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关键词： Adalimumab   Anti-TNF-α   Certolizumab pegol   Etanercept   Golimumab   Hepatitis B   Hepatitis B reactivation infliximab   Tumor necrosis factor-alpha inhibitors  

摘要： Background The widespread use of TNF-α inhibitors (infliximab, adalimumab, golimumab, certolizumab pegol, and etanercept) in gastrointestinal, rheumatologic, and dermatologic disorders raises concerns about hepatitis B reactivation (HBVr). The exact risk remains unclear due to the variability in previous meta-analyses. This study aims to assess the effectiveness of antiviral prophylaxis in preventing HBV reactivation in patients on TNF-α therapy and to investigate the associated reactivation risk.

关键词： Angiosarcoma   Cell proliferation   Cytokine signaling   IL-13 receptor alpha2   Interleukin-13   STAT6  

摘要： Angiosarcoma is a rare and aggressive soft tissue sarcoma with a poor prognosis and limited treatment options. The role of interleukin-13 (IL-13) and its receptors in angiosarcoma pathogenesis has been largely unknown. We first reanalyzed transcriptomic data from a published angiosarcoma cohort and found IL13RA2 mRNA elevated in angiosarcoma versus normal tissue. In addition, high IL13RA2 expression was significantly associated with increased nonsynonymous mutations. We next detected high IL-13 receptor α2 (IL-13Rα2) expression in angiosarcoma cell lines and patient samples compared to other cell types and benign vascular tumors. Moreover, histological analysis showed the presence of IL-13 in the angiosarcoma microenvironment. Functional studies using angiosarcoma cell lines, MO-LAS-B cells, revealed the promoting effect of IL-13 on cell proliferation. The effect was inhibited by siRNA-mediated knockdown of IL13RA2 or neutralizing antibodies against IL-13, suggesting the impact of IL-13/IL-13Rα2 axis in the angiosarcoma proliferation. In addition, IL-13 stimulation increased mRNA levels of IL13RA2 and VEGFA, suggesting an underlying positive feedback mechanism, which was attenuated by a STAT6 inhibitor. These findings highlight the importance of the IL-13/IL-13Rα2 axis in angiosarcoma progression and its potential as a novel therapeutic target for this challenging malignancy.

关键词： Polyunsaturated fatty acids   Brain disorders   Shared genetic basis   Causal relationship   Genetic correlations   1KGP   1000 Genomes Project   AD   Alcohol dependence   ADARB1   Adenosine Deaminase RNA Specific B1   ADHD   Attention deficit-hyperactivity disorder   ALZ   Alzheimer’s disease   AN   Anorexia nervosa   ANX   Anxiety disorders and factors   ASD   Autism spectrum disorder   AUDIT   Alcohol use disorder identification test   AUDIT_C   AUDIT focuses on alcohol consumption   AUDIT_P   AUDIT focuses on the problematic consequences of drinking   AUDIT_T   AUDIT total score   BIP   Bipolar disorder   cPUFA   Circulating polyunsaturated fatty acids   CS   Credible set   CUD   Cannabis use disorder   DHA   Docosahexaenoic acid   FADS   Fatty acid desaturase   GCKR   Glucokinase regulatory protein   GWAS   Genome-wide association study   h2   Heritability   INS   Insomnia   IVW   Inverse weighted variance   LA   Linoleic acid   LD   Linkage disequilibrium   LDSC   LD Score regression   MAF   Minor allele frequency   MDD   Major depression   MHC   Major histocompatibility complex   MOOD   Mood disorders   MR   Mendelian randomization   NAFLD   Nonalcoholic fatty liver disease   nc12   Number of common variants shared between trait1 and trait2   NE   Neuroticism   OCD   Obsessive-compulsive disorder   OD   Opioid dependence   PGC   Psychiatric Genomic Consortium   PP   Posterior probability   PTSD   Post-traumatic stress disorder   PUFA   Polyunsaturated fatty acids   rg   Genetic correlation coefficient   SCZ   Schizophrenia   SNP   Single-nucleotide polymorphism   TS   Tourette syndrome   VEP   Variant Effect Predictor  

摘要： Background Polyunsaturated fatty acids (PUFAs) are indispensable for proper neuronal function. PUFA deficiency and imbalance have been linked to various brain disorders, including major depressive disorder (MDD) and anxiety. However, the effects of PUFAs on brain disorders remain inconclusive, and the extent of their shared genetic determinants is largely unknown. Methods We utilized genome-wide association summary statistics from six phenotypes of circulating PUFAs (N = 114,999) and 20 brain disorders (N = 9,725-762,917). We performed genome-wide analysis for each of the 120 trait pairs. We evaluated the correlation of genetic effects with genetic correlation, estimated the number of shared genetic variants with polygenic overlap, and prioritized potential causal relationships with two-sample Mendelian randomization (MR). We pinpointed specific shared variants with colocalization and statistical fine-mapping. Results Genetic correlation and polygenic overlap analyses revealed a widespread but moderate shared genetic basis for 77 PUFA-brain disorder trait pairs. MR suggested potential causal relationships for 16 pairs. Colocalization identified 40 shared loci (13 unique) and 22 candidate shared causal variants, including rs1260326 ( GCKR ), rs174564 ( FADS2 ), and rs4818766 ( ADARB1 ). These genes were mapped to lipid metabolism pathways. Integrating evidence from multiple approaches, we prioritized four PUFA-brain disorder pairs with potential causal links, including PUFA% with MDD, and omega-6% with alcohol consumption. Conclusions These findings reveal a widespread but moderate shared genetic basis between PUFAs and brain disorders, pinpoint specific shared variants, and provide support for potential effects of PUFAs on certain brain disorders, especially MDD and alcohol consumption. Future studies are needed to elucidate potential causal effects.

关键词： cytokines   IL-4   immunoregulation   SARS-CoV-2   TGF-β  

摘要： The pathology of severe COVID-19 is due to a hyperinflammatory immune response persisting after viral clearance. To understand how the immune response to SARS-CoV-2 is regulated to avoid severe COVID-19, we tested relevant immunoregulatory cytokines. Transforming growth factor β (TGF-β), interleukin (IL)-10, and IL-4 were neutralized upon infection with mouse-adapted SARS-CoV-2 (CMA3p20), a model of mild disease; lung inflammation was quantified by histology and flow cytometry at early and late time points. Mild weight loss and lung inflammation including consolidation and alveolar thickening were evident 3 d postinfection (dpi), and inflammation persisted to 7 dpi. Coinciding with early monocytic infiltrates, CCL2 and granulocyte colony-stimulating factor were transiently produced 3 dpi, while IL-12 and CCL5 persisted to 7 dpi, modeling viral and inflammatory phases of disease. Neutralization of TGF-β, but not IL-10 or IL-4, significantly increased lung inflammatory monocytes and elevated serum but not lung IL-6. Neutralization of IL-4 prolonged weight loss and increased early perivascular infiltration without changing viral titer. Anti-IL-4 reduced expression of Arg1 , a gene associated with alternative activation of macrophages. Neutralizing TGF-β and IL-4 had differential effects on pathology after virus control. Lung perivascular infiltration was reduced 7 dpi by neutralization of IL-4 or TGF-β, and periairway inflammation was affected by anti-TGF-β, while alveolar infiltrates were not affected by either. Anti-IL-4 prolonged IL-12 to 7 dpi along with reduced IL-10 in lungs. Overall, the immunoregulatory cytokines TGF-β and IL-4 dampen initial inflammation in this mouse-adapted SARS-CoV-2 infection, suggesting that promotion of immunoregulation could help patients in early stages of disease.

关键词： Allogeneic hematopoietic stem cell transplantation   FOXP3   IL-10   graft-versus-host disease   single-nucleotide polymorphism  

摘要： Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers a potential cure for hematologic malignancies, but post-transplant complications, particularly graft--host disease (GVHD), remain major challenges. Regulatory T cells and interleukin-10 () play key roles in immune regulation. This retrospective study investigated the impact of donor -3279 (rs3761548) and -819 (rs1800871) single-nucleotide polymorphisms (SNPs) on clinical outcomes in 92 allo-HSCT recipients, with emphasis on umbilical cord blood transplantation (UCBT). Among UCBT recipients, non-C/C and non-T/T donor genotypes were associated with significantly worse progression-free and overall survival, as well as a higher incidence of chronic GVHD. Multivariable analyses confirmed the prognostic impact of these SNPs. These findings suggest that donor-derived SNPs in key immune regulatory genes may influence post-transplant immune reconstitution. and genotyping could serve as useful biomarkers to guide donor selection and risk stratification in UCBT settings, potentially improving transplantation outcomes.

关键词： 甲状腺乳头状癌   肿瘤免疫微环境   肿瘤复发风险   淋巴细胞亚群   细胞因子  

摘要： 目的:分析肿瘤相关免疫细胞及细胞因子与甲状腺乳头状癌（PTC）的关系，探究肿瘤相关免疫细胞与甲状腺癌复发危险分层的相关性。方法:选取天津医科大学总医院普通外科甲状腺乳腺疝外科2022年8月至2023年8月收治的经手术病理证实的58例PTC患者，均予以甲状腺切除术+中央区±侧颈淋巴结清扫，根据是否有淋巴结转移（LNM）分组，分组依据经病理科术后病理证实，分为LNM阴性（22例）和LNM阳性组（36例）。采用流式细胞术检测各组肿瘤相关免疫细胞（T、B、NK细胞）和T细胞中细胞因子（IL-10、IL-17、IL-35、IFN- γ）水平。 结果:与远癌正常组织相比，癌组织NK细胞比例显著升高（ t=-2.11, P=0.032）、CD8 +T细胞比例显著升高（ t=-5.12， P=0.005）;在淋巴结组织中，与LNM阴性相比，LNM阳性组织中CD4 +T细胞比例显著升高（ t=-3.89， P=0.004），CD8 +T细胞比例显著下降（ t=2.41， P=0.004）。癌组织中IL-10水平明显升高（ t=-3.83， P=0.003）、IL-17水平明显升高（ t=-4.83， P=0.003）。LNM阴性与阳性的淋巴结组织中，IL-10和IL-17的水平尽管没有统计学差异，但LNM阳性中IL-10和IL-17的水平普遍高于LNM阴性。将58例按照复发危险分层分为低危组22例（37.9%），中危组36例（62.1%），PTC患者淋巴结中CD4 +T和CD8 +T细胞亚群比例的差异有统计学意义。建立Logistic回归模型分析，PTC患者淋巴结中CD4 +T细胞亚群比例相较于低者，复发风险分层更高（ OR=1.107，95% CI：1.001~1.224）。以预测的概率作为检验变量，"低危和中危"作为状态变量构建ROC曲线。其AUC面积为0.790， P=0.003，说明该模型对因变量有较好的预测效果。 结论:与远癌正常组织相比，癌组织中肿瘤相关免疫细胞比例及细胞因子水平显著升高，癌组织中形成免疫抑制性肿瘤微环境;复发危险分层较高的PTC患者其淋巴结中的CD4 +T细胞亚群比例更大。

关键词： gluten   high‐fat diet (HFD)   hyperinsulinemia   inflammation   liver steatosis  

摘要： Unbalanced lipid metabolism contributes to inflammation in several conditions. Gluten, that triggers celiac disease, may also play a role in diseases associated with a high-fat diet (HFD). Our aim was to investigate the interplay between gluten and HFD in HLA-DQ8 (DQ8) transgenic mice, a model of gluten sensitivity. DQ8 mice were fed the gluten-free diet, the HFD, or the HFD containing 8% gluten (HFD + G) for 12 or 23 weeks. Clinical parameters, liver and intestinal histology, immune parameters were assessed. Twelve weeks of HFD increased body and white adipose tissue weight and reduced glucose tolerance in male DQ8 mice. Gluten increased hyperinsulinemia and lipid accumulation in liver; interferon gamma (IFN-γ) and interleukin-10 (IL-10) transcripts were higher in liver of HFD + G-fed mice. IL-1β, tumor necrosis factor-α (TNF-α), IFN-γ, and IL-10 mRNAs increased in the small intestine of HFD + G-fed mice. However, gliadin-specific immunity and alterations of the intestinal architecture were not induced. Feeding HFD + G for 23 weeks attenuated the gluten effect. A synergic effect between gluten and HFD after 12 weeks was found, which was instrumental to alter specific metabolic and immune functions in DQ8 mice. These findings provide new insights useful to dissect the association between obesity and gluten sensitivity.

关键词： donor-derived cell-free DNA   kidney biopsy   donor-specific antibody   microarrays   antibody-mediated rejection   kidney transplant rejection   ABMR   antibody-mediated rejection   ABMRM   ABMR or Mixed rejection   dd-cfDNA   Donor-derived cell-free DNA   DSA   Donor-specific antibody   HLA   Human leukocyte antigen   INTERCOMEX   International Collaborative Microarray Study Extension   IRB   Institutional review board   MMDx   Molecular Microscope® Diagnostic System   MFI   Mean fluorescence intensity   MVI   microcirculation lesions   NK cells   Natural killer cells   NR   no rejection   NRI   net reclassification improvement   OLI   One Lambda Inc   pABMR   possible ABMR   pTCMR   possible TCMR   PRA   Panel-reactive antibody   PRAHR   PRA-high risk   SN   Non-specific reactivities, high risk for DSA-positivity   SOC   Standard of care   TCMR   T cell-mediated rejection  

摘要： Emerging treatments for antibody-mediated rejection (ABMR, NEJM391(2):122-132) have increased the importance of ABMR detection when donor-specific antibody (DSA) is negative. We addressed this issue in the Trifecta-Kidney study (*** #NCT04239703) using three centralized tests in 690 kidney transplant biopsies: DSA (One Lambda Inc.), blood donor-derived cell-free DNA (dd-cfDNA, Prospera™ test, Natera, Inc.), and molecular biopsy assessment (MMDx). We used an “AutoBanff 2022” algorithm to model the impact of alternative DSA interpretations on the histologic diagnosis of “DSA-negative” ABMR following Banff guidelines, including agreement with dd-cfDNA and molecular ABMR. Lowering MFI cutoffs for DSA-positivity did not improve detection of DSA-negative ABMR. However, simply calling all DSA positive allowed Banff 2022 guidelines to identify 46% more ABMR cases with no measurable DSA, and per Net Reclassification Improvement increased agreement between histologic diagnoses and both dd-cfDNA ( P =7.72E-7) and molecular ABMR ( P =7.69E-7). New ABMR cases were as strongly positive for dd-cfDNA and molecular ABMR as those found using the conventional DSA interpretation. A validation set analysis using INTERCOMEX study data (*** NCT#01299168) confirmed these findings, and found that the new DSA-negative ABMR cases identified by calling all DSA positive had the same risk for graft loss as those found with conventional DSA interpretation. Trifecta-Kidney Study *** #NCT04239703

摘要： Photosensitivity is central to cutaneous lupus erythematosus (CLE) and dermatomyositis (DM), but the mechanisms linking UVB exposure to tissue-specific autoimmunity are poorly defined. Using single-cell RNA sequencing, spatial transcriptomics, UVB provocation, and in vitro modeling, we identify MMP9⁺ CD14⁺ myeloid cells as critical mediators of photosensitivity. These cells expand significantly in lesional skin, produce IFN-b, and colocalize with cytotoxic CD4⁺ T cells at the dermal-epidermal junction. Keratinocytes activate fibroblasts in the superficial dermis, prompting them to release chemokines (CCL2, CCL19, CCL7, CCL8, CXCL12) that recruit MMP9⁺ CD14⁺ cells. IFN-I-primed keratinocytes exposed to UVB release cytokines activating dendritic cells, mirroring in vivo responses. UVB irradiation of non-lesional DM skin rapidly recruits these myeloid cells. In a clinical proof-of-concept study, anti-IFN-I treatment with anifrolumab prevented UVB-induced myeloid infiltration and reduced photosensitivity. Thus, targeting MMP9⁺ CD14⁺ cells may offer therapeutic potential for managing photosensitive autoimmune skin conditions.

关键词： EGFR mutations   Advanced or recurrence NSCLC   EGFR TKIs   HLA typing   Tumor immune microenvironment  

摘要： Previously reported HLA class I correlated with the outcome of early-stage non-small cell lung cancer (NSCLC) in the Japanese population. The binding affinity capability of the EGFR mutation peptide and various HLA-A subtypes could explain this. We conducted a prospective cohort study to explore advanced EGFR-mutated NSCLC patients who received EGFR TKIs in various HLA-A subtypes, the outcomes of treatment, and tumor immune microenvironment (TIME). Eighty-four advanced NSCLC harboring EGFR exon 19 deletion and exon 21 L858R mutations were analyzed. Among these, the interested HLA-A subtypes of exon 19 deletion were composed of HLA-A*03:01 (7.1%), *30:01 (3.7%),*11:01 (82.1%), and *68:01 (7.1%). The interested HLA-A subtypes of exon 21 L858R were HLA-A*30:01 (28.5%), *33:03 (57.1%), and *34:01 (14.4%). Multivariate Cox-regression analysis revealed that the interested HLA-A subtypes were not an independent factor of progression-free or overall survival. No correlation was found between HLA-A subtypes and either inflammatory TIME or the presence of intra-tumoral CD8 TILs. HLA-A subtypes did not correlate with prognostic outcomes in sensitized EGFR mutations. The diverse binding affinity with EGFR peptides was not translated into the TIME patterns.