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关键词： Immune Checkpoint Inhibitor   Tumor microenvironment - TME   Cytokine   Dendritic   Macrophage  

摘要： Background Identifying the mechanisms underlying resistance to immune checkpoint inhibitors (ICIs) has become a major focus in cancer immunotherapy. Our previous work identified F2RL1 expression, encoding the G protein-coupled receptor Protease-Activated Receptor-2 (PAR-2), as a negative biomarker of ICIs responsiveness. This study aims to evaluate the therapeutic potential of targeting PAR-2 to overcome resistance to *** Activated PAR-2 levels in patient serum were quantified using a protein-based assay to assess PAR-2 activation and its association with clinical outcomes. The therapeutic impact of PAR-2 targeting was evaluated in preclinical tumor models using either global F2rl1 gene deletion or pharmacological inhibition with the selective, insurmountable PAR-2 negative allosteric modulator I-117, in combination with anti-PD-1 therapy. To further characterize immune changes associated with PAR-2 targeting, immune cell populations, cytokine profiles, and transcriptional programs were analyzed in tumors and/or tumor-draining lymph nodes (tDLNs). Ex vivo co-culture assays were performed to assess antigen presentation by CD11c+ dendritic *** Activated PAR-2 levels were significantly elevated in the serum of patients with cancer across multiple tumor types and were associated with reduced survival in patients with lung cancer treated with pembrolizumab plus platinum-based chemotherapy. In preclinical models, both global F2rl1 deletion and pharmacological inhibition of PAR-2 with I-117 significantly potentiated the therapeutic efficacy of anti-PD-1 treatment. PAR-2 inhibition altered the tumor immune microenvironment, characterized by a reduction in putative immunosuppressive myeloid cell populations and increased activation of CD8+ T cells in tumors and tDLNs. These immune changes were accompanied by a cytokine shift favoring T helper 1 (Th1)-type responses and reduced immunosuppressive cytokines. Bulk RNA sequencing of myeloid cells indicated that

关键词： Asthma   Tan IIA   airway inflammation   airway remodeling   p38/NF-kappa B   AKT/HIF-1 alpha  

摘要： ObjectiveAirway inflammation and remodeling are key pathological features of bronchial asthma, yet the therapeutic potential and mechanisms of Tanshinone IIA (Tan IIA) remain incompletely understood. This study aimed to evaluate the effects of Tan IIA on airway inflammation and remodeling and to elucidate the underlying signaling *** chronic bronchial asthma mouse model was established and complemented by in vitro studies using human bronchial epithelial cells (16HBEs) and human tracheal smooth muscle cells (HTSMCs). In bronchoalveolar lavage fluid (BALF), inflammatory cell counts and relevant mediators were assessed. Histological analyses were performed to evaluate airway inflammatory injury and remodeling changes. Mechanistic investigations examined p38 and AKT phosphorylation and the nuclear translocation of NF-kappa B and HIF-1 alpha in vivo, with validation in cell-based *** IIA reduced Th2 cytokines (IL-4, IL-5, and IL-13), remodeling-associated factors (VEGF and TGF-beta 1), and the numbers of eosinophils, neutrophils, and lymphocytes in BALF. Histopathological assessment showed that Tan IIA alleviated inflammatory cell infiltration, epithelial damage, basement membrane thickening, goblet cell hyperplasia, mucus hypersecretion, and subepithelial collagen deposition. Mechanistically, Tan IIA decreased phosphorylated p38 (p-p38) and phosphorylated AKT (p-AKT) and inhibited the nuclear translocation of NF-kappa B and HIF-1 alpha in vivo. These findings were corroborated in vitro: in 16HBEs, Tan IIA suppressed p-p38 activation and NF-kappa B nuclear translocation, whereas in HTSMCs, it reduced p-AKT levels and inhibited HIF-1 alpha nuclear *** IIA attenuates airway inflammation and remodeling by inhibiting the p38/NF-kappa B and AKT/HIF-1 alpha signaling pathways, supporting Tan IIA as a promising therapeutic candidate for bronchial asthma.

关键词： Intracerebral hemorrhage   cognitive impairment   multimodal MRI   intercellular adhesion molecule-1   diagnostic value  

摘要： ObjectiveWe aimed to investigate the diagnostic value of multimodal magnetic resonance imaging (MRI) combined with intercellular adhesion molecule-1 (ICAM-1) in detecting cognitive impairment (CI) after intracerebral hemorrhage (ICH).MethodsClinical data were collected from 130 patients with ICH, all of whom received brain MRI to assess imaging characteristics, including white matter lesion (WML) scores, the number of cerebral microbleeds (CMBs), fractional anisotropy (FA) values, and apparent diffusion coefficients. Serum ICAM-1 levels were detected. At a 3-month follow-up, patients were classified into a CI group (n = 57) and an non-CI group (n = 73) according to Montreal Cognitive Assessment. The diagnostic value of multimodal MRI parameters and ICAM-1 levels was analyzed. Logistic regression analysis was performed to identify independent predictors of CI after *** in the CI group were older and had a higher prevalence of hypertension than the non-CI group. They also exhibited higher WML scores, greater CMB counts, and elevated serum ICAM-1 level, and lower FA values in the basal ganglia, parietal lobe, and frontotemporal regions. The combination of multimodal MRI parameters with ICAM-1 levels showed superior diagnostic accuracy compared to individual indicators. Logistic regression identified hypertension, WML score, basal ganglia FA value, parietal lone FA value, and ICAM-1 levels were independent factors of CI after *** MRI parameters and serum ICAM-1 levels have high diagnostic value for identifying CI after ICH. Hypertension, WML score, reduced FA value in specific brain regions, and elevated ICAM-1 levels are closely associated with CI after ICH.