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摘要： PURPOSE:Immune checkpoint inhibitors (ICI) have increasing application in endometrial cancer, underscoring the need for robust biomarkers for patient selection. JAK1 pathogenic variants (PV) have previously been implicated in immune evasion. Here, we identify biomarkers predictive of ICI response in endometrial cancer and the implications of JAK1 PV in this context. EXPERIMENTAL DESIGN:This is a translational study of tumors from 84 endometrial cancer patients treated with ICI. High-throughput proteomic-based profiling was used to quantify 193 phospho-/protein expression levels, including key JAK/STAT signaling pathway components. Associations with clinical outcomes were assessed using multivariate regression analysis. The functional consequences of JAK1 PV were explored through in vitro signaling assays and analyses of TCGA database. RESULTS:MHC-I expression correlated with improved progression-free survival (p = 0.035), validated in orthogonal approaches. Notably, a subset of patients harboring JAK1 PVs demonstrated exceptional survival on ICI. In TCGA cohort of microsatellite instability-high (MSI-H) and DNA polymerase epsilon (POLE)-mutated tumors, homozygous loss of JAK1 (JAK1Hom) trended toward decreased survival, whereas heterozygous loss of JAK1 (JAK1Het) was associated with significantly improved survival (p = 0.026), suggesting partial retention of antigen presentation pathways. Among our ICI-treated MSI-H tumor samples, NK cell marker NCAM1 was associated with improved survival (p=0.02). CONCLUSIONS:These data support MHC-I as a potential predictive biomarker for ICI response in endometrial cancer. Additionally, we show that partial retention of JAK1 signaling in JAK1Het tumors is associated with improved survival, potentially attributable to enhanced NK cell activity in tumors with low MHC-I expression.

关键词： 肝细胞癌(HCC)   细胞迁移   白细胞介素-13受体α2(IL13RA2)   SOX18   转移  

摘要： 目的 研究白细胞介素-13受体α2（IL13RA2）在肝细胞癌（HCC）中的表达、作用及机制。方法 利用公共数据库和临床样本分析IL13RA2在HCC的表达情况，统计并随访临床数据，分析IL13RA2的表达水平与HCC患者预后的相关性。使用IL13RA2敲低或过表达质粒构建IL13RA2稳转细胞株，利用Transwell、划痕等实验技术检测IL13RA2对HCC细胞迁移和侵袭的影响。构建裸鼠肝癌肺转移模型，明确IL13RA2体内影响HCC肺转移的作用。利用转录组测序（RNA-seq）筛选IL13RA2下游靶分子，并利用公共数据库及临床数据分析IL13RA2与靶分子相关性分析。利用SOX18抑制剂Sm4做功能挽救实验，明确SOX18是否参与IL13RA2调控HCC进展的过程。结果 IL13RA2表达的降低与HCC患者的肿瘤分化、肿瘤淋巴结转移和预后不良有关（P<0.05）。体内和体外实验表明，上调IL13RA2可降低HCC的侵袭和转移，而下调IL13RA2则可促进HCC的侵袭与转移（P<0.05）。本研究利用生物测序技术筛选出可能与IL13RA2相互作用的分子SRY-box转录因子18（SOX18）。HCC肿瘤组织中SOX18的表达与IL13RA2的含量呈负相关（P<0.05）。SOX18抑制剂Sm4处理可解除IL13RA2对HCC转移的抑制作用（P<0.05）。结论 IL13RA2在HCC中低表达，SOX18可能介导IL13RA2抗转移作用。IL13RA2/SOX18信号轴可能为HCC的靶向治疗提供新的分子干预靶点。

关键词： Tanshinone IIA   Type 2 diabetes mellitus   Beta-cell dysfunction   Bioinformatics   Inflammation   Endoplasmic reticulum stress  

摘要： Type 2 diabetes mellitus (T2DM) is a severe metabolic disorder in which pancreatic injury plays a pivotal role in disease progression. Tanshinone IIA (TanIIA), a bioactive compound extracted from Salvia miltiorrhiza, has shown therapeutic potential in diabetes management. However, its protective effects on pancreatic injury and underlying pharmacological mechanisms remain unclear. In this study, TanIIA significantly reduced fasting blood glucose, improved insulin resistance, and alleviated islet structural damage and beta-cell apoptosis. Potential TanIIA targets were initially predicted through integrated network pharmacology, weighted gene co-expression network analysis (WGCNA), and differential gene expression analysis. Based on these integrated data, five machine learning algorithms were applied to identify candidate targets. PTGS2, NR4A2, MGLL, GABRA2, and IL-6 were determined to be core targets and were validated by qRT-PCR, with functional enrichment indicating that the JAK-STAT pathway is a key regulatory axis. Molecular docking revealed strong binding affinities between TanIIA and these core targets, with calculated binding energies of -8.7 (PTGS2), -7.6 (NR4A2), -9.8 (MGLL), -8.3 (GABRA2), and - 7.5 (IL-6) kcal/mol. Furthermore, molecular dynamics simulations confirmed the stable interaction between TanIIA and IL-6. In vivo experiments further demonstrated that TanIIA modulated the IL-6/JAK2/STAT3 pathway In vivo experiments further demonstrated that TanIIA modulated the IL-6/JAK2/STAT3 pathway, suppressed proinflammatory cytokines, promoted anti-inflammatory IL-10 expression, and regulated macrophage polarization, thereby improving the inflammatory microenvironment in islets. Additionally, TanIIA activated the PI3K-AKT pathway, alleviated glucolipotoxicity-induced endoplasmic reticulum (ER) stress, and downregulated ER stress-related proteins including p-IRE1 alpha, GRP78, XBP1s, and CHOP, ultimately inhibiting beta-cell apoptosis. Collectively, these find

关键词： Immunodeficiency   Infectious disease and host defense   Innate immunity and inflammation   Immunodeficiency   Infectious disease and host defense   Innate immunity and inflammation  

摘要： Herpes simplex encephalitis (HSE) is a devastating disease with high mortality and serious sequelae. Genetic defects in the IFN-I pathway predispose individuals to HSE, but underlying mechanisms remain unclear. Using transgenic mice with the IRF3 R278Q mutation, ortholog to HSE-associated IRF3 R285Q, and iPSC-derived CNS cells from a pediatric patient carrying the variant, we investigated mechanisms in HSE. IRF3 R278Q transgenic mice exhibited aggravated HSV-1 brain disease and elevated CNS viral loads. Accordingly, microglia from the IRF3 R278Q mice showed reduced HSV-1-induced IFN-I expression. Surprisingly, unaltered Ifnb levels along with elevated levels of inflammatory cytokines were detected in infected transgenic mouse brains, correlating with higher viral load. This was successfully modeled in patient microglia. Multiomics-based immune profiling revealed an inflammatory monocyte population in the infected IRF3 R278Q mouse brain, which was enriched for NF-kappa B activation. NF-kappa B inhibition improved disease outcomes, surpassing the effect of acyclovir. These findings suggest that IFN-I defects lead to elevated levels of HSV-1 replication in the brain, which subsequently enables NF-kappa B-driven immunopathology, offering insights with therapeutic potential.

关键词： Thyroid eye disease   Satralizumab   Interleukin-6   Interleukin-6 receptor   Anti-interleukin-6 receptor  

摘要： IntroductionThyroid eye disease (TED) is a rare, autoimmune, orbital inflammatory disorder that is disfiguring, debilitating, and potentially sight-threatening. There is an unmet need for a fast-acting, durable, systemic disease-modifying therapy in active TED, for which current options are associated with relapses and side effects, and for chronic inactive TED, which is largely managed with surgery. Satralizumab is a recombinant humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody that prevents IL-6 from binding to its receptor, thereby reducing proinflammatory and profibrotic signaling. The SatraGO-1 and SatraGO-2 trials evaluated the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab in participants with active, moderate-to-severe, and chronic inactive ***-1 and SatraGO-2 were two identically designed, 72-week, double-masked, placebo-controlled, multicenter, two-stage randomization, phase 3 trials in adults with active, moderate-to-severe TED or chronic inactive TED. Participants were randomized 1:1 to receive satralizumab or matching placebo. Based on the proptosis response assessed at week 24, nonresponders received satralizumab every 4 weeks (Q4W), while responders were rerandomized in a 1:1 ratio to receive satralizumab or placebo Q4W through week 44. The primary end point was the proportion of participants with active, moderate-to-severe TED who achieved >= 2-mm reduction in proptosis in the study eye from baseline at week ***-1 and SatraGO-2 enrolled 131 and 127 participants, *** SatraGO-1 and SatraGO-2 trials investigated IL-6R inhibition via satralizumab in TED. Satralizumab offers a potential disease-modifying treatment option for TED while minimizing safety risks associated with current *** registration: SatraGO-1 (NCT05987423) and SatraGO-2 (NCT06106828).ConclusionsThe SatraGO-1 and SatraGO-2 trials investigated IL-6R inhibition via satralizumab in TED.

摘要： Aging-related neuroinflammation drives cognitive decline;however, the mechanisms by which gut microbiota-modulating bioactive compounds, such as rice bran peptide KF-8, mitigate this process remain unclear. Here, KF-8 was shown to ameliorate age-related traits in aged mice by reshaping gut microbiota, notably by stabilizing Akkermansia muciniphila (AKK), to suppress systemic inflammation and cognitive deficits. Specifically, antibiotic-treated mice receiving KF-8 exhibited neuroinflammation and declined cognition. KF-8 and AKK synergistically attenuated pro-inflammatory pathways, particularly TNF-alpha, in the blood and in the hippocampus. While TNF-alpha antibodies mirrored KF-8's benefits, TNF-alpha recombinant protein negated KF-8's protective effects. Combined KF-8 and AKK interventions aligned with TNF-alpha antibody outcomes, underscoring TNF-alpha's pivotal role. Our findings reveal that KF-8 enhances healthy aging by modulating gut microbiota, sustaining AKK, and suppressing TNF-alpha-driven neuroinflammation, thereby rescuing cognitive function in aged mice.

关键词： Adipose Tissue   Meal   Protein Turnover   Skeletal Muscle   Stable Isotopes   Tocilizumab  

摘要： CONTEXT:Sarcopenic obesity, the loss of muscle mass and function in people with obesity, may result from altered muscle protein synthesis and degradation. Chronic low-grade inflammation, particularly interleukin-6 (IL-6) has been implicated. OBJECTIVE:To assess the role of IL-6 in protein and amino acid metabolism during fasting and postprandial states in humans with healthy weight or obesity at whole-body, skeletal muscle and subcutaneous adipose tissue levels. METHODS:In this placebo-controlled, non-randomized, participant-blinded study, 12 men with healthy weight and 12 men with obesity received placebo (0.9% saline) or three weeks of IL-6 receptor (IL-6R) blockade with tocilizumab. Isotope dilution/incorporation techniques and arteriovenous balance measurements were applied in fasted and postprandial states. The trial was originally designed to examine IL-6 effects on fat storage (reported previously). Here, we present pre-specified exploratory outcomes on amino acid and protein turnover. RESULTS:Obesity was associated with reduced meal-induced muscle-protein gain driven by impaired suppression of muscle protein degradation, and with reduced appearance of amino acids from meals. In both groups, IL-6R blockade increased fasting and postprandial plasma amino acids, and reduced postprandial plasma protein synthesis without affecting skeletal muscle protein turnover. In the healthy weight group, it also increased amino acid appearance from the meal and postprandial phenylalanine oxidation. CONCLUSION:Obesity impairs meal-induced muscle-protein gain, through insufficient suppression of protein degradation. Basal IL-6 activity does not regulate muscle protein turnover but influences amino acid metabolism and protein synthesis in extra-muscular tissues.

关键词： 结核感染T细胞斑点试验   白细胞介素-2   干扰素-γ   活动性肺结核   诊断效能  

摘要： 目的 探讨结核感染T细胞斑点试验(***)联合细胞因子白细胞介素-2(IL-2)、干扰素-γ(IFN-γ)对活动性肺结核(ATB)与非ATB的鉴别诊断价值。方法 以2021年2月-2024年3月河北省胸科医院收治的186例肺结核(TB)患者为研究对象,以痰MTB培养检查结果为金标准,将患者分为ATB组(n=92)及非ATB组(n=94),对所有患者进行***检测。收集并比较两组患者一般资料,将***、IL-2和IFN-γ作为因变量,临床咳嗽、发热症状作为自变量进行分层回归分析,分析临床特征对***、IL-2和IFN-γ的影响。应用主成分分析(PCA)法和偏最小二乘判别分析(PLS-DA)法评估***联合细胞因子IL-2、IFN-γ对ATB与非ATB的鉴别诊断价值。接收者操作特征(ROC)曲线检验***、IL-2和IFN-γ和预测模型的效能。结果 两组患者在咳嗽、发热、IL-1β、IL-2、IL-6、IL-8和IFN-γ方面差异存在统计学意义(P<0.05)。临床咳嗽、发热症状均会对***、IL-2和IFN-γ存在统计学正向关联(P<0.05)。PCA模型和PLS-DA模型结果显示,ATB和ATB患者个体差异均较小,两组均可明显聚类,2组可显著鉴别。联合模型的曲线下面积(AUC)最高(P<0.05),为0.913(0.875～0.950),其敏感度为90.24%,特异度为74.54%。结论 ***联合IFN-γ和IL-2诊断ATB和非ATB具有较高的准确度和敏感度,可作为ATB的辅助诊断方法,具有较高的临床价值。

摘要： Poor infiltration of CD8+ T cells and dysregulation of major histocompatibility complex 1 (MHC-I) confer resistance to anticancer immunotherapies. Inhibition of the epigenetic regulator lysine-specific demethylase 1 (LSD1) has been shown to increase CD8+ T cell infiltration in head and neck squamous cell carcinoma (HNSCC). In this study, we aimed to elucidate the mechanisms of LSD1 inhibition in antitumor immunity in HNSCC to aid in the development of effective therapeutic strategies. LSD1 inhibition in syngeneic and chronic tobacco carcinogen-induced HNSCC mouse models increased recruitment of activated dendritic cells (DCs), as well as CD4+ and CD8+ T cells, and expression of interferon-gamma (IFNγ) in CD8+ T cells, CXCL9 in DCs, and CXCR3 in CD4+ T cells. Humanized HNSCC mice and patient data validated the inverse correlation of KDM1A with DC markers, CD8+ T cells, and their activating chemokines. Kdm1a knockout in mouse HNSCC and LSD1 inhibitor treatment of human HNSCC cells co-cultured with human peripheral blood mononuclear cells resulted in MHC-I upregulation in cancer cells. LSD1 inhibition promoted CD8+ T cell activation via a DC-dependent mechanism and induced efficient antigen presentation in CD8+ T cells. LSD1 inhibition increased H3K4me2 at the promoters of DC-related markers (BATF3 and CXCL9), T cell markers (CXCR3), and MHC-I (HLA-A). Overall, LSD1 inhibition in tumor cells upregulates MHC-I expression and stimulates CXCL9 secretion by DCs to enhance antigen presentation and promote CD8+ T cell activation via the CXCL9-CXCR3 signaling axis, resulting in increased IFNγ production. This may have implications for treating poorly immunogenic and immunotherapy-resistant cancers.