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关键词： HLA-E   cancer immunotherapy   glioblastoma   CAR T cells   NK cells   NKG2 receptor family  

摘要： Background: Human leukocyte antigen (HLA)-E is overexpressed by a large proportion of solid tumors, including malignant glioblastoma, and acts as a major checkpoint for NKG2A+ CD8+ T cells and natural killer (NK) cells in the tumor microenvironment and circulation. This axis operates alongside PD-L1 to inhibit effector responses by T and NK cells. Methods: We engineered a chimeric A/C switch receptor, combining the high HLA-E binding affinity of the NKG2A receptor ectodomain with the activating signaling of the NKG2C receptor endodomain. The cytotoxic function of A/C switch-transduced NK and T cells was evaluated against tumor cells with varying levels of HLA-E expression. In vivo efficacy was assessed using a xenograft model of glioblastoma. Findings: A/C switch-transduced NK and T cells exhibited superior and specific cytotoxicity against tumor cells with medium to high HLA-E expression. A/C switch-expressing human T cells demonstrated enhanced anti-tumor function in a glioblastoma xenograft model. The activity of the modified T cells was governed by an equilibrium between A/C switch levels and HLA-E expression, creating a therapeutic window to minimize on- target, off-tumor toxicities. Normal cells remained insensitive to A/C switch T cells, even after interferon (IFN)g pretreatment to induce HLA-E expression. Conclusions: The A/C switch receptor effectively targets tumor cells expressing high levels of HLA-E, either alone or in combination with other engineered specificities, to overcome the suppressive NKG2A/HLA-E checkpoint. This approach offers a promising therapeutic strategy with a favorable safety profile for targeting HLA-E-overexpressing tumors.

关键词： glycolysis   interleukin-11   transforming growth factor beta 1   orbital fibroblast   Graves' orbitopathy  

摘要： Objectives Transforming growth factor beta 1 (TGF beta 1)-interleukin 11 (IL11) is a newly found critical signaling pathway in fibrotic diseases such as Graves' orbitopathy (GO). It has now been confirmed that enhanced glycolysis plays a key role in the pathogenesis of GO. However, little is known about the relationship between glycolysis and IL11-mediated fibrosis in GO. This study aimed to identify the relationship between glycolysis and TGF beta 1-IL11 signaling pathway and investigate the role of IL11 in glycolysis-facilitated fibrosis in *** Orbital connective tissues were collected from GO and control patients. Primary orbital fibroblasts (OFs) were cultured from clinical tissues. Patient-derived xenografts were established via intraorbital transplantation of GO orbital tissue in humanized NCG mice. Protein levels were measured using Capillary Western Immunoassay (WES). Small interfering RNA (siRNA) was used to construct transfected OF strains. Lactate production was measured to assess glycolysis status. Animal models were assessed by T2-weighted magnetic resonance (MR) scan. Immunohistochemistry staining was applied to patients' orbital connective *** Orbital connective tissues were collected from GO patients. Immunohistochemical (IHC) staining of GO tissues revealed the phenomenon of pyruvate dehydrogenase kinase 2 (PDK2)-enhanced glycolysis and upregulated IL11-IL11R alpha pathway. In vitro experiments showed successful induction of fibrosis of patient-derived orbital fat/connective tissues, which could be alleviated by dichloroacetic acid (DCA). MRI images and analysis of hematoxylin and eosin (HE) and Masson-stained section demonstrated enhanced glycolysis in GO, facilitating fibrosis of the orbital tissue. Targeting PDK2 decreased IL11 expression to suppress fibrosis. In vivo experiment confirmed anti-fibrotic effect of inhibition of *** PDK2-enhanced glycolysis exacerbates fibrosis via IL11-IL11R alpha signaling pat

摘要： Purpose:This collaborative study, led by the Clinical Genome Resource Severe Combined Immunodeficiency Disease Variant Curation Expert Panel (ClinGen SCID-VCEP), implemented and adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for interpreting germline variants in genes with established relationships to SCID. The effort focused on the 7 most common SCID-related genes identified by SCID newborn screening in North America: , , , , , , and . Methods:The SCID-VCEP conducted a rigorous review of variants that involved database analyses, literature review, and expert feedback to derive gene-specific modifications to the ACMG/AMP guidelines. These specifications were validated using a pilot set of 90 variants. Of these 90 variants, 25 were classified as pathogenic, 21 as likely pathogenic, 14 as variants of uncertain significance (VUS), 18 as likely benign, and 12 as benign. Seventeen variants with conflicting classifications in ClinVar were successfully resolved. The criteria included modifications to 20 of the 28 original ACMG/AMP criteria specific to SCID-related genes. Conclusion:The SCID-specific variant curation guidelines developed by the SCID-VCEP will enhance the precision of SCID genetic diagnosis and provide a robust framework for interpreting variants in SCID-related genes, contributing to appropriate treatment of SCID.

摘要： BackgroundPancreatic ductal adenocarcinoma (PDAC) is characterized by a heterogeneous tumor microenvironment (TME). The mechanism by which this heterogeneity confers resistance against immunotherapy remains unclear. Interleukin- 1 beta (IL-1 beta) is a proinflammatory cytokine that regulates heterogeneous cancer associated fibroblast (CAF) phenotype and promotes an immunosuppressive TME. Anti-IL-1 beta monoclonal antibody significantly enhanced the anti-tumor activity of anti-PD-1 in a preclinical model of PDAC. However, clinical trials have shown limited activity of the anti-IL-1 beta and anti-PD-1 combination. Therefore, we hypothesize that anti-tumor immune response to the combination of anti-IL-1 beta and anti-PD-1 antibodies is context-dependent and would be affected by the TME heterogeneity in ***- and lung-specific metastasis mouse models of PDAC were used to investigate the antitumor activity of anti-IL-1 beta and anti-PD-1 antibodies alone or in combination by ultrasound examination and survival analysis. Their effects on the TME heterogeneity were assessed by flow cytometry and single nuclear RNA *** combination of anti-IL-1 beta and anti-PD-1 antibodies does not slow primary tumor growth but prolongs overall survival and reduces lung metastasis rates in a PDAC orthotopic murine model with lung metastasis tropism. In contrast, combination therapy slows primary tumor growth and prolongs survival, but does not reduce liver metastasis rates in a PDAC murine orthotopic model with liver metastasis tropism. Flow cytometry analysis showed that the combination of anti-IL-1 beta and anti-PD-1 antibodies restores T cell activation negated by the monotherapies. Mechanistically, in the PDAC model with lung metastasis tropism, but not in the model with liver metastasis tropism, combination treatment reverses an increased trend of immunosuppressive myeloid cells as a result of monotherapy. Single-nuclear RNA sequencing analysis of both or

摘要： Th1/Th2 balances may play a vital role in the processes of inflammation and fibrosis. The Th1/Th2 paradigm can be evaluated by representing IFN-gamma for Th1 and IL-4 for Th2. OM-85 BV encouraged preferential development of the Th1-type immunity characterized by amplified IFN-gamma and decreased IL-4 production. This study aimed to evaluate the inhibitory effect of OM85 on bleomycin (BLM)-induced pulmonary fibrosis in C57 and its possible mechanisms. In vitro experiments demonstrated that OM85 exhibited no significant toxicity to HELF cells. OM-85 inhibited the TGF-beta 1-induced protein expression of Notch1 and Hes1 and reduced the fibrosis-related marker profiles, such as collagen I, collagen III, fibronectin, P21, and alpha-SMA, following TGF-beta 1 treatment of these cells. Immunofluorescence also revealed that OM-85 decreased the expression of alpha-SMA induced by TGF-beta 1 in HELF cells. In the vivo experiments, a pulmonary fibrosis model was established by administering three intratracheal doses of BLM (1 mg/kg). The BLM-OM85 group was exposed to an aerosol containing 10.5 mg of OM-85 dissolved in 10 mL of sterile PBS on days 42, 44, 46, 49, 51, and 53. BLM-induced pulmonary fibrosis, leading to increased levels of lung hydroxyproline, total cell count, macrophages, neutrophils, lymphocytes, and the expression of TGF-beta 1 as well as Notch1 and Hes1 in lung tissue, along with fibrosis-associated proteins such as collagen I, collagen III, fibronectin, P21, and alpha-SMA. Additionally, the Th1 response was suppressed, as evidenced by decreased IFN-gamma in the bronchoalveolar lavage fluid (BALF), while the Th2 response was amplified, marked by increased IL-4 levels in BALF. Moreover, morphological assessments showed that BLM caused increased Ashcroft scores, relative collagen content, and an expanded damaged area, as well as an increased optical density (OD) of collagen I. The administration of OM-85 significantly mitigated these effects. These findings sugge

关键词： 1-methylnicotinamide   kupffer cells   hepatocytes   voriconazole   metabolism  

摘要： Background Inflammatory diseases impair the hepatic metabolism of voriconazole (VRC). 1-Methylnicotinamide (1-MNA), a common final metabolite of nicotinamide in the liver, has demonstrated anti-inflammatory effects in recent studies. This study investigated the impact of 1-MNA on VRC metabolism in the *** Mice with a systemic inflammatory response induced by lipopolysaccharide (LPS) were intragastrically administered 1-MNA, and their VRC metabolic capacity was evaluated. Kupffer cells and primary hepatocytes were isolated, and flow cytometry along with molecular knockdown experiments were performed to explore the molecular mechanisms underlying improved drug metabolism. IL-10 knockout (IL-10-/-) mice were used to validate the role of IL-10 in enhancing hepatocyte VRC metabolism under inflammatory *** 1-MNA promoted M2 polarization of liver Kupffer cells, stimulated IL-10 secretion, upregulated CYP2C38 expression in primary hepatocytes, and enhanced VRC metabolism. The mechanism by which IL-10 upregulated CYP2C38 appears to involve the inhibition of the nuclear transcription factor NF-kappa B (p65) in *** 1-MNA regulated Kupffer cell polarization in an LPS-induced inflammatory environment, reduced the inflammatory inhibition of CYP2C38 expression in hepatocytes, and promoted VRC metabolism.

关键词： ulcerative colitis   transcriptomics   mitochondria   anti-TNF  

摘要： Background Recent studies hint at mitochondrial genes influencing UC patient response to anti-TNF treatment. We evaluated this hypothesis by following a targeted strategy to identify gene expression that captures the relationship between mitochondrial dysregulation and response to treatment. Our objective was to initially examine this relationship in colon samples and subsequently assess whether the resulting signal persists in the *** We analyzed the transcriptome of colon samples from an anti-TNF-treated murine model characterized by impaired mitochondrial activity and treatment resistance. We then transferred the findings that linked mitochondrial dysfunction and compromised treatment response to an anti-TNF-treated UC human cohort. We next matched differential expression in the blood using monocytes from the peripheral blood of controls and IBD patients, and we evaluated a classification process at baseline with whole blood samples from UC *** In human colon samples, the derived gene set from the murine model showed differential expression, primarily enriched metabolic pathways, and exhibited similar classification capacity as genes enriching inflammatory pathways. Moreover, the evaluation of the classification signal using blood samples from UC patients at baseline highlighted the involvement of mitochondrial homeostasis in treatment *** Our results highlight the involvement of metabolic pathways and mitochondrial homeostasis in determining treatment response and their ability to provide promising classification signals with detection levels in both the colon and the bloodstream. Research suggests mitochondrial dysfunction may compromise response to anti-TNF treatment in UC patients. Testing this, we induced mitochondrial dysregulation in a mouse model treated with anti-TNF and linked gene expression to non-response. The findings were then corroborated on human cohorts.

摘要： Background: Psoriatic arthritis (PsA) is a chronic arthritis affecting people with psoriasis. If untreated, it may lead to disability. Recommended drugs are non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), biologic DMARDs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs). Tumour necrosis factor inhibitors (TNFi) are the first choice bDMARDs. Objectives: To assess the benefits and harms of TNFi in adults with psoriatic arthritis. Search methods: We searched CENTRAL, MEDLINE, Embase, *** and the World Health Organization trials portal up to 28 March 2024. Selection criteria: We included randomized controlled trials (RCTs) in adults with PsA, comparing TNFi to placebo, physiotherapy, NSAIDs, corticosteroids, and cs/b/tsDMARDs. Major outcomes included clinical improvement, minimal disease activity, physical function, health-related quality of life, radiographic progression, serious adverse events, and withdrawals due to adverse events. Data collection and analysis: We used standard Cochrane methods. The primary comparison was TNFi versus placebo. The primary time point was 12 weeks for clinical improvement;24 weeks for minimal disease activity, function, quality of life, and radiographic progression;and the end of the trial period for serious adverse events and withdrawals due to adverse events. Main results: We included 25 RCTs randomizing 7857 participants. Four studies compared TNFi to methotrexate and one to ustekinumab in DMARD-naïve participants. In csDMARD-inadequate responders, 11 studies compared TNFi to placebo;four studies compared TNFi to placebo and ixekizumab, bimekizumab, tofacitinib, or upadacitinib;and three studies compared TNFi to ixekizumab, secukinumab, and ustekinumab. Two studies compared different TNFi. We found no studies with b/tsDMARD-inadequate responders (b/tsDMARD-IR). No studies compared TNFi to NSAIDs, corticosteroids, or physiothera

关键词： Bordetella pertussis   interferon gamma   interferon lambda   neutrophils   pertussis toxin   respiratory infection  

摘要： Interferon lambda plays diverse roles in bacterial infections. Previously, we showed that interferon lambda is induced in the lungs of Bordetella pertussis-infected adult mice and exacerbates inflammation. Here, we report that mice lacking the interferon lambda receptor 1 specifically on neutrophils (MRP8creIFNLR1fl/fl mice) exhibit reduced lung bacterial load and inflammation compared to wild-type mice during B. pertussis infection. In B. pertussis-infected wild-type mice, lung type I and III IFN responses were higher than in MRP8creIFNLR1fl/fl mice, correlating with increased lung inflammatory pathology. There was an increased proportion of interferon gamma-producing neutrophils in the lungs of MRP8creIFNLR1fl/fl mice compared to wild-type mice. IFNLR1-/- neutrophils incubated with B. pertussis exhibited higher killing compared to wild-type neutrophils. Treatment of wild-type neutrophils with interferon lambda further decreased their bacterial killing capacity and treatment of wild-type mice with interferon lambda increased lung bacterial loads. Contributing to the differential killing, we found that IFNLR1-/- neutrophils exhibit higher levels of reactive oxygen species, myeloperoxidase, matrix metalloproteinase-9 activity, neutrophil extracellular traps, and interferon gamma secretion than wild-type neutrophils, and inhibiting NADPH oxidase inhibited bacterial killing in IFNLR1-/- neutrophils. B. pertussis-induced interferon lambda secretion and IFNLR1 gene expression in mouse and human neutrophils and this was dependent on the bacterial virulence protein pertussis toxin. Pertussis toxin enhanced bacterial loads in wild type but not in MRP8creIFNLR1fl/fl or IFNLR1-/- mice. Thus, pertussis toxin disrupts neutrophil function by enhancing type III IFN signaling, which prevents neutrophils from effectively clearing B. pertussis during infection, leading to higher bacterial loads and exacerbation of lung inflammation.