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关键词： Rheumatoid arthritis   IL17A   rs2275913   single nucleotide polymorphism   ELISA  

摘要： Objectives: IL17A, part of the IL17 cytokine family, is a pivotal player in synovitis present in RA patients. This research focused on assessing how the IL17A rs2275913 genetic variation influences IL17A serum concentration, disease progression, and prognosis in Egyptian RA patients. Methods: It encompassed a group of 100 healthy individuals and 100 RA patients. The rs2275913 genetic polymorphism was analyzed in both groups using the Taqman genotyping assay. Additionally, IL17A serum concentration was examined through the ELISA technique. Results: RA patients demonstrated significantly elevated IL17A serum levels compared to control subjects (122 +/- 32.5 Pg/mL vs 20.5 +/- 2.8 Pg/mL, p < 0.001). Moreover, the prevalence of the rs2275913 G allele was higher in RA patients than in normal individuals (p < 0.001). Those with the GG genotype exhibited increased levels of all parameters related to disease severity and activity. Individuals with the GG genotype exhibited elevated IL17A serum levels in comparison to those with GA and AA genotypes (127.9 +/- 29.9 Pg/mL vs 111.1 +/- 34.6 Pg/mL, p = 0.013). Conclusion: In summary, the IL17A rs2275913 gene polymorphism has an impact on IL17A serum production, therefore it has role in diseases pathogenesis, and it is linked to increased disease severity in Egyptian RA patients.

关键词： Biomarkers   Clear cell renal cell carcinoma (ccRCC)   Immune response   Interleukin-2 Receptor Subunit Gamma (IL2RG)   Long non-coding RNAs (lncRNAs)   Tumor microenvironment (TME)  

摘要： Interleukin-2 Receptor Subunit Gamma (IL2RG) has been implicated in various cancers, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. This study aimed to explore IL2RG expression, its relationship with IL2RG -related lncRNAs (IRLs). Gene expression and clinical data for ccRCC were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus(GEO) database. The IRL signature was constructed using Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis. Clinical data validated the diagnostic value of the signature. The prognostic value of the signal was assessed using Kaplan-Meier analysis and Receiver Operating Characteristic (ROC) curves. The prognostic value of the nomogram was further evaluated through calibration curves, ROC curves, and Decision Curve Analysis (DCA). Gene set enrichment analysis (GSEA), single-sample GSEA (ssGSEA), CIBERSORT algorithms, and TISCH2 database were applied to analyze immune function and immune cell infiltration in different risk groups. Clinical treatment differences among populations with varying risks and susceptibilities were predicted using R packages. The expression of IL2RG and key lncRNAs was validated by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). IL2RG was significantly upregulated in ccRCC tissues and correlated with advanced clinical stages (p < 0.001). High IL2RG expression was linked to worse overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) (p < 0.05). A 6-IRLs signature was identified, and the resulting model accurately predicted survival outcomes. Immune-related pathways were enriched in high-risk patients, and drug sensitivity analysis indicated that high-risk patients were more responsive to sunitinib and temsirolimus. IL2RG and its related 6-IRLs are potential biomarkers for ccRCC progression. The 6-IRLs model provides a robust tool for predicting prognosis and guiding

关键词： IL-15 superagonist   mouse model   nonsmall-cell lung cancer   PD-1/PD-L1 inhibitors   SHR-1501  

摘要： BackgroundInterleukin-15 (IL-15) is a pleiotropic cytokine recognized as a promising therapeutic agent in cancer immunotherapy. IL-15 superagonists have shown efficacy across various cancers, yet their effects in lung cancer immunotherapy remain *** study evaluated the antitumor effects of SHR-1501 through intratumoral injection in two murine lung cancer models: Lewis lung carcinoma (LLC) and Kras G12D/p53-/- (KP). We employed flow cytometry to assess immune cell populations in the tumor microenvironment (TME) and systemic circulation. Immunohistochemistry (IHC) was used to analyze TME changes in tumor tissues, while single-cell RNA sequencing provided insights into TME modulation following SHR-1501 treatment. Additionally, we assessed the synergistic potential of combining SHR-1501 with PD-1 monoclonal antibody (mAb) therapy and explored the abscopal effect of ***-1501 significantly inhibited tumor growth in both KP and LLC models at 5 mu g and 15 mu g doses (p = 0.0022 and p = 0.0002, respectively, for KP;p = 0.0508 and p = 0.0131, respectively, for LLC). Flow cytometry revealed increased infiltration of CD8+ T cells, effector memory CD8+ T cells (TEM), and natural killer (NK) cells in the TME. SHR-1501 also enhanced systemic immune responses, increasing CD8+ T cells and TEM populations in peripheral blood and spleen, with an early NK cell elevation on day 7 post-treatment. Single-cell analysis indicated that SHR-1501 promoted the activity of macrophages, increasing M1 macrophage proportions. Moreover, SHR-1501 enhanced the antitumor immune response by promoting pro-inflammatory changes across multiple cell types within the TME, including neutrophils, fibroblasts, and endothelial cells. When combined with PD-1mAb, SHR-1501 exhibited potent synergistic antitumor effects. The combination therapy significantly prolonged overall survival with no significant toxicity observed. Furthermore, SHR-1501 may have the ability to induce an

关键词： endometrial carcinoma   histopathological parameters   HLA-I   immune phenotype   molecular classification   risk stratification   tumour microenvironment  

摘要： Aims: This study aims to define and characterize human leukocyte antigen class I (HLA-I) expression in a consecutive series of molecularly classified endometrial carcinomas (ECs), and to evaluate its association with clinicopathologic features, spatial cancer-immune phenotypes and patient prognosis, with a focus on the NSMP (no specific molecular profile) subtype. Methods and results: HLA-I expression was assessed by immunohistochemistry on whole tissue sections from 208 ECs, classified into POLE-mutated, MMR-deficient (MMRd), p53-abnormal (p53abn) and NSMP subtypes. Loss of HLA-I was identified in 31% of cases and was associated with adverse features including high-grade, aggressive histotypes, deep myometrial invasion, substantial lymphovascular space invasion (LVSI), extensive tumour necrosis and an 'excluded' immune phenotype. While HLA-I loss showed no significant prognostic impact in POLE, MMRd or p53abn tumours, it significantly correlated with worse disease-free survival in NSMP tumours (P < 0.001). Multivariate analysis confirmed HLA-I loss as an independent prognostic factor in early-stage NSMP ECs, in addition to substantial LVSI, presence of lymph node metastases and spatial cancer-immune phenotypes. Integration of HLA-I status improved the performance of predictive models over time. Conclusions: HLA-I loss defines a biologically aggressive subgroup within NSMP ECs and is associated with adverse clinicopathologic and immune features. Assessment of HLA-I expression could refine risk stratification in NSMP ECs, a group traditionally lacking robust prognostic markers and may help identify patients who could benefit from intensified clinical surveillance and future immunomodulatory treatment strategies.

关键词： Metabolomics   Serum   FTIR   Rheumatoid arthritis   TNFi  

摘要： Introduction Rheumatoid arthritis (RA) is an auto-immune disease which causes irreversible damage to tissue and cartilage within synovial joints. Rapid diagnosis and treatment with disease-modifying therapies is essential to reduce inflammation and prevent joint destruction. RA is a heterogeneous disease, and many patients do not respond to front-line therapies, requiring escalation of treatment onto biologics, of which TNF inhibitors (TNF-i) are the most common. Objectives/methods In this study we determined whether serum metabolomics, using nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) spectroscopy, could discriminate RA blood sera from healthy human controls and whether the technologies could be used to predict response or non-response to TNF inhibitor (TNF-i) therapy. Results NMR spectroscopy identified 35 metabolites in RA sera, with acetic acid being significantly lower in RA sera compared to healthy controls (HC, FDR < 0.05). PLS-DA modelling identified 2-hydroxyisovalericacetic acid, acetoacetic acid, mobile lipids, alanine and leucine as important metabolites for discrimination of RA and HC sera by H-1 NMR spectroscopy (averaged 83.1% balanced accuracy, VIP score > 1). FTIR spectroscopy identified a significant difference between RA and HC sera in the 1000-1200 cm(- 1) spectral area, representing the mixed region of carbohydrates and nucleic acids (FDR < 0.05). Sera from RA patients who responded to TNF-i were significantly different from TNF-i non-responder sera in the 1600-1700 cm(- 1) region (FDR < 0.05). Conclusion We propose that NMR and FTIR serum metabolomics could be used as a diagnostic tool alongside current clinical parameters to diagnose RA and to predict whether someone with severe RA will respond to TNF-i.

摘要： While lymphoid progenitors have demonstrated unexpected plasticity in vivo, their differentiation into myeloid cells under in vitro conditions has been largely dismissed as an artifact or biologically irrelevant. Consequently, the functional properties of these cells remain poorly characterized. In this study, we show that cultured common lymphoid progenitors (cCLPs) differentiate into CD11b(+)CD115(+) monocytic cells (cCLP-Ms) via IL-6-C/EBP beta signaling. Molecular and phenotypic analyses revealed that cCLP-Ms acquire essential features of myeloid cells, including innate immune sensor expression and phagocytic capacity, while retaining unique characteristics distinct from bone marrow-derived macrophages (BMDMs), such as reduced MHC class II expression and TNF-alpha production. Functionally, cCLP-Ms exhibit immunoregulatory properties, effectively suppressing IgE-mediated cutaneous allergic inflammation upon adoptive transfer. These findings highlight the plasticity of lymphoid progenitors and establish a robust platform for investigating the mechanisms underlying myeloid differentiation. This system deepens our understanding of hematopoietic cell lineage flexibility and offers a foundation for exploring therapeutic applications in immune regulation and inflammation.

摘要： Increases in retroelement-derived double-stranded RNAs (dsRNAs) in various types of cancer cells facilitate the activation of antitumor immune responses. The long noncoding RNA EPIC1 interacts with the histone methyltransferase EZH2 and contributes to tumor immune evasion. Here, we found that EPIC1 in tumor cells suppressed cytoplasmic dsRNA accumulation, type I interferon (IFN) responses, and antitumor immunity. In various cancer cell lines, knockdown of EPIC1 stimulated the production of dsRNA from retroelements and an antiviral-like type I IFN response that activated immune cells. EPIC1 inhibited the expression of LINE, SINE, and LTR retroelements that were also repressed by EZH2, suggesting a potential role for the EPIC1-EZH2 interaction in regulating dsRNA production. In a humanized mouse model, in vivo delivery of EPIC1-targeting oligonucleotides enhanced dsRNA accumulation in breast cancer xenografts, reduced tumor growth, and increased the infiltration of T cells and inflammatory macrophages into tumors. Furthermore, EPIC1 knockdown improved the therapeutic efficacy of the immunotherapy drug pembrolizumab, a PD-1 inhibitor, in the humanized mouse model. Together, our findings establish EPIC1 as a key regulator of dsRNA-mediated type I IFN responses and highlight its potential as a therapeutic target to improve the efficacy of immunotherapy.

关键词： cytokines   cytokines and cardiovascular diseases   interleukin-40   pericardial fluid and cytokines  

摘要： : The aim of this study was to investigate IL-40 levels in preoperative blood and intraoperative pericardial fluid samples obtained from healthy individuals and patients with diagnosed heart disease who were scheduled for open heart surgery to determine whether it is a biomarker for cardiovascular diseases. : A total of 90 individuals were included in the study and divided into three groups. Group 1 (Healthy Group, n = 45): Blood was collected from a total of 45 healthy men and women over 18 years of age without any diagnosis of cardiovascular disease. Group 2 (Patient Group 1, n = 45): In this group, blood samples from a total of 45 male and female patients over 18 years of age with a diagnosis of heart disease and scheduled for open heart surgery were studied. Group 3 (Patient Group 2, n = 45): Pericardial fluids were obtained from patients in Group 3 immediately after pericardial incision during surgery. IL-40, TAS, TOS and OSI levels in blood plasma and pericardial fluid were determined by the ELISA kit method. : In the statistical analysis between the groups, IL-40, TOS and OSI levels were found to be higher in the patient group and in the pericardial fluid ( < 0.001), while TAS was higher in the control group. It was considered statistically significant ( < 0.001). : IL-40, TOS and OSI levels were elevated in patient serum and pericardial fluid. Therefore, we suggest that IL-40 may be a new biomarker for the detection of cardiovascular diseases.

关键词： dermatomyositis   EPSTI1   interferon   myoblasts  

摘要： Objectives Epithelial-Stromal Interaction 1 (EPSTI1), an IFN-related gene that has emerged as a gene of notable interest, plays a multifaceted role in cellular function and disease processes. However, the precise role of EPSTI1 in the context of DM remains elusive and requires further *** To investigate EPSTI1 expression in DM, we analysed two transcriptome datasets, peripheral blood mononuclear cells (PBMCs) and muscle tissues from our DM cohort. We further validated the findings using RT-qPCR and immunohistochemical staining within our idiopathic inflammatory myopathy (IIM) cohort. Through small interfering RNA-mediated knockdown, we delved into the function and underlying mechanisms of EPSTI1 in DM *** EPSTI1 is significantly upregulated in both PBMCs and muscle tissues of DM patients. A notable positive correlation between EPSTI1 expression and IFN-stimulating genes accompanies this upregulation. Furthermore, EPSTI1 levels were markedly elevated in IFN-beta-stimulated myoblasts. Functional studies have shown that downregulation of EPSTI1 inhibits multiple immune and inflammatory pathways, including antigen processing and presentation, chemokine-mediated signalling, IFN signalling, IL-1-mediated signalling, nuclear factor (NF)-kappa B-inducing kinase (NIK)/NF-kappa B signalling. EPSTI1 was involved in the expression of HLA-A and the secretion of chemokines in myoblasts mediated by *** EPSTI1 might play an essential role in promoting muscle inflammation in DM by regulating the expression of HLA-A and the secretion of chemokines in myoblasts. Targeting EPSTI1 may represent a novel therapeutic approach for reducing muscle inflammation and damage in dermatomyositis (DM) patients.