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Journal of Translational Medicine Sep 2023Owing to the heterogeneity of Alzheimer's disease (AD), its pathogenic mechanisms are yet to be fully elucidated. Evidence suggests an important role of metabolism in...
BACKGROUND
Owing to the heterogeneity of Alzheimer's disease (AD), its pathogenic mechanisms are yet to be fully elucidated. Evidence suggests an important role of metabolism in the pathophysiology of AD. Herein, we identified the metabolism-related AD subtypes and feature genes.
METHODS
The AD datasets were obtained from the Gene Expression Omnibus database and the metabolism-relevant genes were downloaded from a previously published compilation. Consensus clustering was performed to identify the AD subclasses. The clinical characteristics, correlations with metabolic signatures, and immune infiltration of the AD subclasses were evaluated. Feature genes were screened using weighted correlation network analysis (WGCNA) and processed via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Furthermore, three machine-learning algorithms were used to narrow down the selection of the feature genes. Finally, we identified the diagnostic value and expression of the feature genes using the AD dataset and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis.
RESULTS
Three AD subclasses were identified, namely Metabolism Correlated (MC) A (MCA), MCB, and MCC subclasses. MCA contained signatures associated with high AD progression and may represent a high-risk subclass compared with the other two subclasses. MCA exhibited a high expression of genes related to glycolysis, fructose, and galactose metabolism, whereas genes associated with the citrate cycle and pyruvate metabolism were downregulated and associated with high immune infiltration. Conversely, MCB was associated with citrate cycle genes and exhibited elevated expression of immune checkpoint genes. Using WGCNA, 101 metabolic genes were identified to exhibit the strongest association with poor AD progression. Finally, the application of machine-learning algorithms enabled us to successfully identify eight feature genes, which were employed to develop a nomogram model that could bring distinct clinical benefits for patients with AD. As indicated by the AD datasets and qRT-PCR analysis, these genes were intimately associated with AD progression.
CONCLUSION
Metabolic dysfunction is associated with AD. Hypothetical molecular subclasses of AD based on metabolic genes may provide new insights for developing individualized therapy for AD. The feature genes highly correlated with AD progression included GFAP, CYB5R3, DARS, KIAA0513, EZR, KCNC1, COLEC12, and TST.
Topics: Humans; Alzheimer Disease; Algorithms; Citrates; Citric Acid; Cluster Analysis; Shaw Potassium Channels; Nerve Tissue Proteins
PubMed: 37715200
DOI: 10.1186/s12967-023-04324-y -
International Journal of Cancer Sep 2023Use of artificial sweeteners (AS) such as aspartame, cyclamate, saccharin and sucralose is widespread. We evaluated the association of use of aspartame and other AS with...
Use of artificial sweeteners (AS) such as aspartame, cyclamate, saccharin and sucralose is widespread. We evaluated the association of use of aspartame and other AS with cancer. In total 1881 colorectal, 1510 breast, 972 prostate and 351 stomach cancer and 109 chronic lymphocytic leukaemia (CLL) cases and 3629 population controls from the Spanish Multicase-Control (MCC-Spain) study were recruited (2008-2013). The consumption of AS, from table-top sweeteners and artificially sweetened beverages, was assessed through a self-administered and validated food frequency questionnaire (FFQ). Sex-specific quartiles among controls were determined to compare moderate consumers (
Topics: Male; Female; Humans; Sweetening Agents; Aspartame; Spain; Stomach Neoplasms; Diabetes Mellitus
PubMed: 37323037
DOI: 10.1002/ijc.34577 -
JAAPA : Official Journal of the... Nov 2023Merkel cell carcinoma (MCC) is a rare and aggressive type of metastatic, nonmelanoma skin cancer derived from Merkel cells in the epidermis. MCC can be induced by sun... (Review)
Review
Merkel cell carcinoma (MCC) is a rare and aggressive type of metastatic, nonmelanoma skin cancer derived from Merkel cells in the epidermis. MCC can be induced by sun exposure or via Merkel cell polyomavirus (MCV) gene expression. MCV is found in most patients with MCC and is associated with a lower recurrence rate of MCC. MCC has a wide range of clinical presentations that make diagnosis challenging. Histologic examination is performed using unique markers to differentiate it from other diagnoses. This article reviews the pathogenesis, clinical presentation, histopathology, differential diagnosis, and treatment of MCC.
Topics: Humans; Carcinoma, Merkel Cell; Polyomavirus Infections; Tumor Virus Infections; Skin Neoplasms; Merkel cell polyomavirus
PubMed: 37820270
DOI: 10.1097/01.JAA.0000979460.69305.b7 -
Cell Biology International Dec 2023This study tried to investigate the macrophage autophagy-related pyroptosis in atherosclerosis. The gene expression omnibus (GEO) dataset of GSE100927 was used for...
This study tried to investigate the macrophage autophagy-related pyroptosis in atherosclerosis. The gene expression omnibus (GEO) dataset of GSE100927 was used for differentially expressed genes (DEG) screening, gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG), CIBERSORT, weighted correlation network analysis (WGCNA), receiver operating characteristic (ROC), gene set enrichment analysis (GSEA), and correlation analysis, and GSE159677 was used for single-cell analysis, all conducted in R software. Protein-protein interaction (PPI) was constructed in STRING and analyzed in Cytoscape. Transcription factors, drugs, and tissue co-expression network were explored in NetworkAnalyst. A total of 110 autophagy-related DEG (DEATG) were identified, and GO/KEGG revealed the top items enriched in autophagy, phagosome and lysosome. CIBERSORT showed 11 cell types were markedly differentially expressed (p < .05). WGCNA found the turquoise and yellow module were positively correlated with macrophage M0 (corr = 0.5, P = 6e-6) and M2 (corr = 0.54, P = 1e-6), respectively. Then 35 immune-related DEATG were identified, and functional analysis showed immune effector process, interleukin-6 and myeloid cell activation were enriched besides autophagy. PPI and MCC algorithm identified 6 hub genes in regulating macrophage-related autophagy, and ROC indicated high prediction value (area under curve = 0.961). GSEA enriched 6 common pathways associated with autophagy and atherosclerosis pathogenesis, and immune correlation suggested these hub genes were correlated with macrophages M0/M1, monocytes and T cells. Then venn plot found 3 central genes in mediating macrophage autophagy-associated pyroptosis in atherosclerosis, and single-cell analysis demonstrated cell distribution, then validated in THPA human samples. Our data discovered hub genes responsible for macrophage autophagy-mediated pyroptosis in atherosclerosis, and functional analysis with immune cell distribution evidenced their high phenotype-trait prediction value.
Topics: Humans; Pyroptosis; Autophagy; Macrophages; Biomarkers; Atherosclerosis; Computational Biology
PubMed: 37641197
DOI: 10.1002/cbin.12080 -
PloS One 2023Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the clinic. Aging plays an essential role in the occurrence and development of AF. Herein, we...
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the clinic. Aging plays an essential role in the occurrence and development of AF. Herein, we aimed to identify the aging-related genes associated with AF using bioinformatics analysis. Transcriptome profiles of AF were obtained from the GEO database. Differential expression analysis was performed to identify AF-specific aging-related genes. GO and KEGG enrichment analyses were performed. Subsequently, the LASSO, SVM-RFE, and MCC algorithms were applied to screen aging-related genes. The mRNA expression of the screened genes was validated in the left atrial samples of aged rapid atrial pacing-induced AF canine models and their counterparts. The ROC curves of them were drawn to evaluate their diagnostic potential. Moreover, CIBERSORT was used to estimate immune infiltration. A correlation analysis between screened aging-related genes and infiltrating immune cells was performed. A total of 24 aging-related genes were identified, which were found to be mainly involved in the FoxO signaling pathway, PI3K-Akt signaling pathway, longevity regulating pathway, and peroxisome according to functional enrichment analysis. LASSO, SVM-RFE, and MCC algorithms identified three genes (HSPA9, SOD2, TXN). Furthermore, the expression levels of HSPA9 and SOD2 were validated in aged rapid atrial pacing-induced AF canine models. HSPA9 and SOD2 could be potential diagnostic biomarkers for AF, as evidenced by the ROC curves. Immune infiltration and correlation analysis revealed that HSPA9 and SOD2 were related to immune cell infiltrates. Collectively, these findings provide novel insights into the potential aging-related genes associated with AF. HSPA9 and SOD2 may play a significant role in the occurrence and development of AF.
Topics: Animals; Dogs; Atrial Fibrillation; Phosphatidylinositol 3-Kinases; Aging; Cardiac Conduction System Disease; Longevity
PubMed: 37956134
DOI: 10.1371/journal.pone.0294282 -
Journal of Medical Virology Jul 2023Limited molecular knowledge of Merkel cell polyomavirus (MCPyV)-positive and -negative Merkel cell carcinoma (MCC) subsets (MCCP/MCCN) has prevented so far the...
Limited molecular knowledge of Merkel cell polyomavirus (MCPyV)-positive and -negative Merkel cell carcinoma (MCC) subsets (MCCP/MCCN) has prevented so far the identification of the MCC origin cell type and, therefore, the development of effective therapies. The retinoic gene signature was investigated in various MCCP, MCCN, and control fibroblast/epithelial cell lines to elucidate the heterogeneous nature of MCC. Hierarchical clustering and principal component analysis indicated that MCCP and MCCN cells were clusterizable from each other and control cells, according to their retinoic gene signature. MCCP versus MCCN differentially expressed genes (n = 43) were identified. Protein-protein interaction network indicated SOX2, ISL1, PAX6, FGF8, ASCL1, OLIG2, SHH, and GLI1 as upregulated hub genes and JAG1 and MYC as downregulated hub genes in MCCP compared to MCCN. Numerous MCCP-associated hub genes were DNA-binding/-transcription factors involved in neurological and Merkel cell development and stemness. Enrichment analyses indicated that MCCP versus MCCN differentially expressed genes predominantly encode for to DNA-binding/-transcription factors involved in development, stemness, invasiveness, and cancer. Our findings suggest the neuroendocrine origin of MCCP, by which neuronal precursor cells could undergo an MCPyV-driven transformation. These overarching results might open the way to novel retinoid-based MCC therapies.
Topics: Humans; Carcinoma, Merkel Cell; Merkel cell polyomavirus; Transcription Factors; Skin Neoplasms; DNA
PubMed: 37436928
DOI: 10.1002/jmv.28949 -
Scientific Reports Sep 2023Circulating tumor cells (CTCs) and epigenetic alterations are involved in the development of metastasis from solid tumors, such as colorectal cancer (CRC). The aim of...
Circulating tumor cells (CTCs) and epigenetic alterations are involved in the development of metastasis from solid tumors, such as colorectal cancer (CRC). The aim of this study was to characterize the DNA methylation profile of metastasis-competent CTCs in CRC. The DNA methylome of the human CRC-derived cell line CTC-MCC-41 was analyzed and compared with primary (HT29, Caco2, HCT116, RKO) and metastatic (SW620 and COLO205) CRC cells. The association between methylation and the transcriptional profile of CTC-MCC-41 was also evaluated. Differentially methylated CpGs were validated with pyrosequencing and qMSP. Compared to primary and metastatic CRC cells, the methylation profile of CTC-MCC-41 was globally different and characterized by a slight predominance of hypomethylated CpGs mainly distributed in CpG-poor regions. Promoter CpG islands and shore regions of CTC-MCC-41 displayed a unique methylation profile that was associated with the transcriptional program and relevant cancer pathways, mainly Wnt signaling. The epigenetic regulation of relevant genes in CTC-MCC-41 was validated. This study provides new insights into the epigenomic landscape of metastasis-competent CTCs, revealing biological information for metastasis development, as well as new potential biomarkers and therapeutic targets for CRC patients.
Topics: Humans; Neoplastic Cells, Circulating; DNA Methylation; Caco-2 Cells; Epigenesis, Genetic; Epigenomics; Colonic Neoplasms
PubMed: 37717096
DOI: 10.1038/s41598-023-42037-w -
Frontiers in Cell and Developmental... 2023Therapy resistance is a major challenge in colorectal cancer management. Epigenetic changes, such as DNA methylation, in tumor cells are involved in the development of...
Therapy resistance is a major challenge in colorectal cancer management. Epigenetic changes, such as DNA methylation, in tumor cells are involved in the development of acquired resistance during treatment. Here, we characterized the DNA methylation landscape of colon circulating tumor cells (CTCs) during cancer progression and therapy resistance development. To this aim, we used nine permanent CTC lines that were derived from peripheral blood samples of a patient with metastatic colon cancer collected before treatment initiation (CTC-MCC-41) and during treatment and cancer progression (CTC-MCC-41.4 and CTC-MCC-41.5 [A-G]). We analyzed the DNA methylome of these nine CTC lines using EPIC arrays and also assessed the association between DNA methylation and gene expression profiles. We confirmed DNA methylation and gene expression results by pyrosequencing and RT-qPCR, respectively. The global DNA methylation profiles were different in the pre-treatment CTC line and in CTC lines derived during therapy resistance development. These resistant CTC lines were characterized by a more hypomethylated profile compared with the pre-treatment CTC line. Most of the observed DNA methylation differences were localized at CpG-poor regions and some in CpG islands, shore regions and promoters. We identified a distinctive DNA methylation signature that clearly differentiated the pre-treatment CTC line from the others. Of note, the genes involved in this signature were associated with cancer-relevant pathways, including PI3K/AKT, MAPK, Wnt signaling and metabolism. We identified several epigenetically deregulated genes associated with therapy resistance in CTCs, such as . Our results bring new knowledge on the epigenomic landscape of therapy-resistant CTCs, providing novel mechanisms of resistance as well as potential biomarkers and therapeutic targets for advanced CRC management.
PubMed: 38188020
DOI: 10.3389/fcell.2023.1291179 -
Science Translational Medicine Feb 2024Recombination activating genes () are tightly regulated during lymphoid differentiation, and their mutations cause a spectrum of severe immunological disorders....
Recombination activating genes () are tightly regulated during lymphoid differentiation, and their mutations cause a spectrum of severe immunological disorders. Hematopoietic stem and progenitor cell (HSPC) transplantation is the treatment of choice but is limited by donor availability and toxicity. To overcome these issues, we developed gene editing strategies targeting a corrective sequence into the human gene by homology-directed repair (HDR) and validated them by tailored two-dimensional, three-dimensional, and in vivo xenotransplant platforms to assess rescue of expression and function. Whereas integration into intron 1 of achieved suboptimal correction, in-frame insertion into exon 2 drove physiologic human RAG1 expression and activity, allowing disruption of the dominant-negative effects of unrepaired hypomorphic alleles. Enhanced HDR-mediated gene editing enabled the correction of human in HSPCs from patients with hypomorphic mutations to overcome T and B cell differentiation blocks. Gene correction efficiency exceeded the minimal proportion of functional HSPCs required to rescue immunodeficiency in mice, supporting the clinical translation of HSPC gene editing for the treatment of RAG1 deficiency.
Topics: Animals; Humans; Mice; Exons; Gene Editing; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Homeodomain Proteins
PubMed: 38324638
DOI: 10.1126/scitranslmed.adh8162 -
Clinical Cancer Research : An Official... Mar 2024Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer. Although essentially all MCCs are antigenic through viral antigens or high tumor mutation burden, MCC...
PURPOSE
Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer. Although essentially all MCCs are antigenic through viral antigens or high tumor mutation burden, MCC has a response rate of only approximately 50% to PD-(L)1 blockade suggesting barriers to T-cell responses. Prior studies of MCC immunobiology have focused on CD8 T-cell infiltration and their exhaustion status, while the role of innate immunity, particularly myeloid cells, in MCC remains underexplored.
EXPERIMENTAL DESIGN
We utilized single-cell transcriptomics from 9 patients with MCC and multiplex IHC staining of 54 patients' preimmunotherapy tumors, to identify myeloid cells and evaluate association with immunotherapy response.
RESULTS
Single-cell transcriptomics identified tumor-associated macrophages (TAM) as the dominant myeloid component within MCC tumors. These TAMs express an immunosuppressive gene signature characteristic of monocytic myeloid-derived suppressor cells and importantly express several targetable immune checkpoint molecules, including PD-L1 and LILRB receptors, that are not present on tumor cells. Analysis of 54 preimmunotherapy tumor samples showed that a subset of TAMs (CD163+, CD14+, S100A8+) selectively infiltrated tumors that had significant CD8 T cells. Indeed, higher TAM prevalence was associated with resistance to PD-1 blockade. While spatial interactions between TAMs and CD8 T cells were not associated with response, myeloid transcriptomic data showed evidence for cytokine signaling and expression of LILRB receptors, suggesting potential immunosuppressive mechanisms.
CONCLUSIONS
This study further characterizes TAMs in MCC tumors and provides insights into their possible immunosuppressive mechanism. TAMs may reduce the likelihood of treatment response in MCC by counteracting the benefit of CD8 T-cell infiltration. See related commentary by Silk and Davar, p. 1076.
Topics: Humans; Carcinoma, Merkel Cell; Programmed Cell Death 1 Receptor; Skin Neoplasms; CD8-Positive T-Lymphocytes; Myeloid Cells
PubMed: 37851052
DOI: 10.1158/1078-0432.CCR-23-1957