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关键词： 恶性肿瘤   血液高凝状态   凝血功能   细胞因子   相关性   预测模型  

摘要： 目的:分析晚期恶性肿瘤患者血液高凝状态(hypercoagulability state,HCS)与炎性细胞因子的相关性,探讨炎性细胞因子指标在HCS中的预测价值。方法:选择2022年12月至2023年5月在我院血液肿瘤科住院治疗的100例晚期肿瘤患者,分为高凝状态组(34例)与非高凝状态组(66例)。检测两组患者凝血功能和炎性细胞因子水平,同时分析二者的相关性,及炎性细胞因子指标在HCS中的预测价值。结果:晚期肿瘤高凝状态组患者IL-6、IL-10水平高于非高凝状态组[(43.334±62.204)pg/mL比(13.881±26.642)pg/mL、(2.404±5.602)pg/mL比(1.045±1.608)pg/mL],差异有统计学意义(P<0.05)。KPS评分、IL-6、IL-10和TNF-α共同构建的预测晚期肿瘤患者处于血液高凝状态的模型曲线下面积(area under curve,AUC)为75.0%,敏感性为67.6%,特异性为76.9%。结论:KPS评分、IL-6、IL-10和TNF-α是预测晚期肿瘤患者处于血液高凝状态危险的独立危险因素。基于这些独立危险因素构建的预测模型具有较高的准确性。

摘要： The authors regret that Figure 5A in the original article reanalyzed RNA sequencing data from a previously published study by van Rosmalen et al. ( Cell Reports 2024;43(3):113951, https://***/10.1016/***.2024.113951), but the figure legen...

关键词： 网络药理学   肺炎喘嗽口服液   儿童   急性肺炎   医院制剂   肿瘤坏死因子-α   核因子κB  

摘要： 目的 探索医院制剂肺炎喘嗽口服液(FYCS)对急性肺部炎症的保护作用及其分子机制。方法 通过网络药理学识别潜在靶点和通路,分子对接验证活性化合物和靶点之间的相互作用。利用脂多糖(LPS)诱导的小鼠急性肺部炎症模型和RAW264.7细胞炎症模型评估FYCS的抗炎作用。在动物实验中,检测肺组织的湿重/干重比、肺组织病理变化,评估FYCS对急性肺部炎症的干预效果。同时,采用酶联免疫吸附法、蛋白免疫印迹法、实时荧光定量聚合酶链式反应(RT-qPCR)等方法对动物和细胞样本中信号通路相关蛋白和因子进行检测。结果 基于分子复合物检测(MCODE)、GO功能注释及KEGG通路富集分析结果,锁定肿瘤坏死因子(TNF)/核因子κB(NF-κB)/NOD样受体热蛋白结构域相关蛋白3(NLRP3)炎症通路。实验表明,FYCS可减轻LPS导致的小鼠肺水肿,改善急性肺部炎症病理损伤,并降低炎症细胞因子TNF-α、白细胞介素-1β(IL-1β)分泌水平。蛋白免疫印迹法和RT-qPCR结果显示,与对照组相比,模型组中NLRP3、凋亡相关斑点样蛋白(ASC)、半胱天冬酶-1(Caspase-1)、IL-1β、磷酸化核因子κB(p-NF-κB)和TNF-α的表达水平显著增加,但是这种增加在FYCS处理组得到有效抑制,并显示出与地塞米松和MCC950相似的效果。结论 FYCS具有多成分多靶点的作用,主要通过抑制TNF/NF-κB/NLRP3通路缓解急性肺部炎症,为儿科急性肺部炎症中药开发提供了依据。

关键词： 多酚类   羟基酪醇醋酸酯   类风湿关节炎   成纤维样滑膜细胞  

摘要： 目的探讨羟基酪醇醋酸酯(HT-AC)对肿瘤坏死因子α(TNF-α)诱导类风湿关节炎(RA)成纤维样滑膜细胞(FLS)增殖、迁移、侵袭及炎症反应的抑制作用。方法研究时间2023年6―10月。不同浓度的羟基酪醇醋酸酯(25、50和100μmol/L)预处理后使用10μg/L TNF-α诱导RA-FLS 48 h,采用四甲基偶氮唑盐(MTT)检测细胞增殖情况,划痕实验、Transwell细胞迁移和侵袭实验观察细胞迁移和侵袭,逆转录-聚合酶链式反应(RT-PCR)检测神经型钙黏附蛋白(N-cadherin)、基质金属蛋白酶3(MMP-3)和白细胞介素-1β(IL-1β)的mRNA表达,蛋白质印迹法检测N-cadherin、MMP-3、IL-1β和组蛋白去乙酰化酶3(HDAC3)的蛋白表达。结果与溶剂对照组相比,TNF-α显著促进RA-FLS增殖[(147.90±10.61)%比(100.00±7.80)%]、迁移[(369.30±45.76)个比(213.70±34.43)个]和侵袭[(143.30±17.90)个比(71.33±16.29)个](P<0.05),而50或100μmol/L的羟基酪醇醋酸酯处理显著降低TNF-α诱导的RA-FLS的增殖[(129.90±7.37)%、(123.10±13.77)%](P<0.05),25、50或100μmol/L的羟基酪醇醋酸酯处理显著降低TNF-α诱导的RA-FLS迁移[(273.70±37.45)个、(239.70±26.58)个、(178.70±19.43)个]和侵袭[(106.00±10.00)个、(85.33±11.06)个、(72.00±7.55)个](P<0.05)。TNF-α显著增加RA-FLS中N-cadherin、MMP-3和IL-1β的mRNA和蛋白表达(P<0.05),而50或100μmol/L的羟基酪醇醋酸酯处理显著抑制TNF-α诱导的RA-FLS中N-cadherin、MMP-3和IL-1β的mRNA和蛋白表达(P<0.05)。此外,50或100μmol/L的羟基酪醇醋酸酯处理显著抑制TNF-α诱导的RA-FLS中HDAC3的蛋白表达(P<0.05)。结论羟基酪醇醋酸酯可能通过调控HDAC3的蛋白表达来抑制FLS的增殖、迁移、侵袭及炎症反应在RA疾病中发挥保护作用。

关键词： adult T-cell leukemia/lymphoma   double immunofluorescence staining   drug eruption   human T-cell leukemia virus type 1   mogamulizumab   ATLL   adult T-cell leukemia/lymphoma   CCR4   CC chemokine receptor 4   IL   interleukin  

摘要： A and B, Clinical images of the trunk. C, The lesion on the left abdomen from which a skin biopsy was taken. D, Hematoxylin and eosin (H&E) staining, ×200. E, CD3 staining, ×200. F, CD8 staining, ×200. G, CCR4 staining, ×400. H and I, Clinical ima...

关键词： Luminex   CETSA   Multi-target drug screening   IL-4-IN-1   Pulmonary fibrosis  

摘要： This study established an innovative platform integrating Cellular Thermal Shift Assay (CETSA) with Luminex technology. It overcomes traditional single-target limitations and the complexity of thermal proteome profiling (TPP), enabling rapid, high-throughput multi-target drug screening. The platform detects drug-induced protein stabilisation via CETSA while utilising Luminex for multiplex cytokine quantification. Validation using 21 cytokines and IL-4 inhibitor IL-4-IN-1 revealed distinct modulation: IL-4-IN-1 produced dose-dependent up-regulation of IL-4 and unexpectedly TNF-alpha (P < 0.01). Binding studies (DSF/BLI) confirmed specific IL-4-IN-1 interactions with IL-4 (Delta Tm = 5.83 degrees C) and TNF-alpha (Kd = 1.30 x 10(-6) M;Delta Tm = 5.03 degrees C). Given their association with pulmonary fibrosis, anti-fibrotic investigations showed IL-4-IN-1 significantly suppressed alpha-SMA and COL1A1 expression (P < 0.01) in A549 cells. It also dose-dependently downregulated key fibrosis markers (MMP2, FN1, TGFB1;P < 0.001), substantially reducing FN1, Vimentin, and alpha-SMA (P < 0.001). The CETSA-Luminex platform provides efficient multi-target screening, while IL-4-IN-1 demonstrates therapeutic potential against fibrosis by targeting IL-4/TNF-alpha pathways and inhibiting profibrotic mediators, offering a novel efficient approach for drug target discovery.

关键词： Breast cancer   ECM3 signature   Extracellular matrix   IL-23   Immune suppression   PD-1   SPARC   T cells   Tregs  

摘要： BACKGROUND:High-grade breast cancer (HGBC) is an aggressive disease with poor prognosis, underscoring the need for new treatment strategies. The tumor microenvironment (TME), particularly the extracellular matrix (ECM), plays a pivotal role in tumor progression, therapy resistance, and immune regulation. An ECM-related gene signature (defined ECM3), found in approximately 35% of HGBC cases, is associated with aggressive tumors, epithelial-to-mesenchymal transition (EMT), poor clinical outcome and increased infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs). METHODS:In this study, we investigated the impact of the ECM on T cell regulation in HGBC patients, focusing on the relationship between ECM3 + tumors and T cell phenotypes. We employed mouse models to dissect the molecular mechanisms linking ECM components to T cell regulation, with particular attention to the role of the matricellular protein SPARC, a key component of the ECM3 signature. RESULTS:We revealed a significant correlation between highly suppressive programmed cell death-1 (PD-1) negative regulatory T cells (Tregs) and ECM3 + tumors. In mouse models, SPARC was found to down-regulate PD-1 on Tregs by promoting IL-23 release, which in turn induced SATB1 expression, a repressor of the pdcd1 gene. The selective expression of the IL-23 receptor on Tregs accounted for the targeted effect of IL-23 on these cells. Notably, blocking IL-23 with monoclonal antibodies restored PD-1 expression on Tregs and activated T effector cells. CONCLUSION:These findings extend the immune-regulatory role of the ECM to include regulatory T cells and identify potential new therapeutic targets for high-grade breast cancers. Moreover, they highlight ECM3 as a potential biomarker of resistance to PD-1/PD-L1 immune checkpoint blockade (ICB), suggesting that ECM3⁺ patients may benefit from alternative checkpoint inhibitor therapies beyond PD-1/PD-L1.

关键词： nanobody   VHH   ISG15   protein structure   NMR   USP16   AF3   AlphaFold3   BLI   biolayer interferometry   cDNA   complementary DNA   HRP   horseradish peroxidase   IFN   interferon   IP   immunoprecipitation   ISG15   Interferon Stimulated Gene 15   MS   mass spectrometry   Ni–NTA   nickel–nitrilotriacetic acid   PDB   Protein Data Bank   RRID   Research Resource Identifier   SBP   streptavidin-binding peptide   SEC   size-exclusion chromatography   TBS   Tris-buffered saline   Ub   ubiquitin   USP18   ubiquitin-specific peptidase 18  

摘要： Interferon-induced ubiquitin (Ub)-like modifier Interferon Stimulated Gene 15 (ISG15) functions both intracellularly and as a secreted protein with cytokine-like properties. The ISG15 pathway is implicated in various diseases, including cancer and inflammatory disorders, but understanding its precise roles has been challenging because of limited availability of tools to study ISG15 biology. Here, we report the development of two novel nanobodies that target human ISG15, obtained through alpaca immunization and phage display. These nanobodies, VHH ISG15-A and VHH ISG15-B , exhibit nanomolar binding affinities and recognize distinct epitopes on ISG15's C- and N-terminal domains, respectively, as demonstrated by NMR and X-ray structural analyses. Both nanobodies enable the immunoprecipitation and proteomic identification of ISGylated substrates with minimal background contamination. VHH ISG15-A is compatible with immunoblotting and recognizes unconjugated ISG15 under denaturing conditions. Functional assays showed that VHH ISG15-A , but not VHH ISG15-B , inhibits ubiquitin-specific peptidase 16–mediated deISGylation, likely by steric hindrance at the ISG15-binding interface. These results underscore the utility of VHH ISG15-A and VHH ISG15-B as tools to study ISG15 biology.

关键词： AUROC   Area under the receiver operating characteristic curve   CI   Confidence interval   COPD   Chronic obstructive pulmonary disease   COVID-19   Coronavirus disease 2019   CRP   C-reactive protein   ED   Emergency department   ELISA   Enzyme-linked immunosorbent assay   ENA-78   Epithelial neutrophil-activating protein 78   GLM   Generalized linear model   GLP-1   Glucagon-like peptide 1   ICU   Intensive care unit   IL   Interleukin   IQR   Interquartile range   LASSO   Least absolute shrinkage and selection operator   MMP-8   Matrix metalloproteinase-8   MSD   Mesoscale discovery   MyD88   Myeloid differentiation primary response protein 88   NEWS-2   National early warning score version 2   NF-kB   Nuclear factor kappa B   PD-L1   Programmed death-ligand 1   RFE   Recursive feature elimination   ROC   Receiver operating characteristic   R-PLEX   Custom assay design   RT   Room temperature   SD   Standard deviation   SIRS   Systemic inflammatory response syndrome   SOFA   Sequential failure assessment   TLR   Toll-like receptor   TNF   Tumor necrosis factor   TRAIL   Tumor necrosis factor-related apoptosis-inducing ligand   U-PLEX   Custom multiplex of assay   XGBoost   Extreme gradient boosted tree model   MyD88   PD-L1   Pentraxin-3   Sepsis   Infection  

摘要： Objectives Accurate diagnosis of sepsis is needed to initiate life-saving treatment decisions. Biomarkers capable of identifying both acute infection and sepsis are required to assist clinicians. Methods A real-life heterogeneous cohort of 388 patients with suspected acute infections was recruited at presentation to the ED. Nine emerging host-response biomarkers (MyD88, MMP-8, leptin, ENA-78, fractalkine, PD- L1, pentraxin-3, TRAIL, and GLP-1) were quantified using a multiparameter assay. We performed AUROC analysis for the endpoints bacterial infection, sepsis, and 30-day mortality. We further assessed diagnostic performance when combining these biomarkers using a machine learning algorithm. Results Particularly, MyD88, PD-L1, and pentraxin-3 presented high AUROCs for the endpoints bacterial infection (≥0.87), sepsis (≥0.81), and 30-day mortality (≥0.71). Seven out of the nine investigated biomarkers showed statistically significant discrimination for all three endpoints. A combined algorithm via the XGBoost model using pentraxin-3, MyD88, and GLP-1 was used for sepsis prediction, with an AUROC of 0.89, higher than clinical assessment via NEWS-2 (0.83) or procalcitonin (0.81). Conclusion Pentraxin-3, MyD88, GLP-1, and PD-L1 are a promising complementary set of biomarkers for risk assessment and stratification. When a trained multiparameter classifier is used, the combination of biomarkers results in a valid tool for sepsis diagnosis. Trial registration DRKS00020521, DRKS00017395