shikin's Nikolsky:Y [21 articles]

Abstract

The process for evaluating chemical safety is inefficient, costly, and animal intensive. There is growing consensus that the current process of safety testing needs to be significantly altered to improve efficiency and reduce the number of untested chemicals. In this study, the use of short-term gene expression profiles was evaluated for predicting the increased incidence of mouse lung tumors. Animals were exposed to a total of 26 diverse chemicals with matched vehicle controls over a period of 3 years. Upon completion, ...

Abstract

ABSTRACT The ideal toxicity biomarker is composed of the properties of prediction (is detected prior to traditional pathological signs of injury), accuracy (high sensitivity and specificity), and mechanistic relationships to the endpoint measured (biological relevance). Gene expression-based toxicity biomarkers ("signatures") have shown good predictive power and accuracy, but are difficult to interpret biologically. We have compared different statistical methods of feature selection with knowledge-based approaches, using GeneGo's database of canonical pathway maps, to generate gene sets for the classification of renal ...

Abstract

ABSTRACT: INTRODUCTION: As part of the MicroArray Quality Control (MAQC)-II project, this analysis examines how the choice of univariate feature selection methods and classification algorithms may influence the performance of genomic predictors under varying degrees of prediction difficulty represented by three clinically-relevant endpoints. METHODS: We used gene expression data from 230 breast cancers (grouped into training and independent validation sets) and we examined 40 predictors (five univariate feature selection methods combined with eight different classifiers) for each of the three endpoints. ...

Note (first note only)

Our MAQC-2 article on different feature selection methods and classifiers for BC data sets

Abstract

We have performed a genome-wide analysis of copy number changes in breast and colorectal tumors using approaches that can reliably detect homozygous deletions and amplifications. We found that the number of genes altered by major copy number changes, deletion of all copies or amplification to at least 12 copies per cell, averaged 17 per tumor. We have integrated these data with previous mutation analyses of the Reference Sequence genes in these same tumor types and have identified genes and cellular pathways ...

Abstract

Analysis of microarray, SNPs, proteomics, and other high-throughput (OMICs) data is challenging because of its biological complexity and high level of technical and biological noise. One way to deal with both problems is to perform analysis with a high-fidelity annotated knowledge base of protein interactions, pathways, and functional ontologies. This knowledge base has to be structured in a computer-readable format and must include software tools for managing experimental data, analysis, and reporting. Here we present MetaDiscovery, an integrated platform for functional ...

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ABSTRACT: BACKGROUND: Astrocyte activation is a characteristic response to injury in the central nervous system, and can be either neurotoxic or neuroprotective, while the regulation of both roles remains elusive. METHODS: To decipher the regulatory elements controlling astrocyte-mediated neurotoxicity in glaucoma, we conducted a systems-level functional analysis of gene expression, proteomic and genetic data associated with reactive optic nerve head astrocytes (ONHAs). RESULTS: Our reconstruction of the molecular interactions affected by glaucoma revealed multi-domain biological networks controlling activation of ONHAs at ...

Abstract

A single cancer cell contains large numbers of genetic alterations that in combination create the malignant phenotype. However, whether amplified and mutated genes form functional and physical interaction networks that could explain the selection for cells with combined alterations is unknown. To investigate this issue, we characterized copy number alterations in 191 breast tumors using dense single nucleotide polymorphism arrays and identified 1,747 genes with copy number gain organized into 30 amplicons. Amplicons were distributed unequally throughout the genome. Each amplicon ...

Abstract

BACKGROUND: In recent years, the maturation of microarray technology has allowed the genome-wide analysis of gene expression patterns to identify tissue-specific and ubiquitously expressed ('housekeeping') genes. We have performed a functional and topological analysis of housekeeping and tissue-specific networks to identify universally necessary biological processes, and those unique to or characteristic of particular tissues. RESULTS: We measured whole genome expression in 31 human tissues, identifying 2374 housekeeping genes expressed in all tissues, and genes uniquely expressed in each tissue. Comprehensive functional ...

Abstract

We describe a novel approach to the analysis of toxicogenomics data and elucidation of biological networks affected by drug treatments. In this method approximately 15,000 linear pathway modules were generated from manually assembled pathway maps from MetaCore (GeneGo, Inc.). Microarray expression data from livers of rat exposed to phenobarbital, mestranol and tamoxifen were mapped onto these modules. Using different analytical techniques we have identified sets of "differential" pathways featuring highly correlated expression among multiple repeats of the same treatment while showing strong anti-correlation across different treatments. Network modules distinguishing chemical ...

Abstract

BACKGROUND:The identification of key target nodes within complex molecular networks remains a common objective in scientific research. The results of pathway analyses are usually sets of fairly complex networks or functional processes that are deemed relevant to the condition represented by the molecular profile. To be useful in a research or clinical laboratory, the results need to be translated to the level of testable hypotheses about individual genes and proteins within the condition of interest. RESULTS:In this paper we describe novel ...

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The transition of ductal carcinoma in situ (DCIS) to invasive carcinoma is a poorly understood key event in breast tumor progression. Here, we analyzed the role of myoepithelial cells and fibroblasts in the progression of in situ carcinomas using a model of human DCIS and primary breast tumors. Progression to invasion was promoted by fibroblasts and inhibited by normal myoepithelial cells. Molecular profiles of isolated luminal epithelial and myoepithelial cells identified an intricate interaction network involving TGFbeta, Hedgehog, cell adhesion, and ...

Abstract

Cellular identity and differentiation are determined by epigenetic programs. The characteristics of these programs in normal human mammary epithelium and their similarity to those in stem cells are unknown. To begin investigating these issues, we analyzed the DNA methylation and gene expression profiles of distinct subpopulations of mammary epithelial cells by using MSDK (methylation-specific digital karyotyping) and SAGE (serial analysis of gene expression). We identified discrete cell-type and differentiation state-specific DNA methylation and gene expression patterns that were maintained in a ...

Abstract

There are currently few therapeutic options for patients with pancreatic cancer, and new insights into the pathogenesis of this lethal disease are urgently needed. Towards this end, we performed a comprehensive genetic analysis of 24 pancreatic cancers. We first determined the sequences of 23,219 transcripts, representing 20,661 protein-coding genes, in these samples. Then, we searched for homozygous deletions and amplifications in the tumor DNA by using microarrays containing probes for ~106 single nucleotide polymorphisms (SNPs). We found that pancreatic cancers contain ...

Abstract

Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, we found recurrent mutations in the active ...

Abstract

The complexity of human biology requires a systems approach that uses computational approaches to integrate different data types. Systems biology encompasses the complete biological system of metabolic and signaling pathways, which can be assessed by measuring global gene expression, protein content, metabolic profiles, and individual genetic, clinical, and phenotypic data. High content screening assays can also be used to generate systems biology knowledge. In this review, we will summarize the pathway databases and describe biological network tools used predominantly with this ...

Abstract

BACKGROUND:Increased dietary cholesterol intake is associated with atherosclerosis. Atherosclerosis development requires a lipid and an inflammatory component. It is unclear where and how the inflammatory component develops. To assess a putative role of the liver in the evolution of inflammation, we treated ApoE*3Leiden mice with cholesterol-free (Con), low (LC; 0.25% w/w) and high (HC; 1% w/w) cholesterol diets, scored early atherosclerosis and profiled the (patho)physiological state of the liver using novel whole-genome and metabolome technologies. RESULTS:Whereas Con diet did not induce ...

Abstract

Traditionally, gene signatures are statistically deduced from large gene expression and proteomics datasets and have been applied as an experimental molecular diagnostic technique that is sensitive to experimental design and statistical treatment. We have developed and applied the approach of "signature networks" which overcomes some of the drawbacks of clustering methods. We have demonstrated signature network assembly, functional analysis and logical operations on the networks that can be generated. In addition, we have used this technique in a proof of concept ...

Abstract

Cellular life can be represented and studied as the 'interactome'--a dynamic network of biochemical reactions and signaling interactions between active proteins. Systemic networks analysis can be used for the integration and functional interpretation of high-throughput experimental data, which are abundant in drug discovery but currently poorly utilized. The composition and topology of complex networks are closely associated with vital cellular functions, which have important implications for life science research. Here we outline recent advances in the field, available tools and applications ...

Abstract

Cells with distinct phenotypes including stem-cell-like properties have been proposed to exist in normal human mammary epithelium and breast carcinomas, but their detailed molecular characteristics and clinical significance are unclear. We determined gene expression and genetic profiles of cells purified from cancerous and normal breast tissue using markers previously associated with stem-cell-like properties. CD24+ and CD44+ cells from individual tumors were clonally related but not always identical. CD44+ cell-specific genes included many known stem-cell markers and correlated with decreased patient survival. ...

Abstract

Human cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes. To catalogue the genetic changes that occur during tumorigenesis, we isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene "mountains" ...