课程文献中心 更多>>

关键词： Ovarian ischemia reperfusion   Eplerenone   Aldosterone   Toll like receptor4   Fenofibrate   Peroxisome proliferator activated receptor   alpha  

摘要： Background: The immune system is deeply involved in the pathogenesis of different gynecological disorders including ovarian torsion that commonly occurs during surgical manipulation or within ovarian masses, affecting not only the ovaries, but it has remote effect on different organs particularly cardiac tissue. Early intervention and proper medical treatment are so important to preserve the ovaries and prevent distant organ damage. Accordingly, the aim of this work was to evaluate the possible ameliorative role of eplerenone (EPL) or fenofibrate (FEN) on ovarian and cardiac affection in an experimental model of ovarian ischemia/reperfusion (OIR). Method: Fifty female Wistar albino rats were divided into five groups (n = 10);control, OIR induced group, OIR plus EPL (100 mg/kg), OIR plus FEN (300 mg/kg), OIR plus EPL (100 mg/kg) plus FEN (300 mg/kg). Results: OIR could induce ovarian injury with remote cardiac damage. Data of current study revealed significant increases of the cardiac enzymes, and malondialdehyde (MDA) levels but decreases of total anti-oxidant capacity (TAC) and reduced glutathione (GSH) levels. Moreover, there were increases in toll like receptor 4 (TLR4), myeloid differentiation primary response 88 (MYD88), activation protein 1 (AP1), interleukin 6 (IL-6), nuclear factor kappa b (NF-kappa B) and cleaved caspase-3 with abnormal histological features. However, EPL or FEN co-administration alone or in combination reversed OIR damaging effects by antagonizing aldosterone action by EPL, anti-inflammatory, anti-oxidant, and anti-apoptotic features with modulation of peroxisome proliferator activated receptor alpha (PPAR alpha) by FEN and TLR4/MYD88/ NF-kappa B/AP1/IL-6 pathway. Interestingly, co-administration of both drugs showed more improvement than giving each one alone. Conclusion: EPL and/or FEN had ameliorative properties against OIR induced harmful effects.

关键词： immune checkpoint inhibitor   major histocompatibility complex - MHC   T cell  

摘要： Background Nonsense-mediated messenger RNA decay (NMD) is a highly conserved surveillance system that degrades mRNAs with premature termination codons (PTCs), and regulates the mRNA quantity. Cancer cells hijack NMD to compensate for the imbalanced DNA levels and modulate their antigenicity. We identified the LTO1/YAE1 complex as NMD factors regulating ribosome biogenesis. Our study aimed to investigate their roles in modulating NMD and major histocompatibility complex class I (MHC-I) antigen presentation, which is vital for cancer *** Clustered regularly interspaced short palindromic repeats (CRISPR) and the CRISPR-associated protein 9 (Cas9)-mediated gene knockouts, overexpression, and mutational analysis were used to explore the role of LTO1 and YAE1 in NMD and MHC-I expression across various tumor cell lines, assayed by fluorescent reporter-based assays, fluorescence-activated cell sorting analysis, reverse transcription-quantitative PCR, mRNA decay assay, and polysome profiling. Transcriptomic analyses were used to assess the expression of LTO1/YAE1 and their correlation with MHC-I molecules in human cancers. T cell receptor (TCR)-T cells and tumor cells coculture were employed to monitor the effect of LTO1 and YAE1 loss on T cell activation. Iron chelators were further tested as NMD inhibitors to enhance cancer immunotherapy using in vitro coculture assay and a mouse tumor model for immune checkpoint blockade (ICB) *** We demonstrate that deficiency in LTO1, YAE1, or their downstream target ABCE1 impairs NMD, causes the overexpression of key regulators of MHC-I, including NLR family CARD domain containing 5 (NLRC5), interferon regulatory factor 1 (IRF1), and nuclear factor-kappa B (NF kappa B), which results in enhanced T cell activation and tumor cell killing in TCR-T models. Transcriptomic analyses reveal that the LTO1/YAE1 complex is frequently overexpressed in human cancers, where it negatively regulates MHC-I. Moreover, low d

关键词： 头颅CT   血小板与淋巴细胞比值   D-二聚体   脑卒中   Brunnstrom分期功能训练   康复效果   预测价值  

摘要： 目的 观察头颅CT联合血小板与淋巴细胞比值（PLR）、D-二聚体（D-D）对脑卒中恢复期患者Brunnstrom分期功能训练康复效果的预测价值。方法 选取2023年1月～2024年12月于浙江康复医院行Brunnstrom分期功能训练的脑卒中恢复期患者126例，治疗1月后采用Fugl-Meyer运动功能量表（FMA）评估患者康复效果，并将患者分为效果良好组与效果欠佳组，比较两组患者康复训练前头颅CT检查结果及PLR、D-D水平，采用ROC曲线分析头颅CT联合PLR、D-D对脑卒中恢复期患者Brunnstrom分期功能训练康复效果的预测价值。结果 126例脑卒中恢复期患者行Brunnstrom分期功能训练后，79例（62.70%）患者康复效果良好，FMA评分为49.91±1.02分，47例（37.30%）患者康复效果欠佳，FMA评分为43.57±1.13分。效果欠佳组患者头颅CT异常比例及PLR、D-D水平高于效果良好组（P<0.05）。多因素logistic回归分析显示，头颅CT结果、PLR及D-D是脑卒中恢复期患者Brunnstrom分期功能训练康复效果的独立影响因素（P<0.05）。ROC曲线分析结果显示，PLR、D-D预测脑卒中恢复期患者Brunnstrom分期功能训练康复效果的最佳截断值分别为150.09、208.85 ng/mL，且头颅CT联合PLR、D-D预测脑卒中恢复期患者Brunnstrom分期功能训练康复效果的AUC为0.822，特异度为89.87%，均高于指标单独预测的AUC及特异度（P<0.05）。结论 头颅CT检查结果及PLR、D-D水平是脑卒中恢复期患者Brunnstrom分期功能训练康复效果的独立影响因素，且头颅CT联合PLR、D-D有助于提高对脑卒中恢复期患者Brunnstrom分期功能训练康复效果的预测价值。

关键词： Dermatology   Immunology   T cells  

摘要： Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disorder marked by erythematous pustules and desquamation on the palms and soles. While IL-17 pathways are implicated in PPP, IL-17 blockers have shown modest efficacy, underscoring the need for a deeper understanding of IL-17 involvement. To dissect the cellular and spatial architecture of PPP, we performed single-cell RNA-Seq (scRNA-Seq) on lesional, nonlesional, and healthy acral skin to examine cellular composition, transcriptomic profiles, and cell-cell interactions. Unbiased clustering revealed 9 major cell types, including an inflammatory keratinocyte subset enriched in IL-17A/TNF signatures and marked by high IL-36G expression. Within the lymphocyte compartment, we identified a hybrid "regTh17" population coexpressing regulatory markers (FOXP3, CTLA4, TIGIT), IL17F, and IL26. This regTh17 subset was distinguished by elevated IL1R1 and CD39, suggesting an IL-1 beta-driven differentiation. Spatial analyses demonstrated significant neighborhood enrichment of regTh17 cells with IL-36G+ supraspinous keratinocytes. RegTh17 cells were the predominant source of IL-17F and IL-26 signals, whereas keratinocytes were predicted as their main receivers. We further observed regTh17 coexpressing TNFRSF4 (OX40) and TNFRSF18 (GITR) specifically at sites of IL36G+ keratinocyte interactions, implicating these pathways in amplification of the IL-17/IL-36 inflammatory loop. Together, our integrated single-cell and spatial profiling uncovers Th17 plasticity in PPP, identifies a regTh17-keratinocyte interaction, and highlights IL-17F, IL-26, OX40/OX40L, and GITR/GITRL as candidate targets for precision therapies in this challenging disease.

关键词： 感染   肝素结合蛋白   原核表达   单克隆抗体   胶体金免疫层析法  

摘要： 脓毒症是一种由感染引起的全身性炎症反应综合征，患者常并发器官功能障碍，这是导致重症感染患者死亡的关键因素。肝素结合蛋白(heparin-binding protein，HBP)是一种源自中性粒细胞的多功能介质，其水平与脓毒症的严重程度密切相关，在脓毒症早期诊断和预后评估方面具有作为生物标志物的巨大潜力。本研究经载体构建、原核表达，将纯化的重组HBP作为免疫原免疫小鼠；随后，通过细胞融合等技术筛选了4株稳定分泌抗HBP抗体的细胞株，并通过间接酶联免疫吸附试验(enzyme linked immunosorbent assay，ELISA)分析了抗体性质；最后，选择mAb 11为标记抗体，mAb 18为捕获抗体，建立了针对HBP的胶体金免疫层析法。本研究利用重组HBP成功制备了抗HBP的单克隆抗体，并初步建立了HBP的快速检测方法，该方法在资源有限的地区或需要快速判断感染严重程度的场景中具有重要意义。

摘要： 顺铂作为一种药物载体,在对抗癌症的过程中发挥了不可或缺的角色,它能够实现药物有针对性的传输,但同时,其潜在的毒性和副作用也是不能被轻视的。通过使用G250单克隆抗体来修饰顺铂纳米胶束,我们可以进一步确保抗体的稳定性和一致性,从而提高药物的靶向性和疗效,进一步降低药物的毒性和副作用。

关键词： FABP5   macrophages   saturated fats   psoriasis   IL-1β   IL-17  

摘要： High fat diet (HFD)-induced obesity increases the risk and severity of psoriasis. However, the immunoregulatory effects of different HFDs on psoriasis pathogenesis remains poorly understood. Here, mimicking human dietary fat profiles, four HFDs-saturated, monounsaturated, omega-6, and omega-3 fats-were designed and used to induce obesity in mice. Despite comparable obesity levels across groups, only the saturated HFD exacerbated imiquimod (IMQ)-induced psoriasis. This exacerbation correlated with elevated levels of IL-1D-producing macrophages, IL-17A-producing yS T cells, and neutrophils within psoriatic lesions. Mechanistically, saturated fatty acids (FAs) promoted IL-1D/IL-17A signaling via fatty acid-binding protein 5 (FABP5)-mediated mitochondrial FA oxidation and extracellular ATP release in skin macrophages. Deletion of FABP5, either globally or specifically in macrophages, attenuated IL-1D/IL-17A signaling and alleviated IMQ-induced psoriasis. These findings identify FABP5 as a key mediator of saturated HFD-driven psoriasis via the IL-1D/IL-17 axis, offering insights into the interplay between dietary fats, obesity, and psoriasis.

关键词： Oral squamous cell carcinoma   Chronic kidney disease   TNF-alpha plus neutrophils  

摘要： Background and aims: The risk of cancer in patients with chronic kidney disease (CKD), particularly in those on dialysis is high. However, the underlying mechanism remains unclear. Moreover, the involvement of CKD in the progression of oral squamous cell carcinoma (OSCC) is still not fully understood. In this study, we aimed to investigate the role and mechanism of CKD in OSCC. Methods: The correlation between peripheral blood cell analysis and clinical characteristics was tested in patients with OSCC with CKD or non-CKD. Immune cell infiltration in the tumor microenvironment of OSCC was assessed using multicolor immunofluorescences. In addition, a mouse model of OSCC under CKD conditions was established and the effect of CKD on tumor growth was examined. Single-cell RNA sequencing (scRNA-seq) was performed using fresh tumor samples obtained from the mouse model. The interactions between OSCC cells and neutrophils were evaluated in vitro. Results: A cohort of 52 patients with OSCC was included in the study, among whom 23 had CKD. Patients in the CKD group showed a significant decrease of lymphocyte counts in peripheral blood compared with those in the non-CKD group. Furthermore, patients with CKD exhibited more aggressive lymph node metastasis than did those in the non-CKD group. The subcutaneous tumor mouse model under CKD conditions showed greater proliferative capacity than did the non-CKD group. The scRNA-seq results indicated that the percentages of neutrophils and T lymphocytes were decreased in the tumor tissues of CKD mice compare to non-CKD mice. A total of five neutrophil subpopulations were identified in the tumor microenvironment, including Hexb+, tumor necrosis factor-alpha + (TNF-alpha+), Retnig+, Cxcl10, and CD74 neutrophils. Among these, the proportion of TNF-alpha + neutrophils significantly decreased, which inhibited proliferation and promoted apoptosis via releasing TNF-alpha + in OSCC cell lines. In addition, a total of ten lymphocyte subpopulati

关键词： HLA-DR   Monocyte   Sepsis   Septic shock   Immunosuppression  

摘要： Purpose: Septic patients simultaneously experience hyperinflammation and immunosuppression, the latter driving ICU-acquired infections, prolonged stays in ICU, and increased mortality. As immunostimulant therapies enter clinical trials, effective stratification is critical to identify patients with the most profound immune dysfunction. Monocyte HLA-DR expression (mHLA-DR) has emerged as the most reliable and actionable biomarker of sepsis-induced immunosuppression. Methods: We conducted a real-world, 20-year cohort study of 1023 septic shock patients, measuring mHLA-DR by standardized flow cytometry during the first week of ICU admission. Primary outcomes included day-28 and day-90 mortality, and ICU-acquired infections. Results: Low mHLA-DR (< 8000 AB/C, a threshold already used in phase II trials) was significantly associated with increased mortality and ICU-acquired infections. This association held across static and dynamic measures, multivariate analyses, Kaplan-Meier survival curves, and trajectory clustering (K-means). Conclusions: This large real-world study confirms that mHLA-DR is a robust enrichment biomarker for identifying the most immunosuppressed septic shock patients at higher risk of adverse outcomes. Importantly, time-course analysis suggests that early immune downregulation may represent a physiological adaptation, while delayed and persistent immunosuppression is associated with worse outcomes. Early single time-point measurements may fail to identify patients who are unlikely to develop delayed immunosuppression. Tracking mHLA-DR trajectories after the initial ICU days is essential for detecting persistent immune dysfunction and selecting patients in case of immunostimulant approaches.

关键词： immune checkpoint inhibitor   immunotherapy   myositis   HLA   immune related adverse event - irAE  

摘要： Background Immune-related myotoxicity (irM), including irMyocarditis and irMyositis, is a severe complication of immune checkpoint inhibitors (ICIs). Markers to identify patients at risk are missing. In this retrospective multicenter cohort study, we aimed to determine whether specific human leukocyte antigen (HLA) variants are associated with *** Twenty patients with irMyocarditis and/or irMyositis (median age (IQR), 67 (60-73) years;7/20 female) and 60 cancer controls (CC) without immune-related adverse events (median age (IQR), 68 (62-74) years;26/60 female) presenting to Charit & eacute;- Universit & auml;tsmedizin Berlin, Germany, or Kantonsspital St. Gallen, Switzerland, between September 2017 and June 2024, were included. As a second control cohort, we used HLA data from a historic dataset of 5.1x10(6) German healthy donors (G-HD). Allele frequencies (AF) of two-field HLA types were compared between patients with irM, CC, and G-HD using logistic regression and two-sided z-tests of odds ratios (OR).Results Comparison of single HLA AF between patients with irM and G-HD revealed moderate associations for irM with B*07:02 (OR 2.29;95% CI 1.12 to 4.69;p=0.023), B*40:01 (OR 2.75;95% CI 1.08 to 7.02;p=0.035), C*03:04 (OR 2.46;95% CI 1.09 to 5.56;p=0.031), DPB1*04:02 (OR 2.37;95% CI 1.16 to 4.85;p=0.018), and DQB1*06:02 (OR 2.28;95% CI 1.12 to 4.67;p=0.024). No statistically significant differences were observed between patients with irM and CC. By contrast, multi-allelic HLA analysis identified a strong association between HLA-A*01:01-B*08:01-C*07:01, a component of the 8.1 ancestral haplotype (8.1 AH), and early-onset irM (onset <= 3 months after ICI initiation, n=11), compared with G-HD (22.7% vs 7.6%;OR 3.59;95% CI 1.33 to 9.74;p=0.012) and CC (22.7% vs 7.5%;OR 3.62;95% CI 1.09 to 12.12;p=0.036). Intriguingly, early-onset irM was linked to higher troponin T levels compared with late-onset irM (p=0.005, Cohen's r=0.63).Conclusions Our results provide first