Background Tyrosine protein tyrosine kinase binding protein (TYROBP) binds non-covalently to activated receptors on the surface of various immune cells, and mediates signal transduction and cellular activation. It is dysregulated in various malignancies, although little is known regarding its role in low-grade glioma. The aim of this study is to explore the clinicopathological significance, prognostic value and immune signature of TYROBP expression in low-grade glioma (LGG). Methods The differentially expressed genes (DEGs) between glioma samples and normal tissues were identified from two GEO microarray datasets using the limma package. The DEGs overlapping across both datasets were functionally annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. STRING database was used to establish the protein-protein interaction (PPI) of the DEGs. The PPI network was visualized by Cytoscape and cytoHubba, and the core module and hub genes were identified. The expression profile of TYROBP and patient survival were validated in the Oncomine, GEPIA2 and CGGA databases. The correlation between TYROBP expression and the clinicopathologic characteristics were evaluated. Gene Set Enrichment Analysis (GSEA) and single-sample GSEA (ssGSEA) were performed by R based on the LGG data from TCGA. The TIMER2.0 database was used to determine the correlation between TYROBP expression and tumor immune infiltrating cells in the LGG patients. Univariate and multivariate Cox regression analyses were performed to determine the prognostic impact of clinicopathological factors via TCGA database. Results Sixty-two overlapping DEGs were identified in the 2 datasets, and were mainly enriched in the response to wounding, focal adhesion, GTPase activity and Parkinson disease pathways. TYROBP was identified through the PPI network and cytoHubba. TYROBP expression levels were significantly higher in the LGG tissues compared to the normal tissues, and was associated with worse prognosis and poor clinicopathological parameters. In addition, GSEA showed that TYROBP was positively correlated to neutrophil chemotaxis, macrophage activation, chemokine signaling pathway, JAK-STAT signaling pathway, and negatively associated with gamma aminobutyric acid signaling pathway, neurotransmitter transport, neuroactive ligand receptor intersection etc. TIMER2.0 and ssGSEA showed that TYROBP expression was significantly associated with the infiltration of neutrophils, macrophages, myeloid dendritic cells and monocytes. The infiltration of the M2 phenotype macrophages, cancer-associated fibroblasts and myeloid dendritic cells correlated to worse prognosis in LGG patients. Finally, multivariate analysis showed that elevated TYROBP expression is an independent risk factor for LGG. Conclusion TYROBP is dysregulated in LGG and correlates with immune infiltration. It is a potential therapeutic target and prognostic marker for LGG.
Purpose: Metabolic impairment is one key contributor to heart failure (HF) pathogenesis and progression. The major causes of HF, coronary heart disease (CHD), dilated cardiomyopathy (DCM), and valvular heart disease (VHD) remains poorly characterized in patients with HF from the view of metabolic profile. We sought to determine metabolic differences in CHD-, VHD-, and DCM-induced HF patients and identify significantly altered metabolites and their correlations.Procedure: In this study, a total of 96 HF cases and 97 controls were enrolled. The contents of 23 amino acids and 26 carnitines in fasting plasma were measured by a targeted liquid chromatography and mass spectrometry (LC-MS) approach.Results: Nine metabolites (Histidine, Arginine, Citrulline, Glutamine, Valine, hydroxyhexadecenyl-carnitine, acylcarnitine C22, hydroxytetradecanoyl-carnitine, and carnitine) were found to be related with the occurrence of HF. Arginine, Glutamine and hydroxytetradecanoyl-carnitine could effectively distinguish CHD and DCM patients, and hydroxytetradecanoyl-carnitine and aspartic acid were able to classify CHD and VHD cohorts.Conclusion: This study indicated that circulating amino acids and long-chain acylcarnitine levels were closely associated with progression of heart failure. Monitoring these metabolic alterations by LC-MS may help the differentiation of CHD, VHD, and DCM in the early stage, and provide new diagnostics targets or therapeutic interventions.
Alzheimer’s disease (AD) is a form of neurodegenerative disease in the elderly with no cure at present. In a previous study, we found that the scaffold protein DISC1 is downregulated in the AD brains, and ectopic expression of DISC1 can delay the progression of AD by protecting synaptic plasticity and down-regulating BACE1. However, the underlying mechanisms remain not to be elucidated. In the present study, we compared the proteomes of normal and DISC1high AD cells expressing the amyloid precursor protein (APP) using isobaric tag for relative and absolute quantitation (iTRAQ) and mass spectrometry (MS). The differentially expressed proteins (DEPs) were identified, and the protein-protein interaction (PPI) network was constructed to identify the interacting partners of DISC1. Based on the interaction scores, NDE1, GRM3, PTGER3 and KATNA1 were identified as functionally or physically related to DISC1, and may therefore regulate AD development. The DEPs were functionally annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases with the DAVID software, and the eggNOG database was used to determine their evolutionary relationships. The DEPs were significantly enriched in microtubules and mitochondria-related pathways. Gene set enrichment analysis (GSEA) was performed to identify genes and pathways that are activated when DISC1 is overexpressed. Our findings provide novel insights into the regulatory mechanisms underlying DISC1 function in AD.
Despite emerging evidence revealing the remarkable roles of protein phosphatase 1 regulatory inhibitor subunit 14A (PPP1R14A) in cancer tumorigenesis and progression, no pan-cancer analysis is available. A comprehensive investigation of the potential carcinogenic mechanism of PPP1R14A across 33 tumors using bioinformatic techniques is reported for the first time. PPP1R14A is downregulated in major malignancies, and there is a significant correlation between the PPP1R14A expression and the prognosis of patients. The high expression of PPP1R14A in most cases was associated with poor overall survival (OS), disease-specific survival (DSS), and progress-free interval (PFI) across patients with various malignant tumors, including adrenocortical carcinoma (ACC) and bladder urothelial carcinoma (BLCA), indicated through pan-cancer survival analysis. Receiver operating characteristic (ROC) analysis subsequently exhibited that the molecule has high reference significance in diagnosing a variety of cancers. The frequency of PPP1R14A genetic changes including genetic mutations and copy number alterations (CNAs) in uterine carcinosarcoma reached 16.07%, and these alterations brought misfortune to the survival and prognosis of cancer patients. In addition, methylation within the promoter region of PPP1R14A DNA was enhanced in a majority of cancers. Downregulated phosphorylation levels of phosphorylation sites including S26, T38, and others in most cases took place in several tumors, such as breast cancer and colon cancer. PPP1R14A remarkably correlated with the levels of infiltrating cells and immune checkpoint genes. Our research on the carcinogenic effect of PPP1R14A in different tumors is comprehensively summarized and analyzed and provides a theoretical basis for future therapeutic and immunotherapy strategies.
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