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关键词： Graves' disease   methylation   CpG   IL-10   machine learning model  

摘要： Objective: Epigenetic modifications, particularly deoxyribonucleic acid (DNA) methylation, regulate the expression of immune-mediated factors. This study aimed to investigate the methylation landscape of the interleukin-10 (IL10) gene in Graves' disease (GD). Methods: This study quantitatively profiled DNA methylation levels within the IL-10 gene using peripheral blood samples from GD patients and healthy controls. Machine learning models were constructed based on CpG methylation features to classify disease status. Furthermore, correlation between specific CpG sites methylation and clinical indicators were analyzed. Results: This study enrolled 60 patients diagnosed with GD and 51 healthy controls. Methylation analysis revealed significantly elevated methylation at multiple IL-10 CpG sites in the GD group compared to the healthy controls (p < 0.01), forming a hypermethylated cluster. Interestingly, the newly-diagnosed GD (NGD) group also showed higher methylation at specific sites compared to the recurrent GD (RGD) group. Correlation analysis showed that methylation at chr1_206947188_R and chr1_206947135_R were positively correlated with FT3 and TRAb levels, indicating that site-specific methylation changes were associated with disease severity and immune activity in GD. Conclusions: Our findings highlight distinct methylation patterns of the IL-10 gene in GD, with specific CpG sites carrying potential implications for disease diagnosis, stratification, and monitoring.

关键词： circRNAs   HuR   NSCLC   SFPQ   ubiquitylation  

摘要： Among lung cancers, non-small-cell lung cancer (NSCLC) is the most common type. Evidence demonstrates that abnormal expression of circular RNAs (circRNAs) is associated with cancer progression through interactions with RNA-binding proteins (RBPs). Therefore, further elucidation of the role of circular RNAs may provide new therapeutic targets for NSCLC patients. This study identified a novel circRNA, circHMGCS1 (hsa_circ_0072387), using circRNA microarrays. Validation and characterization of circHMGCS1 were performed by Sanger sequencing and RNase R treatment. CCK-8 and Transwell assays were used to determine the function of circHMGCS1 in cell proliferation and migration. The interaction between circHMGCS1 and human antigen R (HuR) protein was verified by RNA pull-down and RNA immunoprecipitation (RIP) assays. The effect of HuR on the stability of splicing factor proline- and glutamine-rich (SFPQ) mRNA was verified by dual-luciferase reporter gene assay and actinomycin D treatment. We found that circHMGCS1 was upregulated in NSCLC cells and tissues. Mechanistically, circHMGCS1 binds to HuR, and its high expression stabilizes HuR by inhibiting its ubiquitin-mediated degradation. HuR was shown to mediate the stability of SFPQ mRNA and promote the progression of NSCLC. RNA sequencing analysis indicated that SFPQ may inhibit apoptosis by suppressing tumor necrosis factor (TNF) signaling. This study revealed that circHMGCS1 contributes to NSCLC progression by stabilizing oncogenic HuR and promoting post-transcriptional upregulation of SFPQ, highlighting its potential as a diagnostic and prognostic biomarker for NSCLC.

摘要： Neoadjuvant immunotherapy is a first-line treatment for recurrent and metastatic head and neck squamous cell carcinoma (HNSCC). However, only a fraction of patients with advanced HNSCC benefit from immunotherapy. Identifying accurate and accessible biomarkers is essential for optimal patient selection. In this study, we integrated single-cell RNA sequencing and T-cell receptor sequencing to comprehensively characterize the tumor immune microenvironment (TIME) of HNSCC biopsies prior to a phase II neoadjuvant immunotherapy clinical trial. Tumor-specific MHC-II (tsMHC-II) was identified as a superior predictor of response to neoadjuvant immunotherapy in HNSCC compared with PD-L1. Mechanistically, tsMHC-II ignited a hot TIME and enhanced the effect of PD-1 blockade by recruiting T cells through the induction of chemokines, particularly CCL5. Moreover, tsMHC-II triggered a Th1 response and activated CD4+ and CD8+ T-cell expansion, suppressing HNSCC growth in a CD4+ T-cell-dependent manner. Simultaneously, tsMHC-II facilitated an increase in PD-1+CD4+ T cells and a modest elevation in tumor PD-L1, thereby enhancing sensitivity to anti-PD-1 therapy. This study highlights that tsMHC-II, by generating an inflamed TIME, is crucial in enhancing the effectiveness of neoadjuvant immunotherapy in ***: scRNA-seq analysis identifies tumor-specific MHC-II as a predictor for neoadjuvant immunotherapy response in HNSCC and provides insights into the complex networks that ignite a hot tumor immune microenvironment and regulate T-cell infiltration.

关键词： 儿童   EBF1-PDGFRB阳性   Ph-like ALL   中枢神经系统白血病   TKIs   达沙替尼   药学监护  

摘要： 报道了1例儿童EBF1-PDGFRB融合基因阳性费城染色体样急性淋巴细胞白血病（Ph-like ALL）合并中枢神经系统白血病（CNSL）的临床病例。患儿在初诊后接受中国儿童白血病协作组（CCLG）-ALL-2018标准化疗方案诱导治疗未获缓解，后续采用含二代酪氨酸激酶抑制剂（TKI）达沙替尼的挽救治疗方案。治疗期间通过治疗药物监测（TDM）及不良反应监测动态调整达沙替尼用药方案，联合方案疗效显著，患儿PDGFRB融合基因及脑脊液微小残留病灶（MRD）持续维持阴性状态。CCLG-ALL-2018化疗方案联合达沙替尼是治疗此类患儿的有效手段，临床药师参与方案优化及实施药学监护对保障用药安全合理至关重要。

摘要： In the original publication [...].

关键词： neuroendocrine tumors   peptide receptor radionuclide therapy   IL-33   sST2  

摘要： Despite a high disease control rate in the treatment of unresectable or metastatic well-differentiated, somatostatin receptor-positive neuroendocrine tumors (NETs) with peptide receptor radionuclide therapy (PRRT), a certain percentage of patients will experience an unfavorable outcome. Besides clinical, hematological, and biochemical parameters, including widely used inflammatory markers, as well as literature-recognized inflammatory indices, there is a growing need for the identification of novel biomarkers as prognostic factors of therapeutic response. In this prospective single-center study, 51 NET patients treated with PRRT were included and divided into two groups: responders and non-responders in accordance with therapeutic outcome. Cytokine, clinical, and biochemical data were analyzed. Non-responders had significantly higher serum concentrations of IL-33 and IL-4 in comparison to responders, while sST2 was increased in responders. A positive correlation was measured between IL-33 and IL-4, as well as between IL-33 and disease progression. A negative correlation was noted between IL-33 and the neutrophil count %. ROC curve analysis identified values of IL-33 >146.5 pg/mL as a predictor of poor early therapeutic response, and logistic regression confirmed its independent prognostic value. Elevated IL-33 and IL-4 favor the development of a type 2 immune response associated with unfavored therapeutic outcome, while increased sST2 mitigates the IL-33's effect in responders, contributing to a more favorable response. These findings emphasize IL-33 as an important biomarker of early response in NET patients undergoing PRRT.

关键词： IFN-γ   双调蛋白   肠成纤维细胞   克罗恩病   肠纤维化  

摘要： 目的：克罗恩病（Crohn’s disease,CD）肠纤维化是临床治疗的难点，其分子机制尚未完全阐明。本研究系统探讨干扰素-γ(interferon-gamma,IFN-γ)在CD肠纤维化中的调控作用及机制。方法：提取分离CD患者肠成纤维细胞，体外予以不同的细胞因子（IFN-γ、IL-17A、IL-1β、IL-33、IL-36α、TNF-α）处理，RT-PCR检测人肠成纤维细胞中双调蛋白（amphiregulin,Areg）基因表达水平。20 ng/mL IFN-γ处理人肠成纤维细胞48 h后，进行转录组测序（RNA-seq），结合STRING数据库构建蛋白质互作（protein-protein interaction,PPI）网络。免疫荧光检测α平滑肌肌动蛋白（α-smooth muscle actin,α-SMA）、抗原Kiel 67(antigen Kiel67,Ki67)等肌成纤维细胞标志物，评估IFN-γ对人肠道成纤维细胞活化、增殖的影响。结果：Areg显著促进肠成纤维细胞活化、增殖及胶原合成；IFN-γ可显著抑制肠成纤维细胞Areg表达，并下调α-SMA、COL1A1和COL6A1等纤维化相关基因，同时IFN-γ抑制成纤维细胞增殖与活化能力。RNA-seq分析发现IFN-γ调控的差异基因显著富集于细胞外基质（extracellular matrix,ECM）重构通路，PPI网络鉴定出肉瘤原癌基因（sarcoma proto-oncogene,SRC）为核心节点，提示其可能介导IFN-γ的抗纤维化作用。结论：本研究证实Areg是促CD肠纤维化关键介质，IFN-γ通过转录调控抑制Areg表达，并发现SRC可能是IFN-γ下游的关键效应分子。IFN-γ可能通过抑制SRC/Areg信号轴来发挥其抗纤维化作用。这些发现为开发靶向IFN-γ/SRC/Areg通路的抗纤维化策略提供了理论依据。

关键词： Rheumatic diseases   TNF inhibitors   drug response prediction   cell-based assays   biomarkers   peripheral blood mononuclear cells   immune responses  

摘要： IntroductionTumor necrosis factor inhibitors (TNFi) have revolutionized rheumatic and inflammatory diseases therapy. Despite their efficacy, at least 30% of patients do not respond to TNFi therapy. There are five FDA-approved TNFis and several TNFi biosimilars, which are equivalent to their reference drugs. Although all TNFi drugs neutralize the TNF cytokine, they differ in many structural and pharmacokinetic properties. These differences may lead to varying patient responses, making one TNFi, but not another, effective for a given patient. An accurate prediction of a priori responsiveness to therapy, rather than trial and error, would therefore be of great value. Biomarkers that may guide the optimal TNFi choice are an unmet *** coveredThe authors discuss the diagnostic and predictive utilities of Cell-Based Assays (CBAs) for individualized TNFi therapy. Selection of TNFi can be based upon a given patient's immune cell response to the various TNFi drugs to predict their clinical outcomes to those *** opinionCBAs allow to assess the response of multiple TNFi drugs simultaneously by measuring biomarkers that could distinguish between TNFi responders and non-responders, effectively prioritizing the TNFi of choice. This literature search focuses on biomarkers and techniques that could be used as predictive CBAs for clinical response to TNFi.

关键词： HBV   HLA-Ib   rs41551813   HIF-1   genetic association   HBV outcome  

摘要： Background The natural history of HBV infection is highly heterogeneous. Failure to clear the virus during the acute phase of infection allows for viral persistence and progression to chronicity. Investigating the immune mechanisms involved in this process is crucial for effectively managing infection outcome. HLA-Ib molecules (HLA-G, HLA-E and HLA-F) play a critical role in regulating the immune response. Objectives: Primary objective we investigate the potential impact of functional polymorphisms in HLA-F*01:03 (rs1736924), HLA-E*01:01/01:03 (rs1264457), and two selected HLA-G polymorphisms in Exon 2 (+292 A > T (rs41551813) and +372 G > A (rs1130355)) on HBV infection outcome. Secondary objective: we evaluate the expression of soluble HLA-E in our cohort. Methods We evaluated these polymorphisms in a cohort of 200 patients with chronic HBV infection and 100 individuals who spontaneously resolved the infection, using SSP-PCR and Sanger sequencing. Additionally, we measured soluble HLA-E (sHLA-E) levels using ELISA. Results Our results showed a significant association of HLA-G (rs41551813) and HLA-E (rs1264457) polymorphisms with HBV infection outcome, where carriers of the A allele in both HLA-G (rs41551813) and HLA-E (rs1264457) had a significantly higher likelihood of spontaneous HBV clearance (all p < 0.01). Furthermore, we demonstrate that elevated sHLA-E expression favours HBV persistence. Additionally, our findings has revealed that the HLA-G + 292 A > T polymorphism (rs41551813) is associated with regulation of sHLA-G expression. Haplotype analysis further identified the 'TAAA' haplotype as linked to spontaneous HBV clearance. Conclusion this study demonstrates, for the first time, the critical role of HLA-Ib on HBV infection outcome, providing insights for potential therapeutic interventions.

关键词： Phytochemicals   Free energy   Oils   Binding analysis   Cytokines   Drug interactions   Psoriasis   Hydrogen bonding  

摘要： Psoriasis, a persistent inflammatory condition with a complex origin, lacks a definitive cure despite the availability of diverse treatments. Vetpalai thailam (VT), a Siddha formulation, is commonly used for addressing various skin ailments. Analysis via GC-MS of a sample of VT oil unveiled the existence of 65 compounds. These identified phytochemical structures were then examined through molecular docking against the proinflammatory cytokines TNF-alpha and IL-17A, resulting in the shortlisting of seven compounds. Among these, four displayed binding potential against TNF-alpha, while three exhibited similar potential against IL-17A. Further, the individual shortlisted phytochemical and protein complexes were subjected to molecular dynamics and documented their RMSDs, RMSFs, SASA, Rg, MMPBSA, and PCA profiles. Other informatics web tools were employed to predict physicochemical properties, bioactivity, drug-likeness, and toxicity scores. Three compounds identified from VT oil displayed binding potential against IL-17A, showcasing binding energies varied between -8.427 and -6.739 kcal/mol, while four compounds exhibited potential against TNF-alpha, with binding energies ranging from -9.873 to -8.644 kcal/mol. The physicochemical attributes, bioactivity, compliance with Lipinski's rule of five, and ADMET profiles of the shortlisted compounds demonstrated favorable pharmacokinetic characteristics. Consequently, this research provides valuable insights into the binding ability of phytoconstituents of VT oil against IL-17A and TNF-alpha, paving the way for the development of novel drugs for the treatment of psoriasis.