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关键词： IL-22   claudins   inflammatory-triggered abortion   pregnancy loss   tight junctions  

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摘要： Crohn's disease pathology is modeled in TNF Delta ARE+/- mice that overproduce tumor necrosis factor (TNF) to drive disease through TNF receptors. An alternative ligand for TNF receptors, soluble LT alpha 3, is produced by B cells, but has received scarce attention because LT alpha also partners with LT beta to generate membrane-tethered LT alpha beta 2 that promotes tertiary lymphoid tissue-another feature of Crohn's disease. We hypothesized that B cell-derived LT alpha beta 2 would critically affect ileitis in TNF Delta ARE+/- mice. However, whereas deleting LT beta in B cells was essential for tertiary lymphoid tissue, disease pathology was minimally affected. By contrast, loss of B cell-derived LT alpha increased intestinal permeability, shrunk the pool of IgA+ ileal plasma cells, elevated cytokines and prompted weight loss, including loss of muscle mass-a systemic feature of Crohn's disease. Neutralizing antibodies to LT alpha 3 strongly augmented the cachexic-like effects of TNF. Thus, B cell-produced LT alpha beta 2 and LT alpha 3 have distinct roles in ileitis, with the role of LT alpha 3 unexpectedly protective through counterbalancing TNF.

关键词： Small bowel Crohn's disease (CD   Terminal ileal (TI) stricture diagnosis   Magnetic resonance enterography (MRE)   Computed tomography enterography (CTE)  

摘要： PurposeCrohn's disease (CD) is characterized by enteric inflammation, often resulting in strictures and penetrating complications, which may alter patient management prior to the initiation of biologic therapy. Our aim is to assess the frequency of missed stricturing and internal penetrating complications in CD patients on computed tomography enterography (CTE) and magnetic resonance enterography (MRE) performed prior to anti-TNF *** retrospectively reviewed patients from two tertiary centers who underwent CTE\MRE within six months before starting anti-TNF therapy. Patients with prior intestinal surgery, anti-TNF therapy, or radiology reports indicating strictures or penetrating complications were excluded. Two GI radiologists re-evaluated CTE\MRE images for active inflammation, small bowel strictures (SAR/AGA/SPR criteria), and internal penetrating complications. Senior radiologists reviewed CTE/MRE exams with missed findings and identified potential causes of error. Descriptive statistics were used to summarize the prevalence of missed findings. Where applicable, comparisons were made using chi-square ***250 CD patients were included. 239 (96%) exhibited active terminal ileal (TI) inflammation by expert review of CTE\MRE images. Missed TI strictures were identified in 56 patients (22%). 16 patients (6.4%) had unreported penetrating complications, including ileoappendiceal fistulas (n = 6), sinus tracts (n = 6), complex fistulas (n = 4), inflammatory masses (n = 3), ileocecal fistula (n = 1), and abscess (n = 1). There were no significant differences between institutions in the rates of strictures (18/69 vs. 38/181, P = 0.4) or penetrating complications (5/69 vs. 11/181, P = 0.77). 46% of the strictures appeared obvious upon re-evaluation by senior radiologists, potentially implicating a failure to measure associated small bowel dilation. 38% of missed strictures had multifocal areas of luminal narrowing, and maximal proximal dilation was loc

关键词： multiple myeloma   multi-omics atlas   non-immune cells   signaling pathway   metabolic reprogramming-targeted  

摘要： Multiple myeloma (MM) is highly heterogeneous, with relapse occurring in the majority of cases, and recent advancements in single-cell RNA sequencing (scRNA-seq), sc-metabolism profiling, and bulk RNA-seq have facilitated the identification of cell subpopulations and metabolic reprogramming at the single-cell level, uncovering novel molecular mechanisms. This study aims to establish a multi-omics atlas of MM, characterizing the cell subpopulations and signaling pathways that drive immune evasion and disease progression. Additionally, sc-metabolic profiling identifies reprogramming patterns and informs therapeutic screening. We integrated scRNA-seq and bulk RNA-seq data using R to analyze immune and non-immune cell features and pathways in MM. Metabolic reprogramming was assessed via sc-metabolic profiling, and drug candidates were screened through multi-omics integration, with efficacy evaluated in vitro using CCK-8 assays, flow cytometry, Western blotting, and CalcuSyn software. Novel MM subpopulations were identified, including myeloma-activated hematopoietic stem cells and ISG15+ B cells, which correlated with survival and were validated by multiplex immunofluorescence. IFN-gamma is primarily secreted by effector memory CD8+T cells, and IFN-alpha is primarily secreted by non-classical monocytes, driving an IFN-gamma/alpha-B2M feedback loop. Multi-omics identified four drug candidates, each demonstrating anti-tumor effects against myeloma cell lines.

关键词： chronic hepatitis B   serum ferritin   HBsAg   PEG IFN-alpha 2b   ALT  

摘要： Background: Chronic hepatitis B (CHB) caused by HBV infection leads to persistent liver inflammation. PEG IFN alpha-2b shows higher functional cure rates than oral antivirals, but identifying optimal candidates remains challenging. This study evaluates serum ferritin as a predictive biomarker for PEG IFN alpha-2b efficacy. Methods: Serum ferritin, HBsAg and transaminase were monitored in CHB patients treated with PEG IFN alpha-2b at baseline (0w), 12w and 24w. Patients were divided into the effective group (HBsAg reduction >= 1 log10 IU/mL or clearance) and the ineffective group (HBsAg reduction <1 log10 IU/mL) at 24 weeks. Similarly, for the results at 48 weeks, the patients were divided into the clearance group (achieving HBsAg clearance) and the non-clearance group (not achieving HBsAg clearance). To analyze the correlation between serum ferritin and the decrease of HBsAg, a multivariate logistic regression model was constructed. Potential confounding factors such as age, gender, HBeAg and HBV DNA status, ALT, AST, and iron metabolism indicators (FE, TIBC, TS) were included to evaluate the independent predictive effect of ferritin levels on the therapeutic effectiveness, calculate the corrected OR value and 95% CI. The predictive effect was evaluated by the ROC curve. Results: Among patients with chronic hepatitis B (CHB) who completed the PEG IFN alpha-2b course of treatment, the serum ferritin levels of all patients showed an increasing trend at baseline and during the treatment process, and the serum ferritin level in the effective treatment group (HBsAg reduction >= 1 log10 IU/mL or clearance) was significantly higher than that in the ineffective treatment group. It was confirmed by Spearman's rank correlation analysis that the serum ferritin level was positively correlated with the decrease in HBsAg. Further analysis through the multivariate logistic regression model revealed that serum ferritin remained an independent predictor of the antiviral efficacy of

摘要： INTRODUCTION:The residual risk of chronic kidney disease (CKD) progression remains high in clinical trials of kidney protective drugs in patients with diabetic kidney disease (DKD). METHODS:In a prospective study, we assessed whether 16 plasma and 10 urine cytokine levels can inform the residual risk of CKD progression in 93 incident patients with DKD treated by Nephrology according to clinical guidelines. RESULTS:Plasma and urine levels of 12 plasma and 7 urinary cytokines differed between patients with DKD and from healthy controls. Participants were categorized into CKD G1-G2 (preserved GFR) and CKD G3-G5 (GFR <60 ml/min/1.73 m2). After a median of 7.27 years (IQR; 5.34-9.56), 13/40 (32.5%) patients with CKD G1-G2 at baseline had progressed to CKD G3-G5. Progressors had higher plasma IL-22 and TNF-α levels than non-progressors. Plasma IL-22 and TNF-α levels in progressors were similar to those in patients already in CKD G3-G5 at baseline, suggesting that cytokine dysregulation precedes CKD progression. In patients with CKD G1-G2, cut-off points for plasma IL-22 and TNF-α predicted progression with an AUC of 0.76 and 0.77, respectively. Additionally, patients with CKD G1-G2 and plasma TNF-α or IL-22 levels equal to or above the cut-off value had significantly lower eGFR values at the end of follow-up and had more frequently progressed to a very high risk KDIGO category. In cluster analysis, clusters displaying the highest urinary or plasma cytokine levels were associated with worse GFR outcomes. CONCLUSION:Plasma IL-22 and TNF-α may help to identify patients with early DKD with a high residual risk of CKD progression despite treatment.

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关键词： TNF-alpha   PCOS   Polymorphism   Insulin resistance   Kashmir  

摘要： Background Polycystic ovary syndrome (PCOS) is a chronic inflammatory disease characterized by a hyperandrogenic state, irregular menses, and polycystic ovaries (PCO). Tumor necrosis factor-alpha (TNF-alpha), a key pro-inflammatory cytokine, plays a significant role in this process of inflammation. Studying TNF-alpha polymorphisms is important as genetic variations may influence TNF-alpha expression, potentially affecting individual susceptibility to disease and its severity. The -1031 (T > C) single-nucleotide polymorphism (SNP) in the TNF-alpha has been linked to inflammatory and metabolic disorders, but its association with PCOS, particularly in Kashmiri population, is not well explored. Objectives The objective of the study was to assess the impact of -1031 (T > C) SNP in the TNF-alpha on the vulnerability of PCOS in women from Kashmir and to find out its correlation with clinical, hormonal, and metabolic parameters. Methods This study enrolled 210 PCOS patients and 203 age and body mass index (BMI) matched healthy controls. Genotyping of -1031 (T > C) SNP was performed using the restriction fragment length polymorphism (RFLP) method. Biochemical, hormonal, and metabolic profiles were investigated. The study primarily employed Chi-square tests, t tests, and ANOVA. Results TC genotype was significantly more frequent in PCOS cases (43.8%) vs. controls (21.6%) [odds ratio (OR) = 2.81;95% confidence interval (CI) 1.83-4.33;p = 0.001)]. The C allele frequency was higher in cases (21.9%) vs. controls (10.83%) (OR = 2.30;95% CI 1.56-3.40;p = 0.001). TC genotype carriers showed higher fasting insulin, homeostasis model assessment insulin resistance index (HOMA-IR), triglyceride levels, and reduced quantitative insulin sensitivity check index (QUICKI), indicating insulin resistance (IR) (p < 0.05). Conclusion The -1031 (T > C) SNP in the TNF-alpha gene is significantly associated with increased susceptibility to PCOS in Kashmiri women, with the TC genotype linked to high

关键词： guselkumab   IL-23   psoriasis   psoriatic arthritis  

摘要： Background: Psoriasis is a chronic inflammatory condition that may develop into psoriatic arthritis (PsA) in a significant number of patients. Clinical signs such as enthesitis and nail involvement have been suggested as early indicators of this progression. IL-23 inhibitors have demonstrated effectiveness in psoriasis and, more recently, in PsA. This article aims to evaluate the effect of IL-23 inhibitors on clinical outcomes and progression of PsA in patients with moderate-to-severe psoriasis and early musculoskeletal involvement. Methods: This was a retrospective, multicentre observational study conducted in Italy. Data were collected from 207 adult patients who had already started treatment with guselkumab, risankizumab or tildrakizumab prior to inclusion. All clinical data, including baseline characteristics and follow-up outcomes, were retrieved retrospectively from medical records across eight dermatology centres. Results: Enthesitis was observed in 44.8% of patients with joint involvement. Guselkumab was the most commonly used treatment (57%) and demonstrated sustained improvements in Psoriasis Area and Severity Index, Visual Analogue Scale pain and Dermatology Life Quality Index scores. Importantly, no patients with enthesitis treated with guselkumab progressed to overt PsA. At 52 weeks, the average Psoriasis Area and Severity Index score was 0.61, Visual Analogue Scale pain score was 0.59 and Dermatology Life Quality Index score was 0.91. Conclusion: IL-23 inhibitors have proven effective in managing both skin and joint symptoms in patients with psoriasis at risk for PsA. Whilst the findings suggest that IL-23 inhibitors may help control early musculoskeletal symptoms in patients with psoriasis at risk of PsA, the absence of systematic rheumatological evaluation and the retrospective design preclude definitive conclusions about their disease-modifying potential. These results suggest a potential disease-modifying role that warrants further prospective vali