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关键词： eosinophil   inflammation   methotrexate   plasma cytokine   plasma metabolites   prurigo nodularis   FC   fold changes   IL   interleukin   PN   prurigo nodularis  

摘要： Plasma cytokine changes associated with methotrexate treatment. IL-5 (A), CXCL10 (B), and CCL18 (C) concentrations in blood plasma decreased following methotrexate treatment to levels similar to those found in the healthy control. HC, Healthy cont...

关键词： human alveolar epithelial organoids   Mycobacterium tuberculosis   coculture model   cell–cell interaction   ferroptosis   AEC   alveolar epithelial cell   AQP5   aquaporin 5   BCG   Bacillus Calmette–Guérin   BDNF   brain-derived neurotrophic factor   cDNA   complementary DNA   DE   differentially expressed   DEG   differentially expressed gene   DMEM   Dulbecco's modified Eagle's medium   GSVA   gene set variation analysis   KEGG   Kyoto Encyclopedia of Genes and Genomes   MDA   malondialdehyde   Mtb   Mycobacterium tuberculosis   PBMC   peripheral blood mononuclear cell   PBST   PBS with Triton X-100   PPI   protein–protein interaction   qPCR   quantitative PCR   SP-C   surfactant protein C   TB   tuberculosis   TNF   tumor necrosis factor   t-SNE   t-distributed stochastic neighbor embedding  

摘要： Emerging studies have identified alveolar epithelial cells as a conducive niche for Mycobacterium tuberculosis (Mtb) replication and spread during early infection. However, the host–pathogen interactions and intercellular crosstalk within the lung epithelial microenvironment remain inadequately understood. Here, we developed a lung epithelial organoid coculture model and exposed it to the virulent H37Rv strain or the avirulent Bacillus Calmette–Guérin (BCG) strain to investigate tuberculosis (TB) pathogenesis. Transcriptomic analyses revealed that Mtb infection markedly alters cell death patterns in organoids and modulates signal transduction pathways in peripheral blood mononuclear cells (PBMCs). Western blot indicates the H37Rv strain induced ferroptosis, autophagy, and apoptosis while suppressing necroptosis in organoids. In contrast, BCG predominantly enhanced autophagy. PBMCs also exhibited strain-specific responses, with BCG strongly activating the Hippo and Notch signaling pathways, whereas H37Rv primarily engaged the tumor necrosis factor (TNF) signaling pathway. Furthermore, Mtb significantly reshaped the paracrine and autocrine signaling dynamics between PBMCs and organoids. NicheNet network analysis identified TNFSF15 and brain-derived neurotrophic factor (BDNF), induced by H37Rv, as key mediators. Experimentally, overexpression of TNFSF15 and BDNF suggested that TNFSF15 from organoids promoted BDNF expression in PBMCs via paracrine signaling. In turn, BDNF from PBMCs then inhibited ferroptosis in organoids, contributing to restrict Mtb growth. Overall, our study provides a conceptual framework for understanding the mechanisms of TB pathogenesis within alveolar epithelial cells and offers valuable insights to prevent and control TB transmission in humans.

摘要： Objectives Inflammatory lung disease in Still’s disease (SD) has recently been described. Among its manifestations, pulmonary arterial hypertension (PAH) is a rare and life-threatening event, with only a few case reports published. The objective was to report the largest adult cohort of PAH occurring in the context of SD. Methods We identified 16 adult SD patients with PAH (PAH+) by a call for observations from the CRI-IMIDIATE (Club Rhumatismes & Inflammation - Immune-Mediated Inflammatory Disease Alliance for Translational and Clinical Research) network (https://***/recherche/reseau-CRI-Imidiate/) and a search of the French pulmonary hypertension network registry. Patient characteristics and disease evolution were retrospectively compared with those of 111 SD controls without PAH (PAH-) followed in a reference centre. Results The profile of patients in the PAH+ and PAH- groups differed: 100% versus 69.4% female ( P = .006), 75% versus 17.1% Black ( P < .0001), more active SD both at diagnosis and throughout the disease course, and more likely to present macrophage activation syndrome (62.5% vs 14.4%, P < .0001) and exhibit eosinophilia during the disease course (68.7% vs 7.2%, P < .0001). For the 84 out of 127 patients with genetic typing, the HLA-DRB1*15 allele was more prevalent in PAH+ than PAH- patients (8/11 [72.7%] vs 22/73 [30.1%], P = .014). PAH+ patients more frequently received canakinumab and immunosuppressants than did PAH- patients and had higher frequency of drug reactions to interleukin 1 (IL-1) and/or IL-6 inhibitors (37.5% vs 7.2%, P = .002). Mortality was higher in PAH+ than PAH- patients (37.5% vs 0.9%, P < .0001), and all deaths were related to SD flare . Conclusions These results reinforce the association between the HLA-DRB1*15 allele and severe forms of SD and raise the question of therapeutic optimisation in such patients.

关键词： 调节性T细胞   CD8^(+)T细胞   肺癌   转化生长因子-β  

摘要： 目的:探讨肺癌中调节性T细胞(Treg)介导CD8^(+)T淋巴细胞功能受损的机制,为肺癌的免疫治疗提供线索。方法:用流式细胞仪分析肺癌及良性对照患者胸水和外周血中Treg细胞、CD8^(+)T细胞所占比例的差异;磁珠分选Treg与CD8^(+)T细胞进行体外共培养实验,ELISA检测共培养上清液中TGF-β和IL-10的含量,并分别添加抗TGF-β、抗IL-10的中和抗体来验证其对CD8^(+)T细胞功能的影响;通过转录组RNA测序筛选TGF-β刺激的CD8^(+)T细胞与未刺激CD8^(+)T的差异mRNA,探究TGF-β对CD8^(+)T细胞可能的调控机制。结果:Treg细胞在肺癌患者中大量浸润,而CD8^(+)T细胞数量明显下降。ELISA检测结果显示共培养上清液中TGF-β的含量远高于IL-10的含量。当Treg与CD8^(+)T细胞共培养时,CD8^(+)T细胞表面PD-1的表达水平明显高于对照组,分泌颗粒酶B(Granzyme B)的水平显著低于对照组,而添加抗TGF-β抗体可恢复受损T细胞的杀伤活性。TGF-β可能通过调控CKAP2L和LPCAT2基因的表达,促进CD8^(+)T细胞功能耗竭,使肿瘤发生免疫逃逸。结论:Treg细胞主要通过分泌TGF-β介导CD8^(+)T淋巴细胞功能受损。因此,开发针对TGF-β通路的治疗策略对肺癌的免疫治疗具有重要意义。

关键词： CDI   cysteine-deprivation-induced   COX-2   cyclooxygenase-2   EGFR   epidermal growth factor receptor   EMT   epithelial-mesenchymal transition   ETC   electron transport chain   GOF   gain of function   GPX4   glutathione peroxidase 4   GSH   reduced glutathione   HSAEC   Primary Small Airway Epithelial Cells Human   Hsp90   heat shock protein 90   LCC   large cell lung carcinoma   LNM   lymph node metastasis   LUAD   lung adenocarcinoma   MMP   mitochondrial membrane potential   MTT   3-4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide   NAD   nicotinamide adenine dinucleotide   NOX   NADPH oxidase   NSCLC   non-small cell lung cancer   PTGS2   prostaglandin-endoperoxide synthase 2   PUFA   polyunsaturated fatty acids   ROS   reactive oxygen species   RXR   retinoid X receptor   SCC   squamous cell lung cancer   SRB   sulforhodamine B   TNF   tumor necrosis factor   VDR   vitamin D receptor   VDRE   vitamin D response element   Lung cancer   SIRT1   Vitamin D   Ferroptosis  

摘要： A number of studies showed that vitamin D reveals antiproliferative activity against cancer cells, however some lung cancer cells are more sensitive than others. Secondly, there are some controversies around the role of SIRT1 in lung cancer: on one hand it was demonstrated that SIRT1 contributed to the development of lung cancer, on the other hand SIRT1 was showed to be downregulated in lung cancer. Third, it was demonstrated that VDR is posttranslationally modified via deacetylation by SIRT1 what potentiated VDR activity. In this study, we first showed an inverse correlation between VDR and SIRT1 expression level in lung cancer. We further revealed that vitamin D and SIRT1 activator SRT2104 cooperate in inhibiting lung cancer cells proliferation. SRT2104 enhanced transcriptional activity of calcitriol in lung cancer cells, since the expression of CYP24A1 was significantly higher after the treatment with calcitriol and SRT2104 compared with calcitriol alone. Calcitriol and SRT2104 affected the metabolic rate of lung cancer cells, increased ROS and superoxide production, decreased GSH/GSSG ratio and induced lipid peroxidation. Calcitriol and SRT2104 also significantly induced the expression of COX-2 and reduced the level of Hsp90 and mutp53 in EGFR mutant lung cancer cells. The study showed that the use of calcitriol in combination with SRT2104 SIRT1 activator shows stronger antitumor activity in lung cancer. This effect may be due to the induction of ferroptosis. These insights pave the way for potential to use SIRT1 activators with vitamin D derivatives in the treatment of lung cancer.

关键词： alopecia areata   atopic dermatitis   dupilumab   trachyonychia   AA   alopecia areata   IL   interleukin   Th2   T helper 2  

摘要： Significant improvement of pitting and superficial longitudinal ridging of the fingernails; minimal residual thickened hyperkeratotic cuticles after 3 months of dupilumab 300 mg every 4 weeks. Introduction Trachyonychia is an inflammatory disease ...

关键词： 艰难梭菌   谷氨酸脱氢酶   B细胞抗原表位   驼源   单域抗体  

摘要： 目的 研制能够特异性识别艰难梭菌谷氨酸脱氢酶（CD-GDH）中构象B细胞抗原表位的驼源单域抗体，应用于酶联免疫吸附检测（ELISA）和蛋白斑点印迹杂交（DB）等方法。方法 采用重组表达并纯化的CD-GDH作为捕获抗原从驼源天然纳米抗体噬菌体展示库中筛选获得特异性结合的噬菌体克隆，阳性克隆经ELISA初筛和WB验证后对其VHH基因序列进行测序分析，随后通过密码子优化策略合成抗体基因并将其克隆至pET-28a表达载体，诱导表达并纯化后用于DB和ELISA检测CD-GDH蛋白。结果 获得1个驼源单域抗体阳性克隆GH12，其基因在大肠杆菌中重组表达并纯化。GH12与CD-GDH结合的亲和力良好、EC50为（2.91±0.03）nmol/L用于ELISA和DB都能特异性地识别重组表达和内源性的CD-GDH蛋白。结论 成功制备并获得了一株识别CD-GDH蛋白中构象B细胞抗原表位的驼源单域抗体，为检测CD-GDH蛋白提供了一个有效工具。

关键词： atherosclerosis   hypertriglyceridemia   hypotriglyceridemia   T cells   transcriptomics   triglycerides   Apo   apolipoprotein   CPDA   citrate phosphate dextrose adenine   DEG   differentially expressed gene   FCS   familial hyperchylomicronemia syndrome   FDR   false discovery rate   GLM   generalized linear model   hsCRP   high sensitivity C-reactive protein   IL   interleukin   Lp(a)   lipoprotein (a)   TGRL   triglyceride-rich lipoprotein  

摘要： Triglycerides and T cells play a key role in atherosclerosis, the leading cause of cardiovascular disease (CVD). Moderately elevated triglycerides have emerged as a causal risk factor, and T cells are a prominent component of atherosclerotic plaques. This cross-sectional study examined transcriptomic differences in T cells among patients with varying triglyceride levels via RNA sequencing. We analyzed CD4 + and CD8 + T cells from 49 participants, including those with primary (genetic) and secondary moderate hypertriglyceridemia, severe hypertriglyceridemia, and hypotriglyceridemia. Patients with primary moderate hypertriglyceridemia exhibited a proinflammatory transcriptomic profile, including increased interleukin-6 receptor ( IL6R ) expression, which is implicated in CVD risk. Similar patterns appeared in CD8 + T cells and, to a lesser extent, in secondary moderate hypertriglyceridemia patients. Conversely, transcriptomic differences were reversed in hypotriglyceridemia and absent in severe hypertriglyceridemia patients. These findings suggest that elevated triglycerides may contribute to CVD by promoting a proinflammatory transcriptomic profile in T cells.

关键词： 14-3-3   PIPKIγi5   PI4,5P   2   YAP1   tumorsphere   ALDH1A1   Aldehyde Dehydrogenase 1 Family Member A1   BSA   bovine serum albumin   DMEM   Dulbecco's modified Eagle's medium   FBS   fetal bovine serum   HEK-293   human embryonic kidney 293 cell line   IFN   interferon   IP   immunoprecipitation   LATS1/2   large tumor suppressor kinase 1 and 2   MST1/2   mammalian STE20-like protein kinase 1/2   PI3,5P2   phosphatidylinositol-3,5-bisphosphate   PI4,5P2   phosphatidylinositol-4,5-bisphosphate   PIPKI   type I phosphoinositide phosphate kinase   PIPKIα   phosphatidylinositol 4-phosphate 5-kinase type 1α   PIPKIγi5   type I gamma phosphatidylinositol phosphate kinase i5   STAT1   signal transducer and activator of transcription 1   TEAD   transcriptional enhanced associate domain   YAP1   Yes-associated protein 1  

摘要： Dysregulation of the Hippo/Yes-associated protein (YAP) signaling pathway has been associated with several diseases, including cancer, neurological disorders, and cardiovascular conditions. However, the precise molecular mechanisms governing Hippo/YAP signaling are not fully understood, and additional regulators of this pathway need to be identified. Our research has identified type I gamma phosphatidylinositol phosphate kinase i5 (PIPKIγi5) as a regulator of Hippo/YAP signaling. PIPKIγi5 is a kinase responsible for synthesizing phosphatidylinositol-4,5-bisphosphate (PI4,5P 2 ). By directly interacting with YAP1, PIPKIγi5 prevents the nuclear translocation of YAP1, thereby suppressing YAP1-mediated gene transcription. Thus, PIPKIγi5 functions as a suppressor of YAP1-mediated signaling. The kinase activity of PIPKIγi5, which generates PI4,5P 2 , is essential for controlling YAP1 function. PI4,5P 2 promotes the interaction of YAP1 with the 14-3-3 protein, which retains YAP1 in the cytosol. Given the role of YAP1 signaling in cancer cell stemness, depletion of PIPKIγi5 enhances YAP1 signaling and promotes tumorsphere formation in head and neck squamous cell carcinoma. These findings highlight a PI4,5P 2 -modulated signaling nexus that exerts specific control over Hippo/YAP signaling and its biological functions.

关键词： Anti-TNF agents   Fertility   Paternal factors   Pregnancy outcomes  

摘要： Anti-TNF drugs are effective in the treatment of inflammatory arthritis. However, concerns about the impact of anti-TNF therapy on fertility, particularly in male patients, have been insufficiently explored. This study aimed to investigate the effects of anti-TNFs on male fertility and examine the pregnancy outcomes of their partners. This study was conducted on male patients with inflammatory arthritis undergoing anti-TNF therapy. Male patients whose female partners became pregnant during the anti-TNF therapy were evaluated regarding their partners' pregnancy outcomes. The characteristics of infertile patients were also analyzed. Additional evaluations included patient age, disease duration, anti-TNF treatment duration, as well as partners' comorbid conditions and the pregnancy outcomes of their partners prior to the initiation of anti-TNF therapy. A total of 101 male patients were included in the study. Of the total cohort, 70 male patients (69.3 %) did not desire children and were using contraception. The female partners of 27 male patients successfully conceived while their partners were receiving anti-TNF therapy. The remaining 4 couples were considered infertile. There were 52 pregnancies in total. Of these, 36 resulted in term births, 1 in a preterm birth, 1 in a stillbirth, 4 in elective abortions, and 10 in spontaneous abortions. Among the 27 female partners who conceived during anti-TNF therapy, 11 had also experienced pregnancies prior to the initiation of treatment. There were no statistically significant differences between the two periods in either the number of pregnancies or pregnancy outcomes. Anti-TNF therapy appears to be safe in terms of both fertility and pregnancy outcomes, although further investigations are warranted to better clarify its impact on male reproductive health.