Discovering DNA methylation patterns for long non-coding RNAs associated with cancer subtypes

Despite growing evidence demonstrates that the long non-coding ribonucleic acids (lncRNAs) are critical modulators for cancers, the knowledge about the DNA methylation patterns of lncRNAs is quite limited. We develop a systematic analysis pipeline to discover DNA methylation patterns for lncRNAs across multiple cancer subtypes from probe, gene and network levels. By using The Cancer Genome Atlas (TCGA) breast cancer methylation data, the pipeline discovers various DNA methylation patterns for lncRNAs across four major subtypes such as luminal A, luminal B, her2-enriched as well as basal-like. On the probe and gene level, we find that both differentially methylated probes and lncRNAs are subtype specific, while the lncRNAs are not as specific as probes. On the network level, the pipeline constructs differential co-methylation lncRNA network for each subtype. Then, it identifies both subtype specific and common lncRNA modules by simultaneously analyzing multiple networks. We show that the lncRNAs in subtype specific and common modules differ greatly in terms of topological structure, sequence conservation as well as expression. Furthermore, the subtype specific lncRNA modules serve as biomarkers to improve significantly the accuracy of breast cancer subtypes prediction. Finally, the common lncRNA modules associate with survival time of patients, which is critical for cancer therapy.     

Transient interfacial patterns and instabilities associated with liquid film adhesion and spreading

A surface force apparatus was used to study surface shape changes during the adhesion and spreading of a polymer melt on a bare mica surface. Transient fingers were observed during the initial, rapid spreading process, pointing radially out from the initial adhesive contact point. The fingers had microscopic widths and lengths but submicroscopic thicknesses. They eventually disappeared, leaving a more slowly growing circular neck with a smooth, featureless polymer-air surface. The mean radius of the spreading meniscus (neck) was found to follow a scaling relationship with time of the form (ri + ro)/2 proportional, variant tn, with n = 0.128, while the ends of the fingers grew according to ro proportional, variant tn, with n = 0.10. These rates agree with the values of n = 0.100-0.125 predicted by classical wetting theories for circular macroscopic droplets (i.e., radially symmetric, without fingers) spreading on a solid surface. The lifetime of the transient fingering patterns increases with the polymer viscosity as tau proportional, variant etan, with n = 2.1 +/- 0.2. A circular trough or depression in the film was observed just beyond where the fingers ended, which appears to be a source of the material for the advancing fingers. In addition, beyond the trough, circular ripples/waves were observed on the polymer melt film surface. Such patterns may arise quite generally whenever a perturbation occurs that changes the local forces, thereby inducing a bulge or depression in a liquid film or surface. Thus, we observe similar fingers and ripples/waves during the spreading of liquid polybutadiene on (the immiscible and more viscous) liquid poly(dimethylsiloxane), suggesting that the phenomenon may exist in various liquid adhesion and spreading situations. For low viscosity liquids such as water and low molecular weight oils, our scaling relations suggest that the transient patterns will exist for only a few microseconds; this is likely the reason for why they have not yet been observed.     

Gene expression profiling using advanced mass spectrometric approaches

In the era of systems biology, computational and high-throughput experimental biological approaches are increasingly being combined to provide global snapshots of entire genomes and proteomes under tissue- and disease-specific conditions. The aim is to identify proteins changing in concentration and/or post-translational state and/or location, and develop a better molecular level understanding of the operation of biological systems. Here we describe an approach for comparative proteomics that builds upon the combination of high-performance nano-scale separations with the high-mass measurement accuracy, mass-resolving power and sensitivity of Fourier transform ion cyclotron resonance mass spectrometry to provide broad dynamic range, comprehensive and quantitative proteome measurements.     

The effect of ELOVL6 fatty acid elongase inhibition on the expression of genes associated with the metastasis of breast cancer

Russian Chemical Bulletin - The paper addresses the effect of a new fatty acid elongase 6 (ELOVL6) inhibitor on the migration of breast cancer cells (estrogen receptor positive MCF7 cells and...     

Protein secondary structure conformations and associated hydrophobicity scales

We have developed conformational preference functions and a hierarchy of algorithms that can evaluate the success of each hydrophobicity scale in predicting protein secondary conformation. The results of such evaluation are shown for fiftyfive different scales with respect to their ability to predict -helix, -sheet and coil structure in three testing sets of proteins: five integral membrane proteins, twelve -class and sixteen -class soluble proteins. Our scale of conformational parameters is the best predictor of secondary structure segments in membrane proteins and -class proteins. The success rate and correlation coefficient for -helix conformation in membrane proteins are 76% and 0.46 respectively, which is superior to the performance measures attained with other prediction schemes. Evaluation of solution hydrophobicity scales, often used to predict transmembrane segments in membrane proteins, indicated absence of correlation in prediction of helix segments and experimental results for the conformation of membrane proteins. Such scales have better performance (correlation coefficient around 0.30) in predicting sheet conformation in the -class proteins.     

Novel fluoroimmunoassay for ovarian cancer biomarker CA-125

Cancer antigen 125 (CA-125) is a glycoprotein biomarker that denotes the presence of ovarian and reproductive cancers in women, with serum concentrations of CA-125 greater than 35 U/ml considered indicative of potential malignancies. A fluorescent immunoassay recently developed in our laboratory employing the ALYGNSA antibody-orientation system has been used to measure CA-125 levels. This system displayed significantly increased sensitivity with a detection limit of 1.5 U/ml compared to that of a commercial CA-125 enzyme-linked immunosorbent assay (15 U/ml) This tenfold lower level of detection of the ALYGNSA CA-125 assay should permit better identification and monitoring of ovarian cancer.     

Targeted therapies for advanced non-small cell lung cancer

The incorporation of targeted agents has considerably improved the management of patients with advanced non-small cell lung cancer (NSCLC) over the last years. The main targets include the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF). Currently available agents with established role in NSCLC include the anti-EGFR tyrosine-kinase inhibitors (TKIs) erlotinib/gefitinib and the anti-VEGF monoclonal antibody bevacizumab. Moreover, several other agents targeting critical pathways in lung carcinogenesis are currently under preclinical or clinical evaluation. This review presents an update on the role of targeted agents in advanced NSCLC. In addition, we present the main clinical studies investigating the activity of these agents in NSCLC and we provide recent data with respect to future therapeutic strategies.     

A graph-based multi-sample test for identifying pathways associated with cancer progression

Cancer is in general not a result of an abnormality of a single gene but a consequence of changes in many genes, it is therefore of great importance to understand the roles of different oncogenic and tumor suppressor pathways in tumorigenesis. In recent years, there have been many computational models developed to study the genetic alterations of different pathways in the evolutionary process of cancer. However, most of the methods are knowledge-based enrichment analyses and inflexible to analyze user-defined pathways or gene sets. In this paper, we develop a nonparametric and data-driven approach to testing for the dynamic changes of pathways over the cancer progression. Our method is based on an expansion and refinement of the pathway being studied, followed by a graph-based multivariate test, which is very easy to implement in practice. The new test is applied to the rich Cancer Genome Atlas data to study the (epi)genetic alterations of 186 KEGG pathways in the development of serous ovarian cancer. To make use of the comprehensive data, we incorporate three data types in the analysis representing gene expression level, copy number and DNA methylation level. Our analysis suggests a list of nine pathways that are closely associated with serous ovarian cancer progression, including cell cycle, ERBB, JAK-STAT signaling and p53 signaling pathways. By pairwise tests, we found that most of the identified pathways contribute only to a particular transition step. For instance, the cell cycle and ERBB pathways play key roles in the early-stage transition, while the ECM receptor and apoptosis pathways contribute to the progression from stage III to stage IV. The proposed computational pipeline is powerful in detecting important pathways and gene sets that drive cancers at certain stage(s). It offers new insights into the understanding of molecular mechanism of cancer initiation and progression.     

Multivariate analysis approach to the plasma protein profile of patients with advanced colorectal cancer

The aim of the present study was to identify the pattern of plasma protein species of interest as markers of colorectal cancer (CRC). Using matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS), the plasma protein profile was determined in nine stage IV CRC patients (study group) and nine clean-colon healthy subjects (control group). Multivariate analysis methods were employed to identify distinctive disease patterns at protein spectrum. In the study and control groups, cluster analysis (CA) on the complete MALDI-MS spectra plasma protein profile showed a distinction between CRC patients and healthy subjects, thus allowing the identification of the most discriminating ionic species. Principal component analysis (PCA) and linear discriminant analysis (LDA) yielded similar grouping results. LDA with leave-one-out cross validation achieved a correct classification rate of 89% in both the patients and the healthy subjects.     

Green synthesized selenium nanoparticles for ovarian cancer cell apoptosis

Research on Chemical Intermediates - Over recent years, selenium nanoparticles (Se-NP) have been widely applied in nanomedicine science due to their exceptional physicochemical and biological...     

Synthesis and characterization of folic acid-chitosan nanoparticles loaded with thymoquinone to target ovarian cancer cells

The aim of the present research was to formulate and characterize radioiodinated folic acid-chitosan conjugated thymoquinone nanoparticles (FATQCSNPs) and to increase targeting ability on ovarian cancer cell. The dose of drug-loading into the FATQCSNPs and the amount of folic acid on the FATQCSNPs surface were determined as a 20.0?±?1% and 46.0?±?0.5%, respectively. Cell viabilities (%) determined on SKOV-3 and Caco-2 cells for 48 h. TQ, TQCS and FATQCS were very cytotoxic with lower IC₅₀ values on both cell lines. At specific-activity-dependent incorporation study, the incorporation efficiencies of ¹³¹I-FATQCSNPs was higher than that of ¹³¹I-TQ on SKOV3 cell lines.

     

Tumor pleural effusion proteome profiling for ovarian cancer biomarkers mining

Mass spectrometric proteome profiling of tumor pleural effusion (TPE) liquid fraction from ovarian cancer patients was performed to identify the potential biomarkers of the disease. The methodology of analysis of the TPE protein composition included the removal of high-abundant proteins by affinity chromatography, additional fractionation of the low-abundant proteins based on their lipophilicity, and high-resolution mass spectrometric analysis. As a result, 190 proteins were indentified, 49% of them belonging to the groups of extracellular and membrane proteins. The application of several criteria to data analysis allowed us to generate a group of 26 proteins that are promising candidates for testing as ovarian cancer biomarkers.     

Lysophosphatidic acid receptor 2 and Gi/Src pathway mediate cell motility through cyclooxygenase 2 expression in CAOV-3 ovarian cancer cells

Lysophosphatidic acid (LPA) is a bioactive phospholipids and involves in various cellular events, including tumor cell migration. In the present study, we investigated LPA receptor and its transactivation to EGFR for cyclooxygenase-2 (COX-2) expression and cell migration in CAOV-3 ovarian cancer cells. LPA induced COX-2 expression in a dose-dependent manner, and pretreatment of the cells with pharmacological inhibitors of Gi (pertussis toxin), Src (PP2), EGF receptor (EGFR) (AG1478), ERK (PD98059) significantly inhibited LPA-induced COX-2 expression. Consistent to these results, transfection of the cells with selective Src siRNA attenuated COX-2 expression by LPA. LPA stimulated CAOV-3 cell migration that was abrogated by pharmacological inhibitors and antibody of EP2. Higher expression of LPA2 mRNA was observed in CAOV-3 cells, and transfection of the cells with a selective LPA2 siRNA significantly inhibited LPA-induced activation of EGFR and ERK, as well as COX-2 expression. Importantly, LPA2 siRNA also blocked LPA-induced ovarian cancer cell migration. Collectively, our results clearly show the significance of LPA2 and Gi/Src pathway for LPA-induced COX-2 expression and cell migration that could be a promising drug target for ovarian cancer cell metastasis.     

Identification of the carboxymethyllysine residue in the advanced stage of glycated human serum albumin.

As an advanced stage of glycation, glycated human serum albumin (G-HSA; glucose content, 2 mol of 5-hydroxymethylfurfural equivalent/mol of HSA) was incubated at 37 degrees C up to 30 d in 0.2 M phosphate buffer, pH 7.4, with 100 microM Fe3+. G-HSA incubated for 30 d (G-HSA-30(Fe)) was subsequently hydrolyzed at 110 degrees C for 24 h in 6 N HCl. In the hydrolysate, N epsilon-carboxymethyllysine (CML) was identified by cochromatography with synthesized CML on an amino acid analyzer. pI of HSA (4.8) shifted to 4.5 in G-HSA. A more acidic fraction, pI 4.3, appeared in G-HSA-30(Fe). CML content (mol of CML/mol of HSA) of HSA and G-HSA was as follows; 0 in HSA, 0.2 in HSA-30(Fe), 0.4 in G-HSA and 1.5 in G-HSA-30(Fe) pI 4.3. The amino acid compositions also changed in lysine, arginine and tyrosine at the advanced stage of the reaction.     

Protein patterns of gel-entrapped Escherichia coli cells differ from those of free-floating organisms

The two-dimensional electrophoretic patterns of cellular proteins from gel-entrapped Escherichia coli cells were compared to those of exponential- and stationary-phase free-floating organisms. The amounts of several proteins in immobilized cells were significantly different from those in free bacteria. Immobilized organisms rapidly produced a high level of dipeptide permease and a single-strand binding protein, and progressively accumulated an aldehyde dehydrogenase. Immobilization also induced a decrease in the levels of two proteins, i.e., the YFID protein and a DNA-binding, stationary-phase protein. The possible role of these proteins in the high resistance of immobilized bacteria to stresses is discussed.