课程文献中心 更多>>

关键词： TNF-alpha   EBV reactivation   Ferroptosis   GPX4  

摘要： Epstein-Barr virus (EBV) is a carcinogenic gamma-herpesvirus that remains latent in more than 95% of adults. The virus can undergo lytic activation when immune function is suppressed or when stimulated by drugs or pathogens. EBV reactivation poses a significant threat to human health and is closely associated with various cancers, such as Burkitt's lymphoma and nasopharyngeal carcinoma. Inhibiting EBV reactivation is a current clinical challenge. Tumour necrosis factor-alpha (TNF-alpha), an important cytokine, has different effects on various viruses. It also exerts varying effects on the same virus depending on the type of infected cell. This study aimed to investigate the impact of TNF-alpha on EBV reactivation and its underlying mechanisms. Our experimental research revealed that TNF-alpha significantly inhibits EBV reactivation and that this inhibitory effect is mediated primarily through its receptor TNFR1. Furthermore, TNF-alpha affects the expression of the GPX4 protein and regulates the potential ferroptosis state of cells. Using transmission electron microscopy and other methods, we observed typical characteristics of ferroptosis, such as changes in mitochondrial morphology and Fe2 + accumulation. Additionally, we established stable GPX4-knockdown cell lines, which demonstrated the crucial role of GPX4 in the process of TNF-alpha-mediated inhibition of EBV reactivation. Overall, TNF-alpha acts on the TNFR1 receptor, thereby affecting the GPX4 protein and the ferroptosis pathway to achieve its inhibitory effect on EBV reactivation. These findings provide new insights into the mechanisms of EBV reactivation and may offer new perspectives for the early treatment of EBV-related diseases.

关键词： Beh & ccedil   et's   Vasculitis   HLA-B51   Uveitis   Colchicine   United Arab Emirates  

摘要： Beh & ccedil;et's disease (BD) is a rare multisystem vasculitis. Globally, BD exhibits a unique geographic distribution, with the highest prevalence along the historic Silk Road. To study the demographics, clinical characteristics, and outcomes of BD in the United Arab Emirates (UAE). A multicenter retrospective chart review study was conducted at hospitals in the UAE from 2008 to 2024. All adult and pediatric patients who were diagnosed with BD by a rheumatologist and treated within the timeframe were included in the study while those who received any alternative final diagnosis were excluded. The results were analyzed using descriptive and inferential statistics. One hundred and twenty-three patients were treated and monitored for BD. Most were female (n = 70, 57%). Their median age was 32 years (24-41), and approximately two-thirds were Emirati (n = 82, 67%). Twelve patients (10%) had a family history of BD, including 7 (6%) with first-degree BD. The time from the initial symptoms to diagnosis was 11.9 months (2.3-31.0). The most common clinical manifestations were oral ulcers (n = 99, 81%), arthralgia (n = 63, 51%), genital ulcers (n = 62, 50%), and ocular involvement (n = 37, 30%). Most of the patients were HLA-B51 positive (n = 92, 84%). At diagnosis, 36 (29%) met the ISG criteria, 73 (59%) met the ICBD criteria, and 50 (41%) met neither criteria. The male patients exhibited more major organ involvement (ocular, neurological, vascular, and cardiac), greater use of corticosteroids and anti-TNFa medications, and greater disease activity than the female patients. Among the patients with isolated ocular manifestations (n = 9) who met neither classification criteria, most were female (56%), with a median age of 37 years (26.5-3.5). None had a family history of autoimmune conditions, and all were HLA-B51 positive. Most of these patients (n = 8, 89%) received corticosteroids, 5 (56%) received azathioprine, and 2 (22%) received anti-TNFa therapies. These findings prov

关键词： Combination therapy   Cytokine   Cytokine release syndrome   Immune related adverse event - irAE   Antibody  

摘要： Background The administration of recombinant interleukin 2 (IL-2) in oncology is frequently hampered by dose-limiting toxicities, including potentially lethal vascular leak syndrome. Antibody-IL-2 fusion proteins capable of preferential tumor localization have shown encouraging signs of activity in clinical trials;however, they typically cause side effects shortly after intravenous administration, which may limit escalation to curative doses. There is an urgent need to engineer IL-2 products with "activity-on-demand" able to mask on-target off-tumor IL-2 activity without compromising therapeutic *** To design IL-2 biopharmaceuticals with "activity-on-demand", which would be non-toxic on administration but regain activity at the tumor site, we explored the therapeutic potential of the co-administration of signaling inhibitors with matched pharmacokinetic properties. In this work, we used the tumor-homing F8-IL2 fusion protein, specific to a splice variant of fibronectin, and masked off-tumor toxicity by co-administration of upadacitinib, which rapidly clears from circulation. Vascular leak syndrome was monitored by histopathological analysis, the extent of peripheral edema, and cytokine levels. Immune profiling of the tumors and secondary lymphoid organs was performed by flow *** In immunocompetent tumor-bearing mice, the combinatorial treatment significantly improved tolerability without any detectable loss of therapeutic activity, protecting the mice from body weight loss, uncontrolled systemic cytokine release, and severe vascular leak syndrome manifestations, including peripheral edema. F8-IL2 efficiently controlled tumor growth and retained its immunological activity within the neoplastic mass, as evidenced by the massive natural killer and cytotoxic T-cell *** This study suggests that combinatorial treatments enable the administration of potentially curative doses of targeted IL-2 products while sparing healthy org

关键词： rheumatoid arthritis   IL-17A   IL-17F   IL-23   disease activity  

摘要： The aim of the study was to determine the clinical and diagnostic value of IL-17A, IL-17F, and IL-23 in RA patients in the advanced stage of the disease. Materials and methods. We examined 154 patients with a reliable diagnosis of RA according to ACR/EULAR criteria (2010), predominantly (73.4%) female, middle-aged (56.0 (50.0;64.0) years), disease duration of 9.4 (3.0;13.0) years, radiologic stages II (34.4%) and III (37.0%), and moderate to high activity (DAS28-ESR 5.40 (4.65;6.00). Of these, 83.8% patients were seropositive for IgM rheumatoid factor (IgM RF), and 68.8% had antibodies to cyclic citrullinated peptide (ACCP). As many as 144 (93.5%) patients were taking DMARDs (methotrexate, leflunamide, and sulfasalazine), as well as nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids (GCs) up to 10 mg/day in terms of prednisolone. The serum levels of IL-17A, IL-17F, and IL-23 were investigated using multiplex xMAR technology. The upper limit of the norm (M+3 sigma) in 20 sera of healthy donors was 1.78 pg/mL for IL-17A, 9.5 pg/mL for IL-17F, and 91.55 pg/mL for IL-23. Results. IL-17A (1.16 (0.50;2.39) pg/mL) and IL-17F (5.02 (1.00;138.80) pg/mL) concentrations in RA patients were not significantly different from controls (0.78 (0.00;1.65) pg/mL and 4.02 (1.46;7.31) pg/mL, p > 0.05). In contrast, IL-23 levels were significantly higher in patients than in donors (21.36 (2.50;4626.22) pg/mL and 14.63 (0.00;91.55) pg/mL, p < 0.05). High values of IL-17F (71 patients, 46.1%) and IL-23 (66 patients, 42.9%) were significantly more frequently detected than IL-17A (46 patients, 29.9%: p = 0.003 and p = 0.02, respectively). Overproduction of IL-17A and IL-17F was simultaneously observed in 37 (24.0%) patients, and 32 (20.8%) patients had an increase in IL-17A, IL-17F, and IL-23. Correlations between IL-17A and IL-17F concentrations (r = 0.44, p < 0.05), IL-17A and IL-23 (r = 0.40, p < 0.05), IL-17F and IL-23 (r = 0.94, p < 0.05) were found. No statistically signi

关键词： Statistical Analysis C   Rheumatic Diseases   Spondylitis   Ankylosing  

摘要： Background: This study aimed to evaluate the frequency of human leukocyte antigen (HLA)-B27 in 488 patients with ankylosing spondylitis (AS) from the Thrace region of Turkey and to assess its association with clinical and radiological features. Material/Methods: A retrospective analysis was conducted on patients diagnosed with AS according to the modified New York criteria and/or Assessment of Spondyloarthritis International Society (ASAS) classification criteria. HLA-B27 status was determined using real-time polymerase chain reaction (PCR). Clinical data, including disease activity (CRP), erythrocyte sedimentation rate (ESR), and radiological findings were analyzed. Statistical comparisons were performed using chi-square, Mann-Whitney U, Spearman's correlation, and logistic regression models. Results: Among 488 AS patients, 59.43% were HLA-B27 positive. HLA-B27 positivity was significantly associated with male sex (p=0.020), earlier disease onset (p=0.021), higher CRP (p=0.020) and ESR (p=0.04) levels, and the initial BASDAI and initial BASFI scores (p=0.042 and p=0.044). A strong correlation was found between HLA-B27 positivity and sacroiliitis severity on X-ray (p=0.016, OR: 1.518) and magnetic resonance imaging (MRI) (p=0.001, OR: 1.199). No significant associations were observed between HLA-B27 status and extra-articular manifestations. Conclusions: The HLA-B27 frequency in Thracian AS patients (59.43%) was lower than reported in Western populations but consistent with some Turkish studies. HLA-B27 positivity was associated with earlier disease onset, male predominance, and more severe sacroiliitis. These findings highlight regional variations in AS presentation and the role of HLA-B27 in disease severity.

关键词： Crohn's disease   immunofluorescence imaging   inflammation   lymphatic vessel   mesentery  

摘要： Crohn's disease (CD) is a chronic inflammatory bowel disease, which also encompasses significant alterations of the mesenteric lymphatic system. Whether these changes are a mere consequence of or directly contribute to the inflammation is unknown. Here, we characterized the spatial and temporal development of these events in the TNF Delta ARE/+ mouse, which develops CD-like ileitis and significant mesenteric lymphatic alterations. At 8, 12, 20, and 28 wk of age, specific pathogen-free (SPF), germ-free (GF) TNF Delta ARE/+ and wild-type (WT) mice were assessed for ileitis via myeloperoxidase (MPO) activity while mesenteric lymphatic alterations were assessed by confocal immunofluorescence imaging. Lymphatic alterations in the SPF TNF Delta ARE/+ occurred in a stepwise manner between 8 and 28 wk of age beginning with the development of mesenteric lymphadenopathy at 8 wk despite no significant ileitis. By 12-wk ileal MPO significantly elevates concomitantly with lymphangiectasia of the mesenteric collecting lymphatic vessels (CLVs) and clustering of CD45(+) immune cells around them. At 20 wk, significant lymphangiogenesis of the initials (initial lymphatic vessel) and tertiary lymphoid organs aligned along lymphatic collectors (CA-TLOs) had developed. At 28 wk, lymphangiectasia, lymphangiogenesis, and CA-TLOs increased. However, 28-wk-old GF TNF Delta ARE/+, while displaying no ileitis, presented with mesenteric lymphadenopathy, lymphangiectasia, and lymphangiogenesis but no immune cell clustering nor CA-TLOs. The TNF Delta ARE/+ mice develop terminal ileitis and lymphatic alterations in a stepwise manner beginning with mesenteric lymph node lymphadenopathy and ileal inflammation, followed by CLV dilation and lymphangiogenesis. These lymphatic alterations are exacerbated by the gut microbiome, with immune cell clustering and tertiary lymphoid organ formation being entirely dependent of its presence. NEW & NOTEWORTHY The mesenteric lymphatic system displays striking mor

关键词： Malignant pleural effusion   Lung cancer   IL-6   PD-L1   Cancer-associated fibroblast   Immunotherapy  

摘要： BackgroundMalignant pleural effusion (MPE) is a severe complication in lung cancer, characterized by an immunosuppressive tumor microenvironment (TME) and limited therapeutic options. This study investigates the role of IL-6 in regulating immune suppression and tumor progression in MPE and evaluates the efficacy of dual IL-6 and PD-L1 ***-6 levels were measured in MPE and paired serum samples from lung cancer patients, and correlations with PD-L1 expression and clinical outcomes were analyzed using publicly available datasets. RNA sequencing and immune deconvolution were used to assess immune cell infiltration. CAFs and immune cell infiltration were further evaluated using flow cytometry, immunohistochemistry, and multiplex immunofluorescence. In vitro co-culture systems were employed to simulate the MPE microenvironment and explore IL-6 interactions with CAFs, as well as its regulatory effect on tumor cell PD-L1 ***-6 levels were significantly elevated in MPE compared to paired serum and correlated with higher PD-L1 expression and poor survival outcomes in lung cancer patients. In the MPE mouse model, combination therapy with IL-6 and PD-L1 blockade reduced MPE volume, tumor burden, and PD-L1 expression, while enhancing T cell infiltration and alleviating TME immunosuppression. IL-6 was found to drive a positive feedback loop with iCAFs, promoting an immunosuppressive environment. In vitro, IL-6 from the MPE upregulated tumor cell PD-L1 expression the IL-6/STAT3 *** study identifies IL-6 as a critical contributor of immune suppression and tumor progression in MPE. The combination of IL-6 and PD-L1 blockade effectively alleviated immunosuppression and reduced tumor burden, offering a potential therapeutic approach for MPE management.

摘要： Innate immunity is the first line of host defense and contributes to pain. However, how innate immune system interacts with sensory neurons to govern pain remains poorly understood. Here, we report that interleukin 33(IL-33) initiates pain hypersensitivity that requires chemokine (C-C motif) ligand 2 (CCL2) secretion from infiltrated macrophages and neutrophils and activation of transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential melastatin 8 (TRPM8) channels in sensory neurons. Blocking CCL2 receptor (CCR2) attenuates IL-33- induced and Complete Freund's adjuvant (CFA)-induced thermal hyperalgesia and blocking TRPV1 and TRPM8 attenuates IL-33-induced mechanical and thermal hypersensitivity and cold allodynia respectively. Furthermore, depletion of macrophages reduces IL-33-induced pain and expression of CCL2 and suppression of tumorigenicity 2 (ST2) in hindpaw skin and inhibition of CCR2 prevents recruitment of macrophages and neutrophils. Our findings reveal an unrecognized neuroimmune crosstalk of IL-33-CCL2 signaling from infiltrated immune cells with TRPV1/TRPM8 in sensory neurons to facilitate pain states.

摘要： Introducing Bruton's tyrosine kinase (BTK) inhibitors has significantly improved outcomes for patients with B-cell malignancies and autoimmune disorders. However, resistance, either primary or acquired, remains a major clinical challenge. To better understand the underlying resistance mechanisms to BTK inhibitors, we established an ibrutinib-resistant model from a patient-derived splenic marginal zone lymphoma (MZL) cell line (VL51) through prolonged drug exposure. Resistant cells exhibited a 15-fold increase in ibrutinib's IC50, along with distinct morphological changes, mitochondrial activation, and cross-resistance to covalent, non-covalent BTK inhibitors and BTK degraders. Integrated transcriptomic, epigenomic, and proteomic analyses identified overexpression and secretion of IL-16 as a key feature of resistance, driven by chromatin remodeling and activation of the FLI1 transcription factor. IL-16 conferred ibrutinib resistance via CD9-mediated activation of the NF-κB and AKT signaling pathways and was found to be elevated in the serum of ibrutinib-refractory CLL patients. Functional studies showed that targeting the IL-16/CD9 axis using neutralizing antibodies or CD9-binding peptides restored sensitivity to BTK inhibitors and R-CHOP chemotherapy in MZL, mantle cell lymphoma, and diffuse large B-cell lymphoma models. These findings reveal a novel, targetable resistance mechanism with potential therapeutic implications for overcoming BTK inhibitor resistance in B-cell lymphomas.

关键词： post-COVID-19 condition   long-COVID-19   vitamin D-3 supplementation   cholecalciferol   interleukin-6   glutathione peroxidase activity   respiratory symptoms   anxiety   depression  

摘要： Coronavirus disease 2019 (COVID-19) presents with various symptoms, and some patients develop post-COVID-19 condition (PCC). Vitamin D has shown therapeutic potential in COVID-19 and may offer benefits for PCC. The aim of this study was to evaluate the differences associated with two supplementation strategies (bolus and daily) on interleukin-6 (IL-6) levels, glutathione peroxidase (GPx) activity, and clinical outcomes in PCC patients, regardless of whether target 25 (OH) D levels reached the ideal range. We conducted a self-controlled study in which 54 participants with PCC were supplemented with vitamin D-3 (n = 28 bolus and n = 26 daily) for 2 months. Blood samples were collected to measure IL-6 levels and GPx activity using spectrophotometric methods. The Hospital Anxiety and Depression Scale (HADS) was used to assess mental function. Both bolus and daily vitamin D supplementation were significantly associated with increased GPx activity and decreased IL-6 levels. Daily supplementation was additionally associated with a significant reduction in anxiety and depression scores. However, neither regimen was associated with improvements in cough, dyspnea, or fatigue. These findings suggest a potential association between vitamin D supplementation and improvements in antioxidant and neuropsychiatric parameters in PCC, possibly mediated by its immunomodulatory and antioxidant properties. Further placebo-controlled trials are warranted to determine whether these observed associations reflect causal relationships.