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关键词： 肺淋巴上皮癌   PD-L1   CTLA-4   肿瘤微环境   免疫检查点  

摘要： 目的 探讨CTLA-4和PD-L1在肺淋巴上皮癌（pulmonary lymphoepithelial carcinoma,PLEC）中的表达情况及其与患者预后、肿瘤浸润性淋巴细胞（tumor-infiltrating lymphocyte,TIL）之间的关系。方法 收集50例PLEC,另选取癌旁肺组织23例。采用免疫组化法检测CTLA4、PD-L1在PLEC和癌旁肺组织中的表达情况及肿瘤微环境中CD4+T淋巴细胞、CD8+T淋巴细胞的浸润情况。分析CTLA4、PD-L1及肿瘤微环境中CD4+T淋巴细胞、CD8+T淋巴细胞的分布特征与PLEC临床病理特征的相关性。结果CTLA-4在PLEC中的阳性率高于癌旁肺组织,差异有统计学意义（P<0.05）;PD-L1在PLEC TNM各分期中的表达差异有统计学意义（P<0.05）,且其表达与PLEC TNM分期呈正相关（r=0.31,P=0.03）;CD4+T淋巴细胞、CD8+T淋巴细胞主要浸润于肿瘤间质中且CD4+T淋巴细胞浸润密度高于CD8+T淋巴细胞浸润密度,差异有统计学意义（P<0.05）;而在癌巢中,CD8+T淋巴细胞的浸润密度明显高于CD4+T淋巴细胞的浸润密度,差异有统计学意义（P<0.05）。结论 PD-L1、CTLA4在PLEC中阳性率较高,提示PD-L1、CTLA4是PLEC潜在的免疫治疗靶点;肿瘤微环境中的淋巴细胞主要浸润于间质,且CD4+T淋巴细胞浸润密度高于CD8+T细胞。

摘要： Although multiple single-cell RNA sequencing (scRNA-seq) based studies have explored rheumatoid arthritis (RA), most have focused on synovial tissue, limiting the ability to perform paired pre- and post-treatment comparisons and to elucidate dynamic changes. Moreover, the single-cell impact of TNF-α and JAK inhibitors on RA remains poorly understood, hindering effects toward precision medicine for RA. Here, we present a comprehensive scRNA-seq analysis of synovial fluid samples of RA patients treated with tofacitinib or adalimumab, both pre- and post-treatment. Following stringent quality control, we analyzed 100,387 high-quality cells, providing an in-depth characterization of cell composition, molecular signaling pathways, and functional properties. This rich dataset offers a valuable resource to address diverse research questions, from uncovering the mechanisms of action of TNF-α and JAK inhibitors, to identifying novel therapeutic targets for RA, and advancing our understanding of the pathogenesis of inflammatory diseases.

关键词： PIEZO1   Psoriasis   IL-17   NF-kB   Inflammation   Keratinocyte   Th17 cells  

摘要： Background Psoriasis is a chronic inflammatory skin disorder characterized by hyperproliferative keratinocytes and an altered immune response. PIEZO1, a mechanically activated ion channel, has been implicated in various cellular processes, but its role in psoriasis pathogenesis remains unclear. Methods We examined PIEZO1 expression in skin samples from psoriatic patients and healthy individuals using western blot, immunohistochemistry, and mRNA expression analyses. Subsequently, we employed PIEZO1 knock-out (KO) mice to establish imiquimod (IMQ)-induced psoriasiform models for in vivo experiments. Additionally, we conducted in vitro experiments with PIEZO1-silenced human keratinocytes (HaCaT cells) to investigate the impact on keratinocyte function and the expression of inflammatory cytokines. Results PIEZO1 expression was significantly upregulated in the basal layer of psoriatic lesions compared to healthy controls. In vivo, PIEZO1 KO mice showed attenuated psoriasis-like symptoms, reduced keratinocyte proliferation, inflammatory cell infiltration, and less Th17 cells compared to wild-type mice. Loss of PIEZO1 in vitro inhibited keratinocyte proliferation and migration, while inducing apoptosis. Transcriptome sequencing and subsequent analyses revealed that PIEZO1 knockdown modulates the NF-kB signaling pathway and associated inflammatory genes. The in vitro activation of NF-kB signaling was diminished by PIEZO1 silencing in keratinocytes, resulting in decreased inflammatory cytokine and chemokine expression. Furthermore, PIEZO1 facilitated keratinocyte-mediated CD4 + T cell differentiation into Th17 cells, a key pathogenic factor in psoriasis. Conclusion This study highlights the critical role of PIEZO1 in psoriatic skin inflammation and suggests that PIEZO1 may serve as a novel therapeutic target for psoriasis treatment. Our findings reveal that PIEZO1 modulates keratinocyte proliferation, immune cell infiltration, and T cell differentiation through the NF-kB sig

关键词： CD200   CD200R   Central Nervous System   Experimental Autoimmune Encephalomyelitis   Interferon beta  

摘要： Background:Interferon-b (IFN-β), a glycoprotein released during viral infections, plays a crucial role in modulating T cells involved in multiple sclerosis (MS). CD200 is an immunomodulatory molecule expressed in many cell types, including neurons. It reduces the progression of MS and experimental autoimmune encephalomyelitis (EAE) by interacting with CD200R, mainly expressed on myeloid lineage cells. This interaction prevents brain damage and slows the progression of the disease. Objective:This study investigated changes in the expression of CD200 and CD200R genes in the brains of mice induced with EAE. Methods:Female C57B/L6 mice were divided into three distinct groups: 1) EAE-induced and treated with IFN-b, 2) EAE-induced and treated with phosphate-buffered saline (PBS), and 3) a healthy control group. Two weeks after treatment, the mice were euthanized, and whole-brain tissues were used for mRNA extraction. After cDNA synthesis, the expression of CD200 and CD200R genes was evaluated using Taqman Real-Time PCR. Leukocyte infiltration and demyelination were assessed using Hematoxylin and Eosin staining (H&E) as well as Luxol fast blue (LFB). Results:IFN-β treatment significantly reduced disease progression and demyelination. Furthermore, mice treated with IFN-β showed improved weight gain. The findings also indicated no notable change in CD200 gene expression across the groups examined. However, the expression of CD200R decreased in the IFN-β-treated group, but significantly increased in the untreated group. Conclusion:Our findings suggest that IFN-β treatment may decrease CD200R expression by reducing inflammation. Additionally, the elevated expression in the untreated group may explain why EAE is self-limiting.

关键词： Adjuvant therapy   Bone marrow microenvironment   IL-17   Immunotherapy   MM progression   Multiple myeloma  

摘要： Multiple myeloma (MM), a plasma cell malignancy, despite the progress in treatment, is still a challenge for both clinicians and affected patients. Modern treatment regimens including monoclonal antibodies, bispecific antibodies, CAR-T cell therapy as well as new generations of immunomodulatory drugs and proteasome inhibitors significantly improved clinical outcomes. Nonetheless, there is still a room for improvement and novel therapeutic strategies. IL-17-related signaling is a relatively undiscovered area in MM research. It was established that IL-17 is the growth factor for plasma cells including their malignant counterparts, is associated with myelomagenesis and disease progression. Furthermore, IL-17 axis can be pharmacologically targeted by monoclonal antibodies currently being used in different indications. In this narrative review we summarized the role of IL-17 axis in MM. Specifically, we focused on the role of IL-17 in MM development and progression with a particular emphasis upon clinical implications. Moreover, we have briefly summarized the potential role of therapeutic interference with IL-17-related singling and have outlined future research directions.

关键词： Bacterial infections   Infectious disease   Pulmonology   Sodium channels   Therapeutics  

摘要： Bacterial pneumonia is the most common cause of acute respiratory distress syndrome (ARDS), characterized by disrupted pulmonary endothelial barrier function, hyperinflammation, and impaired alveolar epithelial fluid clearance. ARDS has a high mortality rate and no proven pharmacological treatments, stressing the need for new targeted therapies. The TIP peptide, mimicking the lectin-like domain of TNF, directly binds to the α subunit of the epithelial Na+ channel, expressed in both alveolar epithelial and capillary endothelial cells, and may increase lung endothelial barrier function and alveolar fluid clearance during bacterial infection. This study tested these potential therapeutic mechanisms of the TIP peptide in a clinically relevant preparation of the ex vivo-perfused human lung injured by Streptococcus pneumoniae. Therapeutic administration of the TIP peptide reduced pulmonary barrier permeability to protein and lung edema formation, increased alveolar edema fluid clearance, and produced an antiinflammatory effect in the airspaces with reductions in IL-6 and IL-8 levels. Additionally, the TIP peptide reduced the translocation of bacteria into the circulation. These findings establish 3 mechanisms of benefit with the TIP peptide to reduce injury in the human lung and support the clinical relevance as a potential therapeutic for pneumococcal bacterial pneumonia.

关键词： Crohn's disease   Omvoh   Skyrizi   Stelara   Tremfya   adverse effects   dosage   drug interactions   efficacy   guselkumab   lactation   mirikizumab   pregnancy   risankizumab   safety   ustekinumab  

摘要： BackgroundGX-I7 (rhIL-7-hyFc, efineptakin alfa) is a hybrid Fc-fused long-acting interleukin-7 (IL-7) with the aim of correcting T-cell deficiency, thereby strengthening the immune response to fight against cancer. This Phase 1b, dose-escalation study was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GX-I7 in patients with locally advanced or metastatic solid *** study, conducted in patients with advanced solid tumours at three hospitals in Korea, involved intramuscular GX-I7 administration across eight dose levels (60-1700 mu g/kg) in 3- and 6-week cohorts. A dose-expansion phase at 720 and 1200 mu g/kg further assessed GX-I7's safety and ***-tumour responses showed either stable disease (SD) or disease progression (PD). GX-I7 demonstrated dose-dependent increases in the maximum serum concentration (Cmax) and area under the curve up to the last measurable concentration (AUClast). In addition, a dose-dependent increase in circulating CD8+/CD4+ T cells was observed. In five patients who consented for biopsy, a statistically significant increase in tumour-infiltrating lymphocytes (TILs) followed GX-I7 *** suggest GX-I7 is a safe T cell-amplifying agent with peripheral immune activation. Ongoing studies are exploring its ability to enhance immune responses in peripheral immune cells and tumour cells when combined with other anti-cancer *** Trial registrationNCT03478995

关键词： anti-inflammatory   diabetes   electrostatic complexation   Il-1Ra   interleukin-1   nanoparticles   protein delivery  

摘要： Diabetes is a prevalent and potentially serious endocrine disorder characterized by elevated blood glucose levels and beta-cell destruction. Interleukin-1 receptor antagonist (IL-1Ra), a competitive inhibitor of the IL-1 receptor, downregulates inflammatory pathways contributing to beta-cell destruction. However, its short half-life (4-6 h) and rapid clearance hinder its clinical effectiveness. In this study, a dual-polymeric system comprising cationic and lipid-based polymers is developed for IL-1Ra delivery. IL-1Ra nanocomplexes (IL-1Ra NCs) are formed through electrostatic interactions, confirmed by SDS-PAGE, TEM, and particle size analysis (167.57 +/- 1.08 nm for IL-1Ra NCs vs 153.21 +/- 1.85 nm for blank NCs) with zeta potentials of +8.66 +/- 0.46 mV versus +24.03 +/- 1.1 mV. In vitro, IL-1Ra NCs demonstrate anti-inflammatory activity against IL-1 beta-induced inflammation in cells. In vivo pharmacokinetic studies show significant improvements in Cmax, AUC, half-life (t1/2), and mean residence time (MRT) for IL-1Ra NCs compared to free IL-1Ra, suggesting reduced dosing frequency and enhanced patient compliance. Mice treated with IL-1Ra NCs exhibit a significant reduction in fasting blood glucose levels (232.25 +/- 23.64 mg dL-1 vs 367.88 +/- 21.83 mg dL-1 in the diabetic control). Furthermore, IL-1Ra NCs preserve beta-cell integrity and exhibit an improved anti-inflammatory response as assessed by H&E and IHC analysis.