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关键词： arthritogenic alphaviruses   chikungunya virus   Mayaro virus   G-CSF   neutrophils  

摘要： Introduction Arthritogenic alphaviruses, including chikungunya (CHIKV) and Mayaro virus (MAYV), cause disease characterized by fever, rash, and incapacitating joint pain. Alphavirus arthritis is associated with infiltration of myeloid cells and increases in several cytokines systemically, including granulocyte colony-stimulating factor (G-CSF). G-CSF is secreted by endothelial cells, fibroblasts, macrophages, and monocytes and binds to colony-stimulating factor 3 receptor (CSF3R, also known as G-CSFR) on the surface of myeloid cells. G-CSFR signaling initiates the proliferation, differentiation, and maturation of myeloid cells, especially neutrophils. Importantly, G-CSF has been found at high levels in both the acute and chronic phases of chikungunya disease;however, the role of G-CSF in arthritogenic alphavirus disease remains *** Here, we sought to test the effect of G-CSF on CHIKV and MAYV infection using G-CSFR-deficient mice (G-CSFR-/-).Results Compared to wild-type mice, we observed sustained weight loss in G-CSFR-/- mice following CHIKV and MAYV infection. Furthermore, G-CSFR-/- mice had a significantly higher percentage of inflammatory monocytes and a reduction in neutrophils throughout infection. The difference in weight loss in G-CSFR-/- mice induced by alphavirus infection was corrected by blocking type I IFN *** In summary, these studies suggest that type I IFN signaling contributes to G-CSFR-mediated control of arthritogenic alphavirus disease. Therefore, G-CSF or G-CSFR may be therapeutic targets to modulate host immune responses against arthritogenic alphavirus disease.

关键词： 新生抗原   单核苷酸突变   基因融合   可变剪接   流程  

摘要： 基于体细胞突变产生的新生抗原因其肿瘤特异性高、免疫原性强且不表达于正常组织的特点，成为激活抗肿瘤T细胞应答的理想靶点。目前能全面检测来自不同变异来源的新生抗原的生物信息学工具仍然很匮乏。基于Snakemake流程管理工具，我们开发了Neo-Pred肿瘤新生抗原检测流程，它可以读取高通量测序数据，检测单核苷酸变异（Single nucleotide variant， SNV）、插入缺失（Insertion-deletion， InDel）、基因融合、可变剪接多种变异衍生的新生抗原。我们在肿瘤新生抗原筛选联盟提供的基准数据集上进行了测试，其新生抗原检出的性能为精确率-召回率曲线下面积（Area under the precision-recall curve， AUPRC）0.71，领先于肿瘤新生抗原筛选联盟其他参与团队（全部参与机构均值为0.221，其中表现最好的团队均值为0.540），筛选性能提升31.5%-～221.3%，展示出领先的新生抗原检测能力。通过Singularity容器化和模块化设计，Neo-Pred实现了良好的稳定性、可移植性与动态扩展性。

关键词： Chondrocyte   HIF-1 alpha   Il-1 beta   Lopinavir/ritonavir   SOX9  

摘要： Background This study aimed to investigate the effects of Lopinavir/Ritonavir (Lop/r) on chondrocyte structure and extracellular matrix (ECM) integrity, as well as its impact on key proteins involved in anabolic and catabolic pathways, using both in vitro and in silico approaches. Methods Drug-target interaction networks were constructed through bioinformatics analyses, and molecular docking was performed. Human primary chondrocytes were treated with Lop/r, and untreated cells served as controls. Cell viability, proliferation, and protein expression levels were assessed using standard in vitro techniques, including spectrophotometric assays and Western blotting. Results Molecular docking analyses revealed strong binding affinities between Lop/r and osteoarthritis-related targets such as HIF-1 alpha, EP300, TNF, IL-6, KCNA5, and IL-1 beta, suggesting modulation of hypoxia, inflammatory, and epigenetic pathways. In vitro, Lop/r did not alter chondrocyte morphology or ECM structure and was not cytotoxic (p < 0.05). However, it significantly reduced the expression of critical proteins including HIF-1 alpha, SOX9, and IL-1 beta (p < 0.05). Conclusion These findings suggest that Lop/r may exert regulatory effects on cartilage-related molecular pathways and holds promise as a repurposed therapeutic agent for osteoarthritis. Further studies are warranted to confirm its potential in clinical applications.

关键词： IL-36 Signaling   Crohn's Disease   Personalized Therapy   Genetics  

摘要： The IL-36 signaling pathway has recently been identified as a key regulator of intestinal homeostasis and inflammation. However, the role of mutations in the IL-36R signaling pathway in the pathogenesis of inflammatory bowel disease remains unclear. We here identified four Crohn's disease patients with heterozygous missense mutations in the IL-36 receptor antagonist (IL36RN, IL-36RA). Experimental overexpression and functional assays demonstrated that two identified mutations resulted in reduced expression of IL-36RA. In-depth immune profiling of one IL36RN-mutated patient revealed an increased response of PBMCs to IL-36 stimulation and elevated serum levels of IL-36-regulated cytokines. Administration of the IL-36R-blocking antibody spesolimab to this patient resulted in a reduction of intestinal inflammation and alterations in immune cell composition and function. Our findings indicate that pathogenic IL36RN mutations may contribute to the pathogenesis of Crohn's disease in a subset of patients and that inhibiting IL-36 signaling could offer a personalized therapeutic approach for these patients.

摘要： Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by social communication deficits and restricted, repetitive behaviors. Growing evidence implicates neuroinflammation-induced blood-brain barrier (BBB) dysfunction as a key pathogenic mechanism in ASD, although the underlying molecular pathways remain poorly understood. This study aimed to identify critical genes linking BBB function and neuroinflammatory activation, with the ultimate goal of evaluating potential therapeutic targets. Through integrative analysis combining differential gene expression profiling with three machine learning algorithms - Least Absolute Shrinkage and Selection Operator (LASSO) regression, Support Vector Machine Recursive Feature Elimination (SVM-RFE), and RandomForest combined with eXtreme Gradient Boosting (XGBoost) - we identified four hub genes, with JUN emerging as a core regulator. JUN demonstrated strong associations with both BBB integrity and microglial activation in ASD pathogenesis. Using a maternal immune activation (MIA) mouse model of ASD, we observed significant downregulation of cortical tight junction proteins ZO-1 and occludin, confirmed through immunofluorescence and qPCR analysis. Bioinformatics analysis revealed a close correlation between JUN and IL-6/MMP-9 signaling in ASD-associated microglial activation. These findings were validated in vivo, with immunofluorescence and qPCR demonstrating elevated IL-6 and MMP-9 expression in ASD mice. Pharmacological intervention using ventricular JNK inhibitor administration effectively downregulated JUN and MMP-9 expression. In vitro studies using IL-6-stimulated BV-2 microglial cells replicated these findings, showing JNK inhibitor-mediated suppression of JUN and MMP-9 upregulation. These results collectively identify the IL-6/JUN/MMP-9 pathway as a specific mediator of barrier dysfunction in ASD, representing a promising target for personalized therapeutic interventions.

关键词： allogeneic hematopoietic stem cell transplantation   acute graft-versus-host disease   cytokines   diagnosis   therapeutic efficacy  

摘要： Objectives To investigate the correlation between cytokines at different time points after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the onset, severity, and therapeutic efficacy of acute graft-versus-host disease (aGVHD).Methods We performed a retrospective analysis of patients who underwent allo-HSCT from January 2019 to December 2021. Patients were divided into a training (first two years) and validation cohort (third year). Serum cytokines levels (TNF-alpha, IL-2, IL-4, IL-6, IL-10) on days +7, +14, +21, and +28 were measured and compared between patients developed aGVHD and those did not. Clinical characteristics were analyzed. Training cohort results were verified in the validation cohort to identify potential predictive markers for *** The training cohort included 89 patients who underwent allo-HSCT, in which 29 patients developed aGVHD. Forty patients were enrolled in the validation cohort and 17 patients suffered aGVHD. Significant differences were observed in the doses of infused CD34+ and mononuclear cells between the two cohorts, whereas other baseline clinical characteristics were comparable. In the training set, the ratio of IL-2/IL-4 >= 1.103 on day +7 associated with an 8.87-fold increased risk of aGVHD. After excluding sepsis and engraftment syndrome cases, the IL-2/IL-4 ratio on day +7 remained associated with aGVHD. Under these conditions, IL-2/IL-4 >= 0.989 on day +7 suggested a 5.875-fold increased aGVHD risk. The validation set confirmed IL-2/IL-4 as an early and reliable aGVHD indicator. Among the 29 patients with aGVHD in the training set, 17 had grade I and 12 had grade II-IV aGVHD. TNF-alpha (day +7) and IL-2 (day +28) significantly increased in grade I aGVHD. After excluding sepsis and ES cases, 19 had aGVHD (12 grade I and 7 grade II-IV aGVHD). No cytokine was significantly associated with aGVHD severity. Twenty-two of 29 patients received corticosteroids as first-line treatment;the complete remission (C

关键词： Axial spondylarthritis   Lifestyle   Smoking   Alcohol   Body mass index  

摘要： ObjectivesTo quantify the influence of lifestyle factors on tumour necrosis factor inhibitor (TNFi) treatment response, in axial spondyloarthritis (axSpA).MethodsData on biologics-na & iuml;ve adults with axSpA were captured from European rheumatology registries. Information on lifestyle factors (smoking, overweight/obesity, and/or alcohol consumption) were identified +/- 30 days of commencing their first TNFi. Treatment response (BASDAI-50, ASDAS or ASAS response criteria) was determined at 3 and 12 months. In separate models, the relationship between treatment response and baseline smoking, BMI and alcohol was assessed using logistic regression, adjusted for age, sex, country, calendar year of treatment initiation, disease duration and baseline disease *** 14 registries, 14,885 patients were included. Of those with available data, 29% were current smokers, 49% current drinkers, 37% were overweight and 21% were obese. At 12 months, smokers were less likely to achieve BASDAI-50 treatment response compared to non-smokers (adjusted odds ratio: 0.77;95%CI: 0.68-0.86). A similar effect was observed among overweight (0.76;0.66-0.87) or obese patients (0.53;0.45-0.63). In contrast, alcohol drinkers experienced a seemingly beneficial effect (1.47;1.16-1.87). These associations were also observed with other measures of treatment response and were robust to further adjustment for clinical *** and high BMI decrease the odds of bDMARD treatment success in axSpA. Rheumatologists should consider referral to smoking cessation and/or weight management interventions at the time of commencing therapy, to enhance treatment response. The relationship between alcohol and treatment response is unlikely to be causal and warrants further investigation. What is already known about this subject?It has been shown that adverse lifestyle factors (smoking, high body mass index, alcohol consumption) are associated with poorer outcomes in axial spond

关键词： HAIC   免疫治疗   超敏反应   风险预测模型构建   分层护理策略  

摘要： 探讨肝动脉灌注化疗(HAIC)联合免疫治疗患者发生超敏反应的危险因素,构建风险预测模型,并制定分层护理策略,以优化临床干预措施。方法 回顾性分析2022年1月至2023年6月收治的80例接受HAIC联合免疫治疗患者的临床资料。根据患者是否发生超敏反应对患者进行分组,发生超敏反应的患者为病例组,未发生超敏反应的患者为对照组。先通过单因素分析筛选超敏反应相关因素,再对显著变量(P<0.05)进行多因素Logistic回归,确定独立危险因素并建立预测模型。利用ROC曲线评估模型效能,并根据风险评分实施分层护理。结果 过敏史、多药联用及高IgE是超敏反应的独立危险因素。基于此建立的预测模型AUC为0.89,效能良好。对比研究证实,应用模型后超敏反应发生率显著降低。结论 既往过敏史、联合用药≥3种及血清IgE升高是HAIC联合免疫治疗患者发生超敏反应的独立预测因素。基于此构建的风险预测模型具有良好区分度,结合分层护理可有效降低超敏反应发生率,为临床个体化管理提供依据。

关键词： IDO-1   IFN-gamma   SPRi   bladder cancer  

摘要： Indoleamine 2,3-dioxygenase 1 (IDO-1) and interferon-gamma (IFN-gamma) are proteins that play a significant role in inflammatory conditions and tumor development. The detection of IDO1 and IFN-gamma is crucial for understanding their interplay in immune responses. This study introduced a novel method for the simultaneous quantitative determination of IDO-1 and IFN-gamma in different biological samples/materials. The method is based on an optical biosensor, with surface plasmon resonance detection carried out by the imaging version of the sensor (SPRi). Biotinylated antibodies immobilized on the surfaces of the linker and carboxymethylated dextran served as the recognition elements for the developed biosensor. Relevant studies were conducted to optimize the activities of the biosensor by employing appropriate reagent concentrations. Validation was performed for each protein separately;low detection and quantification limits were obtained (for IDO-1 LOD = 0.27 ng/mL, LOQ = 0.81 ng/mL;for IFN-gamma LOD = 1.76 pg/mL and LOQ = 5.29 pg/mL). The sensor operating ranges were 0.001-10 ng/mL for IDO-1 and 0.1-1000 pg/mL for IFN-gamma. The constructed biosensor demonstrated its sensitivity and precision when the appropriate analytical parameters were determined, based on the proposed method. It can also selectively capture IDO-1 and IFN-gamma from a large sample matrix. The biosensor efficiency was confirmed by the determination of IDO-1 and IFN-gamma in simultaneous measurements of the plasma and urine samples of patients diagnosed with bladder cancer and the control group. The outcomes were compared to those obtained using a certified ELISA test, demonstrating convergence between the two methodologies. The preliminary findings demonstrate the biosensor's efficacy and suitability for comprehensive analyses of the examined biological samples.