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关键词： Maternal obesity   fetal programming   vascular function   endothelial homeostasis   hypertension  

摘要： This study investigated the impact of maternal high-fat diet on vascular function and endothelial homeostasis in offspring. We found that offspring exposed to maternal high-fat diet exhibited elevated blood pressure, impaired abdominal aortic vascular function, and endothelial homeostasis imbalance. These changes were accompanied by increased levels of reactive oxygen species (ROS) and upregulation of pro-inflammatory cytokines (including IL-1 beta, TNF-alpha, IL-6, and IL-10). Treatment with NLRP3 or IL-1 beta inhibitors prevented the deterioration in vascular function, reduced endothelial NO production, and inflammation induced by maternal high-fat diet exposure compared to the control group. The findings suggest that during pregnancy, mitigating the vascular impairments in offspring induced by maternal high-fat diet can be achieved by inhibiting the NLRP3/IL-1 beta pathway.

关键词： Interleukin-8   urological cancers   biomarker   prognosis   meta-analysis  

摘要： BackgroundInterleukin-8 (IL-8) is a key cytokine that has been implicated in multiple aspects of cancer progression and therapeutic resistance. Elevated levels of circulating IL-8 (cIL-8) have been implicated in adverse clinical outcomes among patients with urological cancers. However, definitive evidence consolidating these observations remains lacking. The present study aims to synthesize the existing research findings to provide a comprehensive, evidence-based reference for clinical *** systematic literature search was conducted to identify relevant studies that reported on the prognostic impact of cIL-8 levels in urological cancer patients. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were extracted and pooled to estimate the overall effect. Furthermore, Kaplan-Meier's survival analyses were conducted using RNA-seq data from The Cancer Genome Atlas (TCGA) through the Gene Expression Profiling Interactive Analysis 2 (GEPIA 2) online tool to validate the observed *** total of 19 cohorts encompassing 2740 patients from 12 studies were included in the meta-analysis. The findings revealed that elevated cIL-8 levels were significantly associated with inferior OS (HR: 1.86;95% confidence intervals (CI): 1.72-2.02) and PFS (HR: 1.59;95%CI: 1.25-2.03) in patients with urological cancers. The consistency and validity of these results were further supported by survival analyses performed using the GEPIA 2 *** study, which is the first meta-analysis to systematically examine the prognostic significance of cIL-8 in urological cancers, supported by bioinformatics validation, confirms that elevated cIL-8 levels serve as a potential biomarker for predicting adverse outcomes. Our findings underscore the importance of targeting IL-8 as a therapeutic strategy to overcome treatment resistance and improve outcomes for urological cancer patients. Further research into IL-8-targeted therapies and the

关键词： Interferon gamma   Fas   tumor immunotherapy   membrane-bound form   secretory form  

摘要： Interferon gamma (IFN gamma) is well-known for its ability to stimulate immune cells in response to pathogen infections and cancer. To develop an effective cancer therapeutic vaccine, CT26 colon carcinoma cells were genetically modified to express IFN gamma either as a secreted form (sIFN gamma) or as a membrane-bound form. For the membrane-bound expression, IFN gamma was fused with Fas (mbIFN gamma/Fas), incorporating the extracellular cysteine-rich domains, transmembrane, and cytoplasmic domains of Fas. The tumor cells expressing sIFN gamma and mbIFN gamma/Fas showed slower growth rates compared to the mock-transfected cells. Furthermore, the tumorigenicity of the CT26 cells expressing mbIFN gamma/Fas was significantly lower than that of cells expressing sIFN gamma or the mock control. Remarkably, about 85% of the mice injected with the mbIFN gamma/Fas-expressing tumors remained tumor-free for over two months. Mice that rejected mbIFN gamma/Fas-expressing tumors developed systemic anti-tumor immunity against CT26 cells, which was characterized by enhanced levels of CD4+ and CD8+ T cells, as well as natural killer (NK) cells. Interestingly, splenocytes activated with the mbIFN gamma/Fas-expressing tumors exhibited higher cytotoxicity than those activated with tumor cells expressing sIFN gamma. These findings suggest that expressing the mbIFN gamma/Fas chimera in tumor cells could be a promising strategy for developing whole tumor cell vaccines or gene therapies for cancer immunotherapy.

关键词： italic>Parvimonas micra   host-microbe interaction   colorectal cancer   tumor microenvironment  

摘要： Parvimonas micra (Pm), a periodontal pathogen, has been implicated in the impairment of anti-tumor responses in colorectal cancer (CRC). The tumor microenvironment in CRC involves tumor-associated macrophages (TAMs), which are pivotal in modulating tumor-associated immune responses. The polarization of TAMs towards an M2-like phenotype promotes CRC progression by suppressing the immune system. However, the mechanisms by which Pm affects the progression of CRC remain inadequately elucidated. In this study, we explored the impact of Pm infection on CRC cell characteristics, including proliferation, chemoresistance, migration, and macrophage polarization. We found that Pm-infected THP-1-derived macrophages exhibited elevated interleukin-10 levels, a well-established M2 marker. Conditioned media from Pm-treated THP-1 cells significantly enhanced CRC cell proliferation, cisplatin resistance, and migration, and interleukin-8 was identified as a key factor. Consistent with the in vitro results, an azoxymethane/dextran sodium sulfate mouse model treated with oral Pm showed accelerated CRC tumor growth. These results offer mechanistic insights into the influence of Pm infection on tumor microenvironment in CRC through M2-like macrophage polarization. The identified pathways may serve as potential targets for therapeutic interventions for CRC.

关键词： CHIKV   gut microbiota   interferon   gastrointestinal infection   integrative analysis  

摘要： Chikungunya virus (CHIKV) infection causes joint damage and gastrointestinal clinical symptoms, including vomiting and diarrhea, particularly in elderly populations, reflecting the potential role of gut immunity in infection. However, the mechanisms by which CHIKV induces gastrointestinal diseases remain largely unexplored. This study investigated the characteristics of fecal and gut microbiota, gut metabolites, and gut immunity post-infection using multi-omics analysis. The role of gut microbiota was further validated through Oral antibiotic depletion (Abx). Importantly, a systematic comparison of age-dependent differences in gut microbiota composition and immune responses following CHIKV infection was conducted to elucidate the involvement of gut microbiota in CHIKV pathogenesis. CHIKV joint inoculation induces gastrointestinal infection and histological damage, drives fluctuations in gut microbiota, markedly increasing the abundance of Bacteroides fragilis and Prevotella sp. and upregulates conjugates of taurine and bile acids. CHIKV infection further exacerbates systemic inflammatory burden and activates intestinal interferon (IFN) signaling cascades, which supports gut repair and mucosal regeneration, but low antiviral responses to CHIKV infection compared with that of adult animals. Our results suggest that the gastrointestinal tract, along with its microbes and metabolites, modulates CHIKV infection in an age-dependent manner, providing critical insights for diagnosis, treatment, and novel therapeutic development.

关键词： Immunotherapy   immune checkpoint inhibitor   IL-2R agonist   T and NK cell exhaustion   IgG-binding domain  

摘要： As T and NK cell exhaustion is attributed to increased expression of immune checkpoints and decreased production of proliferative cytokines by these cells, immune checkpoint-targeted delivery of proliferative cytokines might induce robust and sustained antitumor immune responses. Here, the expression profile of NKG2A was first found to be narrower than that of PD-1 in tumor-infiltrated immune cells. Moreover, unlike PD-1, NKG2A was predominantly co-expressed with IL-2R beta gamma in tumor-infiltrated CD8+ T and NK cells, but not in Tregs, suggesting that NKG2A might be an ideal target for delivery of IL-2R beta gamma agonists to overcome T and NK exhausting. For NKG2A-targeted delivery of an IL-2R beta gamma agonist, a single molecule of de novo designed N215 endowed with Immunoglobin G(IgG)-binding ability was coupled to an antibody against NKG2A (alpha NKG2A) to produce alpha NKG2A-N215. NKG2A- and IL-2R beta gamma-binding were well preserved in alpha NKG2A-N215, allowing alpha NKG2A-N215 to act as both an immune checkpoint inhibitor and a T and NK cell stimulator. Intravenously injected alpha NKG2A-N215 predominantly induced expansion of tumor-infiltrated CD8+ T and NK cells while showing little stimulation of Tregs. Compared with the separate combination using alpha NKG2A and N215, alpha NKG2A-N215 exerted a greater antitumor effect in mice bearing MC38 or B16/F1 tumors. 50% of mice bearing MC38 tumors were cured by alpha NKG2A-N215, and long-term immunological memory against the tumor was induced in these mice. These results indicate that NKG2A is another ideal target for delivery of an IL-2R beta gamma agonist, and alpha NKG2A-N215, with specificities for both NKG2A and IL-2R beta gamma, might be developed as a novel agent for immunotherapy.

关键词： Chronic hepatitis B   peginterferon alpha-2a   hepatitis B surface antigen clearance   B-cell  

摘要： Background B-cell may participate in the cellular immune process of hepatitis B antigen clearance. However, the function and specific mechanism of B-cell during interferon-pegylated interferon alpha-2a (Peg-IFN-alpha) treatment in chronic hepatitis B (CHB) patients have not yet been described. Methods A total of 150 CHB patients enrolled in this study, who received 48 weeks of Peg-IFN alpha treatment. The differentiation clusters CD19, CD24, CD27, CD38, CD40, and CD80 of B cell surface markers in CHB patients were detected by flow cytometry. Spearman correlation and Logistic regression analysis were performed for the analysis. Results The clearance rate of HBsAg increased significantly with the duration of Peg-IFN-alpha treatment, reaching 32.2% by 48 weeks. During the Peg-IFN-alpha therapy, the frequency of B-cell and its subsets increased significantly. However, we did not observe any significant difference in the frequency of the B-cell and its subsets in patients with or without HBsAg clearance after 48 weeks Peg-IFN-alpha treatment. The change in HBsAg value was negatively related to the change in plasmablasts (CD19(+)CD38(+)) level before and after 48 weeks treatment (r = -0.326, p = 0.006). Moreover, the results showed that HBsAg <288.70 IU/mL at baseline and HBsAg <58.05 IU/mL at 12 weeks were strong predictors of HBsAg clearance in patients with 48 weeks Peg-IFN-alpha treatment. Conclusion The remodeling of B cell subsets, especially plasmablasts (CD19(+)CD38(+)), during Peg-IFN-alpha treatment was closed associated with the clearance of hepatitis B antigen.

关键词： Anti-IL-23   anti-IL-17   psoriasis   neoplasms  

摘要： Background: Interleukin (IL) inhibitors are increasingly used in the management of moderate-to-severe plaque psoriasis. However, their use in patients with a history of cancer is ***: We conducted a multicenter retrospective study across nine Italian Dermatology Units to assess the real-world effectiveness and safety of IL inhibitors (IL-23, IL-17, IL-12/23) in 136 oncological patients with moderate-to-severe plaque psoriasis. In particular, we evaluated 116 patients who developed the neoplasm before starting the biologic with a mean time from diagnosis of neoplasia to the first biologic dose of 8.31 years. We also assessed 20 patients who received a diagnosis of neoplasm during treatment with IL inhibitors after a mean time of 2.41 years from the start of the biologic with a cumulative incidence of 3.06 per 1000 ***: Three patients experienced neoplasm recurrence during treatment with IL inhibitors, which led to the discontinuation of these drugs. In our study, biologics have demonstrated safety and effectiveness as treatment options for patients with both a history of neoplasm and those with concurrent tumors. However, further investigation is needed, particularly through larger and longer multicenter studies.

关键词： Group A Streptococcus   immunization   protective immunity   adaptive immune memory   innate immune memory  

摘要： Group A Streptococcus (GAS;Streptococcus pyogenes) is an important bacterial pathogen causing over 700 million superficial infections and around 500.000 deaths due to invasive disease or severe post-infection sequelae yearly. In spite of this major impact on society, there is currently no vaccine available against this bacterium. GAS strains can be separated into >250 distinct emm (M)-types, and protective immunity against GAS is believed to in part be dependent on type-specific antibodies. Here, we analyse the nature of protective immunity generated against GAS in a model of intraperitoneal immunization in mice. We demonstrate that multiple immunizations are required for the ability to survive a subsequent lethal challenge, and although significant levels of GAS-specific antibodies are produced, these are redundant for protection. Instead, our data show that the immunization-dependent protection in this model is induced in the absence of B and T cells and is accompanied by the induction of an altered acute cytokine profile upon subsequent infection, noticeable e.g. by the absence of classical pro-inflammatory cytokines and increased IFN-gamma production. Further, the ability of immunized mice to survive a lethal infection is dependent on macrophages and the macrophage-activating cytokine IFN-gamma. To our knowledge these findings are the first to suggest that GAS may have the ability to induce forms of trained innate immunity. Taken together, the current study proposes a novel role for the innate immune system in response to GAS infections that potentially could be leveraged for future development of effective vaccines.

关键词： Advanced cancer   HLA subtype   immune checkpoint   predictive biomarkers  

摘要： Specific shared HLA-I alleles were linked to the response to immune checkpoint blockade (ICB). We aimed to identify the HLA-A subtypes associated with maximum benefit from ICB. We compiled a clinical dataset of patients who underwent a CLIA-approved germline HLA status testing as part of various advanced immune and cell therapy trials undertaken at the Christie NHS Foundation Trust. A total of 285 patients were eligible for final analysis. We identified 15 HLA-A subtypes, the most common alleles being HLA-A02, HLA-A01, and HLA-A03. A02:01 showed a tumor lineage-specific distribution. One hundred and forty patients received ICB and had evaluable response status. Patients with A01 were associated with better clinical outcomes. No significant associations were observed between HLA-A subtypes and the incidence of immune-related adverse effects. HLA genotyping should be incorporated early in the diagnostic work-up of patients with solid cancers as a predictive and selective biomarker.