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关键词： Interleukin-17E   Non-small cell lung cancer   Cell proliferation   Epithelial-mesenchymal transition   NF-kappa B pathway  

摘要： Objective: Interleukin-17 E (IL-17E) is a pro-inflammatory cytokine that participates in the inflammatory response and tumorigenesis. However, the function of IL-17E in non-small cell lung cancer (NSCLC) remains largely unknown. Methods: The clinical value of IL-17E was determined by immunohistochemistry (IHC) in 75 cases of NSCLC tissues. Furthermore, A549 cells were added with recombinant human IL-17E (rhIL-17E) or transfected with IL17E siRNAs to evaluate the impact on cell proliferation, apoptosis, and epithelial-mesenchymal transition (EMT), as well as explore the link between IL-17E and the NF-kappa B pathway. Experimental techniques include CCK-8, EdU, colony formation, RT-qPCR, western blotting, flow cytometry, wound-healing, transwell and immunofluorescence assay. Results: IL-17E levels was elevated in NSCLC tissues and cells, which was related to higher TNM staging, positive lymph node metastasis and decreased tumor differentiation degree. Exogenous recombinant human IL-17E (rhIL17E) treatment promoted cell proliferation, reduced cell apoptosis, and increased the level of Bcl-2/BAX. Moreover, it enhanced cell migration, invasion, EMT and phosphorylation levels of NF-kappa B p65. Inversely, knocking down endogenous IL-17E in A549 cells had the opposite effect. Blocking the NF-kappa B pathway with BAY117082 reduced IL-17E expression and reversed the malignant effects induced by IL-17E on A549 cells. Conclusion: IL-17E facilitates NSCLC progression by promoting cell proliferation and EMT via the NF-kappa B pathway. IL-17E could serve as a potential strategy for NSCLC treatment.

关键词： Breast cancer   TNF-alpha   Single-nucleotide polymorphism   Carcinogenesis   Risk factor   Predictive index  

摘要： Background Compared with all other cancer types, Breast cancer (BC) among women has now exceeded them all as the primary reason for cancer worldwide. The BC represents 11.7% of all cancer cases and accounts for a predestined 2.3 million new cases. It is the fourth primary reason for cancer-associated deaths in women. With a staggering 200-400% increase in the relative incidence of BC in Egypt, there is an urgent need for new diagnostic or predictive markers. Purpose The current investigation aims to explore the connection of the functional TNF-alpha-308G > A (rs1800629) single-nucleotide polymorphism (SNP) with different breast cancer predictive indices. Methods The ARMS-PCR method was used for genotyping TNF-alpha(-308)G > A SNP. Three groups were recruited for the study: 79 patients with benign breast inflammation (BBI);163 with breast cancer (BC) and 144 controls (C). Results The TNF-alpha(-308)G > A SNP was distributed among different groups in a unique pattern;in the control group 63.9% of cases were in the GG, 34% were in the GA, and 2.1% were in the AA. The BC group had 14% GG, 79% GA, and 7% AA, while the BBI group had 24% GG, 76% GA, and 0% AA. The AA genotype and A allele represented a strong significant correlation with risk factors in the BC group (ORAA: 14.67 [95% CI = 3.78-56.91] and ORA: 0.27 [95% CI = 0.19-0.39], respectively;P < 0.0001) in contrast to the control group. However, in the BBI group, a strong significant correlation was noted with the GA genotype (ORGA: 5.93 [95% CI = 3.18-11.04] P < 0.0001). In the BC group, the AA genotype shows a significant increase in Nottingham Prognostic Index (NPI) in positive ER and PR in contrast to the relevant negative ones (P = 0.02 and 0.002, respectively). However, the GA genotype significantly increased NPI in positive Her2 and metastatic patients (P = 0.03 and 0.01, respectively). Conclusion This research is the first to correlate TNF-alpha(-308)G > A (rs1800629) SNP in Egyptian BC patients. The A allel

摘要： OBJECTIVE More than 10% of patients with type 1 diabetes (T1D) do not have high-risk HLA-DR3 or -DR4 haplotypes with distinct clinical features, such as later onset and reduced insulin dependence. We aimed to identify genetic drivers of T1D in the absence of DR3/DR4 and improve prediction of T1D risk in these *** DESIGN AND METHODS We performed T1D association and fine-mapping analyses in 12,316 non-DR3/DR4 samples. Next, we performed heterogeneity tests to examine differences in T1D risk variants in individuals without versus those with DR3/DR4 haplotypes. We further assessed genome-wide differences in gene regulatory element and biological pathway enrichments between the non-DR3/DR4 and DR3/DR4 cohorts. Finally, we developed a genetic risk score (GRS) to predict T1D in individuals without DR3/DR4 and compared with an existing T1D *** A total of 18 T1D risk variants in non-DR3/DR4 samples were identified. Risk variants at the MHC and multiple other loci genome wide had heterogeneity in effects on T1D dependent on DR3/DR4 status, and non-DR3/DR4 T1D had evidence for a greater polygenic burden. T1D-associated variants in non-DR3/DR4 were more enriched for regulatory elements and pathways involved in antigen presentation, innate immunity, and beta-cells and depleted in T cells compared with DR3/DR4. A non-DR3/DR4 GRS outperformed an existing risk score GRS2 in discriminating non-DR3/DR4 T1D from no diabetes (area under the curve 0.867;P = 7.48 x 10-32) and type 2 diabetes (0.907;P = 4.94 x 10-44).CONCLUSIONS In total, we identified heterogeneity in T1D genetic risk dependent on high-risk HLA-DR3/DR4 haplotype, which uncovers disease mechanisms and enables more accurate prediction of T1D across the HLA background.

关键词： IgE   IL-10   IP-10   monocyte   SHIP-1  

摘要： IgE-mediated stimulation of monocytes regulates multiple cellular functions including cellular maturation, cytokine release, antiviral responses, and T-cell differentiation. Expression of the high-affinity IgE receptor, Fc epsilon RI, is closely linked to serum IgE levels and atopic disease. The signaling molecules regulating Fc epsilon RI effector functions have been well studied in mast cells and basophils;however, less is known about the signaling and regulatory mechanisms in monocytes. This study sought to identify regulators of IgE-mediated cytokine release in human monocytes. SHIP-1 was identified as a negative regulator of IgE-induced IL-10 production. It was also determined that IgE-mediated stimulation and SHIP-1 inhibition decreased antiviral IP-10 production after liposomal poly(I:C) stimulation, indicating differential regulation by SHIP-1 in IgE-driven and antiviral response pathways. SHIP-1 and NF-kappa B were activated following IgE-mediated stimulation of monocytes, and NF-kappa B activation was related to both SHIP-1 and Fc epsilon RI alpha cellular expression levels. To our knowledge, this is the first study to identify a role for SHIP-1 in regulating IgE-mediated and antiviral responses in human monocytes. Given the importance of monocytes in inflammation and immune responses, a better understanding of the signaling and regulatory mechanisms downstream of the Fc epsilon RI receptor could lead to new therapeutic targets in allergic disease.

关键词： ADM   amyopathic dermatomyositis   ARS   anti-RNA synthetase (antibody)   BALF   bronchoalveolar lavage fluid   DM   dermatomyositis   COVID-19   Coronavirus Disease 2019   DAMPs   damage-associated molecular patterns   ELISA   enzyme-linked immunosorbent assay   GGO   ground-glass opacity   HR-CT   high-resolution computed tomography   IIM   Idiopathic inflammatory myopathy   ILD   interstitial lung disease   IFN   interferon   MDA5   anti-melanoma differentiation-associated protein 5 (antibody)   NSIP   non-specific interstitial pneumonia   PaO2   partial pressure of oxygen   RP-ILD   rapidly progressive interstitial lung disease   SLE   systemic lupus erythematosus   UIP   usual interstitial pneimonia  

摘要： The present study aimed to determine the pulmonary cytokine profiles of patients with anti-RNA synthetase (ARS) and anti-melanoma differentiation-associated protein 5 (MDA5) antibodies. The study included patients with ARS and MDA5 whose serum or bronchoalveolar fluid (BALF) was available. Sandwich enzyme-linked immunoassay microarray multiplex assay was used to measure 18 cytokine levels in serum and BALF. The cytokine patterns were investigated using factor and cluster analyses. Pulmonary cytokine production was examined using the BALF/Seum cytokine ratio. Forty participants were enrolled in the study: 19 with ARS and 21 with MDA5. All patients had interstitial lung disease (ILD). BALF was collected from 10 patients with ARS and 6 with MDA5. Serum type 1 IFN, IP-10, MCP-1, and TNF-alpha were elevated in both ARS and MDA5. IL-6, IL-10, and IL-15 were elevated in MDA5. Serum cytokine patterns differed between ARS and MDA5. In BALF, IFN-alpha, IP-10, MCP-1, and ferritin were increased in both ARS and MDA5. Higher levels of IFN-alpha, IL-6, and ferritin were observed in MDA5. One patient with severe MDA5-ILD showed higher levels of multiple cytokines, including IL-6 and IFN-alpha. BALF cytokine patterns were similar in ARS and MDA5 cases except the one with severe MDA5-ILD. IL-6, IP-10, IL-15, MCP-1, and ferritin were produced in the lungs in ARS and MDA5 and IFN-alpha in MDA5. In conclusion, IFN-alpha and pulmonary macrophage activation play important roles in ILD development in both ARS and MDA5-ILD. MDA5-ILD could be characterized by higher production of multiple cytokines and macrophage activation, particularly in severe cases.

关键词： enterotoxigenic Escherichia coli   colonization factor   cytokine   toxin  

摘要： Enterotoxigenic Escherichia coli (ETEC) produces two types of enterotoxins, LTs and STs, as well as several colonization factors (CFs), including CS21, CS3 fimbriae, and flagellar structures. This study investigated how these structures contribute to ETEC colonization and the immune response in HT-29 and HuTu-80 intestinal cells. ETEC strains with single, double, and triple mutations in the lngA, cstH, and fliC genes were generated and confirmed using PCR and Western blotting. The colonization of HT-29 and HuTu-80 intestinal cells by the ETEC E9034A strain, which was fully sequenced using a hybrid approach involving both Illumina and Oxford Nanopore technologies, was used to generate the mutant and recombinant proteins. The colonization and adherence of E9034A and its mutants were assessed through colony-forming unit (CFU) counts. Cytokine levels were assessed using flow cytometry and analyzed via FlowJo 7.6.1. Quantitative analysis revealed that the absence of the lngA, cstH, and fliC genes significantly (p < 0.01) reduced ETEC adherence to HT-29 and HutU-80 cells. In addition, only ETEC strains expressing the FliC protein induced IL-8 secretion. These findings suggest that LngA, CstH, and FliC in ETEC E9034A enhance adherence to intestinal cells and trigger the release of IL-8.

关键词： HLA‐DQB1*05:355   HLA   novel allele   sequencing‐based typing  

摘要： HLA-DQB1*05:355 differs from HLA-DQB1*05:01:01:01 by one nucleotide substitution in codon 197 in exon 4.

摘要： HLA typing is crucial for clinical and research applications, including transplantation, disease association studies and personalised medicine. This study provides an in-depth analysis of five key challenges in computational HLA typing methods: varying lengths, high polymorphism, complex phylogenetic structures, high sequence similarity and the requirement for frequent updates. This study evaluates 27 computation-based HLA typing tools developed over the past 12 years, using a novel sequencing dataset of A549 cell lines with matched short-read RNA-Seq and long-read Iso-Seq data. We comprehensively investigated these 27 tools in terms of accessibility, capability, reliability, reproducibility, scalability and performance. In addition, we discuss the advantages and disadvantages of current tools and identify critical areas for future research and development to advance HLA typing technologies.

关键词： Interleukin 6 (IL-6)   Soluble interleukin 6 receptor (sIL-6R)   Transforming growth factor beta (TGF-beta)   Schlemm's canal endothelial cells (SC cells)  

摘要： Intraocular pressure (IOP) is regulated through the balance of production and drainage of aqueous humor. The main route of aqueous-humor outflow comprises the trabecular meshwork (TM) and Schlemm's canal (SC). We reported that IL-6 trans-signaling can inhibit TGF-beta signaling in TM cells and may affect regulation of IOP. However, the function of IL-6 trans-signaling in SC cells remains unclear. Therefore, we investigated the role of IL-6 trans-signaling in monkey SC cells. Simultaneous treatment with IL-6 and soluble IL-6 receptor (sIL-6R) significantly decreased the trans-endothelial electrical resistance (TER) of SC cells and reduced aqueous-humor outflow resistance. Moreover, activation of IL-6 trans-signaling significantly reduced expression of fibronectin, ZO-1 and claudin-5, and increased that of several matrix metalloproteinases. We also investigated the effect of IL6 trans-signaling on TGF-beta 2-induced changes in SC cells. Simultaneous treatment with IL-6 and sIL-6R significantly suppressed the TGF-beta 2-induced increase in the TER of SC cells but did not affect the activity of the TGF-beta 2 signaling pathway. By contrast, the TGF-beta 2-induced increases in the expression of fibronectin and collagen type I were significantly decreased upon simultaneous treatment with IL-6 and sIL-6R. The results show that IL-6 transsignaling suppressed TGF-beta 2-induced increase in outflow resistance.