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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.

摘要： Conventional mRNA cancer vaccines can expand the quantity of tumor-specific CD8 T cells, but their effector function might be compromised. Specific cytokine signaling may enhance T cell differentiation for better tumor killing. We screened various cytokines and identified IL-12 as a potent adjuvant for mRNA vaccines, though with significant systemic toxicity. To balance efficacy and toxicity, we developed a membrane-tethered IL-12 (mtIL12) adjuvant mRNA vaccine. This design restricts mtIL12 expression to the surface of antigen-presenting cells, thereby selectively activating antigen-specific T cells without affecting bystander T or NK cells. mtIL12 adjuvant mRNA vaccination induced a unique pre-effector T cell subset that gives rise to highly responsive effector T cells, resulting in superior anti-tumor activity. Moreover, this approach overcame immune checkpoint therapy resistance and prevented cancer metastasis. Our study highlights that next-generation mRNA vaccines encoding membrane-tethered cytokine adjuvants can generate potent effector T cells, offering effective tumor control with reduced toxicity.

关键词： 显齿蛇葡萄   免疫功能   细胞免疫   体液免疫   单核-巨噬细胞功能  

摘要： 为了研究显齿蛇葡萄叶水提物对正常小鼠免疫功能的影响，制备显齿蛇葡萄叶的水提物，将96只小鼠分为三个大组，第一组测定脏器/体重比值、迟发型变态反应和半数溶血值；第二组测定碳廓清实验的吞噬指数；第三组测定NK细胞活性。以上大组再分为四个小组：每组8只，正常对照组、显齿蛇葡萄叶水提物低剂量组（0.5 g/kg/day）、中剂量组（1.0 g/kg/day）和高剂量组（2.0 g/kg/day），分别灌胃给药30 d。结果显示，迟发型变态反应和NK细胞活性两个实验组结果均呈阳性；与正常对照组比较，迟发型变态反应实验的中剂量组和高剂量组小鼠的足趾肿胀度均显著增加。NK细胞活性组与正常对照组比较，三个剂量组小鼠的NK细胞活性均显著升高。由此推断显齿蛇葡萄叶水提物具有增强正常小鼠免疫的功效。

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。

关键词： Colorectal cancer   Explosive tumor growth   Lynch syndrome   Immunotherapy  

摘要： BackgroundExplosive tumor growth is characterized by rapid tumor growth in a short time period. Currently, there is no precise scientific definition for the condition, which is often accompanied with a poor clinical prognosis. Herein, we presented a study of a young patient with colon cancer who experienced explosive tumor growth. A clinical multidisciplinary team (MDT) collaborated with bioinformaticians to provide precise treatment and elucidate the biological mechanisms underpinning this *** 28-year-old male patient diagnosed with colon cancer experienced explosive tumor growth. Peripheral bloods (PB) during immunotherapy were collected for immune cytokine analyses and flow cytometry assays on immune cell subsets. To further examine the underlying mechanisms of this explosive-growth, we conducted whole exome sequencing (WES) and RNA-sequencing (RNA-seq) of samples taken at different time *** patient was diagnosed with Lynch syndrome. We implemented an immunotherapy and performed PB immune cytokine assays before, during, and after this therapy. Our observations suggested that immunotherapy may remodel interferon-gamma (IFN-gamma) signaling and enhance T cell-mediated immune responses. By exploring explosive tumor growth mechanisms, we observed that tumors had significantly less insertion and deletion (INDEL) mutations and INDEL-derived neoantigens. Additionally, they had deficient antigen presentation functions as characterized by decreased IFN-gamma signaling *** loss and decreased IFN-gamma signaling activity contributed to explosive tumor growth in this patient. Recovered IFN-gamma signaling may lead to effective immunotherapy outcomes.

摘要： The contribution of interleukin-10 (IL-10), secreted by tumoral B cells, to the progression and shaping of the microenvironment in diffuse large B-cell lymphoma (DLBCL) with activated B-cell-like (ABC) phenotype is not yet completely understood. To shed light on this issue, we generated an immunocompetent mouse model of ABC-DLBCL with conditional knockout of IL-10 specifically in malignant B cells. Paradoxically, these mice had significantly worse overall survival when left untreated but experienced increased sensitivity to conventional anti-CD20 immunotherapy or regulatory T-cell depletion. We identified various immunomodulatory mechanisms involved in this behavior. In particular, we show that IL-10-deficient lymphomas acquire a highly immunosuppressed and T-cell-exhausted microenvironment with increased angiogenesis that results in a more aggressive phenotype, which is refractory to PD-1 immune checkpoint blockade. However, the response of IL-10-deficient mice to anti-CD20 immunotherapy was greatly enhanced by upregulation of calcium channels in B cells. In general, IL-10 autocrine signaling promotes the survival of malignant B cells, whereas the paracrine action of B-cell-derived IL-10 maintains an immunoreactive microenvironment that influences the efficacy of emerging immunotherapy strategies targeting the lymphoma microenvironment. Furthermore, IL-10-associated transcriptional signatures derived from our studies may correctly predict clinical outcomes of patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Thus, our work provides important functional and mechanistic insights into the role of B-cell-derived IL-10 in the biology of ABC-DLBCL.

关键词： Fentanyl   Overdose deaths   COVID-19   Spatiotemporal analysis   Chicago  

摘要： Overdose deaths involving fentanyl represent a major public health crisis in the USA. This study investigates the spatiotemporal dynamics of fentanyl-involved deaths before, during, and after the COVID-19 pandemic and examines how sociodemographic factors influence these deaths across geographic regions. Using a retrospective ecological approach, we analyzed data on ZIP code-level fentanyl-related deaths in Cook County, IL, between 2018 and 2023, obtained from the Medical Examiner's Office and linked with sociodemographic data from the American Community Survey. We first mapped area-level death rates to assess their distribution and then conducted global and local clustering analyses to identify spatial autocorrelations and the locations of high- or low-death-rate areas. A geographically weighted Poisson regression (GWPR) model evaluated the associations between area-level fentanyl-related death rates and the area-level proportion of young adults, males, and individuals with at least a college degree, disability rate, and poverty rate. Spatial analyses found stronger spatial autocorrelations during (2020-2021) and after (2022-2023) the pandemic. Initially, high death rates were concentrated in the downtown area of Chicago, and they expanded to the surrounding areas during and after the pandemic. The GWPR model revealed that an increase in the area-level proportions of poverty, disability, and young adult residents increased the fentanyl-related death rates in most of the areas. Our findings highlight the urgent need to address the evolving dynamics of fentanyl-related overdoses through tailored public health interventions that account for the unique socioeconomic determinants of different regions. Importantly, a comprehensive approach to addressing differences in overdose death rates and their risk factors will be crucial to mitigating this public health crisis.

关键词： PUE   Chemotaxis   Macrophages   CD4(+)T cells   EAM  

摘要： Autoimmune myocarditis can result in dilated cardiomyopathy and heart failure, but effective drugs and clear therapeutic targets are still lacking. Experimental autoimmune myocarditis (EAM) serves as the primary animal model utilized for investigating human myocarditis. Puerarin (PUE), a compound derived from the root of Pueraria lobata, exhibits a broad spectrum of antioxidant and anti-inflammatory effects;nevertheless, its underlying mechanism remains elusive. The findings of this study suggested that PUE may attenuate the infiltration of inflammatory cells into the cardiac tissue by suppressing the secretion of chemokine CCL2 from endothelial cells and macrophages at the site of injury, as well as inhibiting the interaction between CCR2 and CCL2 in recruited inflammatory cells such as macrophages and Th1 cells. In this study, the focus was on investigating the impact of PUE on the chemotactic signal axis TNF-alpha/CCL2/CCR2. Through the utilization of Small Animal Ultrasound, Real-Time quantitative PCR, Co-Immunoprecipitation (Co-IP), and Immunofluorescence techniques on both cellular and animal models, it has been demonstrated that PUE effectively inhibits the production of CCL2 by disrupting the TNF-alpha/TNFR signaling pathway in macrophages and endothelial cells through its binding affinity with TNF-alpha. Additionally, PUE disrupts the transmission of chemotactic signals mediated by CCL2/CCR2 interaction through its binding to *** ultimately leads to a reduction in the infiltration of inflammatory cells into the heart. Moreover, the study highlights that PUE can effectively inhibit the transduction of the TNF alpha/CCL2/CCR2 chemotactic signal, resulting in decreased infiltration of macrophages and Th1 cells in the heart and subsequently reducing inflammatory damage to myocardial tissue in EAM mice.