Based on the severity of liver fibrosis, low or high-risk profile of developing end-stage liver disease was present in nonalcoholic fatty liver disease (NAFLD). However, the mechanisms inducing transition from mild to advanced NAFLD are still elusive. We performed a system-level study on fibrosing-NAFLD by weighted gene co-expression network analysis (WGCNA) to identify significant modules in the network, and followed by functional and pathway enrichment analyses. Moreover, hub genes in the module were analyzed by network feature selection. As a result, fourteen distinct gene modules were identified, and seven modules showed significant associations with the status of NAFLD. Module preservation analysis confirmed that these modules can also be found in diverse independent datasets. After network feature analysis, the magenta module demonstrated a remarkably correlation with NAFLD fibrosis. The top hub genes with high connectivity or gene significance in the module were ultimately determined, including LUM, THBS2, FBN1 and EFEMP1. These genes were further verified in clinical samples. Finally, the potential regulators of magenta module were characterized. These findings highlighted a module and affiliated genes as playing important roles in the regulation of fibrosis in NAFLD, which may point to potential targets for therapeutic interventions.
Acute myeloid leukaemia (AML) is haematologic malignancy with high heterogeneity, characterized by uncontrolled proliferation of myeloid progenitor cells gradually replacing the normal haematopoietic function of bone marrow. With the continuous exploration and research at the cellular and molecular level on the pathogenesis of AML, the choice of novel treatment modalities has surged over the past few years, including targeted small-molecule inhibitors, antibody-drug conjugate, tumour-targeted immunotherapy and so on. 1,2 The prognosis of majority of young AML patients has improved, and most patients have access to complete remission. However, more than half of young adult patients and approximately 90% of older patients still die of their diseases. 3 Hence, a reliable prognostic Abstract Acute myeloid leukaemia (AML) is the most common type of adult acute leukaemia and has a poor prognosis. Thus, optimal risk stratification is of greatest importance for reasonable choice of treatment and prognostic evaluation. For our study, a total of 1707 samples of AML patients from three public databases were divided into meta-training, meta-testing and validation sets. The meta-training set was used to build risk prediction model, and the other four data sets were employed for validation. By log-rank test and univariate COX regression analysis as well as LASSO-COX, AML patients were divided into high-risk and low-risk groups based on AML risk score (AMLRS) which was constituted by 10 survival-related genes. In meta-training, meta-testing and validation sets, the patient in the low-risk group all had a significantly longer OS (overall survival) than those in the high-risk group (P < .001), and the area under ROC curve (AUC) by time-dependent ROC was 0.5854-0.7905 for 1 year, 0.6652-0.8066 for 3 years and 0.6622-0.8034 for 5 years. Multivariate COX regression analysis indicated that AMLRS was an independent prognostic factor in four data sets. Nomogram combining the AMLRS and two clinical parameters performed well in predicting 1-year, 3-year and 5-year OS. Finally, we created a webbased prognostic model to predict the prognosis of AML patients (https://tcgi.shiny apps.io/amlrs_nomog ram/). K E Y W O R D Sacute myeloid leukaemia, gene expression profiling, nomogram, prognosis, signature | 4511 YANG et Al.stratification system which can be applied to clinical risk evaluation is of high importance for the choice of therapy and follow-up in AML patients.Whether it is an established classification system, such as the French-American-British (FAB) classification system in 1976, 4 WorldHealth Organization (WHO) classification in 2008 5 and 2016 6 incorporating genetic information, or prognostic factors, for instance, clinical factors including mounting age and poor performance status, 7 cytogenetic changes 8 and gene mutation, 9 all have their downsides for risk stratification, such as the insufficiency of generalization capacity, the uncertainty in the accuracy of prediction. Hence, recently increasing sight has turned to studies o...
Background/Aims: Isocitrate dehydrogenase 2 (IDH2) is a mitochondrial NADP-dependent isocitrate dehydrogenase, and has been found to be a tumor suppressor in several types of tumors. However, the roles of IDH2 in hepatocellular carcinoma (HCC) as well as underlying mechanisms remain unknown. Methods: The IDH2 and matrix metalloproteinase 9 (MMP9) levels in the specimens from 24 HCC patients were investigated by Western blot and ELISA, respectively. Their relationship was examined by correlation analyses. Patient survival with high IDH2 levels and low IDH2 levels was compared. IDH2 levels and MMP9 levels were modified in a human HCC cell line. The effects of IDH2 or MMP9 modulation on the expression of the other were analyzed. The effects of IDH2 on cell invasion were analyzed in a transwell cell invasion assay. The dependence of nuclear factor κB (NF-κB) signaling was examined using a specific inhibitor. Results: The IDH2 levels significantly decreased in HCC, and were lower in HCC with metastases, compared to those without metastases. IDH2 levels inversely correlated with MMP9 levels in HCC. HCC patients with Low IDH2 had lower 5-year survival. MMP9 levels did not regulate IDH2 levels, while IDH2 inhibited MMP9 levels in HCC cells, in a NF-κB signaling dependent manner, possibly through iκB, to suppress HCC cell invasion. Conclusions: Down regulation of IDH2 may promote HCC cell invasion via NF-κB-dependent increases in MMP9 activity. IDH2 may be a potential therapeutic target for HCC.
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