Meta-analysis of cancer gene expression signatures reveals new cancer genes, SAGE tags and tumor associated regions of co-regulation

Cancer is among the major causes of human death and its mechanism(s) are not fully understood. We applied a novel meta-analysis approach to multiple sets of merged serial analysis of gene expression and microarray cancer data in order to analyze transcriptome alterations in human cancer. Our methodology, which we denote ‘COgnate Gene Expression patterNing in tumours’ (COGENT), unmasked numerous genes that were differentially expressed in multiple cancers. COGENT detected well-known tumor-associated (TA) genes such as TP53, EGFR and VEGF, as well as many multi-cancer, but not-yet-tumor-associated genes. In addition, we identified 81 co-regulated regions on the human genome (RIDGEs) by using expression data from all cancers. Some RIDGEs (28%) consist of paralog genes while another subset (30%) are specifically dysregulated in tumors but not in normal tissues. Furthermore, a significant number of RIDGEs are associated with GC-rich regions on the genome. All assembled data is freely available online (www.oncoreveal.org) as a tool implementing COGENT analysis of multi-cancer genes and RIDGEs. These findings engender a deeper understanding of cancer biology by demonstrating the existence of a pool of under-studied multi-cancer genes and by highlighting the cancer-specificity of some TA-RIDGEs

Continuous Energy Values of 3-Amino-4-Nitraminofurazan Molecule by Modern Optimization Techniques

The conformational energy values of 3-amino-4-nitraminofurazan (C2N4O3H2) molecule changing with two torsion angles were firstly calculated using density functional theory (DFT) with Lee-Young-Parr correlation functional and 6-31 G(d) basis set on Gaussian Program. And then, these obtained discrete data were made continuous by using Fuzzy Logic Modelling (FLM) and Artificial Neural Network (ANN). This allowed us to make predictions about the untested data and, to obtain the optimized energy value depending on two torsion angles with reasonable computational cost, great efficiency and high accuracy. The obtained results were compared with the DFT results by using regression analysis

Abstract

Ilhan Koman was one of the innovative sculptors of the 20th century [9, 10]. He frequently used mathematical concepts in creating his sculptures and discovered a wide variety of sculptural forms that can be of interest for the art+math community. In this paper, we focus on developable sculptural forms he invented approximately 25 years ago, during a period that covers the late 1970’s and early 1980’s

Prenatal Expressions of Hyperpolarization-activated Cyclic-Nucleotide-Gated Channel (HCN) Genes in Dysplastic Hippocampi in Rats

AIM: Hyperpolarization-activated cyclic nucleotide-gated (HCN or h-channel) channels mediate hyperpolarization-activating currents in the hippocampus and neocortex. The aim of this study is to present prenatal h-channel gene expressions (HCN1 and HCN2; HCN1-Entrez-Gene ID: 84390; HCN2- Entrez Gene ID: 114244) in dysplastic hippocampal pyramidal neurons induced by in utero irradiation in rats

Lithium-mediated inhibition of GSK3β leads to β-catenin accumulation and increase in <i>MENA</i> mRNA levels.

<p>(A) Western blot analysis of Huh7 cells treated with either 25 mM NaCl or 25 mM LiCl for indicated timepoints. RT-PCR (B) and qRT-PCR (C) analysis of Huh7 cells treated with either 25 mM NaCl or 25 mM LiCl for indicated timepoints. (D) RT-PCR analysis of U373, Sk-Mel-103 and Sk-Mel-19 cells treated with LiCl for 24 hrs. Each image is a representative of at least two independent experiments.</p

Overexpression of β-catenin-S33Y and Wnt ligans leads to increase in <i>MENA</i> transcription.

<p>(A) β-catenin-S33Y mutant was stably overexpressed in Huh7 cells and <i>MENA</i> and Axin2 mRNA levels were analyzed using qRT-PCR. (B) β-catenin-S33Y was transiently overexpressed (48 hrs) in U373 cells and <i>MENA</i> and β-catenin mRNA levels were compared using RT-PCR. (C) Wnt1 or Wnt3a ligans were overexpressed in Huh7 cells (48 hrs) and <i>MENA</i> mRNA levels were compared using RT-PCR.</p

<i>Ena</i> knock-down induces tumor formation and metastasis <i>in vivo</i>.

<p><i>Ena</i> (A), <i>white</i> (B) and <i>axin</i> (C) knock-down was confirmed by RT-PCR. Actin was used as an internal control. Significant increase of tumor formation (D and E) and metastasis (F and G) in eyeful (Eyf) (D, F) and sensitized (St) (E, G) flies upon knock-down of <i>ena</i> and <i>axin</i> genes is observed, when <i>white</i> knock-down is used as a control. (* indicates p<0.05; *** indicates p<0.001 as analyzed by the chi-square test). Representative images of tumor and metastasis formations in eyeful and sensitized flies upon knock-down of <i>Ena</i> (H-O). (H and I) ey-GAL4, UAS-Dl, eyeful/+; UAS-EnaRNAi/+ (“+”: wild-type chromosome) flies showing tumors in the eye tissue. Every fold in the eye tissue is counted as a single tumor. (J and K) ey-Gal4, UAS-Dl/+, UAS-EnaRNAi/+ flies with tumors in the eye. (L and M) ey-GAL4, UAS-Dl, eyeful/+; UAS-EnaRNAi/+ flies showing metastasis on the abdomen and thorax. (N and O) ey-Gal4, UAS-Dl/+, UAS-EnaRNAi/+ flies with metastasis on the back and abdomen.</p

Promoters of mammalian <i>MENA</i> orthologs have functional Tcf4-binding elements (TBEs) that are regulated by the Wnt/β-catenin pathway.

<p>(A) Schematic representation of the promoters and the identified putative TBEs. The location of the TBEs is indicated by boxes and the sequences and locations with respect to transcriptional start sites (denoted by arrows) are shown under the boxes. Predicted binding motifs for other transcription factors are also indicated. The length of the bar is 100 bp. The WWCAAWG sequence is the consensus sequence for TBEs. (B) Alignment of proximal (TBE#1) and distal (TBE#2) TBE sequences. (C, D and E) Huh7 cells or HeLa cells were transfected with pGL3-<i>MENA</i> reporter plasmid and the promoter activity was stimulated by co-transfecting degradation-resistant β-catenin, Tcf4 or Wnt ligans or inhibited by co-transfecting dominant-negative Tcf4 (ΔNTcf4). The bars are given as averages (n = 3) normalized to Renilla luciferase activity, which was used an internal control. Error bars represent standard deviation (* = p<0.05, ** = p<0.01 and *** = p<0.005, Student's t-test). Each graph is a representative of at least two independent experiments. “β-cat” denotes the quadruple-mutant β-catenin-4m (See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037013#s4" target="_blank">Materials & Methods</a>). (F) Chromatin immunoprecipitation assay was done with monoclonal anti-β-catenin antibody and PCR (35–40 cycles) was used to detect <i>MENA</i> promoter fragments. β-catenin was found to interact with <i>MENA</i> promoter in Huh7 and HEK293T cell context, as well as in mouse brain tissue and liver tissue contexts. All experiments were repeated at least twice. An unrelated monoclonal antibody was used as the control IgG. The lower bands that appear in the mouse brain gel image are the primer-dimer bands. The arrow indicates the band of the expected size.</p