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关键词： Lassa virus   T cell vaccine   emerging viruses   glycoprotein   modified vaccinia virus Ankara   nucleoprotein   viral vector vaccine  

摘要： Lassa virus (LASV) is circulating in rodents in several countries in West Africa and is the causative agent of the zoonotic disease Lassa fever. Several vaccine candidates have been successfully tested in preclinical and clinical research, while no LASV-specific vaccines or antiviral treatments have been licensed to date. Approximately 500,000 human cases of Lassa fever are estimated to occur every year. However, the high percentage (~80%) of asymptomatic cases and the low frequency of reporting systems in endemic regions demonstrate that Lassa fever cases are highly underreported. Given the frequent spread of the virus by travellers to non-endemic regions, the need for effective vaccines and treatments becomes clear. Here, we describe the generation and preclinical evaluation of two recombinant Lassa virus candidate vaccines, MVA-GP and MVA-NP, which are based on the highly attenuated modified vaccinia virus Ankara (MVA) strain. Constructed in the MVA vector, the MVA-GP vaccine delivers the glycoprotein (GP) of the prototype LASV Josiah strain (lineage IV), whereas the MVA-NP vaccine expresses the nucleoprotein (NP) from the Lassa virus Togo strain (lineage VII). Two immunizations of either MVA-GP or MVA-NP induced substantial polyfunctional Lassa virus-specific CD8 and CD4 T cell responses, respectively, in humanized mice (HLA-A*0201/DR1 transgenic mice). The identified human Lassa virus-specific T cell epitopes were in agreement with recently discovered T cell epitopes found in Lassa fever survivors. Further studies are warranted to characterize these recombinant MVA-Lassa virus vaccine candidates in other preclinical models and investigate their potential to be characterized in clinical studies in humans.

关键词： HLA‐DPB1*1650:01 N   next‐generation sequencing   novel allele  

摘要： HLA-DPB1*1650:01 N differs from HLA-DPB1*135:01:01:01 in exon 2 codon 62 (CAG>TAG), introducing a premature stop codon.

关键词： PHB1   PHB2   IFN-beta   Ducks   Innate immunity  

摘要： PHB1 and PHB2, two subunits of the mitochondrial prohibitin complex, are critical regulators of antiviral innate immunity. Ducks, as natural reservoirs for RNA viruses, exhibit unique antiviral mechanisms. RIG-I is a key receptor for recognizing RNA viruses in ducks. However, the roles of PHB1 and PHB2 in the RIG-I-MAVS-IFN-beta signaling pathway remain unclear. Here, we characterized the duPHB1 and PHB2 structure and functional domains, which contains similar N-terminal transmembrane domain, PHB domain and coil-coiled C-terminal domain, revealing high conservation with avian and mammalian orthologs. Both genes were ubiquitously expressed in duck tissues, with elevated levels in immune-related organs (e.g., pancreas, thymus) and tissues with high metabolic activity and tissue regeneration ability (e.g., heart, liver and muscle) post-NDV infection. We next sought to investigate the functional roles by which duPHB1 and duPHB2 triggered antiviral innate immune response. Overexpression of duPHB1/2 in DEFs enhanced MAVS activation and IFN-beta production upon 5 ' ppp dsRNA stimulation, while siRNA-mediated knockdown suppressed these effects. Co-transfection of duPHB1 and duPHB2 synergistically amplified MAVS-dependent IFN-beta induction. Crucially, MAVS depletion abolished PHB1/ 2-mediated IFN-beta upregulation, demonstrating their dependence on MAVS signaling. Our findings establish duPHB1/2 as key regulators of mitochondrial-mediated antiviral responses in ducks, providing insights into avian innate immunity.

关键词： Saposhnikovia divaricata (Turcz.) Schisch   TNF-alpha   RAGE   Rheumatoid arthritis   UPLC-Q-TOF-MS  

摘要： Saposhnikovia divaricata (Turcz.) Schisch (SADS) is classified as a special-grade traditional Chinese medicine in Shennong's Materia Medical due to its immune-protective effects, including dispelling cold, relieving edema and pain, and its potential in treating rheumatoid arthritis (RA). Over 130 traditional Chinese medicine formulations containing SADS are used for RA treatment. However, the active ingredients and serum metabolites of SADS remain underexplored, and its precise mechanism of action in RA is not fully understood. Therefore, the study aims to explore the active ingredients and serum metabolites of SADS by UPLC-Q-TOF-MS and investigate its therapeutic mechanisms in the context of RA. A total of 5536 compounds were identified in SADS, and 19 active components were finally selected. In serum metabolites following SADS administration, 4945 compounds were identified, of which 17 showed anti-inflammatory activity. Network pharmacology analysis showed that SADS may play a role in the treatment of RA through the TNF and Receptor for Advanced Glycation End-products (RAGE) signaling pathway. SADS alleviated RA symptoms in IL-1RA deficient RA mice. In cellular models, SADS inhibited the abnormal proliferation of fibroblast-like synoviocytes through regulating the TNF-alpha and RAGE pathways. In addition, SADS promoted the polarization of M2 macrophages but inhibited the polarization of M1 macrophages. SADS alleviated the progression of experimental arthritis in a RA mouse model by modulating the TNF-alpha and RAGE signaling pathways, supporting its potential as a therapeutic agent for RA.

关键词： Esophageal cancer   IL-38   Sirt1/HIF-1 alpha   Treg/Th17  

摘要： Objective: This study aimed to identify biomarkers of esophageal cancer and elucidate their mechanisms of action in esophageal cancer. Methods: Differential protein expression between esophageal tumor tissue and adjacent normal tissue was analyzed using proteomics in a mouse model of esophageal cancer. Differential proteins were identified through bioinformatics analysis. The mechanisms of action of differential proteins in esophageal cancer were validated using techniques such as western blotting and immunohistochemistry. Results: Proteomic analysis revealed that IL-38 exhibited the greatest differential expression. Molecular biology techniques including western blotting and immunohistochemistry demonstrated that IL-38 modulates Regulatory T cell (Treg)/ T helper 17 cell (Th17) balance through the Sirtuin 1 (SIRT1)/ hypoxia-inducible factor 1-alpha (HIF-1 alpha) signaling pathway in esophageal cancer. Conclusion: IL-38 is a novel biomarker for esophageal cancer and regulates Treg/Th17 balance through the Sirt1/ HIF-1 alpha signaling pathway, providing new insights for the treatment of esophageal cancer.

关键词： Chemokines   Breast cancer stem cells   PRAME   Anti-Tumor immunity  

摘要： Background/objective: Tumor-associated macrophages (TAMs) and chemokine CCL18 play a pivotal role in breast cancer (BC) metastasis. They also promote breast cancer stem cells (BCSCs) enrichment. The melanomaassociated antigen such as preferentially expressed antigen in Melanoma (PRAME) is abnormally expressed in many cancers and is also associated with BC metastasis, but the specific mechanism is unclear. This study explores the role of PRAME and other tumor-linked antigens in BCSCs and their potential for immunotherapy in specific human leukocytes antigen (HLA) phenotypes. Methods: We analyzed 28 BC tissues (non-metastatic: 17;metastatic: 11) via immunohistochemistry (IHC) and Western blot. Bioinformatics profiling of 1102 BC samples (TCGA/Oncomine) assessed CCL18-PRAME-BCSC correlations. In vitro, CCL18-induced BCSC self-renewal (sphere formation) and PRAME upregulation were validated in MCF-7/MDA-MB-231 cells. HLA-A*11:01 prevalence was determined by PCR/Sanger sequencing. PRAME-derived peptides were screened in silico (NetMHC/EpiJen) and validated in dendritic cell (DC)-T cell cocultures, with Granzyme B activation measured via Luminex assay. Results: CCL18 expression correlated with BCSCs markers (such as CD44+/CD24-/ALDH1A1+) and PRAME in BC tissues. PRAME was significantly upregulated in BCSCs and BC metastasis, increased in human BC under CCL18 induction, and enhanced BCSC self-renewal and metastatic potential. T cells infiltration was activated when PRAME was highly expressed in the HLA-A*1101 phenotype. In this phenotype, PRAME derived peptides (such as SMSVWTSPR, YVDSLFFLR, and ELFSYLIEK) presented by dendritic cells significantly increased the level of granzyme B and activated T cell immunity against tumor cells. Conclusion: The PRAME's interaction with the tumor microenvironment and immune system highlights its potential as a biomarker for BC prognosis and a candidate for targeted immunotherapy, offering new targets for precision medicine in BC treatmen

关键词： ABC   ATP-binding cassette   ADORA2A   adenosine A2A receptor   ccRCC   clear cell type renal cell carcinoma   CML   chronic myeloid leukemia   CNS   central nervous system   CSC   cancer stem cell   CTLA   cytotoxic T-lymphocyte associated protein   EMT   epithelial-mesenchymal transition   EPO   erythropoietin   FDA   U.S. Food and Drug Administration   GVHE   graft vs host effect   GVLE   graft vs leukemia effect   HCC   hepatocellular carcinoma   HIF   hypoxia-inducible factor   HRE   hypoxia response element   ICB   immune checkpoint blockade   LOX   lysyl oxidase   MDSC   myeloid-derived suppressor cell   MHC   major histocompatibility complex   NK   natural killer   PD   programmed cell death   PDL   programmed cell death 1 ligand   RCC   renal cell carcinoma   TAM   tumor-associated macrophage   TKI   tyrosine kinase inhibitor   TNBC   triple-negative breast cancer   Treg   regulatory T cell   VEGFA   vascular endothelial growth factor A   VHL   von Hippel-Lindau tumor suppressor protein  

摘要： The hypoxia-inducible factors (HIFs)& horbar;HIF-1 and HIF-2 & horbar;play critical roles in cancer progression by controlling the transcription of thousands of genes across the full range of human cell types. Inhibition of their activity blocks cancer growth, vascularization, and metastasis in mouse models. Small-molecule HIF inhibitors, with varying degrees of specificity and mechanism of action have been reported to have antitumor activity in mouse models. An HIF-2 inhibitor, belzutifan, has recently been approved for the treatment of renal cell carcinoma. Dual HIF-1/2 inhibitors are being developed and are likely to have utility as cancer therapeutics, particularly in combination with immune checkpoint blockade. Significance Statement: Hypoxia-inducible factor inhibitors represent a powerful new therapeutic approach that has the potential to improve patient survival in many types of cancer when administered in combination with existing therapies. (c) 2025 American Society for Pharmacology and Experimental Therapeutics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： bronchoalveolar lavage fluid   disaturated-phosphatidylcholine   response   surfactant   lung inflammation   late preterm   BW   birth weight   DSPC   Disaturated-phosphatidylcholine   FiO 2   Inspired oxygen fraction   FR   France   GA   Gestational age   IL   Interleukin   IT   Italy   late-PT RDS   Late preterm infants, with a gestational age between 34 +0/7 and 36 +6/7 weeks, who were treated with surfactant for respiratory distress syndrome   Moderately-PT RDS   Moderately preterm infants with a gestational age between 32 +0/7 and 33 +6/7 weeks receiving surfactant treatment for respiratory distress syndrome   NB-BAL   Non-bronchoscopic bronchoalveolar lavage   NICU   Neonatal intensive care unit   NLD   No lung disease   PT   Preterm   RDS   Respiratory distress syndrome   SP-B   Surfactant protein B   SpO 2   Preductal/peripheral hemoglobin saturation   Term-NLD   Term infants with no lung disease   TNF-α   Tumor necrosis factor-α  

摘要： Objective: To evaluate main biophysically active surfactant components and inflammatory mediators, and to identify the factors associated with good response to surfactant, in late preterm infants with respiratory distress syndrome (RDS). Study design: This was a prospective, multicenter, cohort study enrolling late (gestational age 34(+0/7)-36(+6/7) weeks [late-PTRDS]) and moderately (gestational age 32(+0/7)-33(+6/7) weeks, [moderately-PTRDS]) preterm infants with RDS. Term infants with no lung disease (term-NLD) were enrolled as controls. The concentration of disaturated-phosphatidylcholine (DSPC), surfactant protein-B (SP-B), total proteins, interleukin (IL)-1 beta, IL-6, and tumor necrosis factor-alpha in epithelial lining fluids were measured by high-performance liquid chromatography-mass spectrometry, enzyme-linked immunosorbent assay, Lowry, or Luminex techniques, respectively, and corrected using plasma-to-bronchoalveolar lavage fluid urea ratio. Clinical data, including inspired oxygen fraction (FiO(2)) and preductal oxygen hemoglobin saturation (SpO(2)), were recorded in real-time. Results: We studied 55 late-PTRDS, 44 moderately-PTRDS, and 18 term-NLD infants. DSPC was lower in late-PTRDS (43 [24-124] mg/dL) than in term-NLD (249 [147-688] mg/dL, P < .001) but similar to that of moderately-PTRDS (30 [9-80] mg/dL, P = .083). SP-B, total proteins, IL-1 beta, IL-6, and tumor necrosis factor-alpha were similar between late-PTRDS and moderately-PTRDS. SP-B, total proteins, and IL-6 were significantly higher in late-PTRDS than term-NLD. Each hour of delay for surfactant administration, each 5-point increase in FiO(2) threshold, and each 5-point decrease in preductal hemoglobin saturation SpO(2)/FiO(2) ratio before surfactant treatment decreased the likelihood of good response by 12% (P = .002), 28% (P = .019) and 15% (P = .028), respectively. Conclusions: Late-PTRDS had DSPC and SP-B levels similar to moderately-PTRDS. Early administration, lower FiO(2) thresho

关键词： Chronic hepatitis B   Functional cure   Machine learning  

摘要： Background: Functional cure is the ideal treatment goal for chronic hepatitis B (CHB) treatment. We developed and validated machine learning (ML) models to predict functional cure in CHB patients. Methods: This study retrospectively recruited 534 CHB patients who received Peg-IFN treatment to construct model and 269 patients for external validation. We analyzed three strategies: baseline, week 12, week 24. Seven ML models were constructed using selected variables by Boruta and least absolute shrinkage and selection operator regression algorithm, and performance metrics, including area under the curve (AUC), sensitivity, specificity, and F1 score were applied to determine the best model. We utilized SHapley Additive exPlanation to visualize and interpret the best model and built a website to conveniently predict functional cure of CHB. Results: A total of 272 participants were cured in our study. Compared to baseline and week 12 strategies, week 24 using Support Vector Machine (SVM) model can better predict functional cure of CHB, with reliable predictive performance (AUC = 0.981), calibration and clinical applicability in external validation cohort. Age, ALT ratio at week 12, HBsAg at week 24 and HBsAg ratio at week 24 were important features. In order to enhance clinical convenience and effectiveness of the constructed model, a web-based dynamic nomogram was created (Dynamic Nomogram (***)). Conclusion: This study developed SVM model to predict functional cure in CHB patients treated with Peg-IFN. Furthermore, we also built a website that clinicians can individualized predict the efficacy of Peg-IFN therapy in CHB patients.

关键词： Obstructive nephropathy   TNF-alpha/RIPK/Caspase-8 axis   Necroptosis   Nrf2/HO-1 pathway   Renal fibrosis  

摘要： Obstructive nephropathy is a chronic condition that causes progressive kidney damage due to inflammation, oxidative stress, necroptosis, and fibrosis. The present study aimed to evaluate the potential chemopreventive effect of infliximab (TNF-alpha inhibitor) or umbelliferone (UMB, a natural antioxidant) individually and together to treat unilateral ureter ligation (UUL)-induced interstitial renal fibrosis in rats. The therapeutic effects were assessed through renal function biomarkers, histopathology, fibrosis, inflammation, oxidative stress, and necroptosis. UUL-induced renal injury led to increased serum biomarkers (urea, creatinine, uric acid), inflammation markers (TNF-alpha, NF-kappa B, IKK), oxidative stress (elevated NADPH oxidase and MDA, reduced Nrf2/HO-1, GSH, SOD), and necroptosis (upregulated RIPK1/RIPK3/p-RIPK3/MLKL/caspase-8), with substantial collagen deposition and fibrosis. Treatment with infliximab and UMB showed preventive effects by suppressing TNF-alpha signaling, reducing oxidative stress, and boosting antioxidant defense. Combined therapy provided superior results by downregulating TNF-alpha/RIPK/Caspase-8 pathways, enhancing Nrf2/HO-1 activity, reducing fibrosis, and restoring renal structure and function. Computational docking confirmed the ability of UMB to interact with TNF-alpha and RIPK3/MLKL binding sites. In conclusion, the combination of infliximab and UMB offers a promising multi-targeted approach to treat obstructive nephropathy and related chronic kidney diseases and highlights its potential to modulate key pathways involved in kidney fibrosis.