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关键词： periodontitis   host-pathogen interactions   Porphyromonas gingivalis   prostaglandin   inflammation  

摘要： The interaction between pathogenic microorganisms and stromal cells, in particular fibroblasts, significantly contributes to the pathogenesis of many bacterially driven diseases. In periodontitis, oral pathogens penetrate the epithelial barrier and aggravate ongoing gingival inflammation by promoting the production of inflammatory mediators, such as prostaglandin E2 (PGE2). This study aimed to investigate the functional consequences of the interplay between oral pathogens and a pro-inflammatory environment in the activation of the PGE2 pathway in primary human gingival fibroblasts (GFs). GF infection with Fusobacterium nucleatum, Porphyromonas gingivalis, or Filifactor alocis in the presence of tumor necrosis factor (TNF) led to synergistic induction of cyclooxygenase-2 (COX-2), a key enzyme in the PGE2 synthesis pathway, as well as secretion of PGE2. A similar synergy in COX-2 upregulation was observed upon GF infection with oral pathogens in the presence of IL-1 alpha, IL-1 beta, and interferon-alpha (IFN-alpha). This effect required toll-like receptor-2 (TLR2) and the p38 MAP kinase activation and was specific for fibroblasts as infection of macrophages or keratinocytes with oral pathogens in the proinflammatory environment did not cause synergistic COX-2 induction. Finally, we demonstrated that conditioned media from GFs infected with F. nucleatum under inflammatory conditions amplified the expression of the neutrophil chemokine IL8 in macrophages and confirmed that this effect was mediated by synergistic induction of PGE2 in GFs. Collectively, we identify a new mechanism of stromal-immune cross-talk that is driven by synergistic PGE2 induction by oral pathogens and inflammatory cytokines in GFs and may contribute to excessive macrophage activation and neutrophil infiltration in periodontitis. IMPORTANCE Periodontitis is a highly prevalent, dysbiosis-driven chronic inflammatory disease that not only leads to tooth loss but also is associated with severe systemic

关键词： Oncolytic Virus   Neoantigen Vaccines   Peptide-MHC Complexes   Tumor Immunotherapy  

摘要： Neoantigen vaccine is a promising breakthrough in tumor immunotherapy. However, the application of this highly personalized strategy in the treatment of solid tumors is hindered by several obstacles, including very costly and time-consuming preparation steps, uncertainty in prediction algorithms and tumor heterogeneity. Universalization of neoantigen vaccine is an ideal yet currently unattainable solution to such limitations. To overcome these limitations, we engineered oncolytic viruses co-expressing neoantigens and neoantigen-binding major histocompatibility complex (MHC) molecules to force ectopic delivery of peptide-MHC ligands to T cell receptors (TCRs), enabling specific targeting by neoantigen vaccine-primed host immunity. When integrated with neoantigen vaccination, the engineered viruses exhibited potent cytolytic activity in a variety of tumor models irrespective of the neoantigen expression profiles, eliciting robust systemic antitumor immunity to reject tumor rechallenge and inhibit abscopal tumor growth with a favorable safety profile. Thus, this study provides a powerful approach to enhance the universality and efficacy of neoantigen vaccines, meeting the urgent need for universal neoantigen vaccines in the clinic to facilitate the further development of tumor immunotherapy.

关键词： AhR/IL-22   黄芪甲苷   溃疡性结肠炎   肠道屏障  

摘要： 目的：研究黄芪甲苷 （Astragaloside IV，AS-IV）对溃疡性结肠炎（Ulcerative colitis，UC）小鼠肠道屏障功能的影响，并探讨其潜在机制。方法：使用3%葡聚糖硫酸钠（Dextran sulfate sodium，DSS）构建小鼠UC模型，建模成功后分为空白对照组、模型空白对照组、黄芪甲苷低、中、高剂量组（10 mg/kg、20 mg/kg、40 mg/kg），各组灌胃相应药物，每日1次，连续给药10d。Western blotting检测AhR/IL-22通路的蛋白表达水平；荧光原位杂交技术检测结肠组织切片DAPI染色情况；流式细胞术检测细胞凋亡水平；qRT-PCR检测AHR、CYP1A1、IL-22等mRNA表达水平。结果：AS-IV可能通过促进AhR/IL-22通路改善结肠炎小鼠的肠道炎症状态，降低了肠道通透性，并促进了结肠紧密连接结构的修复。AhR拮抗剂CH223191可部分阻断AS-IV的治疗效果，而AhR激动剂FICZ可改善结肠炎小鼠的症状和肠道屏障功能。进一步的体外机制研究发现，AS-IV处理显著提高了MNK-3细胞中AhR下游靶蛋白CYP1A1的表达水平（p<0.01），并通过促进AhR核转位显著增强IL-22的分泌（p<0.01）。重要的是，在AhR基因沉默的MNK-3细胞（shAhR-MNK3）中，AS-IV对CYP1A1表达和IL-22分泌的促进作用被显著抑制（p<0.05），表明AS-IV通过AhR依赖性机制调控IL-22的产生。结论 AS-IV通过ILC3中的AhR/IL-22通路改善肠上皮屏障，改善结肠炎，从而为UC提供潜在的治疗方法。

关键词： IL-27p28   single positive thymocyte   Th2 bias   IFN-gamma   autoimmune disease  

摘要： The newly generated CD4 single-positive (SP) T lymphocytes are featured by enhanced IL-4 but repressed IFN-gamma production. The mechanisms underlying this functional bias remain elusive. Previous studies have reported that CD4(+) T cells from mice harboring dendritic cell (DC)-specific deletion of IL-27p28 display an increased capacity of IFN-gamma production upon TCR stimulation. Here, we demonstrated that similarly altered functionality occurred in CD4SP thymocytes, recent thymic emigrants (RTEs), as well as naive T cells from either Cd11c-p28(f/f) mice or mice deficient in the alpha subunit of IL-27 receptor. Therefore, DC-derived IL-27p28-triggered, IL-27R alpha-mediated signal is critically involved in the establishment of functional bias against IFN-gamma production during their development in the thymus. Epigenetic analyses indicated reduced DNA methylation of the Ifng locus and increased trimethylation of H3K4 at both Ifng and Tbx21 loci in CD4SP thymocytes from Cd11c-p28(f/f) mice. Transcriptome profiling demonstrated that Il27p28 ablation resulted in the coordinated up-regulation of STAT1-activated genes. Concurrently, STAT1 was found to be constitutively activated. Moreover, we observed increased accumulation of STAT1 at the Ifng and Tbx21 loci and a strong correlation between STAT1 binding and H3K4me3 modification of these loci. Of note, Il27p28 deficiency exacerbated the autoimmune phenotype of Aire(-/-) mice. Collectively, this study reveals a novel mechanism underlying the functional bias of newly generated CD4(+) T cells and the potential relevance of such a bias in autoimmunity.

关键词： gamma delta T17 cells   ROR gamma t   -17A   Bmi-1   senescence-associated pathological cardiac hypertrophy  

摘要： New immunosenescence targets for preventing senescence-associated pathological cardiac hypertrophy (SA-PCH) need to be explored. In the present study, with physiologically aged human and mouse samples, the IL-17A level increased with physiological aging, heart failure (HF), and SA-PCH and was negatively correlated with thymic Bmi-1 expression. Bmi-1f/fLckCre+ mice and Bmi-1f/flittermates were generated to determine whether Bmi-1 delayed T cell aging by maintaining thymic T cell development to prevent SA-PCH. As a result, Bmi-1 promoted thymic T cell development by upregulating Notch signaling and prevented DN1 T cells from differentiating into gamma delta T17 cells by downregulating gamma delta T17 cell differentiation signaling. Bmi-1 upregulated Notch signaling by inhibiting p53-mediated Ikzf1 transcription at the-1,863 to-1,849 Ikzf1 promoter region. Bmi-1-RING1B promoted ROR gamma t ubiquitination and degradation byproteas-ome to inhibit the production of IL-17A in gamma delta T17 cells. Bmi-1 also downregulated Rorc transcribed by c-Maf by trimethylating H3K27 at the-1,511 to-1,497 Rorc promoter region. Subsequently, the number of peripheral gamma delta T17 cells infiltrating the heart tissues was reduced, while alleviating IL-17A-dependent cardiac aging, hypertrophy, dysfunction, senescence-associated secretory phenotype (SASP), and macrophage-myofibroblast transition, ultimately improving SA-PCH. The ROR gamma t inhibitor SR1001 and IL-17A neutralizing antibody ixekizumab prevented thymic ROR gamma t-IL-17A-dependent SA-PCH. Furthermore, ROR gamma t bound to Bmi-1 through ARG237 and to RING1B through GLU235, which could be used as a therapeutic strategy for SA-PCH to construct binding peptides promoting Bmi-1-RING1B binding to ROR gamma t and degrading ROR gamma t for inhibiting gamma delta T17 cell differentiation and IL-17A production. Thus, thymic Bmi-1 prevented IL-17A-dependent SA-PCH by decreasing gamma delta T17 cell numbers.

关键词： Gremlin1   白细胞介素-6   慢性肾脏病   预后   预测价值  

摘要： 目的探究血清Gremlin1、白细胞介素-6（IL-6）水平在慢性肾衰竭患者中的表达及不良预后的预测价值。方法随机选取68例慢性肾功能不全患者为试验组，肾功能正常者30例为对照组。试验组慢性肾脏疾病（CKD）分期分为CKD1～2期组（n=35）和CKD3～5期组（n=33），比较试验组、对照组及不同病情严重程度组间血清Gremlin1、IL-6水平；试验组根据随访6个月期间是否进展为终末期肾病分为预后良好组（n=54）及预后不良组（n=14），比较不同预后结果组间血清Gremlin1、IL-6水平，经受试者工作曲线（ROC）评估血清Gremlin1、IL-6水平检测对慢性肾衰竭患者预后早期预测价值。结果试验组WBC、Hb、PLT水平明显低于对照组（P＜0.05）。试验组患者血清Gremlin1、IL-6水平明显高于对照组（P＜0.05）。与CKD1～2期组患者比较，CKD3～5期患者血清Gremlin1、IL-6水平较高（P＜0.05）。预后不良组患者血清Gremlin1、IL-6水平高于预后良好组（P＜0.05）。ROC曲线显示，血清Gremlin1、IL-6水平单独检测及联合检测可作为CKD患者预后的预测指标（P<0.05），其曲线下面积（AUC）分别为0.897、0.745、0.956。结论慢性肾衰竭患者血清Gremlin1、IL-6水平异常升高，二者联合检测对慢性肾衰竭早期预后具有较高的预测价值。

摘要： BACKGROUND:Breast Implant associated anaplastic large cell lymphoma (BIA-ALCL) has affected more than 1700 women. Treatment morbidity is reduced and survival improved by early detection and removal of implant and capsule. OBJECTIVE:To address the need for early detection, we developed a multiplex lateral flow assay (LFA) for soluble IL-10 and CD30 in seromas surrounding implants. METHODS:The range of detection was determined with recombinant CD30 or IL-10 added to a benign seroma to simulate clinical conditions. Then clinical samples from 23 women with BIA-ALCL and 17 benign seromas were analyzed with a multiplex LFA detecting soluble IL-10 and CD30. RESULTS:When recombinant proteins were added to benign seromas, CD30 was detected down to a concentration of 0.5 ng/mL, while IL-10 could be detected to down to 5 ng/mL. Significant differences were found between CD30 and IL-10 test line/control line ratios (TL/CL) of 23 BIA-ALCL and 17 benign seromas. Visual inspection of LFAs resulted in 65% sensitivity improved to 87% using image analysis. CONCLUSIONS:We conclude the multiplex IL-10/CD30 can detect BIA-ALCL with 100% specificity and 65% sensitivity in this group of 40 clinical seromas based on visual assessment of LFA strips. Sensitivity was improved to 87% with image analysis which can provide a screening test for BIA-ALCL. The multiplex LFA demonstrated a perfect positive predictive value (100%), indicating that all positive results correctly identified BIA-ALCL cases. The negative predictive value of 99% can exclude BIA-ALCL.

关键词： 过继性细胞免疫治疗   卵巢癌   临床研究进展   联合治疗策略  

摘要： 卵巢癌的死亡率居女性生殖道恶性肿瘤首位，又因其高复发率和对含铂化疗的继发性耐药，亟需开发新的有效治疗手段。近年来，过继性细胞免疫治疗（adoptive cell immunotherapy,ACT）作为一种新兴的免疫治疗策略，开始在卵巢癌的治疗中展现出巨大潜力。虽然免疫抑制微环境和靶点选择有限仍是当前卵巢癌ACT治疗面临的主要挑战，但通过优化细胞生产技术、联合多种治疗手段，仍有望进一步提高ACT在卵巢癌患者中的疗效。全文通过综述ACT治疗在卵巢癌中的作用机制及最新研究进展，旨在为卵巢癌创新疗法的开发提供参考。

关键词： Glucocorticoids-induced osteonecrosis of the femoral head   Calcified cartilage zone remodeling   IL-1 beta   Cartilage degeneration   Biomechanics  

摘要： Glucocorticoids-induced osteonecrosis of the femoral head (GONFH) is characterized by progressive cartilage degeneration, yet the role of calcified cartilage zone (CCZ) remodeling in this process remains poorly understood. This study investigated how the inflammatory microenvironment within necrotic subchondral bone drove CCZ remodeling and subsequent cartilage degeneration. Using osteochondral tissues from GONFH patients and interleukin-1 beta (IL-1 beta)-treated hypertrophic chondrocytes induced by ATDC5 cells, we combined histology, immunohistochemistry, scanning electron microscopy, energy dispersive spectrometer, transmission electron microscopy, nanoindentation testing, enzyme linked immunosorbent assay and fluorescent tracking to evaluate morphological, biomechanical, and molecular changes. Our findings revealed that CCZ of GONFH exhibited significant thinning, matrix decomposition, demineralization, diminished mechanical strength, and increased porosity. Spatial analysis demonstrated a strong correlation between CCZ remodeling and site-specific cartilage degeneration. Notably, IL-1 beta was overexpressed in necrotic subchondral bone and the site deep zones of cartilage. It potently enhanced catabolic activity in hypertrophic chondrocytes, promoting matrix metalloproteinase expression while impairing mineralization capacity. This study uncovers a novel pathological cascade in GONFH: necrotic subchondral bone-derived IL-1 beta drives CCZ remodeling via biomechanical and biological pathways, leading to cartilage degeneration independent of femoral head collapse. Our findings highlight IL-1 beta as a critical therapeutic target, providing a rationale for subchondral bone-targeted anti-inflammatory strategies to mitigate GONFH *** AbstractNecrotic subchondral bone expresses inflammatory cytokines, especially IL-1 beta, and triggers pathological remodeling of the calcified cartilage zone (CCZ). This remodeling manifests as reduced thickness, matr