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关键词： IL17A   cancer vaccine   humoral response   pancreatic cancer   tumour immune microenvironment  

摘要： BACKGROUND AND AIMS:The pancreatic tumour microenvironment (TME) is a complex ecosystem where tumour cells, cancer-associated fibroblasts and immune cells interact, often in ways that contribute to tumour growth. The role of interleukin (IL17)A in pancreatic cancer progression is now more defined, and it is known to sustain a pro-tumoural microenvironment and inhibit the immune response. Here, we explore the effect of combining IL17A depletion with a cancer vaccine to enhance anti-tumour immunity. METHODS:We used genetically engineered mice proficient or deficient in IL17A, and orthotopically injected mice with pancreatic tumour cells depleted or not in IL17A, to examine the vaccine effects on tumour growth and immune responses. Both humoral and cellular immune responses were analysed following vaccination in IL17A-deficient and control mice. RESULTS:Mice lacking IL17A-either genetically or through pharmacological depletion-exhibited prolonged survival and smaller tumours, compared to vaccinated controls. Vaccination in IL17A-deficient mice significantly increased the influx of immune cells, including Natural Killer (NK) and effector/memory CD8 T cells, which displayed higher cytotoxic activity. CD8 T-cell depletion in these models notably reduced vaccine efficacy, underscoring the essential role of these cells. NK cell depletion in untreated models further demonstrated NK cells' critical function in controlling tumour growth when IL17A was absent. Overall, IL17A depletion enhanced both antigen-specific humoral and cellular immune responses, indicating a shift towards a more robust and responsive immune environment. CONCLUSIONS:Our findings reveal that the absence of IL17A in the pancreatic TME reprograms it into a more immune-supportive environment, favouring the recruitment of effector/memory immune cells upon vaccination. This approach paves the way for novel therapeutic combinations in pancreatic cancer, where IL17A depletion may boost both immunotherapy efficac

关键词： Cardiotoxicity   Post-transplant cyclophosphamide   Graft-versus host disease   North Japan hematology study group  

摘要： IntroductionPost-transplant cyclophosphamide (PTCy)-based prophylaxis for graft-versus-host disease (GVHD) is widely used in HLA-haploidentical hematopoietic cell transplantation (haplo-HCT). One of the major drawbacks of PTCy is the risk of rare but potentially lethal cardiotoxicity, which prompted the development of regimens with reduced doses of *** retrospectively compared the incidence of early cardiotoxicity with standard-dose of PTCy (cyclophosphamide 50 mg/kg/day for 2 days, PTCy100) versus reduced-dose (40 mg/kg/day for 2 days, PTCy80). In total, 179 patients underwent PTCy-based haplo-HCT, including PTCy100 (n = 111) and PTCy80 (n = 68).ResultsThe PTCy80 group included significantly more elderly patients, patients who received reduced-intensity conditioning, and patients with a history of HCT than the PTCy100 group. Nine eligible patients (5.0%) experienced severe cardiotoxicity. The incidence of severe cardiotoxicity did not differ significant between PTCy80 and PTCy100 (4.4% vs. 5.4%;p = 1). The incidence of fatal cardiotoxicity was lower with PTCy80, but the small size may have prevented the difference from reaching statistical *** the cyclophosphamide dose in PTCy-based GVHD prophylaxis may lower the risk of fatal cardiotoxicity without significantly altering the overall incidence of severe cardiotoxicity.

关键词： Mitragyna parvifolia   Green synthesis   Silver nanoparticles   Rheumatoid arthritis   COX-2 inhibition   Molecular targets  

摘要： Green nanotechnology offers a sustainable approach to rheumatoid arthritis (RA) therapy by enabling targeted modulation of key inflammatory markers, addressing the limitations of conventional treatments. This study explores biogenic approach to RA therapy through the one-pot green synthesis of silver nanoparticles (AgNPs) using Mitragyna parvifolia bark extract. The synthesis of AgNPs was optimized by varying parameters such as reaction temperature, time, AgNO3 concentration, extract volume, and pH. The fabricated AgNPs were thoroughly analyzed using UV-visible spectroscopy, dynamic light scattering, Fourier-transform infrared spectroscopy, Energy dispersive X-ray analysis, transmission electron microscopy, and X-ray diffraction, confirming their functional group composition, stability, nano-scale size, spherical shape and face-centered cubic structure. In vitro studies revealed that the AgNPs exhibited superior anti-inflammatory activity compared to the crude plant extract, effectively inhibiting protein denaturation and cyclooxygenase-2 (COX-2) enzyme activity. In vivo assessments using Carrageenan-induced paw edema and Complete Freund's Adjuvant-induced arthritis models revealed significant reductions in paw swelling, inflammatory cytokines (TNF-alpha and IL-6), and hematological markers of inflammation. Histopathological and radiographic analyses confirmed reduced soft tissue swelling and bone erosion in AgNP-treated groups. Network pharmacology and molecular docking studies identified key phytoconstituents of M. parvifolia targeting TNF-alpha (PDB ID: 2AZ5) and modulating key inflammatory pathway (TNF signaling pathway). The integration of green synthesis with phytomedicine presents a promising, sustainable, and biocompatible approach to RA treatment. Our findings establish M. parvifolia-derived silver nanoparticles as a promising therapeutic strategy for RA treatment, offering a targeted, sustainable, and effective alternative to conventional therapies through

关键词： Lactobacillus rhamnosus GG   NOD2   extracellular vesicles   herpes simplex virus type 2   type I interferons  

摘要： The immune evasion strategies and lifelong latency of herpes simplex virus type 2 (HSV-2) present significant challenges for effective treatment. Recent studies have demonstrated that the commensal microbiota plays an important role in regulating immunity against viral infections. We previously reported that Lactobacillus rhamnosus GG (LGG) activates the expression of type I interferons (IFN-I) to inhibit HSV-2 infection. However, the specific molecular mechanisms remain unclear. Bacterial extracellular vesicles (EVs) are small lipid bilayer-bound particles secreted by bacteria, which can serve as intercellular communication vehicles between the host and pathogens, functioning as immunomodulatory vectors defending against viral infections. In this study, we confirmed that LGG-EVs activate the nucleotide-binding oligomerisation domain-containing protein 2 (NOD2)-IFN-I signalling pathway, inducing the expression of interferon-stimulated genes (ISGs) to combat HSV-2 infection both in vivo and in vitro. Furthermore, we explored the specific components within LGG-EVs and identified the presence of muramyl dipeptide (MDP). We demonstrated that MDP-enriched LGG-EVs effectively inhibit HSV-2 infection via activation of the NOD2-IFN-I pathway. These findings suggest that LGG-EVs could serve as a novel therapeutic strategy for HSV-2 and provide a mechanistic foundation for future antiviral research.

摘要： OBJECTIVE: The proper tolerance of pregnancy is based on the interaction between human killer cell immunoglobulin-like receptors (KIR) on dNK cells with HLA-C molecules on extravillous trophoblasts (EVT). Due to their function and protein structur...

摘要： Glioblastoma (GBM) is the most common primary brain cancer in adults and carries a median overall survival (OS) of 12-15 months. Effective therapy for recurrent GBM (rGBM) following frontline chemoradiation is a major unmet medical need. Here we report the dose escalation and exploration phases of a phase 1 trial investigating intracerebroventricular delivery of bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) epitope 806 and interleukin-13 receptor alpha 2 (IL-13R alpha 2), or CART-EGFR-IL13R alpha 2 cells, in patients with EGFR-amplified rGBM. Primary endpoints included dose-limiting toxicity, determination of the maximum tolerated dose and recommended dose for expansion, and occurrence of adverse events. Secondary endpoints included objective radiographic response, duration of response, progression-free survival and OS. A total of 18 patients received CART-EGFR-IL13R alpha 2 cells. The maximum tolerated dose was determined to be 2.5 x 107 cells. Of the 18 patients, 10 (56%) experienced grade 3 neurotoxicity;none had grade 4-5 neurotoxicity. Of 13 patients, 8 (62%) with measurable disease at the time of CAR T cell infusion experienced tumor regression, with one confirmed partial response by Modified Response Assessment in Neuro-Oncology criteria (objective radiographic response, 8%;90% confidence interval, 0-32%) and one patient with ongoing durable stable disease lasting over 16 months. Median progression-free survival was 1.9 months (90% confidence interval, 1.1-3.4 months), and median OS was not yet reached at the time of data cut-off (median follow-up time, 8.1 months). These findings indicate that intracerebroventricular delivery of bivalent CART-EGFR-IL13R alpha 2 is feasible and appears safe. CART-EGFR-IL13R alpha 2 cells are bioactive and exhibit a signal of antitumor effect in rGBM. *** registration: NCT05168423.

关键词： cytokines   DRESS   drug hypersensitivity   HLA   T-lymphocytes   vancomycin  

摘要： Vancomycin, a glycopeptide antibiotic used to treat severe Gram-positive bacterial infections, is associated with the development of drug reaction with eosinophilia and systemic symptoms (DRESS) in individuals expressing HLA-A*32:01. Previous studies have identified the potential role of T-cells using HLA-A*32:01-positive healthy donor models. However, DRESS pathogenesis remains poorly defined, and a deeper mechanistic understanding is required to aid the diagnosis and prediction of vancomycin-induced DRESS. The present study aims to elucidate CD4+ and CD8+ T-cell involvement within the pathogenesis of vancomycin-induced DRESS following the isolation and functional study of cloned T-cells from hypersensitive patients. CD4+ and CD8+ vancomycin-responsive T-cell clones (TCCs) were generated by serial dilution from peripheral blood mononuclear cells collected from suspected vancomycin-DRESS patients. Functionality of drug-responsive TCCs was assessed using T-cell proliferation ([3H]-thymidine). Cytokine analysis was performed using intracellular cytokine staining, enzyme-linked immunospot assay, and LEGENDplex immunoassays. Vancomycin-responsive TCCs expressing CD4+ and CD8+ phenotypes were successfully generated from suspected vancomycin-DRESS patients (n = 3). CD45RO+ memory T-cells were the primary activated population, with both CD4+ and CD8+ T-cells associated with the release of IFN-gamma, IL-5, IL-13, granzyme B, and perforin. Vancomycin-responsive CD4+ and CD8+ T-cells are activated by direct, pharmacological interactions, with antigen presentation possible through HLA class I and HLA class II molecules. This study provides in vitro evidence for the dual role of antigen-specific CD4+ and CD8+ T-cells within the pathogenesis of vancomycin-induced DRESS. This has been demonstrated following the generation of cloned T-cells with strong vancomycin specificity from patients presenting with vancomycin-DRESS and positive for expression of HLA-A*32:01.

关键词： Mg2   IFN   IRF3   SVCV   Antiviral  

摘要： Magnesium ions (Mg2+), essential divalent cations, play a pivotal role in orchestrating a myriad of physiological and biochemical processes. However, the intricate relationship between Mg2+ homeostasis and antiviral immunity in fish remains largely unexplored. In this study, we found that Mg2+ enhances the interferon (IFN) response by increasing the expression of IFN regulatory factor 3 (IRF3) to inhibit spring viraemia of carp virus (SVCV) infection. In vivo studies showed Mg2+ increases the survival rate of SVCV-infected zebrafish while reducing viral transcription and load in liver tissues. Consistent results were obtained in vitro. Further investigations revealed that Mg2+ can enhance the endogenous expression of IRF3. Additionally, upon SVCV infection, Mg2+ rescues the virus-induced degradation of IRF3. These findings underscore the pivotal role of Mg2+ in the antiviral response of lower vertebrates, presenting a promising avenue for addressing fish viral diseases.