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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： 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： Cancer   clinical trials   cytokine   High-dose IL-2 (HD IL-2)   IL-2 receptor (IL-2R)   IL-2R agonist   immunotherapy   Interleukin-2 (IL-2)  

摘要： Immune checkpoint blockade (ICB) has significantly improved the survival for many patients with advanced malignancy. However, fewer than 50% of patients benefit from ICB, highlighting the need for more effective immunotherapy options. High-dose interleukin-2 (HD IL-2) immunotherapy, which is approved for patients with metastatic melanoma and renal cell carcinoma, stimulates CD8+ T cells and NK cells and can generate durable responses in a subset of patients. Moreover, HD IL-2 may have potential efficacy in patients whose disease has progressed following ICB and plays a vital role in expanding tumor-infiltrating lymphocyte (TIL) in TIL therapy. Despite its potential, the use of HD IL-2 is limited by severe toxicities such as hypotension and vascular leak syndrome. Additionally, only a few patients achieve a good outcome after HD IL-2 therapy. To address these challenges, numerous next-generation IL-2 receptor (IL-2 R) agonists have been developed to exhibit treatment effects while minimizing adverse events. This review will explore IL-2 biology, the clinical application of HD IL-2 therapy, and the development of novel IL-2 R agonists for cancer immunotherapy.

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： Fusobacterium   novel species   pangenome   comparative genomics   intestinal microbiota   colorectal cancer  

摘要： Cancerous tissue is a largely unexplored microbial niche that provides a unique environment for the colonization and growth of specific bacterial communities, and with it, the opportunity to identify novel bacterial species. Here, we report distinct features of a novel Fusobacterium species, F. sphaericum sp. nov. (Fs), isolated from primary colon adenocarcinoma tissue. We acquire the complete closed genome and associated methylome of this organism and phylogenetically confirm its classification into the Fusobacterium genus, with F. perfoetens as its closest neighbor. Fs is phenotypically and genetically distinct, with morphological analysis revealing its coccoid shape, that while similar to F. perfoetens is rare for most Fusobacterium members. Fs displays a metabolic profile and antibiotic resistance repertoire consistent with other Fusobacterium species. In vitro, Fs has adherent and immunomodulatory capabilities, as it intimately associates with human colon cancer epithelial cells and promotes IL-8 secretion. An analysis of the prevalence and abundance of Fs in > 20,000 human metagenomic samples shows that it is a rarely detected member within human stool with variable relative abundance, found in both healthy controls and patients with colorectal cancer (CRC). Our study sheds light on a novel bacterial species isolated directly from the human CRC tumor niche and given its in vitro interaction with cancer epithelial cells suggests that its role in human health and disease warrants further investigation.

关键词： Cell-mediated immune response   recombinant adeno-associated virus (AAV)   interferon-gamma ELISpot   gene expression   cytokines   gene therapy  

摘要： Cell-mediated immune (CMI) responses to adeno-associated virus (AAV) can lead to tissue damage and loss of therapeutic transgene expression. Identifying robust biomarkers and mechanisms of CMI can aid clinical practice and advancement of AAV gene therapies. The present work evaluated peripheral blood mononuclear cells (PBMC) from non-human primates (NHP) before and after immunization with adenovirus 5 encoding AAV9 capsid antigen. PBMC were stimulated ex vivo with AAV9 capsid peptides to evaluate CMI responses by interferon (IFN)-gamma ELISpot, intracellular cytokines/activation markers, secreted cytokines, and RNAseq. AAV peptide stimulation produced a robust IFN gamma ELISpot 11 days after immunization and approximate to 4 years after cryopreservation. Flow cytometry revealed increased IFN gamma, interleukin (IL)-2, or tumor necrosis factor (TNF)-positive T-cells. Increases in secreted CXCR3 ligands (IP-10, I-TAC) were detected. Robust changes and correlations to ELISpot responses were revealed by RNAseq, including IFN gamma, IP-10, and I-TAC, many downstream transcripts, and several IFN-independent pathways. These data from AAV-immunized NHP identify biomarkers that could serve as robust and sensitive supplements/alternatives to ELISpot for early detection of CMI responses. Assessment of these biomarkers in non-clinical and clinical studies is a critical next step to determine the translation of this work to administration of a therapeutic AAV vector.

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： Hepatitis B virus   PEGylated interferon alpha   Hepatitis B surface antigen seroclearance   Pres1and preS2 promoters  

摘要： Background & AimsA notable proportion of CHB patients undergoing PEG-IFN alpha based therapy experience lagged serum HBeAg and/or HBV DNA disappearance in patients achieving HBsAg loss. In this study, we explored the molecular mechanisms behind this clinical phenomenon, offering novel insights into the sustainability of chronic HBV *** independent clinical cohorts were enrolled to validate this phenomenon. Then comprehensive analysis was performed using public datasets, coupled with a series of molecular biology *** 17-20% CHB patients underwent PEG-IFN alpha based therapy experienced seroclearance of HBsAg, while serum HBeAg and/or HBV DNA remained positive. These patients are more prone to serum HBsAg reappearance compared to those achieving complete virological response. Analysis of public datasets revealed that compared to the PC/BCP, the SP1/SP2 promoter displayed more pronounced inhibitory epigenetic modifications in HBeAg-negative patients and SP1/SP2 in-frame mutation peaked in immune active patients. In vitro experiments demonstrated that introduced SP1/SP2 inactive mutations would enhance PC/BCP transcriptional activity by a mechanism known as adjacent transcriptional interference. Furthermore, the deletion of L-HBsAg facilitated intracellular cccDNA *** study elucidates that under IFN alpha treatment and low viral load, transcriptional suppression of SP1/SP2 promoters through mutations and/or epigenetic changes would favour the maintenance of sustain chronic HBV infection, via enhancing the transcription activity of BCP to promote cccDNA *** and implicationsIn clinical practice with IFN alpha antiviral treatment for CHB patients, a "paradoxical" phenomenon is observed where serum HBsAg disappears while HBV DNA or/and HBeAg remains at low positive levels, with delayed disappearance. Our study confirms this clinical phenomenon using two independent clinical cohorts and e