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关键词： cancer   GBM   HSV   immunotherapy   oncolytic  

摘要： Glioblastoma (GBM) is a devastating brain cancer with a 5-year survival rate of similar to 5% despite current treatment regimens. Multiple oncolytic herpes simplex viruses (oHSV) have been designed for GBM therapy, but clinical trials have thus far met with limited success. A potential reason for this lack of efficacy is the immunosuppressive tumor microenvironment (TME) of GBM. Here we used an oHSV (KOS strain) armed with interleukin (IL)-12 (oHSV:IL-12) in an attempt to overcome this immunosuppression and analyzed the immunological and therapeutic impact in murine CT2A and GL261N4 orthotopic syngeneic glioma models. Unarmed oHSV failed to enhance survival in animals bearing syngeneic GBM tumors. However, oHSV:IL-12 induced significant and durable therapeutic benefits. TME interrogation following oHSV:IL-12 therapy revealed a significant accumulation of macrophages and cytotoxic T cells. Further investigation using single cell RNA-sequencing of GL261N4 tumors treated with either oHSV or oHSV:IL-12, indicated that oHSV:IL-12 induced robust macrophage accumulation within the TME and encouraged T cell receptor clonotype expansion compared to controls. These data point to the propensity of the IL-12 transgene to manipulate the myeloid compartment within the glioma TME, promote T cell expansion, and improve survival.

关键词： HLA-B*46:107   nanopore sequencing   novel allele  

摘要： HLA-B*46:107 differs from HLA-B*46:01:01:01 by one nucleotide substitution at codon 83 in exon 2.

关键词： psoriatic arthritis   IL-17 inhibitors   IL-12/23 inhibitors   IL-23 inhibitors   network meta-analysis  

摘要： Background: Psoriatic arthritis (PsA) is a chronic inflammatory disease that impacts both the skin and joints. Currently, interleukin (IL)-17, IL-12/23, and IL-23 inhibitors have become integral components of PsA treatment regimens. Nevertheless, the comparative effectiveness of these IL-targeted therapies remains a subject of ongoing debate. This study employs a network meta-analysis (NMA) approach to systematically evaluate the therapeutic efficacy and safety profiles of various IL-17, IL-12/23, and IL-23 inhibitors. Methods: We searched PubMed, Web of Science, and Embase for randomized controlled trials (RCTs) to identify eligible research articles. This NMA was implemented by Stata 14.0 software, with odds ratios (ORs) and 95% confidence intervals (CIs) serving as effect and safety measures to evaluate clinical efficacy and safety profiles. Drugs were ranked based on their efficacy and safety profiles using the surface under the cumulative ranking curve values, enabling a comprehensive comparative assessment of interventional strategies. The CINeMA (Confidence in Network Meta-Analysis) online tool was utilized to evaluate the confidence level of the NMA results. Results: This NMA included 22 RCTs and 9,241 patients. All intervention groups demonstrated superior efficacy to the placebo group. Based on efficacy endpoints and subgroup analyses, bimekizumab, secukinumab, and ixekizumab exhibited superior short-term efficacy. Notably, subgroup analyses suggested that tildrakizumab may represent a promising therapeutic option for PsA. Regarding safety and the risk of adverse events, all treatments demonstrated no significant differences compared to placebo, except bimekizumab 160 mg every 4 weeks (Q4W) (OR = 1.37, 95% CI: 1.08-1.74). There were no significant differences in terms of serious adverse events and upper respiratory tract infection. Bimekizumab 160 mg Q4W showed heightened risk of nasopharyngitis (OR = 2.30, 95% CI: 1.26-4.22). Conclusions: This NMA showed

关键词： Colorectal Cancer   Immune Checkpoint Inhibitors   Immunomodulation   Tumor Microenvironment  

摘要： Background Programmed cell death protein-1 (PD-1)-blocking immune checkpoint inhibitors (ICIs) are effective against highly immunogenic "hot" tumors containing high numbers of cytotoxic T-lymphocytes (CTLs), but not against poorly immunogenic "cold" tumors. We previously reported that the combination of TLR3 agonist rintatolimod with interferon (IFN)-alpha selectively induces CTL-attracting chemokines (CXCL9, CXCL10, CCL5) in the tumor microenvironment (TME), but not healthy tissues, raising the possibility of their systemic application to promote local CTL attraction to *** We used mouse colorectal cancer (CRC) cells implanted in syngeneic mice to test the effects of chemokine modulatory regimen (CKM) in combination with PD-1 blockade applied at different schedules. Tumor-bearing mice were treated and monitored for survival. In addition, we evaluated the reliance of CKM+alpha PD-1 treatment on various immune cell subsets. Finally, we observed treatment-induced changes in immune markers within *** Here, we report that both local or systemic application of CKM, a combination of rintatolimod and IFN-alpha, but not each of them individually, induces intratumoral CTL attractants and sensitizes PD-1-resistant MC38 and CT26 tumors to PD-1 blockade. The CKM/alpha PD-1 combination promotes intratumoral influx of BATF3-positive cDC1s and CTLs, inhibits tumor growth and prolongs survival, inducing cures in 20-100% of animals, depending on the tumor model and stage, and the route of delivery (local or systemic). CKM/alpha PD-1-treated mice develop local and systemic tumor-specific CTL responses and resistance to tumor re-challenge. The effectiveness of CKM requires its application at the time of or directly before PD-1 blockade and is strongly reduced by even a 24-hour delay in alpha PD-1 administration. CKM-driven intratumoral CTL accumulation and antitumor effects require host's BATF3+cDC1s, CD8+T-lymphocytes, and CXCR3 and CCR5 (receptors for CXCL9/CXCL10 an

关键词： 冻结肩   炎症细胞因子   单核细胞趋化蛋白3   基质细胞衍生因子1α   孟德尔随机化分析  

摘要： 背景：冻结肩是骨伤科常见疾病，但无特异性确诊的临床指标，炎症细胞因子与冻结肩有相当大的关联，但具体因果关系尚未明确。此研究采用全基因组关联研究的汇总统计数据进行孟德尔随机化分析，全基因组关联研究数据基于大样本遗传变异信息，可减少环境混杂因素干扰，更可靠地推断炎症细胞因子与冻结肩的因果关系，弥补传统观察性研究无法确定因果关联的局限。目的：运用双向双样本孟德尔随机化方法，探讨炎症细胞因子与冻结肩发病之间的因果关系。方法：利用FinnGen数据库中全基因组关联研究的汇总统计数据，对41种炎性细胞因子和冻结肩的因果关系进行分析。FinnGen数据库由芬兰国立卫生与福利研究院(THL)、赫尔辛基大学等多家芬兰科研机构联合发起，包括2 942例病例和167 641例欧洲血统对照，整合数十万至百万级人群的基因组、临床表型和生化指标数据，支持疾病遗传关联研究。该研究基于公开可用的汇总统计数据库，无需伦理审批。采用逆方差加权法、加权中位数法、加权模型法、简单模型法、MR-Egger回归和敏感性分析(包括MR-Egger、MR-PRESSO、Cochran’s Q检验)进行双向孟德尔随机化分析。结果与结论：单核细胞趋化蛋白3在正反两个方向上均具有显著的因果效应。在正向分析中，单核细胞趋化蛋白3与冻结肩风险呈正相关(OR=1.176,95%CI:1.034-1.338,P=0.014)；在反向分析中，冻结肩与单核细胞趋化蛋白3水平呈负相关(OR=0.782,95%CI:0.625-0.979,P=0.032)。此外，发现肿瘤坏死因子β与冻结肩风险之间有显著关联(OR=1.126,95%CI:1.002-1.264,P=0.046)；在反向分析中，基质细胞衍生因子1α与冻结肩风险之间也有显著关联(OR=1.1,95%CI:1.011-1.196,P=0.028)，表明肿瘤坏死因子β、基质细胞衍生因子1α与冻结肩存在可靠的相关性。此双向孟德尔随机化研究揭示了单核细胞趋化蛋白3与冻结肩之间的复杂相互作用，提示单核细胞趋化蛋白3可能作为一个潜在的治疗靶点。此外，研究还表明肿瘤坏死因子β与冻结肩风险相关，可能是冻结肩潜在的风险因子；而冻结肩亦与基质细胞衍生因子1α水平升高相关，基质细胞衍生因子1α具备成为冻结肩诊断标志物的潜力。但还需进一步研究以阐明这些因果关系背后的生物学机制。此外国际数据库的分析为中国研究提供了候选分子和因果推断范式，但需结合本土数据实现精准转化。

关键词： isoprenoids   IL-1 beta   inflammasome   prenylation   leprosy   mevalonate pathway  

摘要： Leprosy is a chronic infectious disease caused by Mycobacterium leprae and M. lepromatosis. Brazil consistently ranks among the countries with the highest number of leprosy cases. Data from our group showed that M. leprae upregulates the mevalonate pathway (MP), contributing to the accumulation of cholesterol-ester-enriched lipid droplets in infected macrophages, and that the inhibition of this pathway by statins decreases bacterial intracellular viability. It has already been shown that part of the deleterious effect of statins on M. leprae survival is related to the reduced cholesterol levels, which M. leprae oxidizes to generate reductive power. According to the literature, statins, by inhibiting MP, increase the production of the inflammatory cytokine IL-1 beta through the negative modulation of the biosynthesis of the isoprenoid geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP), which are responsible for protein prenylation. In the present study, we tested the hypothesis that part of the effect of statins on the intracellular viability of M. leprae comes from their impact on IL-1 beta production via decreased prenylation. We demonstrate that GGPP is essential in macrophage-M. leprae interaction since the MP inhibitors, pamidronate and GGTI-298, which inhibit the enzymes farnesyl pyrophosphate synthase and geranylgeranyl transferase-1, respectively, decreased the intracellular viability of M. leprae, measured by RT-qPCR. MP inhibitors increased IL-1 beta production by activating the inflammasome, but this effect was reversed with GGPP. IL-1 beta levels were inversely related to bacterial survival. In conclusion, our findings highlight the potential role of protein geranylgeranylation in M. leprae pathogenesis and suggest new therapy options for *** leprae, the bacterium that causes leprosy, survives and replicates inside macrophages. Statins, which inhibit the mevalonate pathway, promote bacterial killing in macroph

关键词： Transgenic mice   MHC I overexpression   Alveolar type ii cells   Immunopathology  

摘要： The major histocompatibility complex class I (MHC I) is crucial in adaptive immunity, enabling CD8 + T cells to detect and eliminate infected and cancerous cells. Recent studies have uncovered significant variability in MHC I expression across tissues, challenging the traditional belief of uniform expression. Lung epithelial cells (LECs) express meager amounts of MHC I, which preserves the lung epithelium from excessive inflammation but renders it more susceptible to cancer and infection. Despite MHC I overexpression in various immunopathologies, its precise role in disease initiation or progression remains unclear due to the absence of suitable in vivo models for studying MHC I overexpression. This study introduces a novel mouse model with targeted surface MHC I upregulation. Leveraging a conditional Cre-lox system, we augmented Nlrc5 expression to specifically upregulate MHC I in alveolar type 2 (AT2) LECs, known for their low basal expression of MHC I and significant overexpression in disease. Our model demonstrated a rapid and sustained tenfold increase in MHC I surface expression persisting for up to a year without triggering pathology or inflammation. Comprehensive characterization and validation of this model indicated that MHC I overexpression does not serve as a primary initiator of respiratory diseases under steady-state conditions and shows a therapeutic window for increasing MHC I without significant damage to the lung epithelium. This adaptable model offers insights into the effects of tissue-specific MHC I regulation and presents new avenues for therapeutic development.

关键词： TNF-alpha   fibroblasts   PMM2-CDG   inflammation   transcriptomics   glycomics  

摘要： Introduction Glycosylation is a post-translational modification that plays a crucial role in immune system activity. Phosphomannomutase 2-Congenital Disorder of Glycosylation (PMM2-CDG) is a rare genetic disease affecting glycosylation with a multi-systemic impact. PMM2-CDG patients commonly show immune disfunction and elevated pro-inflammatory cytokine levels that may link to other symptoms. However, the underlying immune mechanisms remain unclear. Given Tumour Necrosis Factor (TNF)'s key role in inflammation, this study proposes that defective glycosylation of its receptors disrupts intracellular signalling, leading to changes in the immune response of PMM2-CDG *** To address this, we applied an integrative approach, combining transcriptomics, glycomics, and immune-related assays to investigate the impact of TNF-a stimulation via TNF receptor 1 (TNFR1) in a cohort of PMM2-CDG patients' skin *** Our results reveal a multifaceted disruption of TNF-a signalling in PMM2-CDG fibroblasts. We observed structural abnormalities in TNFR1, including altered receptor shedding. PMM2-CDG cells also showed an altered N-glycosylation profile, affecting particularly, high mannose N-glycans. At transcriptional level, PMM2-CDG cells, especially those bearing the R141H heterozygous variant, exhibited a distinct gene expression profile, after stimulation, characterized by dysregulation of immune and signalling pathways. Functionally, these molecular alterations translated into a diminished secretion of key inflammation and infection mediators, such as interleukin-6 (IL-6) and C-C Motif chemokine ligand 5 (CCL5) upon TNF-a stimulation. Similarly, essential signalling kinases including extracellular-signal-regulated kinase (ERK) 1/2, p38 and c-Jun N- terminal kinase (JNK) 2 showed reduced expression in PMM2-CDG cells, and their expression did not alter following TNF-a stimulation, unlike control *** Our findings point to TNFR1 signalling dysregu

关键词： Cognitive function   Flexi-bar exercise   BDNF   TNF-alpha   mircoRNAs  

摘要： PurposeAppropriate physical exercise could prevent, delay, or reverse cognitive decline in aging people, which could improve their quality of life. However, the underlying mechanisms are still elusive. The present study aimed to explore the effects of 8-week Flexi-bar vibration exercise (FE) on the cognitive function in middle-aged and elderly women and uncover the underlying *** middle-aged and elderly women were randomly assigned to the FE group or the control group (n = 15 in each group). Executive function and real-time oxyhemoglobin concentration (oxy-Hb) changes in different cerebral regions were evaluated through the Color-Word Stroop Test and functional near-infrared spectroscopy, respectively. Circulating levels of Brain-derived neurotrophic factor (BDNF) and tumor necrosis factor-alpha (TNF-alpha) were measured by enzyme-linked immunosorbent assay. The expression levels of microRNAs were determined using microRNA sequencing and real-time PCR approaches, followed by an integrated bioinformatics/biostatistics *** data showed that 8 weeks of FE had a positive effect on preventing cognitive decline, with improved blood oxygen content in the dorsolateral prefrontal cortex (DLPFC), up-regulated BDNF level, and down-regulated level of TNF-alpha in serum. Besides, our data showed that 14 microRNAs, which are related to the cognitive function, were up/down-regulated in the FE *** study revealed that 8-week FE could regulate the expression levels of microRNAs related to cognitive function, elevate BDNF level, and decrease TNF-alpha level, and thus improve cognitive performance in middle-aged and elderly women.

关键词： IL-9 signaling   Obesity   Inflammasome   Helminths   Inflammation   insulin resistance  

摘要： Despite the proven beneficial role of type 2 cytokines in diabetes and obesity, IL-9, a predominant Th2 cytokine, has not been investigated in this context. The present study characterized the role of IL-9 signaling in obesity and metabolic dysfunction. We found decreased IL-9 levels in human type 2 diabetes patients and decreased IL-9 signaling in high-fat diet (HFD)-induced obese mice. On the other hand, recombinant IL-9 (rIL-9) treatment reversed insulin insensitivity and inflammation following HFD consumption. IL-9R knockout (KO) mice fed a HFD presented faster weight gain, impaired glucose and insulin tolerance, defective insulin signaling, increased adipocyte size, and decreased energy expenditure. In the adipose tissue of HFD-fed IL-9R KO mice, a significant increase in the number of CD11c+ macrophages and a decrease in the number of RELM alpha+ macrophages, eosinophils and ILC2s were observed, along with increased TNF, decreased adiponectin production and increased expression of NLRP3. In vitro treatment of human and mouse macrophages with rIL-9 decreased the release of NLRP3-induced IL-1 beta and IL-18. In vivo treatment of HFD-fed IL-9R KO mice with a pharmacological inhibitor of the NLRP3 inflammasome rescued body weight, insulin sensitivity and adipose tissue inflammation. Mechanistically, the STAT5 protein was found to be important for the IL-9-induced inhibition of the NLRP3 inflammasome in adipose tissue. In addition, we also demonstrated a potential role for IL-9 in the protective effects of helminth immunomodulation during obesity and insulin resistance in filaria-infected humans and in an animal model. Taken together, the results of this study highlight that IL-9 signaling improves insulin signaling by inhibiting NLRP3-induced inflammation.