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关键词： Axial Spondyloarthritis   Spondylitis, Ankylosing   Tumor Necrosis Factor Inhibitors  

摘要： OBJECTIVES:The objective of this study is to investigate lipopolysaccharid-binding protein (LBP), zonulin and calprotectin as markers of bacterial translocation, disturbed gut barrier and intestinal inflammation in patients with radiographic axial spondyloarthritis (r-axSpA) during tumour necrosis factor inhibitor (TNFi) therapy and to analyze the association between disease activity, response to treatment and biomarker levels. METHODS:Patients with active r-axSpA of the German Spondyloarthritis Inception Cohort starting TNFi were compared with controls with chronic back pain. Serum levels of LBP, zonulin and calprotectin were measured at baseline and after 1 year of TNFi therapy. We analysed the longitudinal association between biomarkers and disease activity, and the relationship between biomarkers and treatment response with regression analysis. RESULTS:121 patients with r-axSpA were compared with 63 controls. At baseline, patients with r-axSpA had higher levels of LBP and calprotectin than controls, which decreased significantly during TNFi treatment. LBP showed a positive association in longitudinal analyses with Axial Spondyloarthritis Disease Activity Score (ASDAS) (ß=0.08, 95% CI 0.06 to 0.10), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (ß=0.08, 95% CI 0.04 to 0.12) and C reactive protein (CRP) (ß=1.69, 95% CI 1.04 to 2.34). Calprotectin was associated with ASDAS (ß=0.04, 95% CI 0.01 to 0.07) and CRP (ß=0.82, 95% CI 0.27 to 1.37). Furthermore, LBP and calprotectin levels at baseline showed an association with a subsequent change in BASDAI. Baseline zonulin levels were not significantly associated with disease activity or treatment response. CONCLUSION:Serum levels of LBP and calprotectin are associated with disease activity in patients with r-axSpA and decrease with TNFi response. In contrast, serum zonulin levels showed no association with disease activity or treatment response, arguing against a strict correlation between intestinal permea

关键词： Salmonella   HLA-B27   reactive arthritis   unfolded protein response   curli   autoimmunity  

摘要： Salmonella enterica serovar Typhimurium (STm) causes gastroenteritis and can progress to reactive arthritis (ReA). STm forms biofilms in the gut that secrete the amyloid curli, which we previously demonstrated can trigger autoimmunity in mice. HLA-B27 is a genetic risk factor for ReA;activation of the unfolded protein response (UPR) due to HLA-B27 misfolding is thought to play a critical role in ReA pathogenesis. To determine whether curli exacerbates HLA-B27-induced UPR, bone marrow-derived macrophages (BMDMs) isolated from HLA-B27 transgenic (tg) mice were used. BMDMs treated with purified curli exhibited elevated UPR compared to C57BL/6, and curli-induced IL-6 was reduced by pre-treating macrophages with inhibitors of the IRE1 alpha branch of the UPR. In BMDMs, intracellular curli colocalized with GRP78, a regulator of the UPR. In vivo, acute infection with wild-type STm increased UPR markers in the ceca of HLA-B27tg mice compared to C57BL/6. STm biofilms that contain curli were visible in the lumen of cecal tissue sections. Furthermore, curli was associated with macrophages in the lamina propria, colocalizing with GRP78. Together, these results suggest that UPR plays a role in the curli-induced inflammatory response, especially in the presence of HLA-B27, a possible mechanistic link between STm infection and genetic susceptibility to ReA. [GRAPHICS] .

关键词： Dogs   cytokines   kidney dysfunction   hemodialysis   inflammation  

摘要： Intermittent hemodialysis (IH) is an important therapy in the context of kidney dysfunction in dogs. However, its impact on pro-inflammatory cytokines is unclear. This study assessed IL-1 beta, IL-6, and TNF-alpha serum concentrations in dogs with chronic kidney disease (CKD) undergoing one session of IH without bypass (IH group, n = 4) and with bypass (IH + bypass group, n = 4). The control group (CG) included four healthy dogs. Cytokine levels were measured before, during, and after the first IH session. Comparative analyses of each cytokine within each group and time point were performed, along with a global comparison between groups. No significant changes were observed in cytokines across evaluation times in the IH groups. IL-1 beta was significantly higher post-session in the IH and IH + bypass groups compared to CG. Globally, IL-1 beta and TNF-alpha concentrations were significantly higher in the IH (11.41 pg/mL (10-16.17) and 2 pg/mL (2-88.54), respectively) and IH + bypass groups (10 pg/mL (10-10) and 2 pg/mL (2-215.5), respectively) compared to CG (0.96 pg/mL (0-3.56) and 0 pg/mL (0-0.003), respectively). The IH group also showed elevated IL-6 concentration (0.1 ng/mL (0.1-0.5)) compared to CG (0 ng/mL (0-0.1)). Higher IL-1 beta and IL-6 concentrations were observed in the IH group (11.41 pg/mL (10-16.17) and 0.1 ng/mL (0.1-0.1), respectively) compared to the IH + bypass group (10 pg/mL (10-10) and 0.1 ng/mL (0.1-0.5), respectively). In conclusion, a single IH session, with or without bypass, did not increase pro-inflammatory cytokines in CKD dogs with uremic syndrome but maintained the inflammatory state. Dogs undergoing IH without bypass may receive a stronger stimulus for cytokine release.

关键词： Adjuvant therapy   EGFR-TKIs   drug resistance   cytokine pathway  

摘要： ContextNon-small cell lung cancer (NSCLC) is the most common type of lung cancer. Gefitinib is a first-line treatment for NSCLC. However, its effectiveness is hindered by the development of drug resistance. At present, Shenqi Fuzheng injection (SFI) is widely accepted as an adjuvant therapy in *** study investigates the molecular mechanism of SFI when combined with gefitinib in regulating cell progression among EGFR-TKI-resistant *** and methodsWe established gefitinib-resistant PC9-GR cells by exposing gefitinib escalation from 10 nM with the indicated concentrations of SFI in PC9 cells (1, 4, and 8 mg/mL). Quantitative real-time polymerase chain reaction was performed to assess gene expression. PC9/GR and H1975 cells were treated with 50 ng/mL of interleukin (IL)-22 alone or in combination with 10 mg/mL of SFI. STAT3, p-STAT3, AKT, and p-AKT expression were evaluated using Western blot. The effects on cell proliferation, clonogenicity, and apoptosis in NSCLC cells were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation and flow cytometry *** treatment alleviated the development of gefitinib resistance in NSCLC. PC9/GR and H1975 cells treated with SFI significantly exhibited a reduction in IL-22 protein and mRNA overexpression levels. SFI effectively counteracted the activation of the STAT3/AKT signaling pathway induced by adding exogenous IL-22 to PC9/GR and H1975 cells. Moreover, IL-22 combined with gefitinib markedly increased cell viability while reducing apoptosis. In contrast, combining SFI with gefitinib and the concurrent treatment of SFI with gefitinib and IL-22 demonstrated the opposite *** and ConclusionSFI can be a valuable therapeutic option to address gefitinib resistance in NSCLC by suppressing the IL-22/STAT3/AKT pathway.

关键词： Autoimmunity   cross-presentation   Type 1 diabetes   molecular mimicry   immunotoxin  

摘要： Molecular mimicry has been proposed to be a possible mechanism of induction of autoimmunity. In some cases, it is believed that such events could lead to a disease such as Type 1 diabetes (T1D). One of the primary MHC-I epitopes in the non-obese diabetic (NOD) mouse model of T1D has been identified as a peptide from the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) protein. In humans, the most common MHC-I model allele is HLA-A02;based on this, the study here identified a potential HLA-A0201-restricted human IGRP epitope as YLKTNLFLFL and also found a homologous A0201-restricted peptide in an Enterococcal protein. Using cells obtained from healthy human donors, it was seen that after a 2-week incubation with the synthetic bacterial protein, healthy A0201+ donor CD8+ cells displayed increased staining for human IGRP-peptide-dextramer. On the other hand, in control cultures, no significant levels of dextramer-staining CD8+ T-cells were detectable. From these outcomes, it is possible to conclude that certain bacterial proteins may initiate CD8+ T-cell-mediated immune reaction toward homologous human antigens.

关键词： CAR-T cells   interleukin 15   CXCL10   infiltration   Claudin18.2  

摘要： Chimeric antigen receptor (CAR) T cells have demonstrated outstanding therapeutic success in hematological malignancies. Yet, their efficacy against solid tumors remains constrained due to inadequate infiltration of cytotoxic T and CAR-T cells in the tumor microenvironment (TME), a factor correlated with poor prognosis in patients with solid tumors. To overcome this limitation, we engineered CAR-T cells to secrete CXCL10 and IL15 (10 x 15 CAR-T), which sustain T cell viability and enhance their recruitment, thereby amplifying the long-term cytotoxic capacity of CAR-T cells in vitro. In a xenograft model employing NUGC4-T21 cells, mice receiving 10 x 15 CAR-T cells showed superior tumor reduction and extended survival rates compared to those treated with second-generation CAR-T cells. Histopathological evaluations indicated a pronounced increase in cytotoxic T cell accumulation in the TME post 10 x 15 CAR-T cell treatment. Therefore, the synergistic secretion of CXCL10 and IL15 in these CAR-T cells enhances T cell recruitment and adaptability within tumor tissues, improving tumor control. This approach may offer a promising strategy for advancing CAR-T therapies in the treatment of solid tumors.

关键词： Hyperbaric oxygen   microbiota   butyrate   clostridioides difficile   innate lymphoid cells   ILC3   HIF-1  

摘要： Hyperbaric oxygen (HBO) therapy is a well-established method for improving tissue oxygenation and is typically used for the treatment of various inflammatory conditions, including infectious diseases. However, its effect on the intestinal mucosa, a microenvironment known to be physiologically hypoxic, remains unclear. Here, we demonstrated that daily treatment with hyperbaric oxygen affects gut microbiome composition, worsening antibiotic-induced dysbiosis. Accordingly, HBO-treated mice were more susceptible to Clostridioides difficile infection (CDI), an enteric pathogen highly associated with antibiotic-induced colitis. These observations were closely linked with a decline in the level of microbiota-derived short-chain fatty acids (SCFAs). Butyrate, a SCFA produced primarily by anaerobic microbial species, mitigated HBO-induced susceptibility to CDI and increased epithelial barrier integrity by improving group 3 innate lymphoid cell (ILC3) responses. Mice displaying tissue-specific deletion of HIF-1 in ROR gamma t-positive cells exhibited no protective effect of butyrate during CDI. In contrast, the reinforcement of HIF-1 signaling in ROR gamma t-positive cells through the conditional deletion of VHL mitigated disease outcome, even after HBO therapy. Taken together, we conclude that HBO induces intestinal dysbiosis and impairs the production of SCFAs affecting the HIF-1 alpha-IL-22 axis in ILC3 and worsening the response of mice to subsequent C. difficile infection.

关键词： Abrocitinib   atopic dermatitis   JAK inhibitors  

摘要： Aim: Abrocitinib is a JAK-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis (AD). We conducted a 16-week multicenter retrospective study to assess the short-term effectiveness and safety of abrocitinib in patients with moderate-to-severe *** retrospective study included 85 adult patients from 14 Italian Dermatology Units affected by moderate-to-severe AD treated with abrocitinib 100/200 ***: Effectiveness of abrocitinib at weeks 4 and 16 was assessed by using the Eczema Area and Severity Index (EASI), the Investigator Global Assessment (IGA), the peak pruritus and sleep- Numerical Rating Scale (PP-NRS and S-NRS, respectively).Results: At week 16, improvement of at least 90% in EASI (EASI90) and IGA 0/1 was observed in 49.4% and 61.2% of patients, respectively. A reduction of at least 4 points in PP-NRS and S-NRS compared with baseline was achieved by 70.6% of patients for both endpoints. No significant safety reports were observed during the study period. Na & iuml;ve patients had better rates of EASI 90 compared to patients who previously failed ***: Our data confirm the effectiveness of abrocitinib in a real-world setting with better clinical responses at weeks 4 and 16, compared with Phase-III clinical trials. Longer analyses are required to further establish the safety profile of ***: At week 16, improvement of at least 90% in EASI (EASI90) and IGA 0/1 was observed in 49.4% and 61.2% of patients, respectively. A reduction of at least 4 points in PP-NRS and S-NRS compared with baseline was achieved by 70.6% of patients for both endpoints. No significant safety reports were observed during the study period. Na & iuml;ve patients had better rates of EASI 90 compared to patients who previously failed ***: Our data confirm the effectiveness of abrocitinib in a real-world setting with better clinical responses at weeks 4 and 16, compared with Phase-III clinical trials. Longer anal

关键词： Abdominal aortic aneurysm   RNA sequencing   Single-cell RNA sequencing   Immune infiltration   IL-7R  

摘要： Abdominal aortic aneurysm (AAA) is a common cardiovascular disease in the elderly, but there are still no therapeutic targets for this disease. In this study, we collected and analyzed bulk RNA sequencing (bulk RNA-seq) and single-cell RNA sequencing (scRNA-seq) data of AAA from the Gene Expression Omnibus (GEO) database. The immune infiltration-related genes were identified and categorized into various cell types, revealing potential key genes and pathways. Examination of three bulk RNA-seq datasets revealed a total of 4087 differentially expressed genes. The expression levels of the immune-related genes IL-7R were significantly elevated in AAA tissues across all three datasets. Furthermore, scRNA-Seq analysis revealed increased expression of IL-7R in CD4+ memory cells within AAA tissues. Immunofluorescence staining corroborated these findings, demonstrating increased expression of IL-7R in CD4+ T cells in AAA tissues. In vitro, activation of IL-7R elevated the activation of JAK/STAT pathway and phenotypic switching in SMCs, while inhibition of IL-7R abolished these effects and suppressed the secretion of IFN-gamma. In conclusion, the activation of IL-7R in CD4+ T cells is a key contributor to the pathogenesis of AAA, as it can promote secretion of IFN-gamma via JAK/STAT pathway and induce phenotypic switching of SMCs.

关键词： BMSCs   exosomes   macrophage polarization   myocardial infarction   TNF-alpha  

摘要： Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) exhibit considerable therapeutic potential for myocardial regeneration. In our investigation, we delved into their impact on various aspects of myocardial infarction (MI), including cardiac function, tissue damage, inflammation, and macrophage polarization in a murine model. We meticulously isolated the exosomes from TNF-alpha-treated BMSCs and evaluated their therapeutic efficacy in a mouse MI model induced by coronary artery ligation surgery. Our comprehensive analysis, incorporating ultrasound, serum assessment, Western blot, and qRT-PCR, revealed that exosomes from TNF-alpha-treated BMSCs demonstrated significant therapeutic potential in reducing MI-induced injury. Treatment with these exosomes resulted in improved cardiac function, reduced infarct area, and increased left ventricular wall thickness in MI mice. On a mechanistic level, exosome treatment fostered M2 macrophage polarization while concurrently suppressing M1 polarization. Hence, exosomes derived from TNF-alpha-treated BMSCs emerge as a promising therapeutic strategy for alleviating MI injury in a mouse model.