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关键词： diabetic foot infection   TNF-alpha   IL-6   IFN-gamma   severity   prognosis  

摘要： Objective: To investigate the relationship between TNF-alpha, IL-6, and IFN-gamma serum levels and the severity of infection and prognosis in patients with diabetic foot infection (DFI). Methods: A total of 144 patients diagnosed with diabetic foot at our hospital from January 2020 to December 2023 were enrolled in the study. Patients were divided into an infection group (70 cases) and a non-infection group (74 cases) based on the presence of infection. The infection group was further categorized into mild (29 cases), moderate (18 cases), and severe infection (23 cases) subgroups according to infection severity. Serum levels of TNF-alpha, IL-6, and IFN-gamma in DFI patients were analyzed, and their predictive value for treatment outcomes was evaluated Results: Serum levels of TNF-alpha, IL-6, and IFN-gamma were significantly higher in the infection group than in the non-infection group (P<0.05). Moreover, there were significant differences in TNF-alpha, IL-6, and IFN-gamma levels among patients with mild, moderate, and severe infections (P<0.05). ROC curve analysis demonstrated that the area under the curve (AUC) for the combined detection of TNF-alpha, IL-6, and IFN-gamma in assessing DFI severity was 0.855, which was significantly higher than that of TNF-alpha (0.811), IL-6 (0.793), and IFN-gamma (0.764) (P<0.05). Furthermore, serum levels of TNF-alpha, IL-6, and IFN-gamma were significantly higher in the poor prognosis group than in the good prognosis group (P<0.05). ROC curve analysis showed that the AUC for predicting poor prognosis in DFI patients was 0.926 when TNF-alpha, IL-6, and IFN-gamma were combined, which was significantly higher than that of TNF-alpha (0.849), IL-6 (0.834), and IFN-gamma (0.809) (P<0.05). Conclusion: Serum levels of TNF-alpha, IL-6, and IFN-gamma are elevated in DFI patients and are closely associated with infection severity and prognosis. The combined detection of these three inflammatory factors can serve as a predictive indicator f

关键词： IL10RA   Apparent homozygosity   Uniparental disomy   Gene deletion  

摘要： Background In East Asia, IL10RA is the predominant pathogenic gene in patients with very early-onset inflammatory bowel disease (VEO-IBD), frequently characterised by refractory diarrhoea and severe perianal disease, resulting in elevated death rates. IL10RA-deficient IBD, an autosomal recessive genetic disorder, has been documented to be inherited through the conventional compound heterozygous or homozygous mutation patterns from both parents. We present two cases with apparent homozygosity resulting from distinct causes, both of which seem homozygous on the genetic map. Further investigation reveals that detecting hidden genetic patterns is essential for accurate diagnosis, genetic counselling, and disease mechanism analysis. Methods Peripheral blood samples were collected from two patients and their parents. Whole-exome sequencing (WES), Sanger sequencing, Comparative genomic hybridisation (CGH) and SNP array, Capture-based CNV (CapCNV) analysis, and real-time quantitative PCR (qPCR) were employed to investigate the genetic mechanisms and variants within the families. Both patients were followed up, and descriptive analyses were performed to characterise their clinical phenotypes, biochemical parameters, endoscopic findings, and intestinal histopathology. Multiple databases were systematically searched to review all cases of IBD with large IL10RA deletions. Results Two families underwent WES, and a homozygous mutation was identified in the IL10RA gene on chromosome 11 in both families. In patient 1, pedigree analysis, CGH and SNP 4 x 180 K microarray testing identified paternal uniparental diploidy (c.301C > T/11q12.3-11q25del) [upd (11) pat] on chromosome 11. Patient 2 had compound heterozygosity (c. 299 T > G/exon2_3del), comprising a point mutation and an overlapping exon deletion mutation in IL10RA, as determined using familial analysis, Sanger sequencing, CapCNV analysis, and qPCR validation. In addition, the study systematically reviewed 15 cases of IBD pat

关键词： renewable energy   SDGs   VECM   deep learning technique   LSTM networks   Ha'il region  

摘要： Today's environmental issues are among the primary themes that researchers explore in their search for practical solutions to achieve the Sustainable Development Goals (SDGs), such as reducing carbon emissions and promoting sustainable practices. Renewable energy is crucial to overcoming future challenges, causing many countries to accelerate their adoption at various levels. In this context, the impact of renewable energy adoption on achieving the Sustainable Development Goals in the Ha'il region has been evaluated. Specifically, two techniques are employed. The first technique is an empirical model based on the Vector Error Correction Model (VECM), which identifies the SDGs related to renewable energy in achieving SDGH. Only three SDGs (SDG7, SDG12, and SDG13) were found to influence SDGH significantly. The second technique uses deep learning, specifically LSTM networks, to forecast SDGH behavior over a ten-year period about the three selected SDGs. The results indicate that these three SDGs play a crucial role in sustainable development in the Ha'il region. Therefore, this research produces strategic recommendations to optimize the adoption of renewable energy in the Ha'il region. These findings provide policymakers with a data-driven framework to enhance strategies, utilize resources more efficiently, and promote broader sustainability initiatives.

摘要： A deeper understanding of the immune landscape in patients with idiopathic multicentric Castleman disease (iMCD) is essential to establish early prognostic stratification and uncover novel therapeutic targets. We used single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from a cohort of 15 patients with iMCD and 4 healthy controls. To explore the sources of interleukin-6 (IL-6), we included lymph node and bone marrow samples for comparison with PBMCs. Our results indicate that IL-6 primarily originates from the lymph nodes, particularly from activated B cells. Similarly, in peripheral blood, activated B cells are also the main source of IL-6. IL-6 receptor is primarily expressed in monocytes in PBMCs, with CCL monocytes showing the strongest activation of the IL-6 signaling pathway. This suggests that CCL monocytes in iMCD may play an important role in driving peripheral inflammatory storms. CellChat analysis reveals that during disease flares, CCL monocytes interact with specific natural killer (NK)/NKT cells through enhanced type II interferon (IFN-II) signaling, whereas this interaction significantly diminishes during remission, indicating a significant role for IFN-II in the pathogenesis of iMCD. Notably, serum IFN-gamma levels positively correlate with both disease severity and treatment resistance, a finding validated by a large independent iMCD cohort. Our findings confirm that the IL-6 pathway remains central to iMCD pathogenesis and highlight a significant role for IFN-II pathway activation in amplifying inflammatory storms. Our findings provide valuable biomarkers for assessing disease severity and identify new therapeutic targets for iMCD.

关键词： Acrylamide   Cardiac toxicity   Cordycepin   Antioxidant   Anti-inflammatory  

摘要： Acrylamide (ACR) is a hazardous and possibly carcinogenic chemical compound that humans are constantly exposed to in their daily life. ACR passively affect many organ systems, including the cardiovascular system. Cordycepin (Cor) is a bioactive molecule derived from various species in the fungal kingdom, especially the genera Cordyceps and Ophiocordyceps. Cordycepin is known for its large-scale pharmacological activities. This study was conducted to evaluate the potential therapeutic effect of Cor on ACR-induced cardiotoxicity. Thirty-two Sprague-Dawley rats were randomly divided into four groups (8 rats/group). Group I represented the control group, Group II received ACR (20 mg/kg/day) orally for 27 days, and Groups III and IV represented the control group. Rats received ACR (20 mg/kg) orally concurrently with Cor (10 and 20 mg/kg, b.w.), respectively, for 27 days. Serum cardiac biomarkers, such as cardiac troponin I (cTnI), creatine kinase (CK)-MB and lactate dehydrogenase (LDH), were evaluated. In addition, the antioxidant status and inflammatory response to ACR were evaluated. Moreover, detailed histopathological and ultrastructural observations were conducted. Our findings revealed that rats subjected to ACR presented increased levels of serum cardiac biomarkers, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (Il-6), malondialdehyde (MDA), annexin V, and Bax values, and programmed death ligand-1 (PD-L1) and decreased activities of nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1) and reduced glutathione (GSH), superoxide dismutase (SOD) and Bcl-2 expression. Conversely, the administration of Cor to rats treated with ACR in a dose-dependent manner succeeded in restoring serum cardiac biomarkers, modulated redox homeostasis and reduced inflammatory and apoptotic biomarkers. Consequently, a marked improvement was observed in the histopathological and ultrastructural images of the heart. In conclusion, Cor provides cardiac prot

关键词： uterine fibroids   IL-1 beta (Interleukin-1 beta)   IL-6 (Interleukin 6)   Nf-kappa beta   myoma  

摘要： Uterine fibroids are benign tumors that occur in a large proportion of women and interfere with the proper functioning of this organ. One of the factors leading to these proliferative changes appears to be the appearance of extracellular matrix (ECM) fibrosis at the site of local inflammatory foci. Due to the potential impact of cytokines in this process, it is interesting to determine their expression levels in fibroids and surrounding tissues, which may contribute to a better understanding of the mechanisms leading to the formation of these tumors. In tissue material from 50 women with uterine fibroids who underwent hysterectomy and 45 women operated on for other reasons (most often prolapse of the reproductive organ), the concentration of inflammatory cytokines IL-1 beta and IL-6 and the concentration of the transcription nuclear factor NF-kappa beta were determined. The tissue from the fibroid, the peripheral myometrium, and the unchanged myometrium were examined in women who underwent surgery for reasons other than uterine fibroids. A significant decrease in IL-1 beta levels was observed in the center of the fibroid compared to both peripheral and control muscle tissue (p=0.001). The concentrations of IL-6 were found to be similar across all three locations examined. The NF-kappa beta levels were significantly lower in the fibroid and peripheral tissues (p<0.001) compared to the control group. The concentration of IL-1 beta was found to be significantly and positively correlated with the concentration of NF-kappa beta in uterine fibroids.

摘要： Immune evasion is a hallmark of gliomas, yet the genetic mechanisms by which tumors escape immune surveillance remain incompletely understood. In this study, we systematically examined the presence of somatic mutations in HLA genes and genes encoding proteins involved in antigen presentation across isocitrate dehydrogenase wild-type and mutant gliomas using targeted next-generation sequencing. To address the challenges associated with detecting somatic mutations in these highly polymorphic and complex regions of the genome, we applied a combination of short-read and long-read sequencing techniques, extended the genetic region of interest (exons and introns), and applied a tailored bioinformatics analysis pipeline, which enabled an accurate evaluation of comprehensive sequencing data. Our analysis identified mutations in HLA class II and nonclassic HLA genes as well as genes associated with antigen presentation, such as TAP1/2 and B2M. Three-dimensional modeling of individual mutations simulated the potential impact of somatic mutations in TAP1 and B2M on the encoded protein configuration. The presence of somatic mutations supports the role of antigen-presenting genes in the pathophysiology and potential immune escape of gliomas. Our data demonstrated an increased frequency of such mutations in recurrent glioblastoma, potentially resulting from a positive selection or mutagenic enrichment of tumor cells during tumor progression. Taken together, this research generates new insights and hypotheses for the functional analysis and optimization of immunotherapy strategies for gliomas, which may guide personalized treatment paradigms.

关键词： caspase substrates   caspase inhibitors   inflammasomes   pyroptosis   apoptosis   in vitro kinetics   Yersinia pseudotuberculosis  

摘要： Caspases are a family of cysteine proteases that act as molecular scissors to cleave substrates and regulate biological processes, such as programmed cell death and inflammation. Extensive efforts have been made to identify caspase substrates and to determine the factors that dictate specificity. We recently discovered that human inflammatory caspases (caspases-1, -4, and -5) cleave the cytokines IL-1 beta and IL-18 in a sequence-dependent manner. Here, we report the development of a new peptide-based probe and inhibitor derived from the tetrapeptide sequence of IL-18 (LESD). The LESD-based inhibitor showed a strong preference for caspase-8 with an IC50 of 50 nM, and was more potent in vitro than the commonly used zIETD-FMK inhibitor, which is considered the most selective and potent caspase-8 inhibitor. We further demonstrated that the LESD-based inhibitor prevents caspase-8 activation during Yersinia pseudotuberculosis infection in primary bone marrow-derived macrophages. In addition, we systematically characterized the selectivity and potency of known substrates and inhibitors of the apoptotic and inflammatory caspases using standardized activity units of each caspase. Our findings reveal that VX-765, a known inhibitor of caspases-1 and -4, also inhibits caspase-8 (IC50 = 1 mu M). Even when specificities are shared, the caspases exhibit different efficiencies and potencies for shared substrates and inhibitors. Altogether, we report the development of new tools that will facilitate the study of caspases and their roles in biology.

关键词： TNF alpha inhibitors   anti-drug antibodies   efficacy   serum level   methotrexate   rheumatoid arthritis   spondyloarthritis  

摘要： Introduction: We aimed to estimate the global prevalence of anti-drug antibodies (ADAb), their impact on treatment response, and associated factors in adults with rheumatoid arthritis (RA) and spondyloarthritis (SpA) treated with TNF alpha inhibitors (TNF-i). Methods: We searched PubMed, MEDLINE, Cochrane, Web of Science, and Scopus for observational population-based studies published between January 2010 and September 2021. We included studies reporting ADAb prevalence and their impact on treatment efficacy in adults treated with TNF-i. Results: The global prevalence of ADAb was 20.8% (95% CI: 6.8-25.5;95% PI: 6.12-51.42) in RA and 24.8% (95% CI: 19.1-31.5;95% PI: 7.31-57.98) in SpA. No significant difference in ADAb prevalence was found between infliximab (IFX) and adalimumab (ADA) in RA (p = 0.21) or SpA (p= 0.46). Significant differences were found between IFX and etanercept (ETN) in RA (p<0.0001) and SpA (p=0.001), and between ADA and ETN in RA (p<0.0001) and SpA (p=0.002). For ADA, mean OR was 0.152 (95% CI: 0.054-0.427);for IFX, 0.144 (95% CI: 0.055-0.378);comparison was not significant (p=0.94). By disease, mean OR was 0.149 (95% CI: 0.064-0.347) in RA and 0.303 (95% CI: 0.103-0.890) in SpA;comparison was not significant. Methotrexate use reduced ADAb development in RA and SpA (OR=0.472;95% CI: 0.324-0.689).Discussion These findings confirm the immunogenic potential of TNF-alpha and support the use of methotrexate co-therapy. ADA and IFX showed similar immunogenicity profiles. Conclusion: ADAb were equally prevalent in RA and SpA. Immunogenicity was associated with treatment response and influenced by the use of methotrexate.

关键词： interleukin-1   recurrent pericarditis   rilonacept   CRP   C-reactive protein   CT   computed tomography   FDG   fluorodeoxyglucose   IL   interleukin   MRI   magnetic resonance imaging   NSAID   nonsteroidal anti-inflammatory drug   PET   positron emission tomography   RP   recurrent pericarditis  

摘要： Recurrent pericarditis complicates 15%-30% of acute pericarditis cases despite initial anti-inflammatory treatment. The RHAPSODY trial (Study to Assess the Efficacy and Safety of Rilonacept Treatment in Participants With Recurrent Pericarditis) showed rilonacept, an interleukin-1 cytokine trap, to be an effective therapeutic option for patients with pericarditis recurrence. This case series demonstrates the utility and challenges of rilonacept use in the types of patients excluded from RHAPSODY.