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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.

关键词： 慢性乙肝病毒   慢性乙型肝炎   恩替卡韦   T淋巴细胞   病毒清除  

摘要： 目的 探讨恩替卡韦治疗慢性乙肝病毒(HBV)感染患者辅助性T淋巴细胞(Th)水平及其对病毒清除的影响。方法 选择2020年1月-2024年1月于昆明市延安医院接受恩替卡韦治疗的149例HBV感染患者,其中慢性乙型肝炎(CHB)82例,慢性乙型肝炎病毒携带者(CHBc)67例。依据治疗72周患者血清乙肝表面抗原(HBs Ag)水平分为清除组(64例)和未清除组(85例)。比较两组临床资料,分析治疗期间Th1、Th2水平变化;多元线性回归模型分析治疗期间病毒学改变与免疫水平关系;logistic回归模型分析病毒未清除的危险因素。结果CHBc治疗组与CHB治疗组年龄、基线至24周谷丙转氨酶(ALT)和HBV DNA水平、基线和12周天冬氨酸转氨酶(AST)水平、24周HBs Ag水平、基线Th1、Th1/Th2水平差异具有统计学意义(P<0.05)。HBVDNA、HBs Ag、乙型肝炎E抗原(HBe Ag)水平分别与Th1、Th2、Th1/Th2水平呈线性相关性(P<0.05)。治疗72周累积HBs Ag清除64例,清除率为42.95%,调整混杂因素后多因素分析显示,Th1、Th2和Th1/Th2高水平是病毒未清除危险因素(P<0.05)。结论 HBV感染者中,CHB和携带者免疫水平存在差异,恩替卡韦治疗期间患者Th1、Th2、Th1/Th2水平与HBVDNA、HBs Ag、HBe Ag、病毒清除效率具有强相关性。

关键词： Th9 cells   interleukin-9 (IL-9)   allergies   autoimmunity   cancer   MTOR activation   PPAR-gamma   ACC1  

摘要： Th9 cells are a CD4 T cell subset that produces interleukin-9 (IL-9), a pleiotropic cytokine implicated in allergies, autoimmunity and cancer. Defining the cellular effects of IL-9 and factors regulating its expression are essential for fully understanding its roles in immunity and disease. IL-9 acts on a variety of immune and non-immune cells through a heterodimeric receptor composed of IL-9R alpha and the common gamma chain. In CD4 T cells, IL-9 promotes mTOR activation, aerobic glycolysis, proliferation and reinforces its own expression. Additional cellular effects include mast cell activation, B cell antibody production and anti-tumor immunity. These biological activities are complemented by recent studies that expand our understanding of Th9 differentiation beyond canonical cytokine and transcription factor pathways. Notably, glycolytic reprogramming and fatty acid metabolism have emerged as key regulators of IL-9 production, mediated through the activities of mTOR, PPAR-gamma and acetyl-CoA carboxylase 1 (ACC1). mTOR-driven aerobic glycolysis is essential for Th9 cell differentiation, supporting survival, proliferation, and IL9 expression through HIF-1 alpha activation. In contrast, ACC1 suppresses IL-9 through fatty acid synthesis, which enhances RAR alpha-mediated transcriptional repression. PPAR-gamma appears to have dual functions: it promotes IL-9 production by increasing glucose uptake and activating mTOR, but reduces IL-9 in response to synthetic agonists that may increase fatty acid uptake. Overall, these findings highlight critical roles for metabolic regulators in Th9 responses and suggest that targeting these pathways may offer new therapeutic strategies for IL-9-driven diseases.

关键词： PM2.5   Vc   Thyroid   Ferroptosis   IL-17A signaling pathway  

摘要： Fine particulate matter (PM2.5) is a ubiquitous environmental pollutant that has been demonstrated to affect the thyroid function in women. However, its specific mechanism remains unclear, and protective drugs are deficient. In the present study, we used female rat thyroid models in vivo and rat FRTL5 cell models in vitro to investigate the thyroid toxicity mechanism of PM2.5 and the protective pathway of vitamin C in female rats. PM2.5 exposure caused the production of inflammatory cells in thyroid tissue;transformations of the mitochondrial morphology;increases in the reactive oxygen species (ROS), ferrous ion (Fe2 +), and malondialdehyde (MDA) content in thyroid cells;and decreases in the glutathione peroxidase 4 (GPX4) levels, which resulted in ferroptosis in rat thyroid tissues. In addition, the Interleukin (IL)-17A/IL-17RA/Nuclear factor activator (Act1) signaling pathway was activated by PM2.5. However, vitamin C treatment improved ferroptosis and significantly reduced the expression of the IL-17A, IL-17RA, and ACT1 signaling pathway-related factors. These findings indicate that vitamin C demonstrates protective effects against thyroid injury and ferroptosis, potentially through the inhibition of the IL-17A signaling pathway.

关键词： Diacerein   Intestinal ischemia reperfusion   Interleukin-1 beta   Inflammasome  

摘要： Intestinal ischemia reperfusion (II/R) is an abdominal critical case especially in neonates and during childhood affecting not only the intestinal tissue but also it could damage other remote organs including cardiac tissue even following surgical intervention. Immune homeostasis during II/R has a major role in controlling its progression. Thus, finding additive medical treatment besides the surgical one becomes an urgent need to keep the tissue. So that, we aimed to evaluate the possible ameliorative effect of diacerein (DIA) on II/R-induced injury in juvenile rats. Forty juvenile rats of Wistar albino species were randomly allocated into four different groups: sham group, DIA given group, II/R group via clamping superior mesenteric artery, DIA-treated group (50 mg/kg) with induction of II/R. Data of current model revealed a significant elevation of the measured cardiac enzymes, cleaved caspase-3, and nuclear factor kappa beta (NF-kappa B) in the untreated ischemic group with disturbed oxidative stress parameters, accompanied with dysregulation of inflammasome/caspase-1/IL-1 beta and Wnt/beta-catenin signaling cascades. Fortunately, upon co-administration of DIA, there is a significant decrease of cardiac enzymes, cleaved caspase-3, and NF-kappa B with normalization of oxidative stress parameters and regulation of inflammasome/caspase-1/IL-1 beta and Wnt/beta-catenin pathways confirmed by marked mitigation of the histopathological changes. This effect of DIA is greatly attributed to its pharmacological properties including IL-1 beta antagonist effect, anti-oxidant, anti-apoptotic, and anti-inflammatory properties. Thus, DIA could be considered as an adjuvant future medical therapy for those cases of II/R.