课程文献中心 更多>>

关键词： Proteinase 3   IL33   Tumor-associated macrophages   Regulatory T cells   Tumor immunotherapy  

摘要： The immunosuppressive tumor microenvironment (TME) shaped by tumor-associated macrophages (TAMs) is essential for lung adenocarcinoma (LUAD) immune tolerance and tumor progression. Here, we first reported that proteinase 3 (PRTN3) promoted the alternative activation (M2) of TAMs and enhanced IL33/regulatory T cells (Tregs)-mediated tumor immunosuppression in LUAD. Firstly, clinical analysis revealed PRTN3 was highly expressed in TAMs and correlated with the tumor progression and poor prognosis in LUAD patients. Meanwhile, by using the myeloid cells-specific Prtn3-knockout mouse model, we demonstrated Prtn3 deficiency in macrophages remolded the immunosuppressive TME and suppressed tumor growth. The mechanism studies uncovered a novel signaling pathway that PRTN3 up-regulated IL33 expression in TAMs by suppressing AKT-mediated ubiquitinated degradation of FOXO1, which subsequently activated Il33 transcription. Furthermore, lack of PRTN3 or FOXO1 in macrophages greatly restrained IL33-induced Treg differentiation. Importantly, selective knockout of Prtn3 in macrophages significantly enhanced the antitumor effect of anti-PD1 therapy in the mouse model of LUAD. Thus, our work demonstrated that PRTN3 in macrophages, served as a key immunoregulator, contributed to impede the antitumor immune response through reinforcing the TAMs/Tregs crosstalk, which provided valuable insights to improve the immunotherapeutic effect by functional remodeling of TAMs to alleviate immunosuppression in LUAD.

关键词： IL-23 p19 inhibitors   inflammatory bowel disease   IBD pharmacotherapy   remission   adverse events  

摘要： Background: The treatment outcomes of inflammatory bowel disease (IBD) have been significantly improved by the advent of new biologics, including ulcerative colitis (UC) and Crohn's disease (CD), particularly for refractory cases. However, the growing number of therapeutic options has also complicated clinical decision-making regarding drug selection and switching. The overall performance of IL-23 p19 inhibitors for the treatment of IBD was evaluated by the systematic review and meta-analysis in this study. Objective: The objective of this study was to combine the multiple indicators to accurately evaluate the efficacy and safety of IL-23 p19 inhibitors, aimed to offer an insight into the development of clinical physicians' medication. Methods: A comprehensive literature review on PubMed, Embase, Web of Science, and Cochrane Library until June 2024 was conducted in this study, which mainly focused on the randomized controlled trials (RCTs) to evaluate the IL-23 p19 inhibitors within adult patients with UC or CD. Additionally, the clinical outcomes, endoscopic findings, histological assessments, and safety profiles were aggregated and subjected to analysis by a random-effects model. Results: Twenty-five RCTs [15 CD, 10 UC] were involved in this study, and it was revealed that IL-23 p19 inhibitors showed significant effects on clinical remission (CR) in IBD, regardless of induction or maintenance treatment (CD, induction: risk ratio [RR] 1.95, 95% confidence interval [CI] 1.71-2.23;I-2 = 0%, p = 0.68;UC, induction: RR 2.69, 95% CI 1.80-4.03;I-2 = 50%, p = 0.09;CD, maintenance: RR 1.24, 95% CI 1.04-1.48;I-2 = 0%, p = 0.57;UC, maintenance: RR 2.62, 95% CI 0.92-7.49;I-2 = 42%, p = 0.19), and the risk of adverse events (AEs) was similar to that of placebo (CD, induction: RR 0.88, 95% CI 0.82-0.94;I-2 = 2%, p = 0.41;UC, induction: RR 0.92, 95% CI 0.82-1.03;I-2 = 0%, p = 0.54;CD, maintenance: RR 1.00, 95% CI 0.89-1.13;I-2 = 29%, p = 0.25;UC, maintenance: RR 0.96, 95% CI 0.8

关键词： serum IL-10   RSV   RV   bronchiolitis   serum IFN-gamma  

摘要： Respiratory syncytial virus (RSV) and rhinovirus (RV)-the two primary causative viruses of bronchiolitis in children-have been studied extensively in terms of their associations with disease severity and serious late disease outcomes. In this study, we explored the differences in the clinical values of IFN-gamma and IL-10 serum levels in RSV and RV bronchiolitis in the Bulgarian childhood population. Eighty-eight children with acute bronchiolitis, aged two months to two years, who were admitted to the General Pediatrics Clinic of University Hospital "Prof. St. Kirkovich", Stara Zagora, Bulgaria served as this study's subjects. The degree of wheezing and respiratory failure were classified. Naso-pharyngeal swabs were collected from all participants, and molecular identification of viruses was performed using real-time PCR. Serum samples were used to determine IFN-gamma and IL-10 quantities using ELISA kits, and data are presented as the median IQR (25-75%). The total serum IL-10 levels were significantly enhanced in RSV-infected children compared to those infected with RV (14.4 (12.2-24.0) vs. 8.9 (7.2-12.5);p < 0.001) and the other viral bronchiolitis groups (14.4 (12.2-24.0) vs. 6.65 (3.9-15.3);p = 0.003). The highest IL-10 levels (14.4 (12.8-27.9)) were found in RSV-positive patients with first-degree respiratory failure. Almost identical serum IFN-gamma levels were determined for RSV- and RV-positive bronchiolitis patients (3.2 (1.6-6.8) and 2.8 (1.1-7.3);p = 0.781). Variance analysis of IL-10 serum levels revealed statistically significant differences among the patient groups depending on the type of viral infection, concerning respiratory failure (p = 0.005) and wheezing severity (p = 0.017). Our findings show that the IL-10 levels and the type of virus have a combined effect on disease severity. These data might contribute to patients' personalized/individualized therapy and the prevention of recurrent wheezing later in life.

关键词： 白癜风   血小板活化因子(PAF)   T淋巴细胞   疾病活动  

摘要： 目的 探讨白癜风患者血清血小板活化因子（PAF）水平、T细胞免疫功能与疾病活动的关系。方法 选择2022-07-18/2023-07-26在我院就诊的白癜风患者102例作为研究对象，根据白癜风疾病活动度评分（VIDA）将患者分为进展期（n=54）和稳定期（n=49），对比两组患者PAF及T淋巴细胞水平，Logistic回归分析PAF水平与疾病活动的关系及其与T细胞亚群的相关性。采用非条件Logistic回归模型分析PAF水平与T细胞亚群在疾病活动中的交互作用。结果 进展期和稳定期患者CD3+水平无显著差异，进展期组患者PAF及CD8+水平显著高于稳定期组患者，CD4+、CD4+/CD8+水平则显著低于稳定期组；PAF水平评估白癜风患者疾病活动，PAF水平为18.24 ng/L时约登指数（0.670）最高，对应灵敏度和特异度分别为84.22%、82.77%，受试者工作特征（ROC）曲线下面积AUC为0.858；PAF水平与疾病活动的关联强度呈非线性剂量-反应关系（非线性检测）；当VIDA评分≥1时，不同PAF水平白癜风患者CD4+及CD8+水平具有显著差异，不同VIDA评分白癜风患者不同PAF水平间CD4+/CD8+均具有差异显著；交互作用分析调整混杂因素后PAF水平与T细胞亚群对白癜风患者疾病活动影响在相加模型[相对超额危险度（RERI）=4.674，95%置信区间（CI）：1.032～11.942；交互作用归因比（AP）=0.763，95%CI：0.336～1.201；交互作用指数（S）=6.854，95%CI：1.904～16.520)]和相乘模型[比值比（OR）相乘=3.461，95%CI：1.365～8.713)]中存在交互作用。结论 白癜风患者血清PAF、CD4+、CD8+水平及CD4+/CD8+比值与疾病活动密切相关，且PAF水平与T细胞亚群(CD4+、CD8+、CD4+/CD8+)在白癜风患者疾病活动中存在交互作用。PAF水平对白癜风患者疾病活动具有一定评估价值。

关键词： NA蛋白   单克隆抗体   中和活性  

摘要： 流感病毒是分节段的负链RNA病毒，高致病性禽流感病毒可导致严重的致死性疾病，已给全球禽类养殖及相关产业造成了巨大损失，并对人类健康造成了极大威胁，流感病毒表面的NA蛋白与流感病毒的功能息息相关，NA蛋白由RNA片段6编码，NA蛋白的主要作用是在新生病毒粒子从细胞膜表面出芽的阶段切割病毒和细胞膜糖蛋白的SA结合以避免病毒粒子的聚集从而从被感染细胞表面释放。为获得NA单克隆抗体为后续实验提供帮助，本实验以H1N1-WSN-NA蛋白质粒作为免疫原免疫小鼠，取高血清效价的小鼠脾细胞与SP2/0细胞融合，通过构建真核表达重组质粒pCAGGS-NA转染293T细胞来瞬时表达NA蛋白作为检测原，并用间接免疫荧光试验（IFA）和WB（Western-blot）试验筛选阳性杂交瘤细胞，最终得到2株识别NA蛋白的单克隆抗体细胞，分别命名为2F1-37-5和3G7-50-7，其中2F1-37-5展现出1:128倍比稀释度的中和活性，说明本试验成功制备出具有高纯度、强特异性、良好反应性的NA蛋白单克隆抗体，为流感病毒防治研究提供了重要工具。

关键词： drug survival   elderly   IL-17 inhibitors   IL-23 inhibitors   psoriasis  

摘要： Biologic therapies targeting interleukin (IL)-17 and IL-23 have transformed psoriasis treatment, yet real-world evidence on the impact of age on treatment responses and drug survival is limited. This study aims to compare early (12/16 weeks), mid term (24 weeks) and long term (52 weeks) Psoriasis Area and Severity Index (PASI) responses and drug survival in psoriasis patients aged < 65 versus >= 65 years receiving IL-17 or IL-23 inhibitors. In this retrospective study, 121 patients with moderate-to-severe plaque psoriasis treated with secukinumab, ixekizumab, guselkumab, or risankizumab were analyzed. Patients were stratified into two age groups (< 65, n = 78;>= 65, n = 43). PASI75, PASI90, and PASI < 2 outcomes were assessed at 12/16, 24, and 52 weeks. Drug survival was evaluated via Kaplan-Meier analysis (censoring at 24 months) and Cox regression was used to identify predictors of discontinuation. At 12/16 weeks, the < 65 group achieved significantly higher PASI75 (90.5% vs. 65.1%, p = 0.010), PASI90 (75.7% vs. 32.6%, p = 0.030) and PASI < 2 (55.8% vs. 79.7%, p = 0.006) responses than the >= 65 group. At 52 weeks, PASI75, PASI90, and PASI < 2 rates were similar between groups (86.3% vs. 97.5%, p = 0.055;78% vs. 90%, p = 0.112;85.1% vs. 92.5%, p = 0.253). There were no significant differences between IL-17 and IL-23 inhibitors within any age group. Overall drug survival at 24 months was high (79.6% for < 65 and 90.3% for >= 65, log-rank p = 0.407), with no difference between biologic classes (mean survival: 21.8 vs. 22.4 months, p = 0.520). In Cox regression, female sex (HR 0.23, p = 0.005) and higher baseline PASI (HR 1.093 per point, p = 0.013) predicted discontinuation, whereas age, biologic class, BMI, and prior biologic use were not significant. Despite a delayed initial response, older patients achieve long-term PASI outcomes comparable to younger patients when treated with IL-17 and IL-23 inhibitors. Drug survival is similarly excellent across age groups an

关键词： Regional inequality   Public intervention   Institutions   Passive modernisation   Decentralisation   Italy   N14   N94   O43  

摘要： This study examines the impact of the decentralisation of a large regional development programme for Southern Italy, the Cassa per il Mezzogiorno, through the lens of the passive modernisation hypothesis (Felice and Vasta, Eur Rev Econ Hist 19(1):44-66, 2015). It focuses on the role of local institutions in exacerbating regional inequalities and hindering Southern economic growth. This paper tests the hypothesis that the devolution of the public investment programme undermined its effectiveness, actively damaging regional convergence. Using the synthetic control method, the results reveal that the decentralisation of developmental policies in 1971 led to an 11% total loss in GDP per capita for Southern Italy in the following decade, shedding new light on the resurgence of the Italian regional divide in the latter half of the twentieth century.

关键词： TAG-72   fusion proteins   colon cancer   breast cancer   radiation therapy   immunotherapy  

摘要： Background/Objectives: Immunocytokines (ICKs) are antibody-cytokine fusion proteins that deliver cytokines directly to tumors to increase immune responses, which are otherwise absent or limited by the delivery of antibodies alone. Tumor-associated glycoprotein-72 (TAG72) is overexpressed in numerous solid tumors. Methods: An anti-TAG72-IL-2 fusion protein was expressed in mammalian cells and tested in vitro for binding and bioactivity, and in vivo in two models. Results: In vitro studies showed high antigen specificity against TAG-72-positive tumor cell lines and IL-2 activity in CD25 (IL-2R)-positive reporter cells. To study the anti-tumor activity of huCC49-IL-2 in an immunocompetent model, the TAG-72 expression was established in murine mammary and colorectal cells by transfection with murine st6galnac-I gene (mSTn). Four daily doses of anti-TAG72-IL-2 monotherapy for TAG-72-expressing orthotopic murine mammary tumors in immunocompetent mice resulted in minimal whole-body toxicity and significant tumor growth reduction mediated by tumor infiltration of IFN gamma+ CD8+ T cells. When mammary tumors were pretreated with image-guided fractionated radiation therapy (IGRT) followed by anti-TAG72-IL-2 therapy, an improved tumor growth inhibition was observed along with an increased tumor infiltration of IFN gamma+ CD8+ T cells and a significant reduction in Foxp3+ CD4+ cells. Anti-TAG72-IL-2 monotherapy in TAG-72+ colorectal tumors led to a significant tumor reduction but also cures (4/7), with a rejection of rechallenges with both TAG-72-positive and -negative MC38 cells, thus demonstrating evidence of immune memory and antigen spreading. Conclusions: antiTAG-72-IL-2 therapy showed strong anti-tumor effects driven by activated CD8+ T cells making it a promising approach to the treatment of TAG-72+ tumors.