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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： Infectious agents   allergic rhinitis   IL   TLR   IFNs  

摘要： Allergic rhinitis (AR) is increasingly prevalent, yet diagnostic and therapeutic approaches remain inadequate. Recent studies show links between infectious diseases and noninfectious disorders, but the underlying mechanisms are largely unknown. We used bidirectional Mendelian randomization (MR) to investigate the impact of antibodies against infectious diseases on AR. Our results indicate that CMV IgG+, human herpesvirus 7 U14 antibodies, anti-varicella zoster virus IgG (VZV IgG+), and varicella zoster virus glycoproteins E/I antibodies are positively correlated with AR, while Epstein-Barr virus EBNA-1, ZEBRA, Merkel cell polyomavirus VP1, BK polyomavirus VP1, anti-human herpesvirus 6 E1A IgG, and human herpesvirus 6 IE1A antibodies are negatively correlated. Reverse MR analysis shows AR increases VZV IgG+ likelihood. These findings suggest a bidirectional causal relationship between infectious disease immune responses and AR, advancing understanding and potential diagnostics.

关键词： Da-Yuan-Yin decoction   damp-heat syndrome   neutrophil extracellular traps   faecal metabolites   gut microbiota   inflammation  

摘要： BackgroundDa-Yuan-Yin Decoction (DYY), used since the early Qing Dynasty in China for damp-heat syndrome, was evaluated for its comprehensive protective *** and methodsRats received a high-fat/high-sugar diet for 14 days, then daily exposure to high temperature/humidity (31.0 +/- 0.5 degrees C, 85%-95%) for 10 hours over 14 days. Damp-heat syndrome was induced on day 29 via intraperitoneal lipopolysaccharide (LPS) injections (1 mg/kg and 0.5 mg/kg after 4 hours). Two hours post-modeling, rats received DYY (400 or 800 mg/kg/day) orally for 5 days. Symptoms were scored. On day 33, kidney, spleen, tongue, lung, liver, stomach, and colon tissues underwent histopathological and immunochemical/immunofluorescence analysis. Serum levels of inflammation factors, C-reactive protein (CRP), cell-free DNA (cfDNA), myeloperoxidase (MPO), and superoxide dismutase (SOD) were quantified. Complete blood count (CBC), blood biochemistry, short-chain fatty acids (SCFAs), gut microbiota composition in the colon, and metabolites in the cecum were *** significantly reduced symptom scores and decreased CRP level, while also regulating parameters in CBC and biochemical profiles. The treatment ameliorated tissue damage in the kidney, spleen, tongue, lung, liver, stomach, and colon. DYY downregulated citrullinated histone H3 (Cit H3), polyclonal peptidylarginine deiminase 4 (PADI4), and MPO expressions in the lung, stomach, and colon. Furthermore, it modulated inflammatory responses, suppressed the interleukin-23 (IL-23)/janus kinase-2 (JAK2)/signal transduction and transcription activator-3 (STAT3) signaling pathway and enhanced antioxidant activity. DYY administration significantly increased total SCFA content. The intervention restored gut microbiota diversity and abundance, while ameliorating metabolic *** pathophysiological alterations were observed in rats with damp-heat syndrome. The comprehensive protective effects of DYY invol

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： YGPs   ovariectomy   bone loss   Th17   NF-kappa B  

摘要： BackgroundOsteoporosis is a chronic metabolic bone disease that causes excessive osteoclast formation, ultimately resulting in massive bone loss. Yougui pills (YGPs) are the classic traditional Chinese medicine formula with an anti-osteoporosis effect, but the underlying mechanisms are *** and methodsThe ameliorative impact of YGPs on bone loss in ovarectomized mice model was examined by Alcian Blue Haematoxylin (ABH) staining and micro-CT scanning. The "YGPs-osteoporosis-target" network was established and analyzed to explore the molecular mechanism of YGPs on osteoporosis. In addition, flow cytometry and immunohistochemistry (IHC) were used to detect the Th17 response and the expression levels of CD4, IL-17A, RANKL, and ROR gamma t. Finally, we examined the expressions of p-P65, nuclear factor of activated T cells 1 (NFATc1), and cathepsin K (CTSK) by IHC and immunofluorescence (IF) staining to investigate the inhibitory effects of YGPs on osteoclast formation and function in vitro and in *** results of ABH staining and micro-CT scanning showed that YGPs can significantly prevent bone loss. The 'YGPs-osteoporosis-target' network found that IL-17 is the key target, and its effects may be closely related to the upstream Th17 cells and the downstream NF-kappa B pathway of IL-17. Meanwhile, Th17 response and the expression levels of CD4, IL-17A, RANKL, and ROR gamma t increased in the OVX group compared with the sham group, while YGPs treatment significantly reduced the above conditions. We also found that the number and function of osteoclasts (OCs) were significantly increased by incubation with IL-17, while YGPs treatment inhibited osteoclast formation and function. Furthermore, YGPs can suppress the expression of p-P65, NFATc1, and CTSK by IHC and IF staining in vitro and in *** can exert anti-osteoporosis effects by regulating osteoimmunity, and the mechanism is to inhibit osteoclast formation and bone loss by suppressing

关键词： Cancer immunotherapy   colorectal cancer   HLA class I match   HLA-A2.1   humanized cancer model   humanized mice   immune checkpoint inhibitors   italic>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： Breast cancer   miR-4319   NLRC5   MHC class I   immunotherapy  

摘要： Sufficient MHC-I expression on cancer cells is essential for the recognition and killing of cancer cells by immune effector cytotoxic T-lymphocyte (CTL). An important mechanism of cancer immune escape is loss or down-regulation of MHC-I. This is frequently associated with reduced expression of NOD-like receptor (NLR) caspase recruitment domain containing protein 5 (NLRC5), genetically and epigenetically. NLRC5, a regulator of MHC-I, has been identified as a potential target of miR-4319 due to its complementary binding site for miR-4319, according to prediction by TargetScan (http://***/). Inhibition of miR-4319 by IFN-gamma (known as MHC-I increasing agent) to upregulate NLRC5 with upregulation of MHC-I in MHC-I-deficient breast cancer cells, however, remains unclear. After treatment with IFN-gamma, miR-4319 was detected with qRT-PCR;NLRC5 protein was detected with western-blot;and MHC-I mRNA and protein were detected with qRT-PCR and western-blot, respectively. It was found statistically that miR-4319 was lower and NLRC5 protein was higher in groups of 50 U/ml and 100 U/ml IFN-gamma, and MHC-I mRNA and protein were higher in all groups of different concentrations of IFN-gamma, except for HLA-A protein in 25 U/ml IFN-gamma group, with dose dependent tendency, compared with the control group. IFN-gamma inhibits miR-4319 and upregulates NLRC5, thereby enhancing expression of MHC-I in SKBR3 breast cancer cells, while limitations include the absence of functional rescue experiments and in vivo validation. Along with direct cytotoxicity on tumor cells, IFN-gamma's immunomodulatory effect strengthens tumor immunogenicity, counteracts immune evasion mechanisms, and potentially improves the efficacy of cancer immunotherapy.