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关键词： diffuse alveolar damage   neutrophil extracellular trap   IL-17A   fibroblast   scRNA-seq  

摘要： Diffuse alveolar damage (DAD), a lethal manifestation of acute lung injury, remains a critical public health concern due to the absence of targeted therapies. However, the underlying cellular and molecular mechanisms responsible for immunopathology during DAD progression are largely undefined. Here, by integrating single cell RNA sequencing, functional assays, and genetic/pharmacological interventions in a mouse model of ricin-induced DAD, we revealed a significant accumulation of neutrophil with an activated phenotype that plays a critical role in immunopathology. We observed the formation of neutrophil extracellular traps (NETs) during DAD, which further intensified inflammation and tissue injury. IL-17A signaling activity was upregulated in DAD-affected lungs, while IL-17A deficiency or functional blockade significantly attenuated neutrophil recruitment, NET generation, and tissue damage. Mechanically, IL-17A stimulates lung resident fibroblasts to produce the neutrophil chemoattractant CXCL1. Notably, type 3 innate lymphoid cells (ILC3) emerged as the dominant source of IL-17A, highlighting a triad of interactions among ILC3, fibroblast, and neutrophil in DAD pathogenesis. This finding delineates a pathogenic IL-17A-neutrophil-NET axis that amplifies lung immunopathology after ricin-induced DAD, a deeper understanding of these relationships may pave the way for mitigate DAD immunopathology and other lung inflammatory disorders.

关键词： SIRT1   Wnt/beta-Catenin signaling   inflammatory   rejection   miRNAs   lncRNAs   IL-1   IL-6  

摘要： Background/Objectives: This study aimed to evaluate the relationship between sirtuin family members (SIRT1, SIRT3, and SIRT6) and Wnt/beta-catenin pathways with inflammation during the rejection process following kidney transplantation, as well as to explore their potential roles as candidate biomarkers. Materials and Methods: Blood samples were collected from 35 kidney transplant rejection patients and 30 healthy controls. The gene expression levels of SIRT1, SIRT3, SIRT6, and Wnt/beta-catenin pathway components were measured using real-time PCR, and miRNA and lncRNA expression levels were analyzed. Statistical analyses were performed using SPSS version 23. Results: Significant alterations in SIRT1, SIRT3, and SIRT6 expression levels were observed in rejection patients, suggesting their potential role in disease pathogenesis and as therapeutic biomarkers. Key altered genes included hsa-miR-34c-1, hsa-miR-122b-5b, MALAT1, HOTAIR, LINC00473, TUG, PVT1, SIRT1, SIRT3, SIRT6, WNT1, TCF-LEF, LRP, AXIN1, IL1B, IL6, and IFNB1, all showing significant changes. However, no significant differences were found for miRNAs such as hsa-miR-21-2, hsa-miR-155-5p, and hsa-miR-200b-3p. SIRT1 expression was significantly decreased in the cellular rejection group, with a more pronounced reduction in these patients. Significant differences in SIRT1 expression were observed with interstitial inflammation and glomerulitis. Increased inflammation severity correlated with decreased SIRT1 and increased TCF-LEF, TUG, and miR-21 levels, while tubulitis severity was associated with elevated TCF-LEF and miR-155 expression. Conclusions: Along with the activation of Wnt/beta-catenin pathways and increased levels of certain miRNAs and long non-coding RNAs (lncRNAs) associated with TCF-LEF transcription factors, the observed decrease in SIRT1 expression may be related to the severity of inflammation and tubulitis. These findings suggest that SIRT1, Wnt/beta-catenin pathways, and non-coding RNAs play

关键词： 银屑病   炎症小体   白细胞介素-18   炎症小体抑制剂  

摘要： 白细胞介素-18（interleukin-18，IL-18）具体多种生物学功能的细胞因子，参与炎症、肿瘤和自身免疫性疾病的发生发展过程。近年来，银屑病临床和动物研究发现，炎症小体（inflammasome）的活化参与了银屑病的发病机制，激活的炎症小体进一步介导IL-18的成熟与释放。银屑病患者及其动物模型的皮损和血清中IL-18的表达水平显著增高，且与银屑病严重程度呈正相关。因此，靶向炎症小体激活以及介导IL-18的释放可能成为银屑病的潜在治疗方向。本文将围绕炎症小体激活介导的IL-18释放及炎症小体抑制剂在银屑病中的作用进行综述。

摘要： Glioblastoma (GBM) frequently expresses cytomegalovirus (CMV) antigens, making CMV-specific CD8＋T cells attractive candidates for adoptive immunotherapy due to their longevity and inherent tumor reactivity. However, these T cells encounter significant immunosuppressive challenges within the GBM microenvironment, including cytokine scarcity and checkpointmediated inhibition, which limit their proliferation and function. Here, we assessed strategies to overcome these limitations by modulating immune checkpoint pathways. Antigen stimulation combined with IL-2 robustly expanded high-avidity (tetramer-high) CMV-specific T cells with significant enrichment of CD62L＋ central memory (TCM) cells. In contrast, antigen stimulation alone modestly expanded tetramer-high cells with limited TCM enrichment. PD-L1 blockade in the absence of IL-2 favored expansion of tetramer-high CMV-specific CD8＋T cells, preserved CD62L expression, and enhanced CD226 expression. Furthermore, combining anti-PD-L1 blockade with an anti-CD226 agonist markedly enhanced proliferation, IFN-γ production, and TCM enrichment in both tetramer-high and tetramer-low populations, reaching levels comparable to IL-2-supported conditions. Together, these findings highlight that simultaneous modulation of PD-L1 and CD226 pathways can restore CMV-specific T cell function, offering a promising strategy to boost TCR-T efficacy in cytokine-deprived environments.

关键词： 浣熊眼   免疫球蛋白轻链淀粉样变性   眶周紫癜  

摘要： 目的　报告1例以“浣熊眼”为特征的免疫球蛋白轻链（AL）淀粉样变性患者的临床资料并文献复习，探讨其典型的病情特征、诊断与治疗，以提高临床医师对该病的认识及诊治水平。方法　报告了1名63岁男性AL淀粉样变性患者的浣熊眼征，并分析该患者临床表现。检索PubMed数据库相关病例报道并进行文献复习，重点总结AL淀粉样变性伴罕见的眶周紫癜的患者的临床表现和治疗预后。结果　从PubMed数据库共检索到15例以“浣熊眼”为特征的AL淀粉样变性患者，结合我们报道的1例，共16例患者纳入分析。其中，男8例，女8例，男性平均年龄为63.7±7.2岁，女性平均年龄为67.8±8.2岁。在16例患者中，有9例出现肾脏受累，8例出现心脏受累。肾脏受累表现为蛋白尿和/或出现肾功能受损。心脏受累主要表现为左心室肥厚及早期N端脑钠肽前体的升高。此外，有些患者还有肝脏、肺脏、神经系统受累和巨舌表现。AL淀粉样变性还可能会出现非特异症状，主要表现为乏力和无意识的体重减轻。有5例患者在出现浣熊眼征之后几个月内死亡。结论　当患者出现“浣熊眼”这一典型症状，临床医师要警惕AL型淀粉样变性的可能，尽快明确诊断和治疗。

关键词： aerobic exercise   atherosclerosis   cognitive impairment   IL-33 signaling   inflammatory cytokines  

摘要： Atherosclerosis (AS), a common cardiovascular condition, is often linked to cognitive dysfunction. This study investigates how aerobic exercise affects cognitive impairments caused by AS in ApoE-/- mice. At 8 weeks old, male ApoE-/- mice were fed a high-fat, high-cholesterol diet (HFHCD) for 6 weeks to induce AS, with C57BL/6J mice on a standard diet as control group (WT). Initially, the study compared aortic plaque and cognitive performance between the WT and AS mice. Then, AS mice were divided into sedentary (AS-SED) and exercise (AS-EX) groups for a 10-week aerobic exercise intervention. Results showed significant aortic plaques and cognitive deficits in AS mice after 6 weeks on the HFHCD diet. However, the 10-week exercise reduced plaque, improved cognition, and enhanced cerebral blood flow. Exercise intervention also decreased IL-33 expression in the hippocampus and inhibited NF-kappa B and I kappa B alpha phosphorylation. Furthermore, aerobic exercise reduces M1 microglial activation and pro-inflammatory cytokines like IL-6, TNF-alpha, and IL-1 beta in the hippocampus of AS mice, thereby decreasing neuroinflammation. In summary, aerobic exercise can effectively improve cognitive function by decreasing IL-33 expression and inhibiting NF-kappa B activation, which in turn reduces microglial activation and the release of inflammatory mediators in the hippocampus. This study provides evidence for aerobic exercise to improve cognitive impairment caused by AS.

关键词： Triple-negative breast cancer   MHC-II   Anthracycline exemption   Immunotherapy   KAT2B  

摘要： BackgroundAnthracycline-based chemotherapy, while foundational in breast cancer treatment, confers substantial cardiotoxicity. Identifying biomarkers to guide anthracycline exemption without compromising efficacy has remained an unresolved clinical challenge for *** conducted multi-cohort spatial-omics and clinical validation integrating 345 early-stage triple-negative breast cancer (eTNBC) and 167 HER2 + breast cancer patients from Fudan University Shanghai Cancer Center (FUSCC) cohorts, alongside 150 eTNBC patients from a validation cohort. Tumor-specific MHC-II (tsMHC-II) expression was quantified via multiplex immunohistochemistry (mIHC). Mechanistic insights were derived from the NeoTRIP immunotherapy spatial cohort, I-SPY2 trial data, TCGA database, ATAC-seq chromatin profiling, ChIP, and patient-derived organoid (PDO)-immune cell co-culture *** eTNBC, high tsMHC-II expression predicted improved disease-free survival (DFS) and comparable overall survival (OS) with paclitaxel-carboplatin (PCb) versus anthracycline-sequential paclitaxel (EC-P), identifying tsMHC-II as a predictive marker for anthracycline exemption. High tsMHC-II correlated with prolonged DFS and OS in both TNBC and HER2 + subtypes. Multi-omics including spatial and transcriptional cohorts revealed tsMHC-II-high tumors harbor immune-rich microenvironments with elevated cytotoxic T cells, B cells, and antigen-presenting cells. Validation in NeoTRIP and I-SPY2 cohorts demonstrated superior immunotherapy response in tsMHC-II-high patients. Mechanistically, ATAC-seq, ChIP and PDO co-culture models confirmed that KAT2B upregulated tsMHC-II via CIITA promoter acetylation, sustaining immunotherapeutic ***-II serves as a dual biomarker for adjuvant anthracycline chemotherapy exemption and neoadjuvant immunotherapy stratification in TNBC, driven by KAT2B-mediated epigenetic remodeling. These findings advance precision strategies to reduce anthracyclin

摘要： Recently long-read sequencing technologies and bioinformatics have enabled the construction of haplotype-resolved genome assemblies. Here, we present the complete and accurate de novo characterization of two challenging genomic regions, the major histocompatibility complex (MHC) and Killer-cell immunoglobulin-like receptors (KIRs), in phased haplotypic form, using the Oxford Nanopore Technology (ONT) Adaptive Sampling sequencing, and a newly developed bioinformatics pipeline. These critical regions for our immune response have been notoriously difficult to characterize due to their sequence variability and structural complexity. The key features of our approach are (i) focused sequencing of specific regions, (ii) exclusive use of ONT, and (iii) a unique phasing methodology that integrates sequencing reads, methylation signals, and a reference panel. Ten samples with known MHC and KIR haplotypes were sequenced and assembled, demonstrating the potential of our approach. We achieved efficient target enrichment resulting in 100% coverage and accuracy ranging from 99.95% to 99.99% across the MHC and KIR. Its simplicity, reproducibility, and affordability distinguish this method as a unique and effective approach for the targeted haplotypic characterization of the MHC and KIR without trios and possibly other specific genomic regions. These efforts will in turn facilitate future studies that further advance the functional deconvolution of our genome. © 2025 The Author(s).