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关键词： Artemisia annua   Allergic rhinitis   IL-17A   Sublingual immunotherapy (SLIT)  

摘要： The mechanisms underlying immune tolerance induction during sublingual immunotherapy (SLIT) of seasonal allergic rhinitis (SAR) remain insufficiently understood. This study aimed to investigate the molecular and immunological process involved in SLIT. RNA sequencing (RNA-seq) and bioinformatics analyses were performed to examine the functions of differentially expressed genes (DEGs) in leukocytes from 11 SAR patients at three time points: baseline, peak pollen phase (PPP), and end-of-treatment. Patients received a 4-month SLIT course with Artemisia annua (A. annua) extract (n = 5) or placebo (n = 6). Plasma cytokine levels were measured in a validation cohort of 15 SAR patients (9 in the SLIT group and 6 in the placebo group) using Luminex assays. The results showed that A. annua SLIT inhibited the upregulation of IL-17A-associated pathways and the expression of inflammatory mediators, including CXCL1, CCL7, and PLPP3, while enhancing myeloid immune cell function by increasing the expression of CD36, TYROBP, FCGR1A, and FCER1G. Additionally, A. annua SLIT reactivated myeloid immune cell-associated genes that were downregulated during PPP and significantly reduced IL-17A and GRO-β levels in plasma, compared to the placebo group. These findings suggest that A. annua SLIT alleviates SAR by modulating IL-17A pathways, reducing inflammatory responses, and enhancing myeloid immune cell function.

关键词： Spinal cord injury   PRP-Derived exosomes   Cerebrolysin   Drug delivery   Target therapy  

摘要： Context/objectiveSpinal cord injury (SCI) is a severe condition characterized by neuronal apoptosis and inflammation, with limited therapeutic options. This study aimed to assess the effects of platelet-rich plasma (PRP)-derived exosomes (Exo), Cerebrolysin (CBL), and Cerebrolysin-loaded exosomes (CLE) on inflammation, apoptosis, tissue organization, and motor function recovery in a mouse model of compression *** experimental study using a mouse model of SCI, investigating the effects of Exo, CBL, and CLE ***-based research in a controlled *** healthy adult female BALB/c mice, aged 8-10 weeks, weighing 24 +/- 2 g were used. SCI was induced via compression to model *** with induced SCI were treated with Exo, CBL, or CLE. Apoptosis was assessed by Bax and Bcl2 expression. Inflammatory markers TNF-alpha and IL-10 were measured. Histological analysis examined tissue organization, and motor function recovery was evaluated using the Basso-Beattie-Bresnahan (BBB) locomotor *** measuresThe study measured Bax and Bcl2 expression, TNF-alpha and IL-10 levels, tissue organization, and motor function *** treatment significantly modulated Bax and Bcl2 expression, reducing apoptosis and enhancing neuronal survival. TNF-alpha levels decreased, indicating reduced inflammation, while IL-10 levels increased, showing anti-inflammatory effects. Histological assessment revealed improved tissue organization, and motor function recovery was significantly enhanced as measured by BBB *** showed neuroprotective and anti-inflammatory effects, reducing apoptosis and inflammation while promoting tissue repair and motor function recovery in SCI, making it a promising therapeutic candidate.

关键词： Airflow limitation   Biomarker   Exacerbation   FEV   1   Neutrophilic inflammation   ACO   Asthma-COPD overlap   ACT   Asthma control test   ATS   American Thoracic Society   CAT   COPD assessment test   COPD   Chronic obstructive pulmonary disease   CRP   C-reactive protein   ERS   European Respiratory Society   FeNO   Fractional exhaled nitric oxide   FEV   1   Forced expiratory volume in 1 second   FVC   Forced vital capacity   GINA   Global Initiative for Asthma   GOLD   Global Initiative for Chronic Obstructive Lung Disease   HRCT   High-resolution computed tomography   IgE   Total immunoglobulin E   IL   Interleukin   IQR   Interquartile range   JRS   Japanese Respiratory Society   mMRC   Modified Medical Research Council   ROC   Receiver operating characteristic   YKL-40   Chitinase-3-like-1 protein  

摘要： Background Chitinase-3-like protein 1 (YKL-40) has been reported as a biomarker of neutrophilic airway inflammation in obstructive airway disorders. However, the pathophysiological features of YKL-40 remain unclear. The aim of the study is to evaluate the associations between YKL-40 and clinical features in patients with asthma, chronic obstructive pulmonary disease (COPD), or asthma-COPD overlap (ACO). Methods Serum and sputum YKL-40 levels were measured in 46 asthmatics, 35 COPD, and 32 ACO patients. Results Serum YKL-40 levels were elevated in the COPD and ACO patients, and sputum YKL-40 levels were higher in the COPD patients compared to the asthmatics. Both serum and sputum YKL-40 levels positively correlated with sputum neutrophils. Only serum YKL-40 levels negatively correlated with FEV 1 (%predicted), FEV 1 /FVC, and annual decline in FEV 1 . In 15 patients whose paired serum samples were obtained within 6 months, changes in serum YKL-40 levels showed a significant positive correlation with those in FEV 1 . Furthermore, patients who had experienced exacerbations either in the past year or the following year showed significantly greater serum, but not sputum, YKL-40 levels. Sputum YKL-40 levels showed significant correlations with scores on the COPD assessment test and modified Medical Research Council dyspnea scale. Conclusions Serum and sputum YKL-40 may reflect distinct clinical features in obstructive airway disorders. Serum YKL-40 may provide beneficial information on predicting obstructive neutrophilic inflammation and exacerbations, whilst sputum YKL-40 may offer valuable insights for evaluating ongoing symptoms. Concomitant measurement of YKL-40 in serum and sputum might be more useful than individual measurement.

关键词： A型口蹄疫病毒   VP1基因   单克隆抗体   cELISA检测方法   血清型特异性  

摘要： 旨在解决传统口蹄疫病毒（FMDV）多克隆抗体ELISA检测中存在的非特异性反应问题，开发针对中国和东南亚地区流行的A型FMDV SEA-97拓扑型毒株的高特异性单克隆抗体的制备与检测方法。通过基于亚洲流行的A型FMDV SEA-97拓扑型毒株的VP1基因，构建重组表达质粒，用原核系统高效表达并纯化VP1蛋白。采用三步筛选策略（间接ELISA初筛、竞争ELISA验证、血清型特异性鉴定），从免疫的BALB/c小鼠中筛选出稳定分泌A型FMDV特异性单克隆抗体的杂交瘤细胞系（10H2-F2），亚型鉴定为IgG1/κ。建立基于单克隆抗体的竞争ELISA，优化抗原包被条件，显著提升检测性能。与O型FMDV及其他9种偶蹄动物病原体（如猪瘟病毒、猪繁殖和呼吸综合征病毒、猪细小病毒、猪圆环病毒、伪狂犬病病毒、蓝舌病病毒、牛病毒性腹泻病毒、羊痘病毒、赤羽病病毒）无交叉反应（抑制率≤22%）；可检测A型FMDV阳性血清256倍稀释样本，较现有方法提升2倍；与血清中和试验的总符合率达97.3%（Kappa=0.945 2）；单克隆抗体在4℃和－20℃保存6个月后抑制率变异系数<0.3%，批间重复性优异（F=0.2，P>0.8）。所以，建立的竞争ELISA方法具有高度特异性、敏感性及稳定性，为亚洲地区A型FMDV抗体精准检测、疫苗免疫效果评估及疫情监测提供了可靠技术支撑，填补了针对区域性流行毒株的特异性诊断工具的空白。

关键词： Melanoma   Bispecific T cell engager - BiTE   Immunotherapy  

摘要： Background Melanoma is a highly aggressive skin cancer, especially in advanced stages. While current treatments such as targeted therapies and immunotherapies have made significant progress, challenges like drug resistance and limited effectiveness in some patients persist. Therefore, ongoing development of novel therapies, particularly for late-stage melanoma, is *** In this study, we explored the expression of interleukin-13 receptor subunit alpha-2 (IL13R alpha 2) in melanoma patient-derived xenograft models. We investigated IL13R alpha 2 as a potential target for melanoma treatment by employing an IL13R alpha 2-CD3 bispecific T-cell engager (BTE). We tested the effect of IL13R alpha 2-CD3 BTE on T cell activity by flow cytometry. We studied the potency of IL13R alpha 2-CD3 BTE in tumor killing assay in vitro. For in vivo studies, we administered DNA expression cassettes encoding IL13R alpha 2-CD3 BTE (IL13R alpha 2-CD3 DNA encoding BTE (dBTE)) into immunodeficient mice for direct in vivo expression. The mice were challenged with A375 cells and then treated with IL-13R alpha 2-CD3 dBTE versus control and reconstituted with human peripheral blood mononuclear cells (PBMCs) or T cells. Tumor development was monitored, and T cell infiltration in the tumor was analyzed throughflow *** Our findings revealed heterogeneous expression of IL-13R alpha 2, particularly in samples from advanced stages of melanoma. The IL13R alpha 2-CD3 BTE facilitated T-cell activation and proliferation by bridging melanoma cells and T cells. We also observed the ability of IL13R alpha 2-CD3 BTE to direct T cells to kill multiple melanoma patient-derived cell lines through xCELLigence assay in vitro, including those with various mutations associated with late-stage metastatic melanoma. IL13R alpha 2-CD3 dBTE expressed in vivo led to notable tumor regression through inducing increased T-cell infiltration and activation within the tumor *** The

关键词： IFNγ ELISpot   SCAR   cotrimoxazole   oral challenge   patch test  

摘要： Background (268 words) Cotrimoxazole is a broad-spectrum antibiotic associated with severe cutaneous adverse drug reactions (SCARs). In persons living with HIV (PLWH), cotrimoxazole is typically used in combination with other SCAR-associated medications creating challenges for culprit drug ascertainment. Objective To investigate the utility of IFNγ release Enzyme-linked immunosorbent spot (ELISpot) in identifying cotrimoxazole as the culprit drug in SCAR. Methods RegiSCAR-validated SCAR cases from the prospective AFRISCAR patient registry with Naranjo and/or ALDEN causality scores completed were eligible. Diagnostic assessments included cotrimoxazole patch testing, IFNγ ELISpot and oral challenge. ELISpot was performed on cryopreserved PBMCs using validated concentrations of cotrimoxazole (TMP/SMX), its metabolite 4-nitroso-sulfamethoxazole (4-NIT) and sulfamethoxazole (SMX). Results Cotrimoxazole was the probable culprit in 79 SCAR cases (55 drug reaction with eosinophilia and systemic symptoms (DRESS);10 Stevens-Johnson syndrome/ toxic epidermal necrolysis (SJS/TEN) ;14 generalized bullous fixed drug eruption (GBFDE)) based on clinical drug causality assessment. Mean (SD) age was 39 (11) years, and 90% were PLWH [median (IQR) CD4 count of 77 (25-142)]. Eighteen (25%) of 73 IFNγ ELISpots were positive of which 9 (50%) reacted only to 4-NIT. Patch tests were all negative including 3/13 with IFNγ ELISpot and 4/13 with oral challenge positivity. IFNγ ELISpot positivity was similar in SJS/TEN (25%) and DRESS (26%), and no test was positive on samples older than 90 days from SCAR onset. IFNγ ELISpot sensitivity and specificity was 38% (95% CI: 9-76) and 100% (95% CI: 40-100) using a cut-off point of SFU/million ≥50 respectively. Conclusion Cotrimoxazole IFNγ ELISpot had overall low but superior sensitivity to patch testing offering good rule-in utility. Ongoing optimization of in vivo and in vitro diagnostic tools for cotrimoxazole SCAR is still required.

关键词： High-throughput computational screening   HTCS   Machine learning (ML)   Covalent organic frameworks   H 2 storage   Ionic liquids  

摘要： Designing efficient adsorbent materials for hydrogen storage was highly desired because of the development of the hydrogen economy. Incorporation of ionic liquids (ILs) to COFs was an effective way to improve the performance of COF materials for gas storage and separation. In this work, a combination of high-throughput computational screening (HTCS) and machine learning (ML) were adopted to explore the potential of the IL/ COF composites for H2 storage. Based on HTCS, the H2 adsorption capacity and the structural properties of IL/ COF composites were assessed. Notably, these results revealed that the incorporation of ILs into COFs significantly improves H2 adsorption capacity and [MMIM][Cl]@JUC-564 was identified as a promising H2 storage material, which exhibits the highest H2 adsorption capacity of 51.5 mmol/g (10.3 wt%) at 298 K and 100 bar, outperforming COFs and MOFs reported in the literature. Furthermore, from a comparison of four ML algorithms (decision tree (DT), random forest (RF), categorical boosting (CatBoost) and extreme gradient boosting (XGBoost)), it was found that the CatBoost model has superior accuracy in predicting the H2 adsorption capacity. According to the feature engineering of the CatBoost model, it was shown that the accessible volume (Vpore), free volume (VF) and pore crystal density (rho) of IL/COFs were the key features that affect the H2 adsorption property. The findings of this study will provide more powerful support for the design and synthesis of IL/COFs new composite materials.

关键词： drug hypersensitivity reactions   abacavir   Treg   type-I IFN   T-cell   HLA   immune tolerance   innate immunity  

摘要： Introduction Clinical use of several small molecule drugs may lead to severe T-cell-mediated idiosyncratic drug hypersensitivity reactions (iDHR) linked to HLA alleles, including abacavir (ABC) with HLA-B*57:01. Due to study limitations in humans, pathogenic networks in iDHR remain elusive. HLA transgenic murine models have been proposed to bridge knowledge gaps in tolerance and susceptibility to *** Mice expressing HLA-B*57:01 and Foxp3-DTR/EGFP were generated to selectively deplete regulatory T-cells (Treg) with diphtheria toxin. ABC was administered for 8 days alone or together with cell- and cytokine-depleting antibodies. Cellular and transcriptomic responses were analyzed by RNA, flow cytometry and fluorescence *** While CD8+ T-cell responses to ABC require HLA presentation, ABC also triggered mitochondrial stress in macrophages in vitro, independently of HLA. In vivo, Treg were the primary mechanism of drug tolerance controlling HLA presentation and costimulation by antigen presenting cells. Treg ablation uncovered immune adverse events linked to activation and proliferation of both drug-specific and bystander CD8+ T-cells through CD28-mediated pathways with support from CD4+ non-Treg. Type-I interferon (IFN-I) and cellular-stress pathways influenced the fate of lymph node cells responding to ABC, implicating innate immune cells such as macrophages and plasmacytoid dendritic cells in the development of T-cell responses against the drug. IFN-I and IL-2 were necessary for CD8+ T-cell differentiation and ABC-induced adverse *** This study unveils novel immune mechanisms driven by drug and host-related factors required for in vivo reactions and sheds light on potential biomarker and therapeutic targets for managing and preventing severe and life-threatening iDHR.

关键词： 胰腺炎   肠内营养   炎症   胃肠道微生物组   时间因素   细胞因子   菌群失调   随机对照试验  

摘要： 目的 探究早期肠内营养（EEN）对急性胰腺炎（AP）患者的炎症反应和肠道菌群的影响。方法 选择2023年1月至2024年9月的180例AP患者，根据随机表法分为观察组A与观察组B，每组90例；给予两者常规治疗外，另外48 h内给予观察组A肠内营养治疗，24 h内给予观察组B肠内营养治疗；比较两者治疗前后血清炎性因子IL-1β、IL-6、TNF-α水平变化以及肠道菌群大肠杆菌、肠球菌、产气荚膜梭菌、乳酸杆菌以及拟杆菌的变化。结果 与48 h内启动肠内营养相比，24 h内启动肠内营养可显著降低AP患者血清IL-1β、IL-6、TNF-α水平（P＜0.05），并有效减少大肠杆菌、肠球菌及产气荚膜梭菌丰度，同时增加乳酸杆菌与拟杆菌丰度（P＜0.05）。结果表明，较早启动肠内营养具有更优的抗炎和肠道菌群调节效果。结论 EEN可以有效治疗AP，降低患者血清炎性因子IL-1β、IL-6、TNF-α和肠道菌群中的不良菌群，提高肠道菌群中的益生菌，且时间越早，效果越好。