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关键词： 乳腺肿瘤   肿瘤浸润淋巴细胞   人表皮生长因子受体2   激素受体   曲妥珠单抗  

摘要： [目的]探讨肿瘤浸润淋巴细胞（tumor infiltrating lymphocytes,TILs）在人表皮生长因子受体2（human epidermal growth factor receptor 2,HER2）阳性（激素受体阴性）型乳腺癌中的表达水平及其对预后的影响。[方法]收集2016年1月至2022年12月共164例女性HER2阳性（激素受体阴性）型乳腺癌病例资料。按照Denkert标准，根据HE染色切片结果分为瘤巢肿瘤浸润淋巴细胞（intratumora tumor infiltrating lymphocytes,ITILs）、间质肿瘤浸润淋巴细胞（stromal tumor infiltrating lymphocytes,STILs）两组，其中>40%为高表达，≤40%为中低表达。收集病理报告中雌激素受体、孕激素受体、HER2和Ki-67表达情况。通过电话、查看病历等多种途径进行随访，随访截止至2023年12月31日。采用SPSS 22.0软件对患者资料进行分析，统计ITILs、STILs在HER2阳性（激素受体阴性）型乳腺癌组织中的表达水平，探索TILs数量对预后的影响。[结果] ITILs和STILs表达水平随着阳性淋巴结数增多而下降，差异具有统计学意义（ITILs组：χ2=6.806,P=0.033;STILs组：χ2=6.487,P=0.039）。ITILs、STILs是HER2阳性（激素受体阴性）型乳腺癌患者总生存期（overall survival,OS）和无病生存期（disease-free survival,DFS）的影响因素（DFS:ITILs:HR=0.094,P=0.007;STILs:HR=0.043,P=0.007。OS:ITILs:HR=0.097,P=0.039;STILs:HR=0.085,P=0.030）。ITILs、STILs表达水平是使用曲妥珠单抗组乳腺癌患者DFS （ITILs：χ2=5.715,P=0.017;STILs：χ2=5.990,P=0.014）和OS（ITILs：χ2=18.816,P=0.000;STILs：χ2=12.522,P<0.001）的影响因素。ITILs、STILs表达水平是未使用曲妥珠单抗组乳腺癌患者DFS （ITILs：χ2=21.141,P=0.000;STILs：χ2=19.902,P=0.000）和OS （ITILs：χ2=13.377,P=0.000;STILs：χ2=16.449,P=0.000）的影响因素。[结论]在HER2阳性（激素受体阴性）型乳腺癌患者中，ITILs、STILs表达水平越高，复发、转移及死亡风险越低，预后越好。

关键词： T淋巴细胞   血糖   脓毒症   预后  

摘要： 目的：探究不同血糖水平脓毒症患者的外周血T淋巴细胞变化及其对患者预后的预测价值。方法：回顾性选择2021年8月至2024年2月本院收治的脓毒症患者（n=170）为研究对象；根据不同空腹血糖（fasting plasma glucose,FPG）水平，分为A组（n=55，≤6.1 mmol/L）、B组（n=48,6.2～8.3 mmol/L）和C组（n=67，≥8.4 mmol/L）；根据患者的28 d预后情况，分为存活组（n=112）和死亡组（n=58）。对比分析各组患者的临床资料。调整混杂因素后，采用多元线性回归（multivariable linear regression,MLR）模型分析相关性。采用多因素logistic回归分析外周血T淋巴细胞亚群水平与28 d死亡风险的相关性。采用KaplanMeier法进行生存分析。结果：与A组相比，B、C组患者的CD3+（t=7.439,P<0.001;t=21.955,P<0.001）、CD4+（t=6.215,P<0.001;t=12.036,P<0.001）水平均更低，CD8+（t=2.367,P=0.020;t=6.302,P<0.001）水平均更高；与B组相比，C组患者的CD3+（t=12.688,P<0.001）、CD4+（t=4.635,P<0.001）水平均更低，CD8+水平均更高（t=3.829,P<0.001）。FPG水平与CD3+（β=-0.397,P<0.001）、CD4+（β=-0.348,P<0.001）均呈负相关，与CD8+呈正相关（β=0.303,P<0.001）。多因素分析显示，CD3+、CD4+、CD8+是28d死亡风险的独立影响因素(均P趋势<0.001)。在不同FPG水平下，CD3+(P趋势=0.006,0.001)、CD4+(P趋势=0.004,<0.001)、CD8+(P趋势=0.008,0.002)与28 d死亡风险的相关性稳定存在，且亚组间均存在交互作用(P交互=0.033,0.025,0.041)。Kaplan-Meier分析显示，在FPG为6.2～8.3 mmol/L以及≥8.4 mmol/L下，CD3+<45.5%组患者的生存率明显低于≥45.5%组（χ2=6.842,P=0.009；χ2=9.376,P=0.002）,CD4+<44.6组患者的生存率明显低于≥44.6组（χ2=4.159,P=0.041；χ2=6.224,P=0.013）,CD8+>42.6组患者的生存率明显低于≤42.6组（χ2=5.317,P=0.021；χ2=7.518,P=0.006）。结论：随着FPG水平的不断升高，脓毒症患者的CD3+、CD4+水平逐渐降低，而CD8+水平逐渐升高。CD3+、CD4+、CD8+水平对脓毒症患者预后判断具有较好的临床参考价值。

关键词： 多聚磷酸盐   抗炎   促炎   补体   免疫逃逸  

摘要： 多聚磷酸盐(polyP)是血液中一种具有促血栓形成和免疫调节功能的分子。在分子水平，polyP既具有促炎活性，又具有抑制补体的功能，其促炎活性表现为增加促炎介质缓激肽的释放和血栓性炎症的产生，激活哺乳动物雷帕霉素靶蛋白(mTOR)、Wnt/β-catenin和核因子κB(NF-κB)信号途径，以及放大核细胞因子[高迁移率族蛋白1(HMGB1)和组蛋白H4(H4)]的促炎信号途径，因此polyP抑制剂可能作为抗炎药物治疗或预防在感染、受伤和(或)各种其他条件下由polyP导致的炎症反应。polyP可通过抑制经典途径、凝集素途径和补体终末途径中的某些阶段从而抑制补体活性，在保护活化的内皮细胞免受补体激活所致破坏的同时，又保留了补体的促血栓和促炎特性。在细胞水平，polyP调节免疫细胞的作用与其长度相关，血小板来源的polyP(短链)具有激活免疫细胞的活性，而细菌来源的polyP(长链)却具有完全相反的抑制作用并促进细菌的免疫逃逸，因此在人类巨噬细胞中采用药物阻断polyP参与的信号途径将促进polyP杀灭巨噬细胞摄入的病原体，这为治疗细胞内感染微生物如结核分枝杆菌相关疾病提供了新的药物靶点。本文综述了polyP在分子和细胞水平的免疫调节作用，以期助力该领域的研究，为促进其未来在临床的可用性提供参考。

关键词： lncRNA   innate defense   italic>Cryptosporidium   intestinal epithelium   U90926   IFN-gamma  

摘要： Cryptosporidium infects the intestine in a wide variety of vertebrates, and intestinal epithelial cells provide the first line of defense against Cryptosporidium infection. Interferon gamma (IFN-gamma) from immune cells infiltrated at the site of infection plays a key role in the epithelial cell-intrinsic defense. Nevertheless, the success of the parasite is the result of its ability to evade the host immune responses. Increasing evidence suggests that long noncoding RNAs (lncRNA) participate in host-pathogen interactions, but the underlying mechanisms are not fully understood. We previously demonstrated that lncRNA U90926 is upregulated in response to infection but appears to be playing a pro-parasitic role given its ability to repress transcription of defense genes and aid the parasite during infection. We show here that inhibition of U90926 during Cryptosporidium infection increased expressions of Irgm2, Igtp, and Iigp1, which are known IFN-gamma-stimulated genes, in a gene-specific manner. Depletion of U90926 results in an increase in histone modifications associated with gene transactivation in the promoter regions of Irgm2, Igtp, and Ilgp1, suggesting U90926 is regulating defense gene expression via epigenetic modifications. U90926 can interact with Ehmt2, a potent euchromatic methyltransferase, in the promoter region of these defense genes to alter histone modifications. Knockout of U90926 enhances IFN-gamma-mediated inhibition of Cryptosporidium infection, suggesting that U90926 may modulate IFN-gamma-induced gene expression to suppress cell-intrinsic antimicrobial defenses. The data highlight a strategy Cryptosporidium has evolved to hijack host cell lncRNA machinery to suppress the immune response and allow for a robust infection.

关键词： 非酒精性脂肪性肝病   C反应蛋白-白蛋白-淋巴细胞指数   死亡率   美国国家健康与营养调查数据库  

摘要： 目的：探究C反应蛋白-白蛋白-淋巴细胞（C-reactive protein-albumin-lymphocyte,CALLY）指数与非酒精性脂肪性肝病（non-alcoholic fatty liver disease,NAFLD）死亡率之间的关系。方法：本研究纳入了美国国家健康与营养调查1999年至2010年的3 346例NAFLD患者。采用加权Cox比例风险回归模型、Kaplan-Meier生存曲线、加权限制性立方样条（restricted cubic spline,RCS）和加权阈值效应分析来探讨CALLY指数与死亡率的关联，采用时间依赖性受试者工作特征（receiver operating characteristic,ROC）分析，评估CALLY指数预测不同时间点生存率的准确性。结果：本研究中位随访时间为12.5年，共记录全因死亡（all-cause mortality,ACM）901例和心脑血管死亡（cardiovascular and cerebrovascular mortality,CCVM）328例。多因素Cox回归模型显示，与CALLY低水平组相比，中、高水平组的ACM风险比分别为0.68 （95%CI=0.56～0.83）和0.58 （95%CI=0.47～0.72）,CCVM风险比分别为0.66（95%CI=0.48～0.90）和0.57 （95%CI=0.40～0.80）。RCS结果显示，ln（CALLY）与ACM、CCVM存在非线性关联(ACM:P非线性=0.003;CCVM:P非线性=0.031)，阈值分别为7.015和4.768。时间依赖性ROC曲线表明，CALLY指数联合常规预后因素预测1、3、5、10年的ACM和CCVM曲线下面积介于0.77～0.86之间。亚组分析显示性别和糖尿病状态存在交互作用(性别：P交互<0.001；糖尿病：P交互=0.016)。结论：CALLY指数是NAFLD患者ACM和CCVM风险的独立保护因素，对死亡风险具有较高的预测价值。

关键词： HIV-1   IL-4   GJB2  

摘要： Macrophages and dendritic cells (DCs) are important targets for HIV-1 replication in vivo. Myeloid cells are collectively more resistant to HIV-1 infection than CD4+ T lymphocytes, but interleukin (IL)-4 has been observed to promote macrophage susceptibility to HIV-1 infection. However, the mechanism remains unclear. Herein, we found that IL-4 enhanced HIV-1 infection in myeloid lineage macrophages by downregulating the novel antiviral factor gap junction protein beta 2 (GJB2) located on the cell membrane. In the absence of GJB2, the IL-4-mediated enhancement of HIV-1 replication was largely impaired in primary macrophages. Conversely, IL-6-mediated enhancement of HIV-1 infection was unaffected by GJB2 depletion. GJB2 was constitutively expressed in myeloid cells but not in CD4+ T cells, and GJB2 silencing enhanced HIV-1 transmission in macrophages and DCs. Additionally, GJB2 required Ca2+ to exert its antiviral activity by interfering with HIV-1 attachment to target cells. Because IL-4 downregulated GJB2 expression to enhance HIV-1 infection in macrophages, GJB2 may be a novel target for the treatment of HIV-1 ***-1 primarily targets two groups of cells in vivo: CD4+ T lymphocytes and myeloid lineage cells, such as macrophages and dendritic cells. Although myeloid cells are more resistant to HIV-1 infection than CD4+ T cells, some cytokines, including interleukin (IL)-4 and IL-6, promote myeloid cell infection. Gap junction protein beta 2 (GJB2) is particularly relevant in the field of auditory science. Here, we identified GJB2 as a novel antiviral factor by demonstrating that IL-4-mediated reduction in GJB2 levels enhanced HIV-1 infection in myeloid cells. Interestingly, GJB2 expression was regulated by IL-4 but not by interferons. The reduction in GJB2 levels was inversely correlated with increased HIV-1 infection levels, suggesting the potential of GJB2 for combating HIV/AIDS.

关键词： Immunopeptidomics   Nextflow   Nf-core   Pipeline   Mass spectrometry   HLA   Immunotherapy   Open-source  

摘要： Confident identification of human leukocyte antigen (HLA)-presented peptides is crucial for advancing cancer immunotherapy. We present MHCquant2, a scalable and modular Nextflow pipeline integrated into nf-core as a reproducible, portable, and standardized workflow for immunopeptidomics. This integration allows a community-driven, robust solution for high-throughput analyses across operating systems and cloud infrastructures. MHCquant2 integrates open-source tools including OpenMS, DeepLC, and MS2PIP, improving peptide identifications by up to 27% across diverse MS platforms, particularly enriching low-abundant peptides. MHCquant2 demonstrates state-of-the-art performance on our novel benignMHCquant2 dataset (n = 92) and expands the benign human immunopeptidome by over 160,000 unique naturally presented HLA peptides.

关键词： C1-mRNA cancer vaccine   cancer immunotherapy   innate immunity   STING agonist   TNF-α  

摘要：