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关键词： FAK   IFN-γ   Immune checkpoint blockade(ICB)   PD-L1   melanoma  

摘要：

关键词： Cancer clone   HPV-positive oropharyngeal cancer   Metastasis   Single-cell transcriptomics   Spatial transcriptomics  

摘要： BACKGROUND: Human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) is increasing in prevalence, but the drivers of metastasis remain poorly understood, which impacts the ability to personalise management decisions. Much of the genomic research to date focuses on the HPV-negative population. Here, we utilise single-cell and spatial single-cell techniques to understand the drivers of metastasis. METHODS: Patients with HPV-positive OPC and cervical lymph node metastases treated with curative surgery had matched samples from the primary and lymph nodes collected for research. Single-cell RNA sequencing, single-cell spatial sequencing (Visium) and in-situ spatial platforms were performed. Cancer clones were delineated using inferred copy number variation. Expression phenotypes and interactions with the tumour microenvironment were compared between the metastasising and non-metastasising cancer clones. RESULTS: Individual cancer clones have varied abilities to metastasise and undergo clonal expansion in the lymph node, with only a subset of clones present in the primary expanding in the lymph node. Four mechanisms were identified as defining the metastatic phenotype, including protein translation adaptation, immunoproteasome dysfunction and immune evasion, suppression of the IFN immune response and cap-independent protein translation. CONCLUSIONS: This research elucidates multiple mechanisms driving the expansion of cancer clones in HPV-positive oropharyngeal cancer. By detailing the roles of translational adaptation, immunoproteasome dysfunction, suppression of the interferon immune response and cap-independent protein translation, we provide insights into how these processes contribute to immune evasion and tumour survival. © 2025. The Author(s).

关键词： colorectal cancer   immune checkpoint blockade   intratumoral bacteria   probiotics   patient-derived autologous organoids and TILs coculture   immunotherapy   Clostridium butyricum   cytotoxic CD8+ T cells  

摘要：

关键词： Hydrocephalus   Intracerebral hemorrhage   Cerebrospinal fluid   Clinical outcomes   Inflammation   Cytokines  

摘要： Post-hemorrhagic hydrocephalus (PHH) necessitates surgical intervention to alleviate symptoms and prevent neurological sequelae. The role of inflammatory cytokines in PHH pathophysiology remains unclear, prompting the need for a comprehensive investigation of their cerebrospinal fluid (CSF) profile. This study aimed to investigate the characteristics of patients with PHH undergoing shunt surgery and evaluate CSF cytokine levels in these patients. We conducted a prospective, multi-center trial to determine the inflammatory cytokine levels and evaluate shunt outcomes in PHH patients during the period from December 2019 to June 2021. Upon identification of candidates for shunt surgery, CSF samples were obtained and stored for subsequent analysis of inflammatory cytokines. Outcome measures included the symptomatic control rate (SCR), shunt failure rate, Evans index, and modified Rankin Scale (mRS) score at 6 months postoperatively. SCR assessed via Kiefer Hydrocephalus Scale (KHS: gait, cognition, incontinence, headache, dizziness). 24 patients were included in the study. CSF cytokine levels were compared between PHH patients and two control groups. The results showed elevated CSF tumor necrosis factor-alpha (TNF-alpha) level in PHH patients compared to controls, indicating potential inflammatory response in these patients. However, no significant differences were observed in other cytokines, including interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, and IL-10. Furthermore, shunting outcomes were evaluated, demonstrating improvements in ventricular parameters and neurofunctional outcomes postoperatively. Although shunt failure occurred in 16.7% of cases, the majority of patients experienced satisfactory outcomes with decreased morbidity and improved quality of life. No severe adverse events were reported during the 6-month follow-up period. There were no statistically significant differences in cytokine levels between the shunt-success and shunt-failure groups for TNF

关键词： 多房棘球蚴病   免疫抑制   免疫微环境   白细胞介素-10  

摘要： 多房棘球蚴病是由多房棘球属绦虫的幼虫（多房棘球蚴）寄生在宿主体内所引起的一种人兽共患寄生虫病。多房棘球蚴作为外源性物质持续感染宿主，导致宿主细胞免疫功能抑制和细胞因子分泌紊乱，在体内形成一种特殊的微环境。其中白细胞介素-10 (IL-10)作为一种抗炎性细胞因子，在棘球蚴病免疫调控中发挥着重要作用。本文介绍了多房棘球蚴病免疫抑制微环境的形成，分析了IL-10的生物学特性、对免疫细胞功能的影响以及细胞因子的相互作用，探讨其在多房棘球蚴病免疫抑制微环境中的作用机制，为多房棘球蚴病的治疗提供新的理论依据和潜在治疗靶点。

摘要： Respiratory viral infections establish tissue-resident memory T cells (TRM) in the lung, which provide optimal protection against subsequent infections, though the underlying mechanisms are incompletely understood. Here, we demonstrate in a mouse model of heterosubtypic influenza infection that lung TRM attenuate inflammation by macrophages during secondary versus primary responses, in part, through production of the immunoregulatory cytokine IL-10. During secondary infections, lung TRM were the predominant producers of early IL-10;inhibiting early IL-10 signaling resulted in increased macrophage-mediated inflammation, morbidity, and lung pathology. Moreover, lung TRM were shown to directly modulate lung macrophage responses and polarization in depletion experiments. Finally, IL-10 enhanced IFN-gamma production by lung memory CD8+ T cells. Human influenza-specific TRM isolated from lungs recapitulated robust IL-10 expression associated with augmented effector responses of murine TRM. These data support a dual role of TRM in coordinating in situ secondary responses-augmenting effector responses for robust viral clearance while dampening inflammation to limit tissue damage.

关键词： IFN gamma   immunotherapy   melanoma   NK cells  

摘要： Melanoma, the deadliest form of skin cancer, poses a significant challenge due to its genetic heterogeneity and high metastatic potential. While cytotoxic T cell (CTL)-based immunotherapies have made remarkable progress in recent years, the therapeutic potential of natural killer-(NK) cells is increasingly recognized. However, resistance mechanisms to both CTL- and NK-cell-mediated immunotherapies hinder effective treatment. To evaluate the exclusive role of NK-cells in anti-melanoma immunity, we performed 2D and 3D co-culture-based cytotoxicity assays under varying conditions. Our findings revealed a protective phenotype in melanoma cells following prolonged exposure to primary NK-cells. By combining experimental data with bioinformatic analyses, we identified key genes and pathways involved in melanoma cell adaptation to NK-cell-mediated killing (NKmK). We found that cytokines such as IFN gamma play a major role in suppressing NKmK with MHC II surface expression being a critical factor. Targeting the master regulator CIITA, which governs MHC II expression and is affected by IFN gamma, significantly reduced melanoma cell resistance to NKmK. This study provides potential strategies to overcome resistance to NK-cell-based immunotherapies and offers novel insights into melanoma immune escape mechanisms.

关键词： 反复种植失败   子宫内膜容受性   白介素IL-1β   核因子NF-κB   血清糖皮质激素诱导激酶1   同源框基因A10  

摘要： 目的 探讨白介素IL-1β及血清糖皮质激素诱导激酶1（SGK1）在反复种植失败（RIF）患者子宫内膜组织中的表达特征及其通过HOXA10调控子宫内膜容受性的分子机制。方法 收集2021年1月至2022年12月在常州市妇幼保健院就诊的RIF患者（试验组，n=9）或因男方因素不孕但成功妊娠女性（对照组，n=8）的分泌中期子宫内膜组织。采用qPCR检测两组子宫内膜组织中IL-1β的mRNA水平以及IL-1β和SGK1对HOXA10表达的影响；蛋白质印迹技术检测两组子宫内膜组织中SGK1和HOXA10的蛋白水平以及Ishikawa细胞中p65、p-p65、SGK1、HOXA10蛋白在相应刺激下的表达水平。结果 与对照组相比，试验组分泌中期子宫内膜组织中IL-1β mRNA及SGK1的蛋白水平升高（1.000 ± 0.043 vs 1.619 ± 0.075，P<0.001；0.656 ± 0.053 vs 1.091 ± 0.064，P<0.001）；而HOXA10的蛋白水平降低（1.159 ± 0.115 vs 0.595 ± 0.060，P<0.001）。IL-1β以浓度依赖性方式激活NF-κB p65磷酸化并上调SGK1的表达，而NF-κB活性抑制剂PDTC可逆转此效应。SGK1抑制Ishikawa细胞中HOXA10 mRNA和蛋白的表达，SGK1特异性siRNA可部分挽救IL-1β对HOXA10的抑制作用。结论 RIF患者分泌中期子宫内膜组织中异常高表达的IL-1β，可能通过激活NF-κB/SGK1通路抑制HOXA10的表达，损害子宫内膜的容受性，导致反复种植失败的发生。