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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： Interleukin 17 (IL-17)   invasive breast cancer (IBC)   immune microenvironment   prognostic biomarkers  

摘要： Background: Recently, interleukin 17 (IL-17) has been found to play a critical role in the development of breast cancer. However, its prognostic significance in invasive breast cancer (IBC) remains unclear. This study aims to determine the role of IL-17-related signatures in IBC to identify novel therapeutic options. Methods: IBC data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used to identify IL- 17-related prognostic genes. A predictive model was developed using TCGA data and validated using METABRIC data. The relationship between IL-17 scores and immune landscape, chemotherapy drug sensitivity [half maximal inhibitory concentration (IC50)], and immune checkpoint gene expression was analyzed. The quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to validate key gene expression in breast tumor and normal tissue samples. Results: The predictive model identified core IL-17-related prognostic genes and successfully estimated the prognosis of IBC patients. The model's validity was confirmed using METABRIC data. Patients with high IL-17 scores had worse overall survival (OS) compared to those with low IL-17 scores. Low IL-17 scores were associated with higher immune checkpoint gene expression and predicted enhanced responses to cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed cell death protein 1 (PD-1) therapies. Patients with low IL-17 scores exhibited a higher abundance of immune microenvironment components. Furthermore, qRT-PCR confirmed the lower expression of OR51E1, NDRG2, RGS2, and TSPAN7 in breast tumors compared to normal tissue. Conclusions: IL-17-related signatures are promising biomarkers for predicting the prognosis of IBC patients. These findings suggest that IL-17-related markers could be used to guide individualized therapeutic strategies, potentially improving outcomes for IBC patients.

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： 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： 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： 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： 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： HLA   Amerindians   Wiwa   Chimila   Way & uacute   u   trans-Pacific contacts   America population   Afro-Americans   Europeans   first free African Americans   Barranquilla   San Basilio Palenque  

摘要： Background/Objectives: The Human Leukocyte Antigen (HLA) system is composed of a set of genes that codify glycoproteins presenting antigenic proteins to clonotypic T cell receptors in order to start the immune response. Class I and Class II classical loci exhibit high allelic diversity;some of them (or their specific combinations that form haplotypes) are quasi-specific or highly frequent in certain populations and thus are useful for population genetic studies. In this study, an HLA genetic comparison of Chimila, Way & uacute;u, Wiwa, and Barranquilla Colombian nonrelated healthy individuals was carried out together with other populations from all over the world to trace their genetic origin, obtain a virtual transplantation list, and inform future epidemiology studies. Methods: HLA-A, -B, -DRB1, and -DQB1 alleles were sequenced using the PCR-SSOP-Luminex method to analyze the HLA genetic profile of each individual. The data obtained were subsequently processed with standard software to obtain HLA alleles, haplotype frequencies, and genetic distances compared with data from global populations to generate relatedness dendrograms and carry out a correspondence analysis. Results: The results obtained place the Chimila, Way & uacute;u, and Wiwa populations phylogenetically close to the other North and South Amerindian populations included in this study. Amerindians are genetically separated from the rest of the world's populations. Chimila, Way & uacute;u, and Wiwa present unique extended HLA haplotypes and specific alleles, such as HLA-B*48 or HLA-A*24:01, shared with Oceanian populations. Conclusions: These genetic results and anthropological data support prehistorical trans-Pacific (bidirectional) contacts that contributed to the settlement of America and also suggest that the effects of ancient European gene flow cannot be discarded.

摘要： Tertiary lymphoid structures (TLSs) are de novo ectopic lymphoid aggregates that regulate immunity in chronically inflamed tissues, including tumours. Although TLSs form due to inflammation-triggered activation of the lymphotoxin (LT)-LT beta receptor (LT beta R) pathway1, the inflammatory signals and cells that induce TLSs remain incompletely identified. Here we show that interleukin-33 (IL-33), the alarmin released by inflamed tissues2, induces TLSs. In mice, Il33 deficiency severely attenuates inflammation- and LT beta R-activation-induced TLSs in models of colitis and pancreatic ductal adenocarcinoma (PDAC). In PDAC, the alarmin domain of IL-33 activates group 2 innate lymphoid cells (ILC2s) expressing LT that engage putative LT beta R+ myeloid organizer cells to initiate tertiary lymphoneogenesis. Notably, lymphoneogenic ILC2s migrate to PDACs from the gut, can be mobilized to PDACs in different tissues and are modulated by gut microbiota. Furthermore, we detect putative lymphoneogenic ILC2s and IL-33-expressing cells within TLSs in human PDAC that correlate with improved prognosis. To harness this lymphoneogenic pathway for immunotherapy, we engineer a recombinant human IL-33 protein that expands intratumoural lymphoneogenic ILC2s and TLSs and demonstrates enhanced anti-tumour activity in PDAC mice. In summary, we identify the molecules and cells of a druggable pathway that induces inflammation-triggered TLSs. More broadly, we reveal a lymphoneogenic function for alarmins and ILC2s.