectrum that is related to pleomorphic carcinomas in terms of PD-L1 expression. Further investigation regarding genetic relation and mechanism of PD-L1 expression in these two NSCLC categories is recommended.     

The expression and prognostic relevance of programmed cell death protein 1 in tongue squamous cell carcinoma

Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor which plays an important role in a patient's immune responses to microbial and cancer antigens. It is expressed in tumor-infiltrating lymphocytes (TILs) with many different malignancies. The aim of the study was to evaluate PD-1 expression and its prognostic value in tongue cancer. The data of tongue squamous cell carcinoma (TSCC) patients (N = 81) treated in Tampere University Hospital between 1999 and 2013 were used. Control data consisted of patients with non-malignant tongue mucous membrane lesions (N = 48). The formalin-fixed paraffin-embedded samples were stained immunohistochemically and scanned via digital microscope. The staining of PD-1 was examined semi-quantitatively. The density and intensity of PD-1 + cells were significantly higher in TSCC than in control samples. The expression of PD-1 correlated with better survival. The expression of PD-1 could be a potential prognostic marker in TSCC. Further research using larger sample size is needed.     

RIP1在细胞程序性死亡中作用的研究进展

近期研究发现受体相互作用蛋白（receptor—interacting protein,RIP）是细胞生存和死亡的重要交叉点,在细胞的凋亡与存活、程序性坏死等过程中发挥着关键性的作用。RIP1为RIP家族中的第一个成员,是一种重要的细胞信号转导调控分子。RIP1的结构与生物学功能及在细胞程序性死亡中的作用具有重要意义。     

慢性乙型肝炎患者HBV特异性细胞毒性T细胞PD-1的表达研究

目的 检测慢性乙型病毒性肝炎患者外周血中HBV特异性CD8 细胞毒性T淋巴细胞表面细胞程序性死亡受体1(programmed cell death 1,PD-1)的表达情况.方法 采集慢性乙型肝炎患者外周血,直接离体情况下利用MHC-I-肽-五聚体技术标定HBV表位特异性细胞毒性T淋巴细胞以及荧光抗体标记细胞表面PD-1分子,经流式细胞仪检测分析.结果 在慢性乙型肝炎患者,HBV核心抗原18-27特异性CTL表达PD-1上调,达(79.0±12.5)%,显著高于总CD8 T细胞(27.7±14.8)%,以及CMV特异性CTL(20.6±5.9)%.结论 慢性乙肝患者HBV特异性CTL高表达PD-1分子,可能与慢性乙肝患者HBV特异性CTL功能低下密切相关.     

A kiss of death—proteasome-mediated membrane fusion and programmed cell death in plant defense against bacterial infection

Eukaryotes have evolved various means for controlled and organized cellular destruction, known as programmed cell death (PCD). In plants, PCD is a crucial regulatory mechanism in multiple physiological processes, including terminal differentiation, senescence, and disease resistance. In this issue of Genes & Development, Hatsugai and colleagues (pp. 2496–2506) demonstrate a novel plant defense strategy to trigger bacteria-induced PCD, involving proteasome-dependent tonoplast and plasma membrane fusion followed by discharge of vacuolar antimicrobial and death-inducing contents into the apoplast.     

非凋亡性程序化细胞死亡的研究概况

细胞有2种基本死亡形式,即被动细胞死亡--细胞坏死和主动细胞死亡--程序化细胞死亡。凋亡是主动性细胞死亡,它是程序化细胞死亡的重要组成部分,但并非其唯一形式。最近研究表明还存在着其它的主动性细胞克亡,该细胞死亡过程中有RNA及蛋白质合成,为caspase非依赖性,形态学表现无细胞凋亡特征。由于有新的基因表达和新的蛋白质合成,因而称之为非凋亡性程序化细胞死亡。目前尚不知其确切的生物学意义,但近期研究表明它与发育和许多生理/病理现象有关。