Group: BTS-PT-AS-CS - library 74 articles

Abstract

The Gene Expression Omnibus (GEO) at the National Center for Biotechnology Information (NCBI) is the largest public repository for high-throughput gene expression data. Additionally, GEO hosts other categories of high-throughput functional genomic data, including those that examine genome copy number variations, chromatin structure, methylation status and transcription factor binding. These data are generated by the research community using high-throughput technologies like microarrays and, more recently, next-generation sequencing. The database has a flexible infrastructure that can capture fully annotated raw and processed ...

Abstract

Motivation: Predicting the metastatic potential of primary malignant tissues has direct bearing on the choice of therapy. Several microarray studies yielded gene sets whose expression profiles successfully predicted survival. Nevertheless, the overlap between these gene sets is almost zero. Such small overlaps were observed also in other complex diseases, and the variables that could account for the differences had evoked a wide interest. One of the main open questions in this context is whether the disparity can be attributed only to ...

Abstract

Breast cancer patients with the same stage of disease can have markedly different treatment responses and overall outcome. The strongest predictors for metastases (for example, lymph node status and histological grade) fail to classify accurately breast tumours according to their clinical behaviour1, 2, 3. Chemotherapy or hormonal therapy reduces the risk of distant metastases by approximately one-third; however, 70–80% of patients receiving this treatment would have survived without it4, 5. None of the signatures of breast cancer gene expression reported to ...

Abstract

Motivation: We consider the problem of estimating values associated with gene expression from oligonucleotide arrays. Such estimates should linearly track concentration, yield non-negative results, have statistical guarantees of robustness against outliers, and allow estimates of significance and variance. Results: A hierarchy of simple models is used to design robust estimators meeting these goals for both stand alone and comparative experiments. This algorithm has been validated against an extensive panel of known spike experiments, and shows comparable performance to existing standards. ...

Abstract

Summary: Quality Control is a fundamental aspect of successful microarray data analysis. Simpleaffy is a BioConductor package that provides access to a variety of QC metrics for assessing the quality of RNA samples and of the intermediate stages of sample preparation and hybridization. Simpleaffy also offers fast implementations of popular algorithms for generating expression summaries and detection calls. Availability: Simpleaffy can be downloaded from http://www.bioconductor.org Contact: cmiller@picr.man.ac.uk Supplementary information: Additional information can be found on the supplementary website ...

Abstract

PurposeA number of microarray studies have reported distinct molecular profiles of breast cancers (BC), such as basal-like, ErbB2-like, and two to three luminal-like subtypes. These were associated with different clinical outcomes. However, although the basal and the ErbB2 subtypes are repeatedly recognized, identification of estrogen receptor (ER) -positive subtypes has been inconsistent. Therefore, refinement of their molecular definition is needed. Materials and MethodsWe have previously reported a gene expression grade index (GGI), which defines histologic grade based on gene expression ...

Abstract

Perturbations of the p53 pathway are associated with more aggressive and therapeutically refractory tumors. However, molecular assessment of p53 status, by using sequence analysis and immunohistochemistry, are incomplete assessors of p53 functional effects. We posited that the transcriptional fingerprint is a more definitive downstream indicator of p53 function. Herein, we analyzed transcript profiles of 251 p53-sequenced primary breast tumors and identified a clinically embedded 32-gene expression signature that distinguishes p53-mutant and wild-type tumors of different histologies and outperforms sequence-based assessments of ...

Abstract

PURPOSE: Recently, a 76-gene prognostic signature able to predict distant metastases in lymph node-negative (N(-)) breast cancer patients was reported. The aims of this study conducted by TRANSBIG were to independently validate these results and to compare the outcome with clinical risk assessment. EXPERIMENTAL DESIGN: Gene expression profiling of frozen samples from 198 N(-) systemically untreated patients was done at the Bordet Institute, blinded to clinical data and independent of Veridex. Genomic risk was defined by Veridex, blinded to clinical data. ...

Abstract

Histologic grading of breast cancer defines morphologic subtypes informative of metastatic potential, although not without considerable interobserver disagreement and clinical heterogeneity particularly among the moderately differentiated grade 2 (G2) tumors. We posited that a gene expression signature capable of discerning tumors of grade 1 (G1) and grade 3 (G3) histology might provide a more objective measure of grade with prognostic benefit for patients with G2 disease. To this end, we studied the expression profiles of 347 primary invasive breast tumors analyzed ...

Abstract

BACKGROUND: Histologic grade in breast cancer provides clinically important prognostic information. However, 30%-60% of tumors are classified as histologic grade 2. This grade is associated with an intermediate risk of recurrence and is thus not informative for clinical decision making. We examined whether histologic grade was associated with gene expression profiles of breast cancers and whether such profiles could be used to improve histologic grading. METHODS: We analyzed microarray data from 189 invasive breast carcinomas and from three published gene expression ...

Abstract

Although cancer types differ substantially, many cancers share common gene expression signatures. Consistent with this observation, we find convergent and representative distributions and correlation vectors that are distinct in cancer and noncancer ensembles. These differences originate in many genes, but comparatively few genes account for the major differences. We identify genes with different combinatorial regulation in cancer and noncancer as indicated by significant differences in their correlation vectors. Among the identified genes are many established oncogenes and apoptotic genes (such as ...

Abstract

MOTIVATION: Numerous microarray studies of aging have been conducted, yet given the noisy nature of gene expression changes with age, elucidating the transcriptional features of aging and how these relate to physiological, biochemical and pathological changes remains a critical problem. RESULTS: We performed a meta-analysis of age-related gene expression profiles using 27 datasets from mice, rats and humans. Our results reveal several common signatures of aging, including 56 genes consistently overexpressed with age, the most significant of which was APOD, and ...

Abstract

BACKGROUND:With the explosion in data generated using microarray technology by different investigators working on similar experiments, it is of interest to combine results across multiple studies.RESULTS:In this article, we describe a general probabilistic framework for combining high-throughput genomic data from several related microarray experiments using mixture models. A key feature of the model is the use of latent variables that represent quantities that can be combined across diverse platforms. We consider two methods for estimation of an index termed the probability ...

Abstract

MOTIVATION: With the increasing availability of cancer microarray data sets there is a growing need for integrative computational methods that evaluate multiple independent microarray data sets investigating a common theme or disorder. Meta-analysis techniques are designed to overcome the low sample size typical to microarray experiments and yield more valid and informative results than each experiment separately. RESULTS: We propose a new meta-analysis technique that aims at finding a set of classifying genes, whose expression level may be used to answering ...

Abstract

BACKGROUND:Prostate cancer is a leading cause of death in the male population, therefore, a comprehensive study about the genes and the molecular networks involved in the tumoral prostate process becomes necessary. In order to understand the biological process behind potential biomarkers, we have analyzed a set of 57 cDNA microarrays containing ~25,000 genes.RESULTS:Principal Component Analysis (PCA) combined with the Maximum-entropy Linear Discriminant Analysis (MLDA) were applied in order to identify genes with the most discriminative information between normal and tumoral prostatic ...

Abstract

MOTIVATION: Standard analysis routines for microarray data aim at differentially expressed genes. In this paper, we address the complementary problem of detecting sets of differentially co-expressed genes in two phenotypically distinct sets of expression profiles. RESULTS: We introduce a score for differential co-expression and suggest a computationally efficient algorithm for finding high scoring sets of genes. The use of our novel method is demonstrated in the context of simulations and on real expression data from a clinical study. ...

Abstract

DNA micro-arrays now permit scientists to screen thousands of genes simultaneously and determine whether those genes are active, hyperactive or silent in normal or cancerous tissue. Because these new micro-array devices generate bewildering amounts of raw data, new analytical methods must be developed to sort out whether cancer tissues have distinctive signatures of gene expression over normal tissues or other types of cancer tissues. ...

Abstract

In the 1990s, a new type of learning algorithm was developed, based on results from statistical learning theory: the Support Vector Machine (SVM). This gave rise to a new class of theoretically elegant learning machines that use a central concept of SVMs—-kernels--for a number of learning tasks. Kernel machines provide a modular framework that can be adapted to different tasks and domains by the choice of the kernel function and the base algorithm. They are replacing neural networks in a variety ...

Abstract

10.1101/gad.1325605 Biological networks are the representation of multiple interactions within a cell, a global view intended to help understand how relationships between molecules dictate cellular behavior. Recent advances in molecular and computational biology have made possible the study of intricate transcriptional regulatory networks that describe gene expression as a function of regulatory inputs specified by interactions between proteins and DNA. Here we review the properties of transcriptional regulatory networks and the rapidly evolving approaches that will enable the elucidation of their ...

Abstract

More than 2000 transcription factors are encoded in the human genome. Such proteins have often been classified according to common structural elements. But because transcription factors evolved in the service of biologic function, we propose an alternative grouping of eukaryotic transcription factors on the basis of characteristics that describe their roles within cellular regulatory circuits. ...

Abstract

BACKGROUND: During their life, multicellular organisms are challenged with oxidative stress. It is generated by several reactive oxygen species (ROS), may limit lifespan and has been related to several human diseases. ROS can generate a wide variety of defects in many cellular components and thus the response of the organism challenged with oxidative stress may share some features with other stress responses. Conversely, in spite of recent progress, a complete functional analysis of the transcriptional responses to different oxidative stresses in ...

Abstract

Cells respond to environmental perturbations with changes in their gene expression that are coordinated in magnitude and time. Timing information about individual genes, rather than clusters, provides a refined way to view and analyze responses, but it is hard to estimate accurately. To analyze response timing of individual genes, we developed a parametric model that captures the typical temporal responses: an abrupt early response followed by a second transition to a steady state. This impulse model explicitly represents natural temporal properties ...

Abstract

Transporters play an important role in the processes of drug absorption, distribution and excretion. In this review, we have focused on the involvement of transporters in drug excretion in the liver and kidney. The rate of transporter-mediated uptake and efflux determines the rate of renal and hepatobiliary elimination. Transporters are thus important as a determinant of the clearance in the body. Even when drugs ultimately undergo metabolism, their elimination rate is sometimes determined by the uptake rate mediated by transporters. Transporters ...

Abstract

This article presents a Bayesian method for model-based clustering of gene expression dynamics. The method represents gene-expression dynamics as autoregressive equations and uses an agglomerative procedure to search for the most probable set of clusters given the available data. The main contributions of this approach are the ability to take into account the dynamic nature of gene expression time series during clustering and a principled way to identify the number of distinct clusters. As the number of possible clustering models grows ...

Abstract

The microarray technology, developed for the simultaneous analysis of a large number of genes, may be useful for the detection of toxicity in an early stage of the development of new drugs. The effect of different hepatotoxins was analyzed at the gene expression level in the rat liver both in vivo and in vitro. As in vitro model system the precision-cut liver slice model was used, in which all liver cell types are present in their natural architecture. This is important ...

Abstract

The impact of transport proteins in the disposition of chemicals is becoming increasingly evident. Alteration in disposition can cause altered pharmacokinetic and pharmacodynamic parameters, potentially leading to reduced efficacy or overt toxicity. We have developed a quantitative in silico model, based upon literature and experimentally derived data, to model the disposition of carboxydichlorofluroscein (CDF), a substrate for the SLCO1A/B and ABCC sub-families of transporters. Kinetic parameters generated by the in silico model closely match both literature and experimentally-derived kinetic values, allowing ...

Abstract

The disposition of atorvastatin, cerivastatin, and indomethacin, established substrates of rat hepatic basolateral uptake transporters, has been evaluated in suspended rat hepatocytes. Cell and media concentration-time data were simultaneously fitted to a model incorporating active uptake, permeation, binding, and metabolism. Use of the model to estimate the ratio of intracellular to extracellular steady-state free drug concentrations demonstrated the strong influence of active uptake on the kinetics of atorvastatin (18:1) and cerivastatin (8:1), in comparison with indomethacin (3.5:1). Indomethacin, however, was shown ...

Abstract

10.1073/pnas.0701068104 The high dimensionality of global transcription profiles, the expression level of 20,000 genes in a much small number of samples, presents challenges that affect the sensitivity and general applicability of analysis results. In principle, it would be better to describe the data in terms of a small number of metagenes, positive linear combinations of genes, which could reduce noise while still capturing the invariant biological features of the data. Here, we describe how to accomplish such a reduction in dimension ...

Abstract

Monitoring the change in expression patterns over time provides the distinct possibility of unraveling the mechanistic drivers characterizing cellular responses. Gene arrays measuring the level of mRNA expression of thousands of genes simultaneously provide a method of high-throughput data collection necessary for obtaining the scope of data required for understanding the complexities of living organisms. Unraveling the coherent complex structures of transcriptional dynamics is the goal of a large family of computational methods aiming at upgrading the information content of time-course gene expression data. In this review, we summarize the ...

Abstract

NN-Tool ist ein Instrument zur Erstellung von Datenmodellen auf der Basis neuronaler Netze. Die Software ist auf Anwendungen im Bereich der Prozeßindustrie und insbesondere der chemischen Industrie zugeschnitten. NN-Tool wird u.a. bei Bayer, BASF, Henkel und Merck für eine Vielzahl neuronaler Netzanwendungen eingesetzt. ...

Abstract

10.1073/pnas.1530509100 With the increase in genomewide experiments and the sequencing of multiple genomes, the analysis of large data sets has become commonplace in biology. It is often the case that thousands of features in a genomewide data set are tested against some null hypothesis, where a number of features are expected to be significant. Here we propose an approach to measuring statistical significance in these genomewide studies based on the concept of the false discovery rate. This approach offers a sensible ...

Abstract

The fatty acid amide (FAA) class of signaling lipids modulates a number of neurobehavioral processes in mammals, including pain, sleep, feeding, and locomotor activity. Representative FAAs include the endogenous cannabinoid anandamide and the sleep-inducing lipid oleamide. Despite activating several neuroreceptor systems in vitro, most FAAs produce only weak and transient behavioral effects in vivo, presumably due to their expeditious catabolism. This review focuses on one enzyme, fatty acid amide hydrolase (FAAH) that appears to play a major role in regulating the ...

Abstract

Organisms are constantly exposed to a wide range of environmental changes, including both short-term changes during their lifetime and longer-term changes across generations. Stress-related gene expression programmes, characterized by distinct transcriptional mechanisms and high levels of noise in their expression patterns, need to be balanced with growth-related gene expression programmes. A range of recent studies give fascinating insight into cellular strategies for keeping gene expression in tune with physiological needs dictated by the environment, promoting adaptation to both short- and long-term ...

Abstract

The reduction of the aflatoxin B 1 (AFB 1) dialdehyde metabolite to its corresponding mono and dialcohols, catalyzed by aflatoxin B 1-aldehyde reductase (AFAR, rat AKR7A1, and human AKR7A3), is greatly increased in livers of rats treated with numerous chemoprotective agents. Recombinant human AKR7A3 has been shown to reduce the AFB 1-dialdehyde at rates greater than those of the rat AKR7A1. The activity of AKR7A1 or AKR7A3 may detoxify the AFB 1-dialdehyde, which reacts with proteins, and thereby inhibits AFB 1-induced ...

Abstract

Cyclin G is one of the earliest p53 target genes to be identified, but its function in the p53 pathway has been elusive. Although the precise mechanisms of cyclin G in this novel network have not been explored, recent studies have demonstrated that cyclin G is a key regulator of the p53-Mdm2 network. Here we present evidence that cyclin G-mediated p53 regulation is dependent upon the status of ataxia-telangiectasia mutated (ATM) protein, which activates p53 in response to DNA damage. Abrogation ...

Abstract

Expression of the cyclin-dependent kinase inhibitor gene p21 is induced after DNA damage and plays a role in cell survival. The exact mechanism of induction is not known, but enhancement of mRNA stability has recently been implicated as an important factor. To obtain further insight into the dynamics of p21 gene expression at the individual cell level, normal fibroblasts, GM1492 fibroblasts from a Bloom's syndrome patient, and U2OS osteosarcoma cells were UVC irradiated, fixed at different time points, and subjected to ...

Abstract

Using a continuous systolic monitor, effects of oral administration of three alpha-adrenergic blockers, i.e. phenoxybenzamine, phentolamine and a new quinazoline compound (2-[4-(n-butyryl)-homopiperazine-1-yl]-4-amino-6, 7-dimethoxy-quinazoline; E-643), on blood pressure and heart rate in normotensive Wistar rats (NWR) and spontaneously hypertensive rats (SHR). 1) An oral dose of 1 mg/kg phenoxybenzamine or E-643 almost completely reversed pressor response to adrenaline (2 microgram/kg i.v). Phentolamine was 3 to 5 times less effective than phenoxybenzamine and E-643. These alpha-blockers reduced pressor response to noradrenaline (2 microgram/kg ...

Abstract

Hypotensive actions of single and repeated administrations of nifedipine were evaluated in comparison with hydralazine in normotensive, spontaneously hypertensive and renal hypertensive rats. Substantial and prolonged falls in blood pressure were observed following oral dosing with 3 mg/kg of nifedipine in renal hypertensive rats, with 10 mg/kg of nifedipine in normotensive and spontaneously hypertensive rats and with 10 mg/dg of hydralazine in all three groups of animals. The hypotensive effect of nifedipine was greater in both forms of hypertensive rats than ...

Abstract

The direct and indirect effects of cefuroxime on the embryo and fetus were studied in vitro and in vivo at different gestation times. The placenta, liver and kidneys of the mother and fetus were investigated morphologically. It was shown that in a dose of 250 mg/kg the antibiotic did not induce disorders in the fetus development. The histological examination of the fetus placenta and liver revealed no changes as compared to the controls. However, in the renal tubules of the mother ...

Abstract

An integrated model for the glucose-insulin system describing oral glucose tolerance test data was developed, extending on a previously introduced model for intravenous glucose provocations. Model extensions comprised the description of glucose absorption by a chain of transit compartments with a mean transit time of 35 minutes, a bioavailability of 80%, and a representation of the incretin effect, expressed as a direct effect of the glucose absorption rate on insulin secretion. The ability of the model to predict the incretin effect ...

Abstract

The complexity of cellular gene, protein, and metabolite networks can hinder attempts to elucidate their structure and function. To address this problem, we used systematic transcriptional perturbations to construct a first-order model of regulatory interactions in a nine-gene subnetwork of the SOS pathway in Escherichia coli. The model correctly identified the major regulatory genes and the transcriptional targets of mitomycin C activity in the subnetwork. This approach, which is experimentally and computationally scalable, provides a framework for elucidating the functional properties ...

Abstract

Animal microRNAs (miRNAs) regulate gene expression by inhibiting translation and/or by inducing degradation of target messenger RNAs. It is unknown how much translational control is exerted by miRNAs on a genome-wide scale. We used a new proteomic approach to measure changes in synthesis of several thousand proteins in response to miRNA transfection or endogenous miRNA knockdown. In parallel, we quantified mRNA levels using microarrays. Here we show that a single miRNA can repress the production of hundreds of proteins, but that ...

Abstract

The purpose of model selection algorithms such as All Subsets, Forward Selection, and Backward Elimination is to choose a linear model on the basis of the same set of data to which the model will be applied. Typically we have available a large collection of possible covariates from which we hope to select a parsimonious set for the eificient pre-diction of a response variable. Least Angle Regression ( " LARS"), a new model selection algorithm, is a useful and less greedy ...

Abstract

Network analysis has been applied widely, providing a unifying language to describe disparate systems ranging from social interactions to power grids. It has recently been used in molecular biology, but so far the resulting networks have only been analysed statically1, 2, 3, 4, 5, 6, 7, 8. Here we present the dynamics of a biological network on a genomic scale, by integrating transcriptional regulatory information9, 10, 11 and gene-expression data12, 13, 14, 15, 16 for multiple conditions in Saccharomyces cerevisiae. We ...

Abstract

Changes in gene expression after treatment of Escherichia coli cultures with mitomycin C were assessed using gene array technology. Unexpectedly, a large number of genes (nearly 30% of all genes) displayed significant changes in their expression level. Analysis and classification of expression profiles of the corresponding genes allowed us to assign this large number of genes into one or two dozen small clusters of genes with similar expression profiles. This assignment allowed us to describe systematically the changes in the level ...

Abstract

Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three ...

Abstract

Fifty chemicals were tested for mutagenic activity in post-meiotic and meiotic germ cells of male Drosophila melanogaster using the sex-linked recessive lethal (SLRL) assay. As in the previous studies in this series, feeding was chosen as the first route of administration. If the compound failed to induce mutations by this route, injection exposure was used. One gaseous chemical (1,3-butadiene) was tested only by inhalation. Those chemicals that were mutagenic in the sex-linked recessive lethal assay were further tested for the ability ...

Abstract

In this article, we identify and characterize p600, a unique 600-kDa retinoblastoma protein- and calmodulin-binding protein. In the nucleus, p600 and retinoblastoma protein seem to act as a chromatin scaffold. In the cytoplasm, p600 and clathrin form a meshwork structure, which could contribute to cytoskeletal organization and membrane morphogenesis. Reduced expression of p600 with interference RNA abrogates integrin-mediated ruffled membrane formation and, furthermore, prevents activation of integrin-mediated survival pathways. Consequently, knockdown of p600 sensitizes cells to apoptosis induced by cell detachment. ...

Abstract

Prohibitin, a potential tumor suppressor, is known to induce growth suppression and repress E2F-mediated transcription. These growth regulatory functions of prohibitin require a physical interaction with the Rb protein. We now find that prohibitin protects cells from apoptosis mediated by camptothecin, a topoisomerase I inhibitor. Camptothecin treatment of Ramos B cells leads to the degradation of Rb protein and phosphorylation of its family members, p107 and p130. This correlates with an increase in the levels of cyclin E as well as ...

Abstract

The ability of cells to maintain genomic integrity is vital for cell survival and proliferation. Lack of fidelity in DNA replication and maintenance can result in deleterious mutations leading to cell death or, in multicellular organisms, cancer. The purpose of this review is to discuss the known signal transduction pathways that regulate cell cycle progression and the mechanisms cells employ to insure DNA stability in the face of genotoxic stress. In particular, we focus on mammalian cell cycle checkpoint functions, their ...