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关键词： Outcome measures   Registries  

关键词： asymptomatic   COVID-19   HLA Class I   SARS-CoV-2  

摘要： The aim of this study was to investigate the influence of HLA-A, -B and -C polymorphisms on the clinical course of SARS-CoV-2 infection and on the progression of COVID-19 in a population from southeastern Brazil. This study included 478 unvaccinated individuals. Of these, 369 were hospitalised with critical/severe (n = 309) or moderate/mild (n = 60) symptoms, and 109 were asymptomatic. The control group consisted of 150 volunteer bone marrow donors, recruited in the pre-pandemic period. The HLA-B*15 allele group (adjusted p value < 0.001) was associated with a protective factor against symptomatic infection. Investigating the effects of the distribution of HLA alleles on susceptibility and resistance to SARS-CoV-2 may provide a better understanding of the clinical course of infection in different geographical regions.

关键词： Cardiovascular system   Targeted synthetic drugs   biological DMARD   Atherosclerosis  

关键词： Targeted synthetic drugs   Clinical Trial   Pain   biological DMARD  

摘要： Effective treatment strategies for diabetes-related pain are limited because of its complex pathogenesis, particularly brain mechanisms underlying this disease. The acid-sensing ion channel 1a (ASIC1a) has emerged as a key player in the development and treatment of various types of pain. We investigated the role of ASIC1a in diabetes-related pain and its molecular mechanisms in the anterior cingulate cortex (ACC). Our findings demonstrate that the upregulation of ASIC1a expression drives enhanced activity of excitatory glutamatergic neurons in the ACC (ACCGlu), promoting the development of pain hypersensitivity in streptozotocin (STZ)-induced diabetic male mice. Pharmacologic inhibition and genetic knockout of ASIC1a in ACCGlu neurons significantly reduced neuronal activity and alleviated mechanical and thermal pain sensitizations in STZ-induced diabetes. Furthermore, increased levels of tumor necrosis factor-alpha (TNF-alpha) in the ACC upregulated ASIC1a by triggering nuclear factor-kappa B (NF-kappa B) pathways, which led to the development of diabetes-related pain. Notably, the clinically used medication, infliximab, exhibited therapeutic effects on diabetes-related pain via its influence on TNF-alpha/NF-kappa B/ASIC1a pathway in STZ-treated mice. Collectively, this study identifies ASIC1a as a potential therapeutic target for diabetes-related pain and shows the neutralization of TNF-alpha leads to pain relief through the TNF-alpha/NF-kappa B/ASIC1a pathway in the ACC. These findings hold promise for the development of new clinical therapeutic strategies for diabetes-related *** Highlights Upregulation of acid-sensing ion channel 1a (ASIC1a) expression in anterior cingulate cortex (ACC) glutamatergic (ACCGlu) neurons drives diabetes-related pain hypersensitivity in mice, and pharmacologic inhibition and genetic knockout of ASIC1a in ACCGlu neurons significantly reduce neuronal hyperactivity and alleviate pain. Tumor necrosis factor-alpha/nuclear factor-

关键词： cancer metastasis   lymphangiogenesis   NLRP3 inflammasome   oral squamous cell carcinoma   sterol O-acyltransferase 1  

摘要： Oral squamous cell carcinoma (OSCC) is a prevalent type of cancer in the head and neck region, significantly impacting patient survival rates and quality of life. Lymph node (LN) metastasis is a lead contributor to the poor prognosis associated with OSCC. SOAT1 plays a critical role in cholesterol metabolism and has been implicated in various cancers, although its specific mechanisms in OSCC are poorly understood. Additionally, NLRP3 inflammasome has been identified as a factor that promotes cancer progression by influencing various processes involved in tumor development, with its activation linked to cancer metastasis. Lymphangiogenesis enhancing cancer metastasis has been identified in OSCC, while the molecule networks of regulating it remains unclear. In our study, we found that SOAT1 is overexpressed in OSCC and promotes proliferation, migration, and invasion of OSCC cells. Knockdown SOAT1 expression impaired OSCC progression both in vitro and in vivo, and reduced the rate of LN metastasis. RNA sequencing analysis revealed that NLRP3 is a downstream regulated by SOAT1, with NLRP3 inflammasome reactivation having recovered cancer malignancy inhibited by SOAT1 knockdown. Furthermore, we revealed that IL-1 beta, released by NLRP3 inflammasome activation, could directly bind to IL-1R-1 in lymphatic endothelial cells (LECs), and enhance tube formation capacity of LECs, indicating the potential role of NLRP3 inflammasome in promoting lymphangiogenesis and metastasis in OSCC. In conclusion, SOAT1 could promote OSCC malignancy and regulate the activation of NLRP3 inflammasome to increase the rate of lymphangiogenesis and cancer metastasis via IL-1 beta/IL-1R-1 axis in OSCC.

关键词： Jie-Geng-Tang   Apigenin   TNF-alpha pathway   Apoptosis  

摘要： Jie-Geng-Tang (JGT), composed of Platycodon grandiflorus (Jacq.) A. DC and Glycyrrhiza uralensis Fisch, is widely used in traditional Chinese medicine for its potential effects in preventing pulmonary fibrosis (PF). This study systematically explored the effects of JGT's water and 70% EtOH extracts in bleomycin (BLM)-induced PF models. In vitro, the 70% EtOH extract significantly reversed BLM-induced reductions in cell viability and apoptosis, whereas the water extract had limited impact. In vivo, the EtOH extract markedly reduced fibrosis markers, such as alpha-SMA and collagen-I, alleviating lung tissue damage and collagen deposition. UPLC-Q-TOF/MS analysis revealed that the EtOH extract contained a higher abundance of flavonoids compared to the water extract. Through network pharmacology analysis of the EtOH extract, four key flavonoids-apigenin, kaempferol, kaempferol 3-glucuronoside, and quercetin-were identified as crucial compounds. These flavonoids were found to reverse BLM-induced cell viability loss, with apigenin showing the most pronounced effect by modulating the TNF-alpha signaling pathway and inhibiting caspase-3 activation. Apigenin, as a primary active component derived from JGT, holds significant potential as a preventive agent against pulmonary fibrosis.

关键词： antibody-mediated rejection   BAFF inhibition   highly-sensitised   HLA-antibody   HLA-specific memory B-cell   renal transplantation   risk-stratification  

摘要： Highly sensitised kidney transplant candidates face substantial barriers to transplantation due to limited donor compatibility. Delisting unacceptable antigens with detectable HLA-specific antibodies can improve transplant access. It is, however, challenging to determine which specificities are safe to delist. Assessment of circulating HLA-specific memory B-cells may support risk stratification. However, current methodologies are limited by the predominant localisation of memory B-cells in secondary lymphoid organs and thus by potential false negativity. BAFF inhibitors, such as belimumab, mobilise memory B-cells into the circulation, which could reduce false-negative evaluations and improve pretransplant risk stratification. We administered off-label treatment with 200 mg of subcutaneous belimumab weekly for 4 weeks to seven highly sensitised patients with limited allocation probability. The clinical aim was to safely increase allocation probability by selectively delisting unacceptable HLA-specificities without detectable B-cell memory. HLA-specific memory B-cell profiles were assessed before and after treatment, revealing significantly broader HLA-specific memory B-cell profiles after belimumab in addition to a significant increase of HLA-antibody MFI in the eluate of stimulated memory B-cells. This strategy may pave the way for a new paradigm in pretransplant immunological risk-stratification, allowing improved assessment of HLA-specific memory B-cell profiles, which could potentially limit the risk of memory responses.