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关键词： Breast Cancer   Immunosuppression   Major histocompatibility complex - MHC  

摘要： Background Breast cancer (BC) continues to be a major health concern with 250,000 new cases diagnosed annually in the USA, 75% of which are hormone receptor positive (HR+), expressing estrogen receptor alpha (ER) and/or the progesterone receptor (PR). Although ER-targeted therapies are available, 30% of patients will develop resistance, underscoring the need for new non-ER/estrogen-based treatments. Notably, HR+BCs exhibit poor lymphocyte infiltration and contain an immunosuppressive microenvironment, which contributes to the limited efficacy of immunotherapies in HR+BC. In this study, we demonstrate that PR/progesterone signaling reduces major histocompatibility complex (MHC) Class I expression, facilitating immune evasion and escape from immune-based clearance of PR+*** To determine the effect of PR/progesterone on MHC Class I expression, we treated human and mouse mammary tumor cell lines with progesterone and/or interferon (IFN) and measured expression of genes involved in antigen processing and presentation (APP), as well as surface MHC Class I expression. We used the OT-I/SIINFEKL model antigen system to measure the impact of progesterone on immune cell-mediated killing of modified tumor cells. We also analyzed two large BC clinical cohorts to determine how PR expression correlates with APP gene expression and MHC Class I expression in ER-positive *** In vitro, we show that PR/progesterone signaling reduces APP gene expression and MHC class I expression in human and breast mammary tumor cell lines. PR-mediated attenuation of APP/MHC Class I expression is more pronounced in the presence of IFN. In immune cell killing assays, PR-expressing mammary tumor cells treated with progesterone are protected from immune-mediated cytotoxicity. We demonstrate that PR expression in vivo prevents immune-mediated rejection of xenoantigen-modified mammary tumor cell lines through mechanisms involving MHC Class I expression and CD8 T cells. Data analysis of

关键词： 苓桂术甘汤   阻塞性睡眠呼吸暂停低通气综合征   脾虚湿阻夹瘀   炎症因子   临床疗效  

摘要： 目的：探讨加味苓桂术甘汤（LGZGT）对阻塞性睡眠呼吸暂停低通气综合征（OSAHS）脾虚湿阻夹瘀型患者的干预作用，揭示其可能的功能机制，为临床中医药治疗OSAHS提供理论依据。方法：80例脾虚湿阻夹瘀型OSAHS患者，采取随机对照数字表法，按1:1比例进行随机分组，分为对照组和观察组，每组40例。对照组予一般基础治疗联合多索茶碱片口服治疗，观察组在一般基础治疗上联合加味LGSGT治疗。酶联免疫吸附测定（ELISA）检测血清巨噬细胞移动抑制因子（MIF）、血清微小RNA-223（MIR-223）及白细胞介素-18（IL-18）炎症因子水平，实时荧光定量聚合酶链式反应（RT-qPCR）检测MIF、MIR-223及IL-18基因mRNA表达，治疗2月后，比较两组临床总有效率及治疗前后睡眠呼吸暂停低通气指数（AHI）、夜间最低血氧饱和度(LSpO2)、体质量指数（BMI）、中医证候积分以及MIF、MIR-223及IL-18表达情况；同时分析MIF、MIR-223及IL-18与AHI、LSpO2的相关性。结果：与对照组比较，观察组的临床总有效率明显升高（P=0.000＜0.01，Z=-3.49）；与本组治疗前比较，对照组AHI、LSpO2、BMI、中医症状积分改善及MIF、MIR-223、IL-18因子及其mRNA表达无差异，观察组AHI、BMI、中医证候积分及MIF、IL-18因子及其mRNA表达明显降低，LSpO2明显升高（P＜0.01）；治疗后与对照组比较，观察组AHI、BMI、中医证候积分及MIF、IL-18因子及其mRNA表达明显降低，LSpO2明显升高（P＜0.01）；MIF、IL-18与AHI呈正相关（P＜0.01），与LSpO2呈负相关（P＜0.01）；MIR-223与AHI呈负相关（P＜0.01），与LSpO2呈正相关（P＜0.01）。结论：“加味LGZGT”可能通过降低气道炎症因子水平，减少气道炎症反应，减轻气道水肿及狭窄，改善气道阻塞，从而发挥治疗脾虚湿阻夹瘀型OSAHS的作用。

关键词： 度普利尤单抗   重度哮喘   白细胞介素   单克隆抗体  

摘要： 支气管哮喘作为一类异质性疾病，其主要的特征是慢性气道炎症和气道高反应性。作为一种常见的慢性气道疾病，其给患者生活质量带来了严重的影响。哮喘常规治疗方法为长期使用吸入性糖皮质激素联合长效β2激动剂，对大部分患者治疗效果较好，可以改善肺功能并减少恶化，显著降低急性发作频率和死亡率。但仍有部分重度哮喘患者对常规治疗不敏感，症状仍难以控制，反复急性加重，具有高度的疾病风险，造成了严重社会经济负担，是哮喘致残、致死的主要原因。近年来，多种针对哮喘的生物制剂获批上市，代表药物为抗IgE,抗IL-4受体，抗IL-5/IL-5受体和抗TSLP单抗，这些均能够有效地应用于2型重度哮喘疾病的治疗。《全球哮喘防治倡议》推荐，在经第4级治疗仍不能控制的重度哮喘的治疗中，可以将上述生物制剂作为附加治疗药物。在我国上述药物纷纷获批应用于临床。度普利尤单抗作为一种新型生物制剂，针对IL-4受体达到阻断IL-4和IL-13双通路效果，前期数据表明其对于治疗重度哮喘患者有显著疗效，能够明显改善患者肺功能，可有效控制患者哮喘，但目前临床上真实世界数据还比较少，其有效性和安全性仍有待进一步探究。本文就度普利尤单抗在真实世界重度哮喘治疗中的作用及研究进展做一综述。

关键词： gout   IL-6   JAK2   STAT1   stat3   inflammation  

摘要： Background Interleukin-6 (IL-6) is a pleiotropic cytokine, with specific effects depending on the immune microenvironment. Extensive research has confirmed the pathological roles of the IL-6/JAK2/STAT1/3 signaling pathway in inflammation, autoimmunity, and cancer, as well as its involvement in the pathogenesis of various rheumatic diseases. However, the role and impact of IL-6 as an upstream regulator of the JAK2-STAT1/3 pathway in gout have seldom been reported. This study explores the influence and role of upstream IL-6 in regulating the JAK2-STAT1/3 signaling pathway on gout inflammation, offering new insights for targeted therapeutic interventions and drug development in gout *** and Results Clinical data and peripheral blood specimens were collected from gout patients and healthy individuals. In vitro and in vivo models of acute gout inflammation were established by stimulating PBMCs, THP-1 cells, and mice with MSU crystals. IL-6 expression was manipulated using IL-6 agonists and IL-6 knockout (KO) mouse technology to investigate the role and impact of the IL-6-mediated JAK2-STAT1/3 signaling pathway in gout models. RT-qPCR, WB, and ELISA were utilized to assess gene and protein expression levels. Paw swelling in mice was measured using a caliper gauge, while HE and IHC staining were conducted to evaluate the inflammatory status of mouse paw pad synovial tissues and detect the positive expression of relevant proteins. Serum IL-6 protein expression levels were significantly elevated in patients with gouty arthritis (GA) compared to healthy individuals, with multifactor logistic regression revealing an odds ratio (OR) of 2.175 for IL-6. In GA patients, mRNA expression of IL-6, JAK2, STAT1/3, and IL-1 beta was notably lower in the gout group compared to the healthy control (HC) group. Moreover, IL-6, JAK2, STAT1/3, p-JAK2, p-STAT1/3, and IL-1 beta proteins were markedly higher in the acute gout (AG) group compared to the intercritical gout (IG) and

关键词： 流行性出血病病毒   VP7蛋白   蛋白表达与纯化   单克隆抗体  

摘要： 流行性出血病是由流行性出血病病毒(EHDV)经库蠓叮咬传播感染牛、羊、鹿等反刍动物的非接触性传染病，EHDVVP7蛋白是该病诊断的靶标蛋白。本研究参照GenBank中已发表的基因序列经密码子优化后人工合成EHDVVP7基因，将该基因克隆至表达质粒pET-28a，构建重组质粒pET-EHDV VP7，将其转化大肠杆菌感受态细胞BL21(DE3)，以IPTG诱导表达且优化表达条件，通过Ni-NTA亲和层析法对表达的VP7蛋白进行纯化并用不同浓度咪唑透析复性，用复性后的VP7蛋白免疫BALB/c小鼠，利用杂交瘤技术制备抗VP7蛋白单克隆抗体。通过间接酶联免疫吸附试验、免疫印迹和细胞免疫荧光试验验证单克隆抗体的特异性。结果显示，利用大肠杆菌表达系统成功表达重组EHDVVP7蛋白，纯化后制备了2株稳定分泌针对EHDVVP7蛋白的单克隆抗体，分别命名为1D10和3C11，这2株单克隆抗体不仅能与大肠杆菌表达的重组EHDVVP7蛋白反应，而且也能与真核细胞表达的重组EHDVVP7蛋白结合，同时这2株单克隆抗体与重组蓝舌病毒VP7蛋白和重组非洲马瘟病毒VP7蛋白不发生反应。本研究成功表达和纯化出了重组EHDV VP7蛋白，制备了特异性抗VP7蛋白单克隆抗体，这为研究EHDV VP7 蛋白的结构功能以及诊断方法的建立奠定了基础。

关键词： 脓毒症   预测模型   细胞因子   淋巴细胞亚群  

摘要： 目的：观察淋巴细胞亚群计数与部分细胞因子、常用临床生物标志物及重症评分对早期脓毒症患者28天预后的影响，探讨对早期脓毒症患者预后最具价值的生物标志物。方法：回顾性分析2021年至2023年连云港市第一人民医院急诊重症监护室收治的脓毒症患者的临床资料。随机抽取病例，70%作为发现队列，30%作为验证队列。将所有变量分为3组，运用7种不同的方式筛选出最终预测变量。采用多因素逻辑回归模型计算出所有组合受试者工作特征曲线（ROC）及曲线下面积（AUC）并筛选出最佳预测变量，通过取交集方式获得最具价值的生物标志物。结果：最终纳入脓毒症患者405例。28 d存活273例，死亡132例，病死率为32.59%。基于发现队列数据分别采用7种变量筛选模式，在纳入综合变量组后所构建模型在验证队列的 ROC曲线下面积（AUC）均在0.888以上。通过取交集方式获得对预后最具价值的生物标志物包括：年龄、白细胞计数(WBC)、C反应蛋白(CRP)、血乳酸(Lac)、合并肺部感染、APACHEⅡ评分、SOFA评分。结论：淋巴细胞亚群计数与部分细胞因子对早期脓毒症患者预后影响不大，以年龄、WBC、CRP、Lac、合并肺部感染、APACHEⅡ评分、SOFA评分构建的多因素逻辑回归模型能够较好预测早期脓毒症患者预后。

关键词： Cytokine   Immunotherapy   Macrophages   Mesothelioma   Tolerance  

摘要： Background Colony stimulating factor-1 receptor (CSF-1R) and its ligands CSF-1 and interleukin (IL)-34 have tumorigenic effects through both induction of suppressive macrophages, and survival/proliferation of tumor cells. In addition, the IL-34 tumorigenic effect can also be mediated by its other receptors, protein-tyrosine phosphatase zeta, Syndecan-1 (CD138) and triggering receptor expressed on myeloid cells 2. Small tyrosine kinase inhibitors are used to block CSF-1R signaling but lack specificity. Neutralizing anti-CSF-1 and/or IL-34 antibodies have been proposed, but their effects are limited. Thus, there is a need for a more specific and yet integrative *** A human mutated form of the extracellular portion of CSF-1R was in silico modelized to trap both IL-34 and CSF-1 with higher affinity than the wild-type CSF-1R by replacing the methionine residue at position 149 with a Lysine (M149K). The extracellular portion of the mutated CSF-1R M149K was dimerized using the immunoglobulin Fc sequence of a silenced human IgG1 (sCSF-1RM149K-Fc). Signaling through CSF-1R, survival of monocytes and differentiation of suppressive macrophages were analyzed using pleural mesothelioma patient's samples and mesothelioma/macrophage spheroids in vitro and in vivo in the presence of sCSF-1RM149K-Fc or sCSF-1R-Fc wild type control (sCSF-1RWT-Fc).Results We defined that the D1 to D5 domains of the extracellular portion of CSF-1R were required for efficient binding to IL-34 and CSF-1. The mutein sCSF-1RM149K-Fc trapped with higher affinity than sCSF-1RWT-Fc both CSF-1 and IL-34 added in culture and naturally produced in mesothelioma pleural effusions. sCSF-1RM149K-Fc inhibited CSF-1R signaling, survival and differentiation of human suppressive macrophage in vitro and in vivo induced by pleural mesothelioma cells. Neutralization of IL-34 and CSF-1 by sCSF-1RM149K-Fc also resulted in higher killing of pleural mesothelioma cells by a tumor-specific CD8+ T cell clone in mesot

关键词： interleukin 10   cancer immunotherapy   pegylated IL-10   IL-10 fusion proteins and delivery systems   engineered IL-10 variants  

摘要： Cytokine-based immunotherapy has revolutionized cancer treatment;however, its efficacy remains limited by insufficient tumor immune infiltration and resistance mechanisms within the tumor microenvironment. Among these cytokines, interleukin-10 (IL-10) has garnered significant interest due to its dual roles in cancer biology, exhibiting both tumor-suppressive and tumor-promoting properties. Despite these contrasting effects, sustained IL-10 signaling has emerged as a promising strategy for cancer immunotherapy, as it effectively activates and expands tumor-specific cytotoxic CD8+ T cells while concurrently mitigating tumor-associated inflammation. This unique anti-tumor multifunctionality positions IL-10 as a compelling candidate for next-generation cancer immunotherapy, particularly in combination regimens with immune checkpoint inhibitors or other immunomodulatory agents. To harness its anti-tumor therapeutic potential and enhance clinical applicability, various bioengineering strategies are being actively explored, with PEGylation serving as a key advancement in improving IL-10's stability, half-life, and pharmacokinetics. Furthermore, innovative delivery platforms, including fusion proteins, bispecific constructs, and nanoparticle-based formulations, are being developed to optimize tumor-specific targeting and therapeutic efficacy. This review critically examines recent progress, ongoing challenges, and emerging advancements in IL-10-directed cancer immunotherapy, highlighting the need for refined delivery strategies, enhanced intratumoral targeting, and synergistic combination approaches. Continued research and technological innovation are imperative to unlock the full therapeutic potential of IL-10, paving the way for more effective and durable cancer immunotherapies across diverse malignancies.

摘要： Pancreatic ductal adenocarcinoma (PDAC) has a poor survival rate and limited treatments. Agonistic CD40 antibodies are promising, but clinical trials have shown only modest efficacy and significant hepatotoxicity. We previously reported that IL-1 pathway blockade enhances agonistic CD40 antibody efficacy against melanoma by depleting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs; CD11bLy6CLy6G). Because PMN-MDSCs also cause liver toxicity, we investigated the impact of IL-1R1 blockade on the efficacy and toxicity of agonistic CD40 antibody therapy in PDAC. Agonistic CD40 antibody therapy induced immune activation and significantly prolonged survival in orthotopic PDAC-bearing mice. IL-1R1 blockade monotherapy downregulated innate and adaptive immune response and exacerbated tumor growth. Although combination therapy upregulated several immune-related pathways and boosted innate and adaptive immune responses. IL-1R1 blockade failed to improve the overall antitumor efficacy of agonistic CD40 antibody therapy and exacerbated liver toxicity. Ly6G cell depletion in mice reduced the efficacy of agonistic CD40 antibody therapy, suggesting that Ly6G immune cells (PMN-MDSCs or neutrophils) exhibit an antitumor rather than immunosuppressive role in PDAC. Our findings underscore the complex role of IL-1 signaling in modulating immune responses in PDAC and caution against pursuing IL-1R1 blockade, either as monotherapy or combined with agonistic CD40 antibodies, in clinical trials for PDAC.