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关键词： biomarkers   cognitive dysfunction   inflammation   neurodegeneration   tumor IDH mutation  

摘要： Background. Cognitive dysfunction is common among patients with malignant glioma, yet the underlying mechanisms of this dysfunction remain unclear. Protein markers of neurodegeneration, inflammation, and vascular damage have been associated with central nervous system pathology and with cognitive changes in neurological diseases, but their clinical utility in gliomas is unknown. This study examined the relationships between cognitive dysfunction, tumor isocitrate dehydrogenase (IDH) mutation status in gliomas, and a panel of blood-based protein biomarkers. Methods. This retrospective cohort study included 73 glioma patients with either IDH-mutant (n = 45) or IDH-wildtype tumors (n = 28) enrolled in a natural history study. Cognitive function was assessed using the Montreal Cognitive Assessment (scores <26 indicated cognitive dysfunction). Serum levels of 17 proteins were measured using ultrasensitive assays. Results. Cognitive dysfunction was present in 53% of participants (n = 39), and more frequently in the IDH-wildtype group (75%) than in the IDH-mutant group (40%). Patients with wildtype tumors had higher levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1, interleukin-6 (IL-6), and tumor necrosis factor-alpha than patients with IDH-mutant tumors, which remained in multivariate analysis. ICAM-1 and IL-10 were higher in patients with cognitive dysfunction compared to those with normal cognition, even after adjusting for tumor IDH-mutation status, age, tumor grade, and surgery history. Conclusions. Cognitive dysfunction was associated with protein markers linked to vascular damage and inflammation regardless of tumor IDH status. Our findings suggest an association of cognitive dysfunction with heightened systemic inflammatory status that requires further interrogation for its role in pathophysiologic mechanisms.

关键词： Fibrosis   collagen   biomechanics   in-vitro   extracellular matrix  

摘要： AimsFibrosis is a multifactorial process characterized by the excessive accumulation of extracellular matrix (ECM), increased tissue stiffness, and decreased elasticity. This study examined how individual cytokines and a cytokine combination alter collagen production and biomechanics in a 3D in vitro model of the human *** human fibroblasts were seeded into a circular agarose trough molded in 24 well plates. The fibroblasts aggregated and formed a 3D ring-shaped tissue that synthesized de novo a collagen-rich human ECM complete with collagen fibrils. Unlike existing models, no macromolecular crowders were added, nor artificial scaffolds or exogenous ECM proteins. Rings were treated with TGF-beta 1, IL-13 or the combination of TGF-beta 1 and IL-13 for up to 3 weeks. Morphology, histology, collagen, DNA, fibril formation, gene expression and tensile properties of the rings were *** the rings compacted, cellularity and total DNA decreased, whereas total collagen accumulated. TGF-beta 1 stimulated collagen accumulation and increased ring biomechanics at day 7, but these increases stalled and declined by day 21. When treated with IL-13, a cytokine exclusive to the immune system, there were no significant differences from control. However, when TGF-beta 1 was combined with IL-13, collagen levels and ring biomechanics increased over the entire three weeks to levels higher than TGF-beta 1 alone. Gene expression was differentially regulated by cytokine treatment over the entire three weeks suggesting that increased collagen accumulation was not due to upregulation of collagen gene *** results suggest that TGF-beta 1 requires a second signal, such as IL-13, to sustain the long-term pathological increases in collagen accumulation and biomechanics that can compromise the function of fibrotic tissues.

关键词： anti-inflammatory   gut microbiome   immune regulation  

摘要： The intestine is home to a complex immune system that is engaged in mutualistic interactions with the microbiome that maintain intestinal homeostasis. A variety of immune-derived anti-inflammatory mediators have been uncovered and shown to be critical for maintaining these beneficial immune-microbiome relation ships. Notably, the gut microbiome actively invokes the induction of anti-inflammatory pathways that limit the development of microbiome-targeted inflammatory immune responses. Despite the importance of this microbiome-driven immunomodulation, detailed knowledge of the microbial factors that promote these responses remains limited. We have previously established that the gut symbiont Bacteroides thetaiotao micron stimulates the production of the anti-inflammatory cytokine IL-10 via soluble factors in a Toll-like receptor 2 (TLR2)-MyD88-dependent manner. Here, using TLR2 activity reporter cell lines, we show that the capacity of B. thetaiotaomicron to stimulate TLR2 activity was not critically dependent on either of the canonical heterodimeric forms of TLR2, TLR2/TLR1, or TLR2/TLR6, that typically mediate its function. Further more, biochemical manipulation of B. thetaiotaomicron-conditioned media suggests that IL-10 induction is mediated by a protease-resistant or non-proteogenic factor. We next uncovered that deletion of gene BT1549, a predicted secreted lipoprotein, significantly impaired the capacity of B. thetaiotaomicron to induce IL-10, while complementation in trans restored IL-10 induction, suggesting a role for BT1549 in the immunomodulatory function of B. thetaiotaomicron. Collectively, these data provide molecular insight into the pathways through which B. thetaiotaomicron operates to promote intestinal immune tolerance and symbiosis.

摘要： Numerous patients with rheumatoid arthritis (RA) manifest severe syndromes, including elevated synovial fluid volumes (SF) with abundant immune cells, which can be controlled by TNF/JAK inhibitors. Here, we apply single-cell RNA sequencing (scRNA-seq) and subsequent validations in SF from RA patients. These analyses of synovial tissue show reduced density of SF-derived pathogenic cells (e.g., SPP1+ macrophages and CXCL13+CD4+ T cells), altered gene expression (e.g., SPP1 and STAT1), molecular pathway changes (e.g., JAK/STAT), and cell-cell communications in drug-specific manners in samples from patients pre-/post-treated with adalimumab/tofacitinib. Particularly, SPP1+ macrophages exhibit pronounced communication with CXCL13+CD4+ T cells, which are abolished after treatment and correlate with treatment efficacy. These pathogenic cell types alone or in combination can augment inflammation of fibroblast-like synoviocytes in vitro, while conditional Spp1 knocking-out reduces RA-related cytokine expression in collagen-induced arthritis mice models. Our study shows the functional role of SF-derived pathogenic cells in progression and drug-specific treatment outcomes in RA.

关键词： lactic acid bacteria   interleukin-10   anti-inflammation   Toll-like receptor 2   macrophage inducible C-type lectin receptor   phagocytosis  

摘要： We showed that Lactiplantibacillus plantarum OLL2712 (OLL2712) strongly induces interleukin (IL)-10 production in immune cells. Although beneficialeffects of this strain have been observed in both mice and humans, the mechanisms underlying IL-10 induction remain unclear. In this study, we found that OLL2712 co-activates two pattern recognition receptors, leading to IL-10 production in the mouse-derived thermosensitive dendritic cell line, tsDC. We first revealed the involvement of the Toll-like receptor (TLR)2-Myeloid differentiation primary response gene (MYD) 88 pathway in OLL2712-induced IL-10 production in tsDCs. However, stimulation with the TLR2 agonist alone was insufficient to induce IL-10 production. Consequently, we explored additional signaling pathways and found that the phosphorylation of spleen tyrosine kinase (Syk) was important in response to OLL2712, which was not triggered by a TLR2 agonist alone. Notably, the activation of Syk was found to depend on macrophage-inducible C-type lectin receptor (Mincle), one of the C-type lectin receptors. However, the surface-expressed Mincle is not responsible for the IL-10 production by OLL2712. Instead, it depends on the incorporation of OLL2712 into tsDCs, suggesting that Mincle recognizes incorporated OLL2712 intracellularly. In summary, OLL2712 is initially recognized by TLR2, which subsequently induces the expression of Mincle to recognize incorporated OLL2712, ultimately inducing IL-10 production.

摘要： The limited infiltration of CD8+ T cells in tumors hampers the effectiveness of T cell-based immunotherapy, yet the mechanisms that limit tumor infiltration by CD8+ T cells remain unclear. Through bulk RNA sequencing of human tumors, we identified a strong correlation between WNT7A expression and reduced CD8+ T-cell infiltration. Further investigation demonstrated that inhibiting WNT7A substantially enhanced MHC-I expression on tumor cells. Mechanistically, WNT7A inhibition inactivated the Wnt/beta-catenin signaling pathway and thus resulted in reduced physical interaction between beta-catenin and p65 in the cytoplasm, which increased the nuclear translocation of p65 and activated the NF-kappa B pathway, ultimately promoting the transcription of genes encoding MHC-I molecules. We found that our lead compound, 1365-0109, disrupted the protein-protein interaction between WNT7A and its receptor FZD5, resulting in the upregulation of MHC-I expression. In murine tumor models, both genetic and pharmaceutical suppression of WNT7A led to increased MHC-I levels on tumor cells, and consequently enhanced the infiltration and functionality of CD8+ T cells, which bolstered antitumor immunity and improved the effectiveness of immune checkpoint blockade therapy. These findings have elucidated the intrinsic mechanisms of WNT7A-induced immune suppression, suggesting that therapeutic interventions targeting WNT7A hold promise for enhancing the efficacy of immunotherapy.

摘要： CD19-directed chimeric antigen receptor (CAR)-T cells are breakthrough therapies for aggressive B-cell lymphomas, but less than half of patients achieve durable responses. We previously showed through whole-genome sequencing of tumors from CAR-T-treated patients that deletions of (3p21.31) are enriched in cases progressing after treatment. 's roles in resistance and pathogenesis are poorly defined, despite loss-of-function alterations that occur in ~20% of newly diagnosed diffuse large B-cell lymphoma (DLBCL) cases. To evaluate mechanisms of CAR-T resistance, we created RHOA-deficient DLBCL systems and confirmed cell-intrinsic loss of response to CAR-19 in vitro and in vivo. RHOA loss promotes AKT activation that impairs cell-intrinsic responses to interferon gamma (IFNγ). Moreover, expression of the CAR target CD19 is consistently down-regulated accompanied by a drive toward plasmablast differentiation. RHOA deficient tumors demonstrate greatly increased sensitivity to AKT-pathway inhibitors, which reverse impaired IFNγ responses. Lymphoma microenvironments in vivo in immunocompetent mice reveal that RHOA loss promotes decreased infiltration by cytotoxic T cells and enrichment of M2-polarized macrophages, known markers of CAR-T resistance in lymphoma clinical cases. Overall, we characterize RHOA deficiency as an AKT-mediated CAR-T resistance driver and implicate avoidance of T-cell mediated killing as a likely reason for RHOA's frequent loss in DLBCL pathogenesis.

关键词： allo-SCT   GVHD   prophylaxis   cyclophosphamide   lymphoma  

摘要： Allogeneic stem cell transplantation (allo-SCT) from HLA-identical donors (HLAid) could be an effective salvage treatment for relapsed/refractory lymphoma. In this setting, standard graft-versus-host disease (GVHD) prophylaxis is based on cyclosporine and methotrexate, with the addition of anti-thymocyte globulin, at least for matched, unrelated donors. Promising data using post-transplant cyclophosphamide (PT-Cy) have been reported from retrospective studies in patients receiving allo-SCT from HLAid donors. Here, we report the results of a single-center, prospective observational study exploring the main outcomes of GVHD prophylaxis based on PT-Cy in 27 patients receiving HLAid donor transplantation for relapsed/refractory lymphoma. With a median follow-up of 38 months, 3-year GVHD-relapse-free survival and PFS and OS were 70.4%, 81.5%, and 88.9%, respectively. The 1-year cumulative incidence (CI) of non-relapse mortality (NRM) was 7.4%. The 6-month CI of acute GVHD was 7.4%, and the 1-year CI of extensive chronic GVHD was 7.7%, with no grade IV GVHD events or deaths from GVHD. Relapse was reported in three patients (1-year relapse incidence: 11%), and two died of progressive disease. No graft failure was observed. This study shows that PT-Cy may be an effective strategy to prevent GVHD in patients with lymphoma receiving HLAid transplantation. It is associated with low NRM and reasonable disease control.

关键词： 食管癌   炎症   炎症细胞   细胞因子   免疫   Esophageal Cancer   Inflammation   Inflammatory Cells   Cytokines   Immunity  

摘要： 食管癌是全球范围内高发且预后不良的恶性肿瘤之一。近年来，越来越多的研究表明，慢性炎症在食管癌的发生、发展和转移过程中扮演着关键角色。本文综述了慢性炎症在食管癌中的作用及其机制研究进展。胃酸/胆汁反流可诱发食管炎症，导致Barrett’s食管的形成。炎症细胞和炎性细胞因子，如IL-8、IL-6、TGF-β、IL-1β及TNF-α等，在食管炎、BE及EAC中发挥着关键作用。NF-κB和STAT3信号通路作为核心炎症信号通路，对食管癌的发生发展具有重要影响。此外，本文还讨论了未来的研究应深入探索炎症在食管癌进展中的机制，开发靶向药物和新的生物标志物，为食管癌的精准治疗提供新的策略与途径。

关键词： 胃癌   CD19   IL-10   B细胞   调节性B细胞   相关性分析  

摘要： 目的探究CD19+IL-10+B在胃癌患者肿瘤免疫微环境中的分布特征及其潜在的临床价值。方法选择2022年1月到2023年12月于我院就诊的胃癌患者100例为研究组，采集胃癌患者的外周血样本、肿瘤组织样本及其对应的癌旁组织样本，随后运用流式细胞术技术，检测CD19+IL-10+B细胞占CD19+B细胞的比例。进一步地，细分并测定CD19+IL-10+CD24hiCD38hiB细胞、CD19+IL-10+CD24intCD38intB细胞、CD19+IL-10+CD24hiCD38-B细胞三种亚群占CD19+B细胞的百分比。另选取在本院体检的健康人100例设为对照组，仅采集其外周血样本，并遵循统一方法分离细胞。比较两组CD19+IL-10+B细胞及亚群在外周血中的含量差异；研究组自身对照进一步了解胃癌患者的外周血、肿瘤组织及癌旁组织中关于特定指标的差异，同时分析这些指标在不同临床特征患者群体中的变异性。根据研究组内胃癌患者的预后状况，将其细分为预后良好组（n=65例）与预后不良组（n=35例），随后对这两组患者的临床基线资料进行全面比较。同时对CD19+IL-10+B细胞及亚群在外周血和肿瘤组织中的含量进行组间差异分析，分析外周血及肿瘤组织中CD19+IL-10+B细胞及亚群与预后的相关性。结果 在PBMC中，CD19+IL-10+B细胞和CD19+IL-10+CD24hiCD38hiB细胞含量在研究组中均明显高于对照组（P<0.05），CD19+IL-10+CD24hiCD38-B细胞含量在研究组中明显低于对照组（P<0.05），而CD19+IL-10+CD24intCD38intB细胞含量在两组间比较差异无统计学意义（P>0.05）。CD19+IL-10+B细胞和CD19+IL-10+CD24hiCD38hiB细胞含量在TIL中的含量明显高于在NIL中（P<0.05），而CD19+IL-10+CD24intCD38intB细胞和CD19+IL-10+CD24hiCD38-B细胞含量在TIL中和NIL中比较差异无统计学意义（P>0.05）。CD19+IL-10+B细胞及其所有亚群(CD24hiCD38hi、CD24intCD38int、CD24hiCD38-)的表达水平在临床分期较晚和CEA水平较高的患者中显著升高（P<0.05）。对预后良好组与预后不良组患者的基本资料进行了对比分析，结果显示两组在临床分期和CEA水平方面存在显著差异（P<0.05）。在PBMC、TIL、NIL中，CD19+IL-10+B细胞和CD19+IL-10+CD24hiCD38hiB细胞含量在预后不良组中均明显高于预后良好组（P<0.05）、CD19+IL-10+CD24hiCD38–B细胞含量在预后不良组中明显低于预后良好组（P<0.05），而CD19+IL-10+CD24intCD38intB细胞含量在两组间比较差异无统计学意义（P>0.05）。CD19+IL-10+B细胞、CD19+IL-10+CD24hiCD38hiB细胞和CD19+IL-10+CD24intCD38intB细胞含量与预后不良呈正相关关系（P＜0.05），CD19+IL-10+CD24hiCD38-B细胞细胞含量与预后不良呈负相关关系（P＜0.05）。结论 在胃癌患者的外周血及癌组织样本中，CD19+IL-10+B细胞明显增高，且其以CD19+IL-10+CD24hiCD38hiB 细胞亚群升高为主，结果提示，CD19+IL-10+B 细胞及其特定亚群可能与胃癌的临床病理特征紧密相关，并对患者的预后评估具有潜在意义。