An approximate confidence interval for recombination fraction in genetic linkage analysis using a two stage Monte Carlo method Gibbs sampling

One of the important parameters in genetic linkage analysis is recombination fraction. In this paper, we proposed a two stage Markov Chain Monte Carlo (MCMC) method to calculate an approximate confidence interval (ACI) for the recombination fraction. We also presented a formula for calculation of simulation size namely: outer and inner Gibbs sample sizes.Key words: Markov Chain Monte Carlo (MCMC), Gibbs sampler, approximate confidence interval, simulation size

A General Framework for Interrogation of mRNA Stability Programs Identifies RNA-Binding Proteins that Govern Cancer Transcriptomes

Widespread remodeling of the transcriptome is a signature of cancer; however, little is known about the post-transcriptional regulatory factors, including RNA-binding proteins (RBPs) that regulate mRNA stability, and the extent to which RBPs contribute to cancer-associated pathways. Here, by modeling the global change in gene expression based on the effect of sequence-specific RBPs on mRNA stability, we show that RBP-mediated stability programs are recurrently deregulated in cancerous tissues. Particularly, we uncovered several RBPs that contribute to the abnormal transcriptome of renal cell carcinoma (RCC), including PCBP2, ESRP2, and MBNL2. Modulation of these proteins in cancer cell lines alters the expression of pathways that are central to the disease and highlights RBPs as driving master regulators of RCC transcriptome. This study presents a framework for the screening of RBP activities based on computational modeling of mRNA stability programs in cancer and highlights the role of post-transcriptional gene dysregulation in RCC. Perron et al. develop a computational approach that models the functional activity of RBPs in individual cancer samples by monitoring their associated RNA stability programs. Applying this method to renal cell carcinoma transcriptomes, the authors identify RBPs that enhance cancer-associated pathways including hypoxia and cell cycle

Loss of chromosome Y leads to down regulation of KDM5D and KDM6C epigenetic modifiers in clear cell renal cell carcinoma

Recent genomic studies of sporadic clear cell renal cell carcinoma (ccRCC) have uncovered novel driver genes and pathways. Given the unequal incidence rates among men and women (male:female incidence ratio approaches 2:1), we compared the genome-wide distribution of the chromosomal abnormalities in both sexes. We observed a higher frequency for the somatic recurrent chromosomal copy number variations (CNVs) of autosomes in male subjects, whereas somatic loss of chromosome X was detected exclusively in female patients (17.1%). Furthermore, somatic loss of chromosome Y (LOY) was detected in about 40% of male subjects, while mosaic LOY was detected in DNA isolated from peripheral blood in 9.6% of them, and was the only recurrent CNV in constitutional DNA samples. LOY in constitutional DNA, but not in tumor DNA was associated with older age. Amongst Y-linked genes that were downregulated due to LOY, KDM5D and KDM6C epigenetic modifiers have functionally-similar X-linked homologs whose deficiency is involved in ccRCC progression. Our findings establish somatic LOY as a highly recurrent genetic defect in ccRCC that leads to downregulation of hitherto unsuspected epigenetic factors, and suggest that different mechanisms may underlie the somatic and mosaic LOY observed in tumors and peripheral blood, respectively

Expression of DRD2 Is Increased in Human Pancreatic Ductal Adenocarcinoma and Inhibitors Slow Tumor Growth in Mice

Background & Aims Incidence of and mortality from pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, are almost equivalent, so better treatments are needed. We studied gene expression profiles of PDACs and the functions of genes with altered expression to identify new therapeutic targets. Methods We performed microarray analysis to analyze gene expression profiles of 195 PDAC and 41 non-tumor pancreatic tissue samples. We undertook an extensive analysis of the PDAC transcriptome by superimposing interaction networks of proteins encoded by aberrantly expressed genes over signaling pathways associated with PDAC development to identify factors that might alter regulation of these pathways during tumor progression. We performed tissue microarray analysis to verify changes in expression of candidate protein using an independent set of 152 samples (40 nontumor pancreatic tissues, 63 PDAC sections, and 49 chronic pancreatitis samples). We validated the functional relevance of the candidate molecule using RNA interference or pharmacologic inhibitors in pancreatic cancer cell lines and analyses of xenograft tumors in mice. Results In an analysis of 38,276 human genes and loci, we identified 1676 genes that were significantly up-regulated and 1166 genes that were significantly down-regulated in PDAC compared with nontumor pancreatic tissues. One gene that was up-regulated and associated with multiple signaling pathways that are dysregulated in PDAC was G protein subunit αi2, which has not been previously associated with PDAC. G protein subunit αi2 mediates the effects of dopamine receptor D2 (DRD2) on cyclic adenosine monophosphate signaling; PDAC tissues had a slight but significant increase in DRD2 messenger RNA. Levels of DRD2 protein were substantially increased in PDACs, compared with non-tumor tissues, in tissue microarray analyses. RNA interference knockdown of DRD2 or inhibition with pharmacologic antagonists (pimozide and haloperidol) reduced proliferation of pancreatic cancer cells, induced endoplasmic reticulum stress and apoptosis, and reduced cell migration. RNA interference knockdown of DRD2 in pancreatic tumor cells reduced growth of xenograft tumors in mice, and administration of the DRD2 inhibitor haloperidol to mice with orthotopic xenograft tumors reduced final tumor size and metastasis. Conclusions In gene expression profile analysis of PDAC samples, we found the DRD2 signaling pathway to be activated. Inhibition of DRD2 in pancreatic cancer cells reduced proliferation and migration, and slowed growth of xenograft tumors in mice. DRD2 antagonists routinely used for management of schizophrenia might be tested in patients with pancreatic cancer

Toughness prediction in functionally graded Al6061/SiCp composites produced by roll-bonding

Functionally graded aluminum matrix composites (FGAMC) are new advanced materials with promising applications due to their unique characteristics in which composite nature is combined with graded structure