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摘要： Importance:Carriage of HLA-B*58:01 has been shown to have a strong association with the development of allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) and drug reaction and eosinophilia and systemic symptoms (DRESS) in many populations globally; however, there is a critical need to determine if this is generalizable to varying populations including those in the United States (US). Objective:To perform HLA class I and II association studies in a cohort of US patients diagnosed with allopurinol-induced SJS/TEN or DRESS compared to allopurinol tolerant and population controls. Design Setting and Participants:We enrolled consenting individuals who had specialist adjudicated allopurinol-induced SJS/TEN or DRESS (collectively allopurinol-SCAR). HLA carriage in these cases was compared to allopurinol tolerant and population controls identified through Vanderbilt University Medical Center (VUMC) BioVU, a biobank which includes 94,489 individuals with imputed human leukocyte antigen (HLA) class I and II typing from genotyping array data. Main Outcomes and Measures:We performed HLA class I and II conditional logistic regression case-control analyses between allopurinol-SCAR cases and both population controls and allopurinol tolerant controls matched on age, sex, and self-identified race. We reported odds ratio (OR) and 95% confidence interval (CI) with Bonferroni corrected ( ) <.05. Results:The conditional logistic regression analyses included allopurinol-SCAR cases (n=16) and 10:1 matched allopurinol tolerant controls (n=160). We found two HLA class I alleles independently associated with increased risk of allopurinol-induced SCAR: HLA-B*58:01 (OR 28 [95% CI, 8.6 - 100.6]) and HLA-A*34:02 (OR 20.6 [95% CI, 3.3 - 131.1]). We did not identify any HLA class II alleles meeting the Pc level of significance. Conclusions and Relevance:We found HLA-B*58:01 to be strongly associated with allopurinol-induced SCAR, generalizing findings from prev

摘要： Intratumoral immunotherapy (ITIT) strives to generate effective antitumor immunity by directly stimulating the immune system in tumors to reverse local tumor-mediated immune suppression. expression of Interleukin-12 (IL-12) using plasmid transfection as an intratumoral cancer immunotherapy entered Phase II clinical trials for metastatic melanoma but to limited clinical success. We sought to improve the efficacy of IL-12 electroporation by the addition of a CD154 (CD40 ligand)- expressing plasmid to the IL-12 encoding plasmid treatment and assessing efficacy against solid tumors. Mice with intradermal B16F10 melanoma or MC38 murine colon carcinoma tumors received 2 weekly intratumoral (IT) injections of plasmids encoding IL-12 and CD154, followed by electroporation. The addition of CD154 to IL-12 was superior to IL-12 alone and resulted in frequent tumor clearance of treated tumors, marked by an increase in CD8 T cells and a drastic reduction in T regulatory cells in the tumor microenvironment. Tumor treatment responses were abrogated in mice which lack conventional DC1 cells (BatF3 KO) or lack CD8 T cells. These findings highlight the potential of adding CD154 to IL-12 plasmid electroporation as a cancer immunotherapy and suggest that other combinations would be therapeutically valuable.

关键词： 心肌梗死   心力衰竭   参蛤散   纤维化   赖氨酰氧化酶样蛋白2/转化生长因子β1/IL-11信号通路   SD大鼠  

摘要： 目的:基于赖氨酰氧化酶样蛋白2(LOXL2)/转化生长因子β1(TGF-β1)/IL-11信号通路探讨参蛤散对心肌梗死后心力衰竭大鼠心肌纤维化的影响.方法:将SD大鼠分为空白对照组、模型对照组、参蛤散小剂量组、参蛤散大剂量组、阳性对照组、参蛤散大剂量+LOXL2激活剂组,每组12只.除空白对照组外,其他组均通过冠状动脉缩窄法构建心肌梗死后心力衰竭模型.建模成功后立即给药,1次/d,持续4周.彩色多普勒超声显像仪检测大鼠左心室短轴缩短率(LVFS)和左心室射血分数(LVEF);酶联免疫吸附试验分析血清中IL-1β和IL-6水平;Masson染色评估大鼠心肌胶原容积分数(CVF);免疫组织化学染色检测心肌组织中Ⅰ型胶原蛋白、α平滑肌肌动蛋白(α-SMA)平均光密度值;定量逆转录聚合酶链反应法检测心肌组织中基质金属蛋白酶9(MMP-9)、组织金属蛋白酶抑制物1(TIMP-1)mRNA表达;蛋白质印迹法检测心肌组织中LOXL2、TGF-β1、IL-11蛋白表达.结果:与空白对照组比较,模型对照组LVFS、LVEF降低,血清中IL-6和IL-1β水平升高,CVF、心肌组织中Ⅰ型胶原蛋白、α-SMA平均光密度值、MMP-9和TIMP-1 mRNA表达以及LOXL2、TGF-β1、IL-11蛋白表达均增加(均P＜0.05).与模型对照组比较,参蛤散小剂量组、参蛤散大剂量组、阳性对照组LVFS、LVEF升高,血清中IL-6和IL-1β水平降低,CVF、心肌组织中Ⅰ型胶原蛋白、α-SMA平均光密度值、MMP-9和TIMP-1 mRNA表达以及LOXL2、TGF-β1、IL-11蛋白表达减少(均P＜0.05).LOXL2激活剂可逆转大剂量参蛤散对心肌梗死后心力衰竭大鼠心肌纤维化的改善作用.结论:参蛤散可能通过调控LOXL2/TGF-β1/IL-11通路抑制心肌梗死后心力衰竭大鼠心肌纤维化.

关键词： Idiopathic nephrotic syndrome   scRNA-seq   IFN   PBMCs  

摘要： BackgroundIdiopathic nephrotic syndrome (INS) is a prevalent condition whose recurrence leads to multiple adverse effects. Previous studies on INS pathogenesis primarily focused on immune dysregulation, particularly T-cell changes and their correlation with cytokine shifts. Accumulating evidence suggests that B-cell dysfunction also plays a role. Nevertheless, a comprehensive understanding of the mechanisms and effective treatment strategies remains *** study investigates changes in gene expressions and cellular interactions of immune cells at a single-cell level using peripheral blood mononuclear cells (PBMCs). And subsequently validated through quantitative PCR (qPCR), enzyme-linked immunosorbent assay (ELISA), and flow *** identified seven main clusters using unsupervised clustering of 103,213 high-quality single cells. Through unsupervised clustering, patient-specific T cells (IFI44L + CD4 + T cells) that exhibited a pronounced elevation of interferon-stimulated genes (ISGs) is identified. Activation of ISGs and interferon (IFN)-related pathways are also observed in other clusters. Specifically, this study demonstrates that interferon-gamma (IFN-gamma) plays a crucial role by promoting the interaction between B-cell activating factor (BAFF) and receptors on B cells. This interaction triggers the release of autoantibodies, thereby initiating INS pathogenesis. Furthermore, telitacicept has shown efficacy in treating pediatric patients with frequent relapse NS(FRNS).ConclusionsOverall, our findings underscore the role of interferon and its related pathways in INS pathogenesis, providing novel therapeutic interventions for NS.

摘要： Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by progressive muscle weakness. With the possible exception of a superoxide dismutase (SOD1)-targeting antisense oligonucleotide for patients with ALS caused by a pa...

关键词： Mouth neoplasms   Cancer   Oral cancer   Tongue neoplasms   Lip neoplasms  

摘要： This study aimed to assess the expression of Gata-3 and Il-4 by verifying the presence of Th2 responses in carcinoma lesions under different clinical conditions. Sixty specimens comprising 30 oral tongue squamous cell carcinomas (OTSCCs) and 30 lower lip squamous cell carcinomas (LLSCCs) were randomly selected for the study. Gata-3 was quantified in parenchymal and stromal cells and Il-4 was semi-quantitatively analyzed. The highest Gata-3+ expressions in LLSCC cases were detected in the total parenchyma (p: 0.000), total stroma (p: 0.000), and total parenchyma/stroma (p: 0.000). Concerning Il-4, higher concentrations were detected in the parenchyma (p: 0.000) in LLSCC cases, while higher concentrations were observed in the stroma (p: 0.000) and in the parenchyma/stroma (p: 0.004) in OTSCC cases. Significant associations between Gata-3 and Il-4 were detected according to the OTSCC region in comparison with LLSCC cases. A higher number of immunolabelled cells for Gata-3 was observed in LLSCCs, suggesting greater Gata-3 expression in less aggressive lesions, potentially reducing the likelihood of tumor invasion and metastasis. Furthermore, higher Il-4 expressions were noted in OTSCC stroma, evidencing not only a higher response (Th2) in this tumor microenvironment but also suggesting that the lower amounts of Il-4 detected in LLSCCs may be associated with a neoplastic growth inhibition mechanism. These findings corroborate the more aggressive OTSCC behavior in comparison with LLSCCs and emphasize the important role of this cytokine and its application in the fight against cancer.

关键词： Astilbin   psoriasis   ferroptosis   cGAS-STING pathway   proinflammatory cytokine  

摘要： Psoriasis, a chronic inflammatory skin disorder, is driven by dysregulated immune responses and keratinocyte dysfunction. Here, we explore the therapeutic potential of Astilbin (AST), a flavonoid with potent anti-inflammatory properties, in modulating ferroptosis and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in IL-17-stimulated HaCaT keratinocytes. Our psoriatic cell model recapitulated key pathological features, including hyperproliferation, membrane integrity loss, mitochondrial dysfunction, and heightened oxidative stress, alongside elevated proinflammatory cytokine levels. Ferroptosis-related biomarkers were significantly altered, with increased malondialdehyde (MDA) accumulation, reduced glutathione (GSH) levels, iron overload (Fe2+), and enhanced lipid peroxidation (detected via C11-BODIPY). Mechanistically, mitochondrial damage triggered cytoplasmic leakage of mitochondrial DNA (mtDNA), activating the cGAS-STING pathway, as evidenced by upregulated pathway-associated protein expression. AST intervention effectively mitigated these pathological changes by suppressing ferroptosis and modulating cGAS-STING signaling. These findings reveal a dual-pathway regulatory mechanism, positioning AST as a promising therapeutic candidate for psoriasis. By elucidating the interplay between ferroptosis and the cGAS-STING pathway, this study provides new insights into psoriatic inflammation and offers a rationale for targeting these pathways in therapeutic strategies.

摘要： Background Amyotrophic lateral sclerosis (ALS) is a life-threatening disease characterised by progressive loss of motor neurons with few therapeutic options. The MIROCALS study tested the hypothesis that low-dose interleukin-2 (IL-2LD) improves survival and function in ALS. Methods In this randomised, double-blind, placebo-controlled trial, male and female riluzole-naive participants, with either a possible, laboratory-supported probable, probable, or definite ALS diagnosis (revised El Escorial criteria), aged 18-76 years, with symptom duration of 24 months or fewer, and slow vital capacity of 70% or more, underwent a riluzole-only 12-18 week run-in period before randomisation in a 1:1 ratio to either 2 million international units (MIU) IL-2LD or placebo by subcutaneous injection daily for 5 days every 28 days over 18 months. The primary endpoint was survival at 640 days (21 months). Secondary outcomes included safety, ALS Functional Rating Scale-Revised (ALSFRS-R) score, and biomarker measurements including regulatory T-cells (Tregs), cerebrospinal fluid (CSF)phosphorylated-neurofilament heavy-chain (CSF-pNFH), and plasma and CSF-chemokine ligand 2 (CCL2). The primary endpoint analysis used unadjusted log-rank and Cox's model adjusted analyses using pre-defined prognostic covariates to control for the disease and treatment response heterogeneity. The study was 80% powered to detect a two-fold decrease in the risk of death by the log-rank test in the intention-to-treat (ITT) population, including all randomly allocated participants. MIROCALS is registered with *** (NCT03039673) and is complete. Findings From June 19, 2017, to Oct 16, 2019, 304 participants were screened, of whom 220 (72%) met all criteria for random allocation after the 12-to-18-week run-in period on riluzole. 136 (62%) of participants were male and 84 participants (38%) were female. 25 (11%) of the 220 randomly allocated participants were defined as having possible ALS under El Escor

关键词： Atopic dermatitis   Management   JAK inhibitors   Elderly patients   Abrocitinib   Baricitinib   Upadacitinib  

摘要： Atopic dermatitis (AD) prevalence in elderly patients is increasing. Clinically, elderly AD may present with atypical phenotypes, making the diagnosis difficult. Moreover, treatment challenges arise due to treatment-resistance, comorbidities, polypharmacy, and contraindications to existing therapies. Janus kinase (JAK) inhibitors (abrocitinib, baricitinib, upadacitinib) may offer a valuable alternative. However, their use in elderly populations remains unclear, as older patients are often excluded from clinical trials, and several concerns have been raised about their safety in this category of subjects. This study aimed to evaluate the efficacy and safety of JAK inhibitors in elderly patients with moderate-to-severe AD. A 52-week, multicenter, real-life study was performed enrolling patients aged >= 60 years affected by moderate-to-severe AD undergoing treatment with JAK inhibitors for at least 16 weeks across 16 dermatological centers in Italy. Disease severity was assessed at baseline, week (W) 4, 16, 24, and 52 using the Eczema Area and Severity Index (EASI), Dermatology Life Quality Index (DLQI), and Pruritus-Numerical Rating Scale (P-NRS). Adverse events (AEs) were recorded at each follow-up. A total of 72 patients met the inclusion criteria [abrocitinib: 13 (18.06%);baricitinib: 6 (8.33%);upadacitinib: 53 (73.61%)]. Of these, 72 (100.0%) achieved W16 follow-up with 33 (45.83%) and 26 (36.11%) subjects reaching W24 and W52, respectively. At baseline, mean EASI, DLQI and P-NRS were 21.22 +/- 10.38, 18.21 +/- 7.33, and 7.84 +/- 1.94, respectively. A significant improvement in all scores was observed starting from W4 [EASI: 4.77 +/- 5.07, DLQI: 4.01 +/- 3.98, P-NRS: 1.66 +/- 1.83 (p < 0.0001 for all)], continuing to improve up to W52 [EASI: 0.81 +/- 1.27, DLQI: 0.31 +/- 0.63, P-NRS: 0.42 +/- 1.03;(p < 0.0001 for all)]. No treatment interruptions or modifications for ineffectiveness or AEs were registered. No statistically significant differences in terms of effic

关键词： LL-37   IL-17   Lung   Lipocalin-2   Regnase-1  

摘要： BackgroundLevels of the human cationic antimicrobial host defence peptide LL-37 are enhanced in the lungs during neutrophilic airway inflammation. LL-37 drives Th17 differentiation, and Th17 cells produce IL-17A and IL-17F which form the biologically active heterodimer IL-17A/F. While IL-17 is a critical mediator of neutrophilic airway inflammation, LL-37 exhibits contradictory functions;LL-37 can both promote and mitigate neutrophil recruitment depending on the inflammatory milieu. The impact of LL-37 on IL-17-induced responses in the context of airway inflammation remains largely unknown. Therefore, we examined signaling intermediates and downstream responses mediated by the interplay of IL-17A/F and LL-37 in human bronchial epithelial cells (HBEC). As LL-37 can become citrullinated during airway inflammation, we also examined LL-37-mediated downstream responses compared to that with citrullinated LL-37 (citLL-37) in *** an aptamer-based proteomics approach, we identified proteins that are altered in response to IL-17A/F in HBEC. Proteins enhanced in response to IL-17A/F were primarily neutrophil chemoattractants, including chemokines and proteins associated with neutrophil migration such as lipocalin-2 (LCN-2). We showed that selective depletion of LCN-2 mitigates neutrophil migration, functionally demonstrating LCN-2 as a critical neutrophil chemoattractant. We further demonstrated that LL-37 and citLL-37 selectively suppress IL-17A/F-induced LCN-2 abundance in HBEC. Mechanistic studies revealed that LL-37 and citLL-37 suppresses IL-17 A/F-mediated enhancement of C/EBP beta, a transcription factor required for LCN-2 production. In contrast, LL-37 and citLL-37 enhance the abundance of ribonuclease Regnase-1, which is a negative regulator of IL-17 and LCN-2 in HBEC. In an animal model of allergen-challenged airway inflammation with elevated IL-17A/F and neutrophil elastase in the lungs, we demonstrated that CRAMP (mouse orthologue of LL-37) negativel