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关键词： hesperidin   CPT-11   CPT-11-induced diarrhea   metabolomics   16S rRNA sequencing   transcriptomics  

摘要： Irinotecan (CPT-11) is a chemotherapy agent commonly used for the treatment of gastrointestinal tumors, with diarrhea being a frequent adverse effect. Hesperidin is a flavonoid abundant in citrus fruits and has shown potential in managing CPT-11-induced diarrhea (CID). However, the mechanisms underlying its effects remain unclear. This study established a mouse model of CID using CPT-11 administration to evaluate the effects of hesperidin on diarrhea severity, intestinal pathology, gut microbiota composition, and metabolite profiles by conducting biochemical analysis, histopathology, immunohistochemistry, 16S rRNA sequencing, and untargeted metabolomics. In addition, transcriptomic analysis, molecular docking, and molecular dynamics simulations were conducted to investigate potential mechanisms of action. Hesperidin supplementation was found to significantly alleviate CID in mice. Analysis of gut microbiota using 16S rRNA sequencing revealed that hesperidin improved microbial composition, with key taxa such as Alistipes, Limosilactobacillus, Rikenella, and Mucispirillum playing a central role in ameliorating CID. Furthermore, hesperidin enhanced intestinal barrier function by upregulating tight junction proteins, mitigating epithelial damage, and reducing the expression of IL-17A, TARF6, p38, phosphorylated-p38 (P-p38), and AP-1 proteins in the colon. These findings suggest that hesperidin supplementation mitigates CID by modulating gut microbiota and inhibiting the IL-17 signaling pathway, thereby improving intestinal barrier integrity.

关键词： Ancient DNA   European Neolithic   Population genetics   Admixture   Immune genes   HLA diversity  

摘要： BackgroundThe northern European Neolithic is characterized by two major demographic events: immigration of early farmers from Anatolia at 7500 years before present, and their admixture with local western hunter-gatherers forming late farmers, from around 6200 years before present. The influence of this admixture event on variation in the immune-relevant human leukocyte antigen (HLA) region is *** analyzed genome-wide data of 125 individuals from seven archeological early farmer and late farmer sites located in present-day Germany. The late farmer group studied here is associated with the Wartberg culture, from around 5500-4800 years before present. We note that late farmers resulted from sex-biased admixture from male western hunter-gatherers. In addition, we observe Y-chromosome haplogroup I as the dominant lineage in late farmers, with site-specific sub-lineages. We analyze true HLA genotypes from 135 Neolithic individuals, the majority of which were produced in this study. We observe significant shifts in HLA allele frequencies from early farmers to late farmers, likely due to admixture with western hunter-gatherers. Especially for the haplotype DQB1*04:01-DRB1*08:01, there is evidence for a western hunter-gatherer origin. The HLA diversity increased from early farmers to late farmers. However, it is considerably lower than in modern *** early farmers and late farmers exhibit a relatively narrow HLA allele spectrum compared to today. This coincides with sparse traces of pathogen DNA, potentially indicating a lower pathogen pressure at the time.

关键词： osteoclast   anakinra   periodontal ligament fibroblast   periodontitis   inflammatory bone disease  

摘要： Rheumatoid arthritis and periodontitis are comorbidities that share mutual pathways. IL-1 beta is a pro-inflammatory cytokine that plays a crucial role in both diseases. One of the treatment options for rheumatoid arthritis is the use of an IL-1 receptor antagonist (IL-1RA) such as anakinra. Anakinra tempers the disease by decreasing bone resorption and it could possibly stimulate bone formation. Here, we investigate the effect of anakinra in a periodontal disease setting on osteoclastogenesis by co-culturing periodontal ligament fibroblasts (PDLFs) and peripheral blood mononuclear cells (PBMCs) that contain monocytes, a source of osteoclast precursors, as well as by culturing PBMCs alone. The effect of anakinra on PDLF-mediated osteogenesis was studied under mineralization conditions. To mimic a chronic infection such as that prevalent in periodontitis, 10 ng/mL of IL-1 beta was added either alone or with 10 mu g/mL of anakinra. Osteoclastogenesis experiments were performed using co-cultures of PDLF and PBMCs and PBMCs only. Osteoclastogenesis was determined through the formation of multinucleated cells in co-cultures of PDLF and PBMCs, as well as PBMCs alone, at day 21, and gene expression through qPCR at day 14. Osteogenesis was determined by measuring alkaline phosphatase activity (ALP) per cell at day 14. Anakinra is effective in downregulating IL-1 beta mediated leukocyte clustering and osteoclastogenesis in the co-cultures of both PDLF and PMBCs and PBMCs alone. Gene expression analysis shows that IL-1 beta increases the expression of the osteoclastogenic marker RANKL and its own expression. This higher expression of IL-1 beta at the RNA level is reduced by anakinra. Moreover, IL-1 beta downregulates OPG expression, which is upregulated by anakinra. No effects of anakinra on osteogenesis were seen. Clinically, these findings suggest that anakinra could have a beneficial systemic effect on periodontal breakdown in rheumatoid arthritis patients taking anakinra.

关键词： peptide-MHC binding   MHC I and II   deep learning   uterine corpus endometrial carcinoma   neoantigen  

摘要： The key roles of Major Histocompatibility Complex (MHC) Class I and II molecules in the immune system are well established. This study aims to develop a novel machine learning framework for predicting antigen peptide presentation by MHC Class I and II molecules. By integrating large-scale mass spectrometry data and other relevant data types, we present a prediction model OnmiMHC based on deep learning. We rigorously assessed its performance using an independent test set, OnmiMHC achieves a PR-AUC score of 0.854 and a TOP20%-PPV of 0.934 in the MHC-I task, which outperforms existing methods. Likewise, in the domain of MHC-II prediction, our model OnmiMHC exhibits a PR-AUC score of 0.606 and a TOP20%-PPV of 0.690, outperforming other baseline methods. These results demonstrate the superiority of our model OnmiMHC in accurately predicting peptide-MHC binding affinities across both MHC-I and MHC-II molecules. With its superior accuracy and predictive capability, our model not only excels in general predictive tasks but also achieves significant results in the prediction of neoantigens for specific cancer types. Particularly for Uterine Corpus Endometrial Carcinoma (UCEC), our model has successfully predicted neoantigens with a high binding probability to common human alleles. This discovery is of great significance for the development of personalized tumor vaccines targeting UCEC.

关键词： MHC I   Immune checkpoint inhibitors   Small molecule compounds   Expression regulation  

摘要： Major histocompatibility complex (MHC) class I load antigens and present them on the cell surface, which transduces the tumor-associated antigens to CD8+ T cells, activating the acquired immune system. However, many tumors downregulate MHC I expression to evade immune surveillance. The low expression of MHC I not only reduce recognition by- and cytotoxicity of CD8+ T cells, but also seriously weakens the anti-tumor effect of immunotherapy by restoring CD8+ T cells, such as immune checkpoint inhibitors (ICIs). Accumulated evidence suggested that restoring MHC I expression is an effective strategy for enhancing tumor immunotherapy. This review focuses on mechanisms underlying MHC I downregulation include gene deletion and mutation, transcriptional inhibition, reduced mRNA stability, increased protein degradation, and disruption of endocytic trafficking. We also provide a comprehensive review of small molecules that restore or upregulate MHC I expression, as well as clinical trials involving the combination of ICIs and these small molecule drugs.

关键词： Pharmacogenetic testing   Pharmacogenetics   Pharmacogenomic   Implementation   DPYD   TPMT   HLA  

摘要： Purpose Although already a lot of research has been done on pharmacogenetic tests to inform the choice and/or dosing of medicines, the implementation and clinical uptake remain limited. This study assessed the implementation of pharmacogenetic (PGx) testing on a national scale by analyzing access to and volumes of reimbursed PGx. Methods The use of pharmacogenetic tests was examined via a cross-sectional online survey among the Belgian laboratories, collecting data on PGx targets, testing volumes and technologies used. The focus was on reimbursed tests. Additional data were sourced from the national reimbursement database to describe uptake of testing per medication. Results The uptake of PGx testing in Belgium varied by medication, with significant implementation for fluoropyrimidines, abacavir, and thiopurines. DPYD gene testing was the most frequently performed PGx test, due to endorsed (inter)national guidelines. Reimbursement rules shape access to PGx, with the majority of PGx tests performed in dedicated centers for human genetics (CHG). Access to HLA laboratories for HLA targets was not optimal and some laboratories without a CHG also included constitutional PGx targets in somatic oncology panels. Conclusion This nationwide study demonstrates that in a country where the prescribers have access to a relatively extensive list of reimbursable PGx tests, the implementation of PGx testing is shaped by the presence of endorsed evidence-based clinical practice guidelines, as well as organizational and logistical factors.

摘要： Excessive inflammation and cytokine release are hallmarks of severe COVID-19. Certain programmed cell death processes can drive inflammation, however, their role in the pathogenesis of severe COVID-19 is unclear. Pyroptosis is a pro-inflammatory form of regulated cell death initiated by inflammasomes and executed by the pore-forming protein gasdermin D (GSDMD). Using an established mouse adapted SARS-CoV-2 virus and a panel of gene-targeted mice we found that deletion of the inflammasome (NLRP1/3 and the adaptor ASC) and pore forming proteins involved in pyroptosis (GSDMA/C/D/E) only marginally reduced IL-1 beta levels and did not impact disease outcome or viral loads. Furthermore, we found that SARS-CoV-2 infection did not trigger GSDMD activation in mouse lungs. Finally, we did not observe any difference between WT animals and mice with compound deficiencies in the pro-inflammatory initiator caspases (C1/11/12-/-). This indicates that the classical canonical and non-canonical pro-inflammatory caspases known to process and activate pro-IL-1 beta, pro-IL-18 and GSDMD do not substantially contribute to SARS-CoV-2 pathogenesis. However, the loss of IL-1 beta, but not the absence of IL-18, ameliorated disease and enhanced survival in SARS-CoV-2 infected animals compared to wildtype mice. Collectively, these findings demonstrate that IL-1 beta is an important factor contributing to severe SARS-CoV-2 disease, but its release was largely independent of inflammasome and pyroptotic pathways.

关键词： cardiac involvement   extrapulmonary involvement   genotyping   HLA polymorphism   Sarcoidosis  

摘要： Background:Although numerous candidate genes have been identified in studies investigating the role of genetics in sarcoidosis, the strongest association has been reported with the Major Histocompatibility Complex/Human Leucocyte Antigen (MHC/HLA) region. This study aimed to evaluate HLA polymorphism and assess its association with cardiac and other extrapulmonary involvement in sarcoidosis ***:The study included 67 patients diagnosed with sarcoidosis. A control group of 100 bone marrow donors, who had undergone HLA genotyping previously, was also included. Blood samples were collected from all participants for HLA gene polymorphism analysis. The differences in HLA genotypes were investigated between patients with and without cardiac and other extrapulmonary involvement, and between these groups and the control ***:Cardiac involvement, was present in 17.9% of the patients. The most frequently affected extrapulmonary organ was the skin (23.8%). HLA DQB103 and HLA DQB106 alleles were expressed more frequently in patients with only pulmonary involvement compared to those with extrapulmonary involvement. Conversely, HLA DQA101 was expressed more frequently in patients with extrapulmonary involvement. No statistically significant difference in the expression of HLA DRB1, HLA DQB1, and HLA DQA1 alleles was observed between sarcoidosis patients with and without cardiac ***:Our findings suggest that HLA DQB103 and HLA DQB106 alleles might be protective against extrapulmonary organ involvement, while HLA DQA101 could be a risk factor. These findings may contribute to the prediction of treatment response and prognosis in sarcoidosis patients.

关键词： Prognosis   Diagnosis   Immune cell infiltrate   Aberrant methylation   Microarray   Biomarker identification  

摘要： PurposeColorectal cancer (CRC) is the third most common cancer globally, necessitating novel biomarkers for early diagnosis and treatment. This study proposes an efficient pipeline leveraging an integrated bioinformatics and machine learning framework to enhance the identification of diagnostic and prognostic biomarkers for *** selection of methylated differentially expressed genes (MeDEGs) and features (genes) was made using both statistical and Machine learning (ML) approaches from publically available datasets. These genes were subjected to STRING network construction and hub genes estimation, separately. Also, essential miRNAs (micro-RNAs) and TFs (Transcription factors) as regulatory elements were revealed and findings were validated through scRNA-seq analysis, promoter methylation, gene expression levels correlated with pathological stage, and interaction with tumor-infiltrating immune *** an integrated analysis pipeline, we identified 27 hub genes, among which CTNNB1, GSK3B, IL-1 beta, MYC, PXDN, TP53, EGFR, SRC, COL1A1, and TGBF1 showed better diagnostic behaviour. Machine learning approach includes the development of K-Nearest Neighbors (KNN), Artificial Neural Networks (ANN), and Random Forest (RF) models using TCGA datasets, achieving an accuracy range between 99 and 100%. The Area Under the Curve (AUC) value for each model is 1.00, signifying good classification performance. The high expression of some diagnostic genes was associated with poor prognosis, concluding IL-1 beta as both a prognostic and diagnostic biomarker. Additionally, the NF-kappa B and microRNAs (miR-548d-3p, miR-548-ac) and TFs (NF kappa B and STAT5A) play a major role in the comprehensive regulatory network for CRC. Furthermore, hub genes such as IL-1 beta, TGFB1, and COL1A1 were significantly correlated with immune infiltrates, suggesting their potential role in CRC ***, the elevated expression of IL-1 beta coupled with abnormal DNA

关键词： Beh & ccedil   et's uveitis   CD44   IL-17A   neutrophil extracellular traps   positive feedback loops  

摘要： Beh & ccedil;et's uveitis (BU) is a severe ocular manifestation of Beh & ccedil;et's disease, typically accompanied by abnormal neutrophil infiltration and hyperactivation. However, the underlying causes of excessive neutrophil extracellular traps (NETs) production and mechanisms by which NETs contribute to the pathogenesis of BU remain incompletely understood. Neutrophils from BU patients exhibit a higher propensity for NETs release compared to healthy controls. In the experimental autoimmune uveitis (EAU), neutrophils are observed to exert pro-inflammatory effects through NETs. Clearing NETs can inhibit T helper 17 (Th17) cell differentiation and significantly alleviate EAU symptoms. In vivo and in vitro experiments demonstrate neutralizing IL-17A markedly reducing neutrophil infiltration and NETs formation in EAU. Single-cell RNA sequencing confirms that CD44 plays a key role in mediating interactions between NETs and Th17 cells. Antagonizing CD44 inhibits the proportion of Th17 cells and NETs formation. Multiplex immunofluorescence and cell communication analyses further demonstrate interactions and colocalization between NETs and CD44(high)CD4(+)T cells in EAU. NETs induce Th17 differentiation via upregulating CD44, and in turn, Th17 cells secrete IL-17A to recruit neutrophils and promote NETs formation. Interrupting NETs-CD44-IL-17A feedback loop may be a potential therapeutic target for BU.