RESUMO
BACKGROUND: The hepatocellular carcinoma (HCC) incident rate is gradually increasing yearly despite all the research and efforts taken by scientific communities and governing bodies. Approximately 90% of all liver cancer cases belong to HCC. Usually, HCC patients approach the treatment in the late stages of this malignancy which becomes the primary cause of high mortality rate. The knowledge about molecular pathogenesis of HCC is limited and needs more attention from researchers to identify the driver genes and miRNAs, which causes to translate this information into clinical practice. Therefore, the key regulators identification of miRNA-mRNA regulatory network is essential to identify HCC-associated genes. METHODOLOGY: We extracted microRNA (miRNA) and messenger RNA (mRNA) expression datasets of normal and tumor HCC patient samples from UCSC Xena followed by identifying differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs). Univariate and multivariate cox-proportional hazard models were utilized to identify DEMs having significant association with overall survival (OS). Kaplan-Meier (KM) plotter was used to validate the presence of prognostic DEMs. A risk-score model was used to evaluate the effectiveness of KM-plotter validated DEMs combination on risk of samples. Target DEGs of prognostic miRNAs were identified via sources such as miRTargetLink and miRWalk followed by their validation in an external microarray cohort and enrichment analysis. RESULTS: 562 DEGs and 388 DEMs were identified followed by seven prognostic miRNAs (i.e., miR-19a, miR-19b, miR-30d-5p, miR-424-5p, miR-3677-5p, miR-3913-5p, miR-7705) post univariate, multivariate, risk-score model evaluation and KM-plotter analyses. ANLN, MRO, CPEB3 were their targets and were also validated in GSE84005 dataset. CONCLUSIONS: The findings of this study decipher that most significant miRNAs and their identified target genes have association with apoptosis, inflammation, cell cycle regulation and cancer-related pathways, which appear to contribute to HCC pathogenesis and therefore, the discovery of new targets.
RESUMO
Sickle cell disease (SCD) is an inherited monogenic disease which is characterized by distorted red blood cells (RBCs) that cause vaso-occlusion and vasculopathy. In the pathogenesis of SCD, polymerized hemoglobin turn RBCs into fragile, less deformable cells, and are subsequently more susceptible to endothelial adhesion after deoxygenation. Presently, electrophoresis and genotyping are used as routine tests for diagnosis of SCD. These techniques are expensive and require specialized laboratories. Lab-on-a-chip technology is a low-cost microfluidics-based diagnostic tool which holds significant promise for rapid screening of RBC deformability. To explore the sickle RBC mechanics for screening purposes, we present a mathematical model for the flow of single RBC with altered rheological properties and slip effect on capillary wall in microcirculation. We consider single-file flow of cells through the axis symmetrical cylindrical duct, applying lubrication theory as plasma trapped between successive red blood cells. The rheological parameters used from published literature for normal RBC and corresponding variation has been taken for the purpose of this simulation to present the condition of the disease. An analytical solution has been found for realistic boundary conditions and results are simulated using MATLAB. We found that the height of plasma film in the capillary increases with increase in cell deformability and compliance which affects the forward flow velocity in the capillary. Rigid RBCs with increased adhesion between cell and capillary wall shows reduction in velocity and occurrence of vaso-occlusion events in extreme conditions. These rheological properties of the cells coupled with microfluidics mechanics can mimic the physiological condition and provides unique insights with novel possibilities for the design of microfluidics base diagnostic kit towards effective therapeutic intervention of SCD.
