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关键词： 慢性牙周炎   IL-33   TNF-α   IL-6   检验效果  

摘要： 在慢性牙周炎的临床检验方面,分析血清白细胞介素-33(IL-33)、肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)的临床检验价值。方法 将本院2023年1月至2024年1月收治的75例慢性牙周炎患者作为观察组,同时将同期75例健康体检者作为对照组,皆实行血清IL-33、TNF-α、IL-6水平检验,结果 进行对比,分析血清IL-33、TNF-α、IL-6检验在慢性牙周炎诊断中的价值。结果 观察组的IL-33水平较对照组更低,而IL-6、TNF-α水平较对照组更高,差异有统计学意义(P<0.05)。重度牙周炎的IL-33水平较轻度牙周炎与中度牙周炎更低,而IL-6、TNF-α水平较轻度牙周炎与中度牙周炎更高,差异有统计学意义(P<0.05)。血清IL-33与TNF-α、IL-6具有相关性,差异有统计学意义(P<0.05)。结论 针对慢性牙周炎开展血清IL-33、TNF-α、IL-6检验,能够帮助诊断疾病,并评估牙周炎病情程度,值得推广。

关键词： HLA   HLA-A*29:02:42   novel allele   sequencing-based typing  

摘要： HLA-A*29:02:42 differs from HLA-A*29:02:01:01 by one nucleotide substitution in codon 193 in exon 4.

关键词： WAS   HIES   DOCK8   STAT3   IL-6  

摘要： Wiskott-Aldrich syndrome (WAS) is an inborn error of immunity caused by loss-of-function mutations in the WAS gene, which encodes WASp, a key regulator of cytoskeletal remodeling. In addition to microthrombocytopenia, affected individuals often present with recurrent infections, eczema, eosinophilia and elevated IgE levels, suggesting a potential pathophysiological overlap with STAT3 hyper-IgE syndrome (HIES). Given these shared features, we investigated the immunogenetic characteristics of three WAS patients and explored the IL-6/STAT3 pathway as a potential underlying mechanism. Flow cytometry revealed absent WASp expression in P1 and P3, while P2 showed reduced level. Genetic analysis identified three hemizygous mutations: A56V substitution within the WH1 domain in P1, and two splice site mutations, c.360 + 1G>T and c.734 + 1G>C, in P2 and P3, respectively. Interestingly, all WAS patients showed impaired STAT3 phosphorylation in T cells following IL-6 stimulation and SOCS3 induction was markedly decreased. These results further suggest a potential link between WASp and STAT3. Considering the interaction of WASp with DOCK8-WIP in lymphocytes and the critical role of DOCK8 in regulating STAT3 phosphorylation following IL-6 stimulation, we analyzed DOCK8 expression in lymphoblastoid cell lines. We demonstrated normal DOCK8 levels suggesting that STAT3 signaling defect is due to the absence of WASp rather than DOCK8 loss. Our results demonstrate the impairment of T cell IL-6/STAT3 pathway in WAS patients which could underlie, in part, the overlapping phenotype with HIES patients.

关键词： asciminib hydrochloride   atherosclerosis   cardio-oncology   endothelial cells   imatinib mesylate   inflammation   ponatinib hydrochloride  

摘要： BACKGROUND:Imatinib, the first Abl-tyrosine kinase inhibitor (TKI), improved leukemia outcomes without cardiovascular side effects. Newer agents, including ponatinib, addressed imatinib resistance, improving cancer remission, but substantially increased arterial thrombotic events, including myocardial infarction (MI) and stroke. The mechanism behind ponatinib-induced thrombosis and the cardiovascular effect of asciminib, a newly approved Abl-TKI, remain ***:The effect of clinically relevant plasma concentrations of imatinib, ponatinib, and asciminib were compared with vehicle in vivo using SR-BI-mut/LDLR-knockout (KO) mice to assess spontaneous MI and stroke risk. The mechanism was interrogated in C57BL/6J mice, assessing leukocyte trafficking and thromboinflammation by intravital microscopy and flow cytometry, respectively, and in ApoE-KO mice, assessing plaque phenotype by flow cytometry and histology. In vitro effects on human umbilical vein endothelial cells (ECs) and human coronary artery ECs were determined by flow cytometry, PCR, and immunoblotting. The role of TNF (tumor necrosis factor) signaling was evaluated by pharmacological inhibition and small interfering RNA ***:In SR-BI-mut/LDLR-KO mice, ponatinib significantly accelerated death from MI and stroke compared with vehicle, imatinib, and asciminib. In human ECs, only ponatinib increased expression of TNF receptors (TNFRs) and adhesion molecules (P-selectin, ICAM1 [intercellular adhesion molecule 1], and VCAM1 [vascular cell adhesion molecule 1]). Ponatinib rapidly induced TNFR2 membrane trafficking and TNF signaling in human umbilical vein ECs. TNFR inhibition or TNFR2 knockdown prevented ponatinib induction of EC adhesion molecules. In vivo, ponatinib increased mesenteric vessel adhesion molecules, leukocyte rolling and adhesion to vessels, leukocyte and platelet activation, and platelet-leukocyte aggregates. In ApoE-KO mice, ponatinib increased plaque necrotic core and inflam

关键词： Coronary artery   Fibrous cap thickness   Inflammation   Interleukin-6   Myocardial Infarction   Optical coherence tomography  

摘要： comprises over 2500 serovars that are responsible for over 90 million annual infections and 100,000 deaths worldwide. Despite this diversity, our understanding of innate immune responses to is based on extensive study of a few serovars, primarily Typhimurium, including strains that cannot replicate within primary murine macrophages. Non-replicating trigger caspase-1 and -11-dependent pyroptosis. Whether the innate immune system distinguishes between replicating and non-replicating intracellular is poorly defined. Here we demonstrate that replicating induce a distinct pathway of TNF- and caspase-8-driven apoptosis via host TLR4 and Pathogenicity Island-2 activity. This pathway is independent of gasdermin D and involves the apoptotic pore protein Pannexin-1. Combined loss of Pannexin-1 and gasdermin D resulted in defective control of systemic , indicating that these pathways function together to promote anti- host defense. Altogether, our findings uncover a previously unappreciated pathway by which macrophages sense intracellular replicating bacteria.

关键词： BCG-unresponsive   N-803   papillary NMIBC  

摘要： PURPOSE:In QUILT-3.032, the efficacy of IL-15 receptor agonist, nogapendekin alfa inbakicept (NAI) in combination with BCG for BCG-unresponsive high-grade papillary-only non-muscle invasive bladder cancer (NMIBC) was assessed. Herein we report the 36-month follow-up among participants with BCG-unresponsive papillary disease (Cohort B). MATERIALS AND METHODS:NCT03022825 is an open-label, multi-center study with BCG-unresponsive high-grade Ta/T1 papillary NMIBC who received 400μg NAI plus 50mg BCG intravesically weekly for six consecutive weeks. The primary endpoint is disease-free survival (DFS) at 12-months. Progression-free survival (PFS), disease-specific survival (DSS), and cystectomy avoidance were assessed. Treatment-related adverse events (TRAEs) were assessed. RESULTS:At July 15, 2024 data cutoff, the DFS rates at 12-, 24-, and 36-months were 58.2% (95% CI 46.6, 68.2), 52.1% (95% CI 40.3, 62.7), and 38.2% (95% CI 25.6, 50.6), respectively. The PFS rates at 12- and 36-months were 94.9% (95% CI 86.9, 98.0) and 83.1% (95% CI 69.5, 91.0). The DSS rates at 12- and 36-months were 98.7% (95% CI 91.4, 99.8) and 96.0% (95% CI 88.2, 98.7). The median DSS has not been reached. Cystectomy avoidance rates at 12- and 36-months were 92.2% (95% CI 83.4, 96.4) and 81.8% (95% CI 68.1, 90.1), with median time to cystectomy not reached. Most TRAEs were grade 1-2 (61%) with 3% grade 3, and no grade 4-5. CONCLUSIONS:The 12- and 36-month DFS, PFS, DSS, and cystectomy avoidance rates demonstrate the effectiveness and safety of NAI plus BCG in the management of BCG-unresponsive papillary disease.

关键词： Galectin-3   idiopathic pulmonary fibrosis   metformin   Smad3   stearic acid  

摘要： Pulmonary fibrosis (PF) is a chronic, inflammatory interstitial lung disease. It is promoted by overproliferation of fibroblasts characterized by the progressive formation of scar tissue in the lung parenchyma, which leads to an inexorable decline in lung function, respiratory failure, and high mortality. This study aims to assess the synergetic consequences of metformin and stearic acid, whether individually or in combination, to ameliorate bleomycin-induced PF in rat models via suppressing Gal-3/Smad3/alpha-SMA and TNF-alpha/NF-kappa beta signaling pathways and mitigate its adverse side effect on kidneys and liver. The antioxidant/oxidative stress shuttle system was estimated in lung, liver, and kidney tissues. Moreover, histopathology assessment and immunohistochemical staining for NF-kappa beta antibodies were performed in the lung and trachea tissues. Additionally, RT-qPCR gene expressions of TNF-alpha, IL-1 beta, IL-6, and alpha-SMA were investigated. The expression levels of Gal-3, p-Gal-3, Smad3, and p-Smad3 protein in lung tissues were determined by western blot analysis. The findings showed that metformin and/or stearic acid exhibited antifibrotic and anti-inflammatory impacts in-vivo as evidenced by enhanced body weight, liver and kidney functions, reduced oxidative stress, increased endogenous antioxidant enzymes, downregulated inflammatory cytokine levels IL-1 beta, IL-6, and TNF-alpha, and attenuation effect on alpha-SMA, a major marker of myofibroblasts. Furthermore, there was a marked improvement in the profibrotic Gal-3/Smad3 signaling pathway. On the other hand, a significant reduction in the histological score of fibrosis and immunohistochemical expression NF-kappa beta levels was detected, especially in the combination-treated group. Overall, our findings elucidate the synergetic antifibrotic impact of metformin and stearic acid which could be used as a potential candidate drug against various chronic inflammatory diseases.

关键词： Breast cancer   Bruceine D   Cancer-associated fibroblasts   IL-6   Tumor angiogenesis  

摘要： Cancer-associated fibroblasts (CAFs) facilitate tumor angiogenesis by secreting cytokines. Bruceine D (BD), a natural quassinoid compound extracted from the Chinese herb Brucea javanica (L.) Merr., has demonstrated potential in inhibiting breast cancer (BC). However, the involvement of CAF-promoted tumor angiogenesis in the antitumor effects of BD remains unclear. This study investigated the effects of BD on CAF-promoted tumor angiogenesis and its underlying mechanisms. In vivo results showed that BD alleviated hypoxia, suppressed CAF activation, and reduced IL-6 secretion in orthotopic BC-bearing mice. These changes led to significant down-regulation of phosphorylation of STAT3, Notch1, and phosphorylation of VEGFR2 expression, ultimately inhibiting tumor angiogenesis and metastasis. Furthermore, BD was demonstrated significantly inhibition of both IL-6 secretion from CAFs and subsequent activation of the STAT3/Notch1/VEGFR2 signaling axis. This effect disrupted CAF-endothelial cell crosstalk, thereby impairing CAF-promoted endothelial cell proliferation, sprouting, invasion, migration, and tube formation. Collectively, these findings identify BD as a promising candidate for inhibiting CAF-driven tumor angiogenesis, offering a novel therapeutic strategy for patients with BC.