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关键词： Mathematical model   Tumor immunity   PD-1/PD-L1   Cytokines   Immunotherapy  

摘要： The tumor microenvironment constitutes a complex system shaped by the intricate interactions among tumor cells, immune cells, and cytokines. Within this environment, the interplay between immune cells and cytokines is crucial in influencing tumor growth and progression. Despite advancements in clinical tumor immunotherapy, there remains a gap in comprehensive simulations of tumor immune responses, particularly regarding cytokine-driven processes. This study aims to address this gap by investigating the regulatory interactions among tumor cells, immune cells, and cytokines to simulate the complexities of tumor immunotherapy. We develop a comprehensive modeling and computational framework incorporating PD-1 inhibitors and interleukin-10 (IL-10) antibodies. Through detailed mathematical analysis, we elucidate the impact of changes in the immune microenvironment on tumor cells number. Our findings highlight the significant therapeutic effect of anti-PD-1 and IL-10 inhibitors, with increased drug dosage correlating with a reduction in tumor burden. Furthermore, combination therapy demonstrates a marked extension of survival with reduced dosages compared to monotherapy. Based on model simulations, we proposed prognostic predictions by assessing the microenvironmental status before treatment. The findings indicate a promising method for enhancing treatment effectiveness and offering potential advantages to patients receiving tumor immunotherapy.

关键词： back pain   asthma   adipokines  

摘要： Similarly, in humans and horses, thoracic and lumbosacral back pain cause more disability and work interruptions worldwide than any other disease. Given that there are few effective treatments for back pain in humans and animals, primary prevention strategies and a reduction in pain factors may be crucial. In the analysed data obtained for the horses studied, the pattern of changes in adipocytokine concentrations, including resistin, visfatin and leptin, was noted for those with back pain compared to the control animals. Concentrations of selected adipocytokines in horses from the back pain group were different in animals with a coexisting diagnosis of asthma and back dysfunction. Very few studies are available on adipokine concentrations in horses. No information was found in relation to back pain and asthma in these animals. In humans, correlations of back pain and asthma with concentrations of selected adipokines have been described.

关键词： aortic aneurysm, abdominal   aortic aneurysm, thoracic   arthritis, rheumatoid   collagen diseases   human genetics  

摘要： BACKGROUND:Abdominal aortic aneurysm (AAA) represents a significant cause of mortality, yet no medical therapies have proven efficacious. The aim of the current study was to leverage human genetic evidence to inform clinical development of IL-6 (interleukin-6) signaling inhibition for the treatment of ***:Associations of rs2228145, a missense variant in the IL6R gene region, are expressed per additional copy of the C allele, corresponding to the genetically predicted effect of IL-6 signaling inhibition. We consider genetic associations with AAA risk in the AAAgen consortium (39 221 cases and 1 086 107 controls) and UK Biobank (1963 cases and 365 680 controls). To validate against known effects of IL-6 signaling inhibition, we present associations with rheumatoid arthritis, polymyalgia rheumatica, and severe COVID-19. To explore mechanism specificity, we present associations with thoracic aortic aneurysm, intracranial aneurysm, and coronary artery disease. We further explored genetic associations in clinically relevant subgroups of the ***:We observed strong genetic associations with AAA risk in the AAAgen consortium, UK Biobank, and FinnGen (odds ratios: 0.91 [95% CI, 0.90-0.92], P=4x10-30;0.90 [95% CI, 0.84-0.96], P=0.001;and 0.86 [95% CI, 0.82-0.91], P=7x10-9, respectively). The association was similar for fatal AAA but with greater uncertainty due to the lower number of events. The association with AAA was of greater magnitude than associations with coronary artery disease and even rheumatological disorders for which IL-6 inhibitors have been approved. No strong associations were observed with thoracic aortic aneurysm or intracranial aneurysm. Associations attenuated toward the null in populations with concomitant rheumatological or connective tissue ***:Inhibition of IL-6 signaling is a promising strategy for treating AAA but not other types of aneurysmal disease. These findings serve to help inform clinical development of

关键词： HLA   HLA-DQB1*05:354   novel allele   sequencing-based typing  

摘要： HLA-DQB1*05:354 differs from HLA-DQB1*05:01:01:01 by one nucleotide substitution in codon 55 in exon 2.

关键词： IL7   prostate cancer   tumor microenvironment  

摘要： Background Prostate cancer's complex interplay with the immune microenvironment prompted an investigation into immune-related pathogenic mechanisms and potential therapeutic targets. Methods Within the GSE176031 data set, Seurat meticulously dissected single-cell profiles from radical prostatectomy patients. Leveraging CellMarker and SingleR cell identities were precisely annotated. Then, monocle traced pseudotime trajectories, illuminating cellular paths, complemented by CellChat's insights into intricate intercellular communications. Furthermore, mendelian randomization (MR) robustly substantiated causal associations within prostate cancer contexts. Results Employing single-cell analysis on intraoperative tumor and normal tissue, we identified 15 distinct cell types, notably observing a significant T cell reduction in tumor samples. Intercellular communication analysis revealed multiple pathways between epithelial cells and T cells, highlighting interleukin (IL)-IL7R-IL2RG interactions. IL7R, crucial in T cell apoptosis, showed differential expression across T cell development stages. Patients with IL7 amplification had poorer outcomes (p < 0.05), supported by MR in two cohorts (ieu-b-4809 cohort: odds ratio [OR] = 1.005, p = 0.002, 95% confidence interval [CI] [1.002-1.008];ebi-a-GCST90018905: OR = 1.063, p = 0.032, 95% CI [1.005-1.125]), confirming IL7 as a prostate cancer risk factor. ConclusionsThese findings suggest T cell depletion via IL7-IL7R signaling may drive prostate cancer progression, offering novel therapeutic insights.

关键词： glabridin   lipoteichoic acid   MAPK pathway   NF-kappa B   IL-1 beta   iNOS   macrophages  

摘要： Inflammation, a fundamental response to infection and injury, involves interactions among immune cells and signaling molecules. Dysregulated inflammation contributes to diseases such as autoimmune disorders and cancer. Interleukin-1 beta (IL-1 beta), produced by macrophages in response to lipoteichoic acid (LTA) from Gram-positive bacteria, is a key inflammatory mediator. Glabridin (GBD), a bioactive compound from licorice root, exhibits anti-inflammatory properties. This study investigates GBD's effects on LTA-induced proinflammatory signaling in RAW 264.7 murine macrophages and alveolar macrophages, MH-S, focusing on IL-1 beta expression and signaling pathways. Cell viability assays confirmed that 20 mu M GBD was non-cytotoxic. Confocal microscopy and quantitative PCR showed that GBD significantly reduced IL-1 beta fluorescence intensity, mRNA, and protein levels. GBD also inhibited inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production. Further analysis revealed that GBD suppressed NF-kappa B p65 nuclear translocation and selectively modulated MAPK pathway activation by reducing JNK and p38 MAPK phosphorylation without affecting ERK. Studies using specific inhibitors demonstrated that IL-1 beta production reduction was mechanistically linked to MAPK pathway inhibition. These findings highlight GBD's potential as a therapeutic agent for inflammatory diseases through its ability to modulate critical inflammatory mediators and signaling pathways.

关键词： HLA-DRB1*03:72:02   novel allele   sequence-based typing  

摘要： HLA-DRB1*03:72:02 differs from HLA-DRB1*03:01:01:01 by one nucleotide substitution at position 247 (codon 54) in exon 2.

关键词： Atopic dermatitis (AD)   interleukin-9 (IL-9)   IL-9 recep- tor (IL-9R)   interleukin-18 (IL-18)   interleukin-18 receptor (IL-18R)   interleukin-1 receptor-associated kinase 4 (IRAK4)   pathogenic T(H)2 cells (pT(H)2)   upstream regulator of T(H)2 cells  

摘要： Background: T(H)2 cells crucially contribute to the pathogenesis of atopic dermatitis (AD) by secreting high levels of IL-13 and IL-22. Yet the upstream regulators that activate T(H)2 cells in AD skin remain unclear. IL-18 is a putative upstream regulator of T(H)2 cells because it is implicated in AD pathogenesis and has the capacity to activate T cells. Objective: We sought to decipher the role of IL-18 in T(H)2 responses in blood and skin of AD patients. Methods: Peripheral blood mononuclear cells and skin biopsy samples from AD patients and healthy donors were used. Functional assays were performed ex vivo using stimulation or blocking experiments. Analysis was performed by flow cytometry, bead-based multiplex assays, RT-qPCR, RNA-Seq, Western blot, and spatial sequencing. Results: IL-18Ra1 T(H)2 cells were enriched in blood and lesional skin of AD patients. Of all the cytokines for which T(H)2 cells express the receptor, only IL-9 was able to induce IL-18R via an IL-9R-JAK1/JAK3-STAT1 signaling pathway. Functionally, stimulation of circulating T(H)2 cells with IL-18 induced secretion of IL-13 and IL-22, an effect that was enhanced by costimulation with IL-9. Mechanistically, IL-18 induced T(H)2 cytokines via activation of IRAK4, NF-kB, and AP-1 signaling in T(H)2 cells, and neutralization of IL-18 inhibited these cytokines in cultured explants of AD skin lesions. Finally, IL-18 protein levels correlated positively with disease severity in lesional AD skin. Conclusion: Our data identify a novel IL-9/IL-18 axis that contributes to T(H)2 responses in AD. Our findings suggest that both IL-9 and IL-18 could represent upstream targets for future treatment of AD. (J Allergy Clin Immunol 2025;155:491-504.)

关键词： vaccination   organs   donor  

摘要： Organ transplantation is the last-resort option to treat organ failure. However, less than 10% of patients benefit from this only option due to lack of major histocompatibility complex (MHC)-matched donor organs and 25%-80% of donated organs could not find MHC-matched recipients. T cell allorecognition is the principal mechanism for allogeneic graft rejection. We herein present a "donor MHC-specific thymus vaccination" (DMTV) strategy to induce T cell tolerance to both autologous and allogeneic donor MHC. Allogeneic MHC molecules were expressed in the recipient thymus through adeno-associated virus-mediated delivery, which led to stable expression of allogeneic MHC together with the autologous MHC in the engineered thymus. During local T cell education, those T cells recognizing either autologous MHC or allogeneic MHC were equally depleted. We constructed C57BL/6-MHC and BALB/c-MHC dual immunocompatible mice via thymus vaccination of C57BL/6-MHC into the BALB/c thymus and observed long-term graft tolerance after transplantation of C57BL/6 skin and C57BL/6 mouse embryonic stem cells into the vaccinated BALB/c mice. We also validated our DMTV strategy in a bone marrow, liver, thymus (BLT)-humanized mouse model for immunocompatible allotransplantation of human embryonic stem cells. Our study suggests that the DMTV strategy is a potent avenue to introduce a donor compatible immune system in recipients, which overcomes the clinical dilemma of the extreme shortage of MHC-matched donor organs for treating patients with end-stage organ failure.

关键词： IL-27   Tuberculosis   Mycobacterium tuberculosis   Macrophages   PI3K/AKT   TLR4/NF-kappa B  

摘要： Interleukin-27 (IL-27) is a cytokine that is reported to be highly expressed in the peripheral blood of patients with pulmonary tuberculosis (PTB). IL-27-mediated signaling pathways, which exhibit anti- Mycobacterium tuberculosis (Mtb) properties, have also been demonstrated in macrophages infected with Mtb. However, the exact mechanism remains unclear. This study aimed to clarify the potential molecular mechanisms through which IL-27 enhances macrophage resistance to Mtb infection. Both normal and PTB patients provided bronchoalveolar lavage fluid (BALF). Peripheral blood mononuclear cells (PBMCs) were isolated from healthy individuals and stimulated with 50 ng/mL macrophage-colony stimulating factor (M-CSF) to obtain monocyte-derived macrophages (MDMs). Using 100 ng/mL phorbol 12-myristate 13-acetate (PMA), THP-1 cells were induced to differentiate into THP-1-derived macrophage-like cells (TDMs). Both MDMs and TDMs were subsequently infected with the Mtb strain H37Rv and treated with 50 ng/mL IL-27 prior to infection. The damage and inflammation of macrophages were examined using flow cytometry, enzyme-linked immunosorbent assay (ELISA), and Western blotting. Patients with PTB had elevated levels of IL-27 in their BALF. Preconditioning with IL-27 was shown to reduce H37Rv-induced MDMs and TDMs apoptosis while also decreasing the levels of Cleaved Caspase-3, Bax and the proinflammatory cytokines TNF-alpha, IL-1 beta, and IL-6, promoting the expression of Bcl-2 and the anti-inflammatory factors IL-10 and IL-4. Silencing of the IL-27 receptor IL-27Ra increased macrophage damage and inflammation triggered by H37Rv. Mechanistically, IL-27 activates autophagy by inhibiting TLR4/NF-kappa B signaling and activating the PI3K/AKT signaling pathway, thereby inhibiting H37Rv-induced macrophage apoptosis and the inflammatory response. Our study suggests that IL-27 alleviates H37Rv-induced macrophage injury and the inflammatory response by activating autophagy and that IL-27 ma