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关键词： Idiosyncratic adverse drug reactions   HLA   pharmacogenomics   SCARs   DILI  

摘要： IntroductionIdiosyncratic adverse drug reactions (IADRs) or drug hypersensitivity reactions (DHRs) represent a major health problem because they are unpredictable and can be severe with potential life-long or even lethal consequences. Their pathophysiology is not clear but thought to be immune mediated, supported by the significant statistical association of these reactions with specific alleles of the human leukocyte antigen (HLA) *** coveredThis comprehensive update review summarizes the currently available evidence on the role of HLA gene locus in IADRs and discusses the present understanding of the pathophysiology of IADRs. We searched the available literature in PubMed and Google Scholar with no date restriction for publications on HLA and adverse drug reactions. Findings are summarized and discussed in the context of the currently available *** opinionThe role of the immune system in IADRs and the role of pharmacogenetic testing in this field is evident. HLA genetic testing is very promising in the management of these reactions. Many obstacles seem to prevent pharmacogenetic testing to meet its full potential including cost and health care providers' education. Further work in needed to provide more evidence and allow widespread use of pharmacogenetic testing in the clinical practice.

关键词： Osteoarthritis   chondrocytes   Long-stranded noncoding RNA   SNHG7   PCBP1  

摘要： Purpose We probed the roles of SNHG7, miR-146b, PCBP1, and IL-beta in the development of osteoarthritis (OA). Materials and methods OA models were established using anterior cruciate ligaments, and chondrocytes were obtained from mouse cartilage tissue. Cells were treated with 10 ng/ml Il-1 beta. RT-qPCR was used to detect the expression of SNHG7, miR-146b, PCBP1, and IL-beta in tissues and cells. Safranin-O/Fast Green staining was performed to analyze the cartilage damage in each group of mice. Results SNHG7 and PCBP1 expressions were down-regulated, and miR-146b expression was up-regulated in OA tissue and IL-1 beta-treated chondrocytes compared to normal cartilage tissue and chondrocytes. Forced SNHG7 expression improved cartilage structure, enhanced proliferative viability of chondrocytes, and inhibited apoptosis and IL-1 beta release in IL-1 beta-treated chondrocytes in OA mice. In contrast, miR-146b upregulation decreased proliferative viability and promoted apoptosis and IL-1 beta release in chondrocytes. Rescue assays showed that miR-146b attenuated the protective effects of SNHG7 on apoptosis and inflammation in IL-1 beta-treated chondrocytes, and activation of PCBP1 expression significantly inhibited the cytotoxic effects of miR-146b. Mechanistically, SNHG7 acted as a competitive endogenous RNA by targeting miR-146b to promote the expression of PCBP1. Conclusions This study confirms that SNHG7 inhibits IL-1 beta-mediated inflammatory responses in chondrocytes via the miR-146b/PCBP1 axis, thereby suppressing IL-1 beta-induced OA.

摘要： MHC-II neoantigens play a critical role in immunotherapy, either as direct effectors or through their influence on CD8 T cells. However, only a small fraction of tumor DNA mutations qualify as functional neoantigens, and current prediction tools often lack accuracy, leading to the low immunogenicity of predicted neoantigens in vivo. Here, we present EpiMII, a Graph Neural Network model for MHC-II epitope design, which learns from the structural features of epitopes to predict their sequences. To train EpiMII, we constructed a reliable, large dataset containing 142,934 MHC-II epitope structures. This approach achieves a 4.2x improvement over ProteinMPNN, with a sequence recovery rate of 78.0% for known MHC-II epitopes in the Protein Data Bank. As a case study, we designed a neoantigen from hepatocellular carcinoma. All five designed epitopes significantly activated CD4 T cells in vitro and induced secretion of IFN-γ and TNF-α. Notably, one epitope treatment significantly reduced tumor volume in mice in vivo. EpiMII offers a novel and efficient approach for identifying MHC-II epitopes/neoantigens, potentially contributing to vaccine development.

关键词： Slc26a9   autoimmune gastritis   SPEM   gastric malignancy  

关键词： Anti-PoRV effect   Lactobacillus plantarum   STING-IFN-I pathway  

摘要： BackgroundRotavirus infection represents a major etiology of severe diarrheal disease in neonatal and weaned piglets, causing substantial economic burdens to the global swine industry. Lactobacillus plantarum, a ubiquitous probiotic in natural ecosystems, has demonstrated multifaceted biological functions. The stimulator of the interferon gene (STING) is involved in type I interferon (IFN-I) mediated host antiviral innate immunity, which is a pivotal adaptor in response to the microbial DNA/RNA-activated signaling pathways. Emerging evidence suggests that certain probiotic strains can activate the STING-dependent pathway to induce IFN-I responses. In the present study, we successfully isolated a strain of Lactobacillus plantarum (designated LP1)from porcine intestinal contents and investigate its potential to counteract porcine rotavirus (PoRV) infection via modulation of antiviral signaling ***1 exhibited superior tolerance to simulated gastrointestinal conditions (pH 3.0 and 0.3% bile salts) compared with other isolated Lactobacillus strains. In vitro adhesion assays demonstrated that LP1effectively colonized porcine intestinal epithelial cells (IPEC-J2) without inducing cytotoxicity or apoptosis. Animal experiments also confirmed the protective effect of LP1 in mice against rotavirus, by reducing body weight loss, promoting viral clearance in feces, and alleviating intestinal mucosal damage. Mechanistic investigations identified STING-IRF3 pathway activation as the pivotal antiviral mechanism. Both phosphorylation of STING and IRF3 in LP1-treated IPEC-J2 cells accompanied by upregulated transcription and secretion of IFN-beta and interferon-stimulated genes (ISGs). Consistent findings were observed in intestinal tissues of LP1-protected mice with STING pathway activation correlating with reduction in viral titers. Crucially, STING inhibitor (C-170) administration could reverse LP1-mediated antiviral ***1 exerts potent anti-PoRV activ

关键词： electroconvulsive therapy (ECT)   treatment-resistant schizophrenia (TRS)   cytokines   interleukins   antipsychotics  

摘要： Background: Resistance to antipsychotic treatment in patients suffering from schizophrenia is linked to immune system disequilibrium. One effective therapeutic option for treatment-resistant schizophrenia is electroconvulsive therapy (ECT);however, its impact on cytokines remains poorly understood. The aim of this study is to evaluate the impact of ECT on cytokines (IL-1 beta, IP-10, IL-17, TNF alpha, IL-10, and soluble receptor for IL-2 (sIL-2R)) in TRS patients. Additionally, correlations between cytokine concentrations and schizophrenia symptoms severity are explored. Methods: Cytokine and receptor concentrations were measured in eight TRS patients before and after ECT and in 13 healthy participants from control group. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate the severity of the symptoms. Results: Before ECT, TRS patients exhibited significantly higher concentrations of IL-1 ss, IL-10, IL-17, and IP-10 compared to the control group, whereas no significant differences were observed in sIL-2R and TNF-alpha. In the TRS patients, ECT induced a significant reduction in IL-10, IL-17 and IP-10 levels, while IL-1 beta, TNF-alpha, and sIL-2R remained unchanged compared to pre-ECT. ECT also led to clinical improvement in schizophrenia symptoms, as measured by PANSS. Furthermore, correlations between cytokine levels and PANSS results were found. Conclusions: The above results suggest that clinical improvement in TRS patients following ECT is associated with immune modulation, especially with the steadiness between pro- and anti-inflammatory systems. However, further research is required to elucidate these mechanisms in greater detail.

摘要： The multifaceted roles and mechanisms of necroptosis in cancer cells remain incompletely understood. Here, we demonstrate that FGFR2 inhibition potently inhibits esophageal squamous cell carcinoma (ESCC) by inducing necroptosis in a RIP1/MLKL-dependent manner and show RIP3 is dispensable in this pathway. Notably, MST1 is identified as a necroptotic pathway component that interacts with RIP1 and MLKL to promote necroptosis by phosphorylating MLKL at Thr216. Additionally, FGFR2 inhibition induces Ser518 phosphorylation and triggers ubiquitin-mediated degradation of NF2, culminating in Hippo pathway suppression. Subsequently, YAP activation promotes RIP1 and MLKL transcriptional upregulation, further amplifying necroptosis. Intriguingly, IL-8 derived from necrotic cells stimulates peripheral surviving tumor cells to increase PD-L1 expression. Dual blockade of FGFR2/PD-L1 or FGFR2/IL-8-CXCR1/2 robustly impedes tumor growth in humanized mouse xenografts. Collectively, our findings delineate an alternative FGFR2-NF2-YAP signaling-dependent necroptotic pathway and shed light on the immunoregulatory role of FGFR2, offering promising avenues for combinatorial therapeutic strategies in clinical cancer management.