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摘要： Dysregulations in protein kinases significantly contribute to the initiation, progression, and drug resistance in non-small cell lung cancer (NSCLC). Identification of novel oncogenic drivers within the human kinome is crucial for targeted therapy. In this study, we conducted a comprehensive analysis of the TCGA database and literature, pinpointing 16 candidate genes in lung cancer exhibiting frequent dysregulation and limited research. Our functional analysis revealed Serine/threonine kinase 31 (STK31) as a key player in driving tumor growth, in immune-competent mice, with minimal impact in nude mice. Further investigations unveiled upregulation of STK31 led to CD8+ T cell exhaustion. Mechanistically, STK31 induced CD8+ T cell exhaustion through the signal transducer and activator of transcription 3 (STAT3) - interleukin 6 (IL-6) signaling pathway. Direct interaction between STK31 and STAT3 activated the transcription of downstream oncogenic targets, such as IL-6, facilitating immune escape. Moreover, STK31 exhibited elevated expression levels in lung cancer tissues compared to adjacent tissues and displayed a significant correlation with poor prognosis in lung cancer patients. This study defines a critical role of STK31 in promoting immune escape through STAT3 activation, positioning it as a promising therapeutic target for lung cancer.

关键词： Glycosylation   Autoimmune disorder   Homology modeling   Molecular docking   Molecular dynamics simulation  

摘要： Interleukin-1 receptor antagonist (IL-1ra) is a vital anti-inflammatory molecule, acting as a decoy protein that competitively binds to Interleukin-1 receptors (IL-1RI and IL-1RII). The deregulation of IL-1 activity has been linked to autoimmune disorders, impaired wound healing, and the occurrence of cytokine storms in the context of infections. At present, *** expressed IL-1ra isoform was used as a therapeutic drug for the treatment of IL-1 mediated inflammatory diseases;however, daily dosing raises concerns about allergens and infection. Notably, the drug lacks glycosylation, an important post-translational modification for protein stability and pharmacodynamics. The present study utilizes computational molecular dynamics simulations to investigate the influence of glycosylation on the stability and binding efficacy of IL-1ra. To study the impact, we introduced mammalian bi-antennary hybrid glycan with terminal sialic acid/ N-Acetylneuraminic acid (Neu5Ac) added to the respective Asparagine (Asn) residue of 3D modeled IL-1ra structure. The molecular dynamics simulations demonstrated that glycosylated IL-1ra increased the structural stability and exhibited a sustained level of binding stability with 24 hydrogen bonds and 8 salt bridges in comparison to non-glycosylated IL-1ra protein with 20 hydrogen bonds and 6 salt bridges as the result of post simulation. This finding underscores the possibility of glycosylation as it means to augment the effectiveness of therapeutic medications that specifically target immune regulation. These understandings help to translate the concept to the complete expression of proteins. Our study addressed the mechanism of how the N-glycan regulates cytokine, which will provide insight into the design of novel anti-inflammatory drugs and specifically glycan play a role in RA.

关键词： Tripterygium wilfordii polyglycoside tablets   Hepatocellular carcinoma   therapeutic drug   IL-6   PI3K/MAPK/STAT3 signaling pathway  

摘要： Tripterygium wilfordii polyglycoside tablets (TWPT) have traditionally been used to treat certain inflammatory diseases. This study validated TWPT as a novel application in hepatocellular carcinoma treatment through multiple targets, thereby expanding its clinical medication scope. TWPT exhibited a low toxicity and a significantly antihepatoma effects in vitro and in vivo. Through network pharmacology analysis, we found TWPT attenuated the progression of hepatocellular carcinoma by multi-targeting, including IL-6, MMP9, TNF-alpha and VEGFA. Additionally, TWPT targeted IL-6 to regulate downstream pathways, including the PI3K/Akt, JAK2/STAT3, and MAPK signaling pathways. Thus, TWPT could be developed as a potential therapeutic drug for hepatocellular carcinoma.

关键词： human leukocyte antigen   tuberculosis   local ancestry   admixture   KhoeSan  

摘要： Previously, the International Tuberculosis Host Genetics Consortium (ITHGC) demonstrated the power of large-scale GWAS analysis across diverse ancestries in identifying tuberculosis (TB) susceptibility loci (Schurz et al., 2024). Despite identifying a significant genetic correlate in the human leukocyte antigen (HLA)-II region, this association did not replicate in the African ancestry-specific analysis, due to small sample size and the inclusion of admixed samples. Our study aimed to build upon the findings from the ITHGC and identify TB susceptibility loci in an admixed South African cohort using the local ancestry allelic adjusted association (LAAA) model. We identified a suggestive association peak (rs3117230, p-value = 5.292 x 10(-6), OR = 0.437, SE = 0.182) in the HLA-DPB1 gene originating from KhoeSan ancestry. These findings extend the work of the ITHGC, underscore the need for innovative strategies in studying complex admixed populations, and confirm the role of the HLA-II region in TB susceptibility in admixed South African samples.

关键词： Adipose tissue   Cell biology   Glucose metabolism   Metabolism   Obesity  

摘要： Type 2 innate lymphoid cells (ILC2s) regulate the proliferation of preadipocytes that give rise to beige adipocytes. Whether and how ILC2 downstream Th2 cytokines control beige adipogenesis remain unclear. We used cell systems and genetic models to examine the mechanism through which IL-13, an ILC2-derived Th2 cytokine, controls beige adipocyte differentiation. IL-13 priming in preadipocytes drove beige adipogenesis by upregulating beige-promoting metabolic programs, including mitochondrial oxidative metabolism and PPAR gamma-related pathways. The latter was mediated by increased expression and activity of PPAR gamma through the IL-13 receptor 1 (IL-13R1) downstream effectors STAT6 and p38 MAPK, respectively. Il13-KO or preadipocyte Il13ra1-KO mice were refractory to cold-or beta 3-adrenergic agonist-induced beiging in inguinal white adipose tissue, whereas Il4-KO mice showed no defects in beige adipogenesis. Il13-KO and Il13ra1-KO mouse models exhibited increased body weight and fat mass and dysregulated glucose metabolism but had a mild cold-intolerant phenotype, likely due to their intact brown adipocyte recruitment. We also found that genetic variants of human IL13RA1 were associated with BMI and type 2 diabetes. These results suggest that IL-13 signaling-regulated beige adipocyte function may play a predominant role in modulating metabolic homeostasis rather than in thermoregulation.

关键词： Disease severity system   Hierarchical intervention   IgA vasculitis nephritis   Immune function   Inflammatory factors  

摘要： The objective of this study is to study the effects of a disease severity-based nursing intervention in children with immunoglobulin A (IgA) vasculitis nephritis, including recombinant human interferon-gamma (IFN-gamma), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). A sample of 104 children treated at the Nephrology Department from May 2021 to May 2023 was selected for this study. The division into groups depended on distinct nursing approaches: the control group (n = 52) received conventional intervention, including basic skin care, dietary advice, and parental communication, without disease severity stratification. The research group (n = 52) received a three-level intervention (grade I, nurse-patient ratio 1:6, 12-hourly rounds, UV irradiation once daily;grade II, nurse-patient ratio 1:3, 9-hourly rounds, protein-restricted diet;grade III, nurse-patient ratio 1:1, 6-hourly rounds, liquid diet and continuous UV) based on severity. Both groups received standardized medications. Comparative analysis was conducted before intervention, 2 weeks, and 4 weeks to evaluate immune function, inflammatory factors, and renal function indicators. Initially, no statistically significant differences in immune indicators, inflammatory factors, or renal function indicators were observed in both groups (p > 0.05). After receiving care for 2 and 4 weeks, the research group displayed notably higher levels of CD3(+) and CD4(+) T cells in differentiated clusters (p < 0.05). Additionally, the research group demonstrated lower levels of natural killer cells, IgA, immunoglobulin G (IgG), and immunoglobulin M (IgM) (p < 0.05). Furthermore, IFN-gamma, IL-6, and TNF-alpha levels were notably lower in the research group (p < 0.05). Key renal function indicators, including erythrocyte count, microalbuminuria (mALB), 24-h urine protein quantity, and serum beta(2)-microglobulin (beta(2)-MG), were significantly reduced in the research group (p < 0.05). Systematic hierarchical

关键词： histocompatibility antigen classes   coronavirus   polymorphism   genetic   HLA-DR beta-chains   in silico model  

摘要： The high variability of human leukocyte antigen (HLA) genes results in each molecule having distinct antigenic peptide binding capacities, potentially influencing the immune response to SARS-CoV-2. This study aimed to investigate associations between HLA class I (A, B) and class II (DRB1) polymorphisms and COVID-19 severity in a South Brazilian population, and to evaluate the binding affinity of alleles to viral peptides. A cross-sectional study included 503 unvaccinated patients with RT-qPCR-confirmed COVID-19: 145 non-severe, 129 severe, and 229 critical. HLA typing was performed using PCR-SSO and Luminex (TM) technology. The DRB1*11 allelic group was significantly associated with protection against severe and critical cases, while DRB1*15 was associated with increased risk;both remained significant after Bonferroni correction. Other allelic groups were associated with disease outcomes but lost significance after correction: B*49 and B*08 (risk);and B*37, B*50, and A*03 (protection). In silico analysis revealed that the DRB1*15 allele group showed a higher proportion of strong binders, mostly from non-structural proteins, while DRB1*11:01 binders, though fewer in number, were concentrated in the M protein. These results suggest functional differences in antigen presentation and reinforce the relevance of class II HLA, particularly DRB1, in modulating COVID-19 severity.

关键词： Systemic sclerosis   Interleukin 40   Biomarkers  

摘要： BackgroundInterleukin 40 (IL-40) is a cytokine implicated in malignancies and rheumatic disorders. Its association with fibrotic mediators has been previously described. Since inflammation and fibrosis are hallmarks of systemic sclerosis (SSc), we aimed to analyze the role of IL-40 in SSc. MethodsIL-40 levels were analyzed in the serum of 90 SSc patients and 75 healthy controls (HCs). IL-40 expression in dermal biopsies from 5 SSc patients and 5 HCs was assessed via immunohistochemistry. IL-40 was analyzed in 39 SSc patients with interstitial lung disease treated with cyclophosphamide (CPA) and in 24 SSc patients with active progressive disease treated with rituximab (RTX). SSc activity was assessed by the European Scleroderma Study Group (ESSG) index. The effect of recombinant IL-40 on peripheral blood mononuclear cells (PBMCs) from 10 SSc patients was determined in vitro. IL-40 was analyzed in 24 individuals at risk of developing SSc (VEDOSS), who were categorized as progressors (n = 11) and nonprogressors (n = 13). ResultsIL-40 expression was elevated in the skin of SSc patients compared to HCs, particularly in fibroblasts and immune infiltrates. Serum IL-40 was increased in SSc compared to HCs (p < 0.0001) and was associated with ESSG (r = 0.372, p = 0.0005) and gastrointestinal involvement (p < 0.05). IL-40 correlated with serum IL-8 (r = 0.270, p = 0.019) and TGF-beta 1 (r = 0.301, p = 0.024) levels. In the CPA and RTX cohort, no significant changes in the serum IL-40 were observed upon treatment. Baseline and changes in IL-40 levels were associated with changes in several clinical parameters. IL-40 was elevated in patients at risk of SSc compared to HCs (p = 0.0003). No significant changes were observed in progressors vs. nonprogressors;however, IL-40 was associated with capillaroscopy findings (p < 0.05). IL-40 induced the upregulation of IL-6 (p = 0.002), MCP-1 (p = 0.002) and IL-10 (p = 0.002) in PBMCs from SSc patients in vitro. ConclusionsIL-40 was upreg

关键词： Lung carcinoma   Molecular pathogenesis   HLA-A   HLA-B   HLA-DR  

摘要： According to GLOBOCAN 2022 estimates, lung cancer is the leading cause of cancer morbidity and mortality in 2022. 5 year survival rate is dismal for the disease, despite advances in therapeutic modalities. Current research into lung cancer therapy is largely focused on molecular advancements. Our study was focused on finding association between the HLA expression in lung carcinoma patients, in northern region of India. It contributes data for basic molecular understanding of pathogenesis in lung cancer patients. This study was conducted in the Department of Pathology and Department of Pulmonary critical care and sleep medicine, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi. A total of 35 lung cancer cases and 35 healthy controls were taken over a period of 18 months and results were compared. In our study the mean age of presentation for lung carcinoma patients was 52.29 years HLA-A11 (p value = 0.028) and HLA-B51 (p value = 0.035), were under expressed in the patients as compared to control group, and HLA-DRB1*15 (p value = 0.037) was over expressed in the patients as compared to control group. However, no statistically significant result was seen in co-relation to the clinical staging. The results of this small sample study provide data for a completely new population and might help to guide in understanding the role of HLA in lung carcinoma patients for future studies.

关键词： syphilis   serofast state   IFN-gamma   polymorphism   SNP   874 T/A   2109 A/G  

摘要： Background: In approximately 20% of patients with early syphilis, the classical serological response pattern is absent following treatment. They experience a serofast state, which manifests as less than a 4-fold decline in non-treponemal titres, without any clinical signs of treatment failure or reinfection. The effectiveness of the immune defense against T. pallidum, as well as its potential failure and the occurrence of the serofast state, depends on the Th1 cellular response, including cytokines such as IFN-gamma. The aim of this prospective observational study was to investigate the impact of IFN-gamma gene polymorphisms on the occurrence of the serofast state. Materials and methods: A cohort of 97 patients with early syphilis (73.2% secondary syphilis, 26.8% early latent syphilis) and 50 healthy volunteers were enrolled. Two single nucleotide polymorphisms (SNPs) in the IFN-gamma gene promoter region, +874 T>A (rs2430561) and +2109 A>G (rs1861494), were analyzed. Serum IFN-gamma levels were measured at baseline, prior to treatment. Patients were stratified into serofast (n=18) and serologically cured (n=79) groups. Results: Serofast patients exhibited significantly lower baseline serum IFN-gamma levels compared to the serologically cured group (p=0.01). All healthy subjects had IFN-gamma levels below the detection limit. Analysis of IFN-gamma gene polymorphisms revealed a significant association with treatment outcomes. The +874 AA and +2109 GG genotypes, associated with low IFN-gamma production, were significantly more frequent in serofast patients (p=0.0004 and p=0.002, respectively), with odds ratios (OR) of 7.1 (95% CI: 2.2-23.2) and 5.5 (95% CI: 1.8-17.3), respectively. Additionally, carriers of the +874A/+2109G haplotype were significantly more likely to remain serofast (OR 4.4, p=0.01). Conversely, the +874 TT and +2109 AA genotypes, associated with high IFN-gamma production, were significantly linked to serological cure (OR 4.4, p=0.03;OR 4.4, p=0.01).