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61.
Immune escape of breast cancer cells contributes to breast cancer pathogenesis. Tumour microenvironment stresses that disrupt protein homeostasis can produce endoplasmic reticulum (ER) stress. The miRNA‐mediated translational repression of mRNAs has been extensively studied in regulating immune escape and ER stress in human cancers. In this study, we identified a novel microRNA (miR)‐27a‐3p and investigated its mechanistic role in promoting immune evasion. The binding affinity between miR‐27a‐3p and MAGI2 was predicted using bioinformatic analysis and verified by dual‐luciferase reporter assay. Ectopic expression and inhibition of miR‐27a‐3p in breast cancer cells were achieved by transduction with mimics and inhibitors. Besides, artificial modulation of MAGI2 and PTEN was done to explore their function in ER stress and immune escape of cancer cells. Of note, exosomes were derived from cancer cells and co‐cultured with macrophages for mechanistic studies. The experimental data suggested that ER stress biomarkers including GRP78, PERK, ATF6, IRE1α and PD‐L1 were overexpressed in breast cancer tissues relative to paracancerous tissues. Endoplasmic reticulum stress promoted exosome secretion and elevated exosomal miR‐27a‐3p expression. Elevation of miR‐27a‐3p and PD‐L1 levels in macrophages was observed in response to exosomes‐overexpressing miR‐27a‐3p in vivo and in vitro. miR‐27a‐3p could target and negatively regulate MAGI2, while MAGI2 down‐regulated PD‐L1 by up‐regulating PTEN to inactivate PI3K/AKT signalling pathway. Less CD4+, CD8+ T cells and IL‐2, and T cells apoptosis were observed in response to co‐culture of macrophages and CD3+ T cells. Conjointly, exosomal miR‐27a‐3p promotes immune evasion by up‐regulating PD‐L1 via MAGI2/PTEN/PI3K axis in breast cancer.  相似文献   
62.
Ovarian carcinoma has the highest mortality among the malignant tumours in gynaecology, and new treatment strategies are urgently needed to improve the clinical status of ovarian carcinoma patients. The Cancer Genome Atlas (TCGA) cohort were performed to explore the immune function of the internal environment of tumours and its clinical correlation with ovarian carcinoma. Finally, four molecular subtypes were obtained based on the global immune-related genes. The correlation analysis and clinical characteristics showed that four subtypes were all significantly related to clinical stage; the immune scoring results indicated that most immune signatures were upregulated in C3 subtype, and the majority of tumour-infiltrating immune cells were upregulated in both C3 and C4 subtypes. Compared with other subtypes, C3 subtype had a higher BRCA1 mutation, higher expression of immune checkpoints, and optimal survival prognosis. These findings of the immunological microenvironment in tumours may provide new ideas for developing immunotherapeutic strategies for ovarian carcinoma.  相似文献   
63.
Glioblastoma (GBM) is a malignant intracranial tumour with the highest proportion and lethality. It is characterized by invasiveness and heterogeneity. However, the currently available therapies are not curative. As an essential environmental cue that maintains glioma stem cells, hypoxia is considered the cause of tumour resistance to chemotherapy and radiation. Growing evidence shows that immunotherapy focusing on the tumour microenvironment is an effective treatment for GBM; however, the current clinicopathological features cannot predict the response to immunotherapy and provide accurate guidance for immunotherapy. Based on the ESTIMATE algorithm, GBM cases of The Cancer Genome Atlas (TCGA) data set were classified into high‐ and low‐immune/stromal score groups, and a four‐gene tumour environment‐related model was constructed. This model exhibited good efficiency at forecasting short‐ and long‐term prognosis and could also act as an independent prognostic biomarker. Additionally, this model and four of its genes (CLECL5A, SERPING1, CHI3L1 and C1R) were found to be associated with immune cell infiltration, and further study demonstrated that these four genes might drive the hypoxic phenotype of perinecrotic GBM, which affects hypoxia‐induced glioma stemness. Therefore, these might be important candidates for immunotherapy of GBM and deserve further exploration.  相似文献   
64.
Indoleamine 2, 3-dioxygenase (IDO)-mediated regulation of tryptophan metabolism plays an important role in immune tolerance in transplantation, but it has not been elucidated which mechanism specifically induces the occurrence of immune tolerance. Our study revealed that IDO exerts immunosuppressive effects through two pathways in mouse heart transplantation, ‘tryptophan depletion’ and ‘tryptophan metabolite accumulation’. The synergism between IDO+DC and TC (tryptophan catabolic products) has stronger inhibitory effects on T lymphocyte proliferation and mouse heart transplant rejection than the two intervention factors alone, and significantly prolong the survival time of donor-derived transplanted skin. This work demonstrates that the combination of IDO+DC and TC can induce immune tolerance to a greater extent, and reduce the rejection of transplanted organs.  相似文献   
65.
Inflammation indicators, such as systemic inflammation response index (SIRI), systemic immune‐inflammation index (SII), neutrophil‐to‐lymphocyte ratio (NLR) and platelet‐lymphocyte ratio (PLR), are associated with poor prognosis in various solid cancers. In this study, we investigated the predictive value of these inflammation indicators in nasopharyngeal carcinoma (NPC). This retrospective study involved 559 patients with NPC and 500 patients with chronic rhinitis, and 255 NPC patients were followed up successfully. Continuous variables and qualitative variables were measured by t test and chi‐square test, respectively. The optimal cut‐off values of various inflammation indicators were determined by receiver operating characteristic (ROC) curve. Moreover, the diagnostic value for NPC was decided by the area under the curves (AUCs). The Kaplan‐Meier methods and the log‐rank test were used to analyse overall survival (OS) and disease‐free survival (DFS). The independent prognostic risk factors for survival and influencing factors of side effects after treatment were analysed by Cox and logistic regression analysis, respectively. Most haematological indexes of NPC and rhinitis were significantly different between the two groups, and PLR was optimal predictive indicators of diagnosis. In the multivariable Cox regression analysis, PLR, WBC, RDW, M stage and age were independent prognostic risk factors. Many inflammation indicators that affected various side effects were evaluated by logistic regression analysis. In conclusion, the combined inflammation indicators were superior to single haematological indicator in the diagnosis and prognosis of NPC. These inflammation indicators can be used to supply the current evaluation system of the TNM staging system to help predict the prognosis in NPC patients.  相似文献   
66.
Naturally occurring CD4+CD25+ regulatory T cells (Tregs) are required to limit immune‐induced pathology and to maintain homeostasis during the early‐phase of sepsis. This study aimed to investigate the role of interleukin (IL)‐38, a newly described member of the IL‐1 cytokine family, in mediated immune response of CD4+CD25+ Tregs in sepsis. Here, we provide evidence that expressions of IL‐38 and its receptor were detected in murine CD4+CD25+ Tregs. Stimulation of CD4+CD25+ Tregs with LPS markedly up‐regulated the expression of IL‐38. Treatment with rmIL‐38 dramatically enhanced the immunosuppressive activity of CD4+CD25+ Tregs after LPS stimulation and in septic mice induced by CLP, resulting in amplification of helper T cell (Th) 2 response and reduction in the proliferation of effector T cells. These effects were robustly abrogated when anti–IL‐38 antibody was administered. Administration of rmIL‐38 improved the survival rate of CLP mice. In addition, CD4+CD25+ Tregs depletion before the onset of sepsis obviously abolished IL‐38–mediated protective response. These findings suggest that IL‐38 enhances the immunosuppressive activity of CD4+CD25+ Tregs, which might contribute to the improvement of host immune function and prognosis in the setting of sepsis.  相似文献   
67.
水痘-带状疱疹病毒(varicella zoster virus,VZV)糖蛋白E(glycoprotein E,gE)是VZV亚单位疫苗的主要候选蛋白,但目前原核表达系统制备的gE蛋白以包涵体形式为主,可溶性差。本研究采用去除第1~30氨基酸序列的VZV gE胞外域基因,将其与原核表达载体pET32a连接,并转化至感受态细胞BL21(DE3)中。使用异丙基-β-D-硫代半乳糖苷(Isopropylβ-D-thiogalactoside,IPTG)诱导表达,His-tag柱纯化重组gE蛋白,蛋白质印迹法(Western blot,WB)检测其特异性。用该重组gE蛋白免疫BALB/c小鼠制备多克隆抗体,酶联免疫吸附试验(enzyme linked immunosorbent assay,ELISA)和间接免疫荧光法检测多克隆抗体效价及特异性。结果显示,BL21/pET32a-VZV gE工程菌可以表达可溶性重组gE蛋白,纯化后纯度约为90%。WB鉴定该重组蛋白具有良好的免疫反应性。ELISA检测显示小鼠抗VZV gE多克隆抗体效价>1∶10 000,间接免疫荧光实验结果显示该抗体特异性较高。结果表明,本研究在原核表达系统中成功表达可溶性重组VZV gE蛋白,同时该蛋白具有较强的免疫原性,这为VZV gE亚单位疫苗的研制和大规模生产奠定了基础。  相似文献   
68.
为了提高实验室人类免疫缺陷病毒(human immunodeficiency virus,HIV)抗体检测能力及对免疫蛋白印迹(Western blot,WB)实验结果的判断能力,对送检至北京市东城区艾滋病确证实验室的268份HIV抗体待确定样本进行确证实验及结果分析。按照试剂说明书和实验室标准作业程序(Standard Operation Procedure,SOP)操作对送检的全部样本进行WB确证实验;了解HIV筛查实验结果与确证实验结果的相关性,并分析不同送检机构、送检人群样本的检测结果差异以及不同试剂、不同检测方法的结果差异。结果显示在筛查出抗体待确定的268份样本中,确证阳性170份,阳性率63.43%;确证阴性51份,阴性率19.03%;不确定结果47份,占筛查有反应的17.54%。确证阳性病例来自监管场所、自愿咨询检测门诊(Voluntary Counseling and Test,VCT)和医疗机构,不同送检单位及不同人群的阳性样本率有显著统计学意义(P<0.01)。WB确证阳性样本带型以全条带和次全条带为主,且所有确证阳性标本均来自双试剂阳性样本。不同检测方法阳性样本率的差异有显著统计学意义(P<0.01),其中化学发光法的样本阳性率占46.27%,酶联免疫吸附实验(ELISA)占88.29%,胶体硒法占43.48%。本研究结果提示,对潜在HIV感染者,应扩大检测面,加强医疗机构检测,并提供一种以上方法的多次检测,以减少漏检的风险。  相似文献   
69.
Antibiotics are designed to affect gut microbiota and subsequently gut homeostasis. However, limited information exists about short- and long-term effects of early antibiotic intervention (EAI) on gut homeostasis (especially for the small intestine) of pigs following antibiotic withdrawal. We investigated the impact of EAI on specific bacterial communities, microbial metabolites and mucosal immune parameters in the small intestine of later-growth-stage pigs fed with diets differing in CP levels. Eighteen litters of piglets were fed creep feed with or without antibiotics from day 7 to day 42. At day 42, pigs within each group were offered a normal- or low-CP diet. Five pigs per group were slaughtered at days 77 and 120. At day 77, EAI increased Enterobacteriaceae counts in the jejunum and ileum and decreased Bifidobacterium counts in the jejunum and ileum (P < 0.05). Moreover, tryptamine, putrescine, secretory immunoglobulin (Ig) A and IgG concentrations in the ileum and interleukin-10 (IL-10) mRNA and protein levels in the jejunum and ileum were decreased in pigs with EAI (P < 0.05). At day 120, EAI only suppressed Clostridium cluster XIVa counts in the jejunum and ileum (P < 0.05). These results suggest that EAI has a short-term effect on specific bacterial communities, amino acid decarboxylation and mucosal immune parameters in the small intestine (particularly in the ileum). At days 77 and 120, feeding a low-CP diet affected Bifidobacterium, Clostridium cluster IV, Clostridium cluster XIVa and Enterobacteriaceae counts in the jejunum or ileum (P < 0.05). Moreover, feeding a low-CP diet increased the concentrations of Igs in the jejunum and decreased pro-inflammatory cytokines levels in the jejunum and ileum (P < 0.05). At day 120, feeding a low-CP diet increased short-chain fatty acid concentrations, reduced ammonia and spermidine concentrations and up-regulated genes related to barrier function in the jejunum and ileum (P < 0.05). These results suggest that feeding a low-CP diet changes specific bacterial communities and intestinal metabolite concentrations and modifies mucosal immune parameters. These findings contribute to our understanding on the duration of the impact of EAI on gut homeostasis and may provide basis data for nutritional modification in young pigs after antibiotic treatment.  相似文献   
70.
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