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关键词： Respiratory syncytial virus   multiepitope   in silico   recombinant subunit vaccine  

摘要： Respiratory syncytial virus (RSV) is a leading cause of lower respiratory infections in infants and the elderly. The burden of RSV-related hospitalizations and deaths is significantly increasing. Recently, RSV vaccines targeting F protein have been approved, but their long-term efficacy is yet to be evaluated. This study aimed to design a polyvalent multi-epitope RSV subunit vaccine tailored to Korean HLA types using in silico methods. Nine prevalent HLA allele types in Korea were used to predict vaccine epitopes. Combinations of selected epitopes were created, and stable combinations were selected and conjugated with human beta-defensin and PADRE. Fifty-five multi-epitope combinations were selected for vaccine construction, and 33 vaccine constructs induced strong immune responses in silico. The final vaccine candidate is a 228-amino acid construct weighing 23,957 Da and effectively induces humoral and cellular immune responses with high population coverage, suggesting potential for further development.

关键词： Severe asthma   anti-IL-5/IL-5(R) therapy   responder   remission   biomarker  

摘要： IntroductionPrevious studies of anti-IL-5/IL-5(R) therapies in severe asthma found that response was mainly predicted by indicators of good baseline disease control. However, long-term response predictors remain *** to anti-IL-5/IL-5(R) therapy in the well-characterised, real-life, international German Asthma Net (GAN) registry were analysed using regression analyses. Response was defined by >= 50% reduction in exacerbations or corticosteroid dose, super-response by a complete stop of both, and remission additionally by controlled asthma (ACT score >= 20).ResultsSeventy-seven percent of 347 patients (55% female, 56.6 +/- 12.3 years, follow-up 20.3 +/- 13 months) were responders and showed improved exacerbation rates, asthma control, and corticosteroid treatment reduction. Response was independently predicted by inhaled corticosteroid dose (odds ratio [OR] 1.5;p = 0.014), exacerbation rate (OR 1.2;p = 0.009), and treatment duration (OR 1.05, p = 0.023). Univariately, blood eosinophil counts notably predicted response (OR 12.4;p = 0.004). Super-response was inversely associated with corticosteroid dependence and depression. Remission was associated with the absence of systemic corticosteroids, better asthma control, and FEV1 in *** results underscore that long-term anti-IL-5/IL-5(R) therapy reduces exacerbation and corticosteroid burden, especially in patients with severe disease and high type 2 inflammatory burden. Contrastingly, low baseline corticosteroid use and markers of good asthma control predicted remission and super-responder status.

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： 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

关键词： Cancer immunotherapy   colorectal cancer   HLA class I match   HLA-A2.1   humanized cancer model   humanized mice   immune checkpoint inhibitors   KRAS   NRG-A2   pancreatic ductal adenocarcinoma  

摘要： Cancer immunotherapy promises to treat challenging cancers including KRAS-mutated colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). However, pre-clinical animal models that better mimic patient tumor and immune system interactions are required. While humanized mice are promising vehicles for pre-clinical immunotherapy testing, currently used cancer models retain limitations, such as lack of a human thymus for human leukocyte antigen (HLA)-based education of human T cells. As cytotoxic T lymphocyte (CTL) activity underlies many immunotherapies, we developed more clinically relevant KRAS-mutated CRC and PDAC humanized cancer models using transgenic NRG-A2 mice expressing HLA-A2.1 to enable HLA-class-I match between mouse tissues (including the thymus), the humanized immune system and human tumors. Using these novel humanized cancer models and a CTL-mediated combination (immuno)therapy with clinical potential, we were able to recapitulate the complexity and therapy-induced changes reported in patient biopsies, demonstrating the use of these HLA-matched models for pre-clinical validation of novel immunotherapies.

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： 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： 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.