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Search Results: 1 - 10 of 97383 matches for " William W. Lockwood "
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Computational Methods for the Analysis of Array Comparative Genomic Hybridization
Raj Chari,William W. Lockwood,Wan L. Lam
Cancer Informatics , 2006,
Abstract: Array comparative genomic hybridization (array CGH) is a technique for assaying the copy number status of cancer genomes. The widespread use of this technology has lead to a rapid accumulation of high throughput data, which in turn has prompted the development of computational strategies for the analysis of array CGH data. Here we explain the principles behind array image processing, data visualization and genomic profile analysis, review currently available software packages, and raise considerations for future software development.
An integrative multi-dimensional genetic and epigenetic strategy to identify aberrant genes and pathways in cancer
Raj Chari, Bradley P Coe, Emily A Vucic, William W Lockwood, Wan L Lam
BMC Systems Biology , 2010, DOI: 10.1186/1752-0509-4-67
Abstract: Here we show how multi-dimensional genomics data analysis would enable the deciphering of mechanisms that disrupt regulatory/signaling cascades and downstream effects. Since not all gene expression changes observed in a tumor are causal to cancer development, we demonstrate an approach based on multiple concerted disruption (MCD) analysis of genes that facilitates the rational deduction of aberrant genes and pathways, which otherwise would be overlooked in single genomic dimension investigations.Notably, this is the first comprehensive study of breast cancer cells by parallel integrative genome wide analyses of DNA copy number, LOH, and DNA methylation status to interpret changes in gene expression pattern. Our findings demonstrate the power of a multi-dimensional approach to elucidate events which would escape conventional single dimensional analysis and as such, reduce the cohort sample size for cancer gene discovery.Genomic analyses have substantially improved our knowledge of cancer. Gene expression profiling, for example, is utilized to delineate subtypes of breast cancer, and has facilitated the derivation of predictive and prognostic signatures [1-5]. However, not all of the gene expression changes observed are causal to cancer development, and global gene expression analysis alone cannot distinguish between causal and reactive changes. Corresponding alteration at the DNA level is regarded as evidence of causality; for example, gene deletion or gene silencing by methylation. Hence, examining genetic and epigenetic events in conjunction with the changes in gene expression pattern should improve the identification of causal changes that lead to disease phenotype.Analysis of gene copy number alone has correlated breast cancer genome features with poor prognosis based on the degree of genomic instability observed [6]. In terms of gene discovery, specific genomic regions containing important loci have been shown to be frequently gained or lost [7-11]. Integrative
The Novel Ubiquitin Ligase Complex, SCFFbxw4, Interacts with the COP9 Signalosome in an F-Box Dependent Manner, Is Mutated, Lost and Under-Expressed in Human Cancers
William W. Lockwood, Sahiba K. Chandel, Greg L. Stewart, Hediye Erdjument-Bromage, Levi J. Beverly
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063610
Abstract: Identification of novel proteins that can potentially contribute to carcinogenesis is a requisite venture. Herein, we report the first biochemical characterization of the novel F-box and WD40 containing protein, FBXW4. We have identified interacting protein partners and demonstrated that FBXW4 is part of a ubiquitin ligase complex. Furthermore, the Fbxw4 locus is a common site of proviral insertion in a variety of retroviral insertional mutagenesis murine cancer models and Fbxw4 mRNA is highly expressed in the involuting murine mammary gland. To begin to characterize the biochemical function of Fbxw4, we used proteomic analysis to demonstrate that Fbxw4 interacts with Skp1 (SKP1), Cullin1 (CUL1), Ring-box1 (RBX1) and all components of the COP9 signalosome. All of these interactions are dependent on an intact F-box domain of Fbxw4. Furthermore, Fbxw4 is capable of interacting with ubiquitinated proteins within cells in an F-box dependent manner. Finally, we demonstrate that FBXW4 is mutated, lost and under-expressed in a variety of human cancer cell lines and clinical patient samples. Importantly, expression of FBXW4 correlates with survival of patients with non-small cell lung cancer. Taken together, we suggest that FBXW4 may be a novel tumor suppressor that regulates important cellular processes.
SIGMA: A System for Integrative Genomic Microarray Analysis of Cancer Genomes
Raj Chari, William W Lockwood, Bradley P Coe, Anna Chu, Devon Macey, Andrew Thomson, Jonathan J Davies, Calum MacAulay, Wan L Lam
BMC Genomics , 2006, DOI: 10.1186/1471-2164-7-324
Abstract: We have created a user-friendly java application to facilitate sophisticated visualization and analysis such as cross-tumor and cross-platform comparisons. To demonstrate the utility of this software, we assembled array CGH data representing Affymetrix SNP chip, Stanford cDNA arrays and whole genome tiling path array platforms for cross comparison. This cancer genome database contains 267 profiles from commonly used cancer cell lines representing 14 different tissue types.In this study we have developed an application for the visualization and analysis of data from high resolution array CGH platforms that can be adapted for analysis of multiple types of high throughput genomic datasets. Furthermore, we invite researchers using array CGH technology to deposit both their raw and processed data, as this will be a continually expanding database of cancer genomes. This publicly available resource, the System for Integrative Genomic Microarray Analysis (SIGMA) of cancer genomes, can be accessed at http://sigma.bccrc.ca webcite.Array comparative genomic hybridization (CGH) is a method used to detect segmental DNA copy number alterations and is widely used to discover chromosomal aberrations in cancer and other genetic diseases [1,2]. In this method, differentially labeled genomic DNA samples are competitively hybridized to chromosomal targets, and the copy number balance between the two samples is reflected by their signal intensity ratio. Numerous array CGH platforms exist; these vary in the type of elements present on the array and their corresponding coverage of the human genome. With the development of high resolution, genome wide arrays, tens of thousands of loci can be evaluated for copy number status, facilitating the high throughput search for genes potentially involved in pathogenesis. This has allowed the identification of discrete regions of alteration that may have been missed by traditional cytogenetic methods and has proven to be a useful platform for explori
Alterations in Genes of the EGFR Signaling Pathway and Their Relationship to EGFR Tyrosine Kinase Inhibitor Sensitivity in Lung Cancer Cell Lines
Jeet Gandhi, Jianling Zhang, Yang Xie, Junichi Soh, Hisayuki Shigematsu, Wei Zhang, Hiromasa Yamamoto, Michael Peyton, Luc Girard, William W. Lockwood, Wan L. Lam, Marileila Varella-Garcia, John D. Minna, Adi F. Gazdar
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004576
Abstract: Background Deregulation of EGFR signaling is common in non-small cell lung cancers (NSCLC) and this finding led to the development of tyrosine kinase inhibitors (TKIs) that are highly effective in a subset of NSCLC. Mutations of EGFR (mEGFR) and copy number gains (CNGs) of EGFR (gEGFR) and HER2 (gHER2) have been reported to predict for TKI response. Mutations in KRAS (mKRAS) are associated with primary resistance to TKIs. Methodology/Principal Findings We investigated the relationship between mutations, CNGs and response to TKIs in a large panel of NSCLC cell lines. Genes studied were EGFR, HER2, HER3 HER4, KRAS, BRAF and PIK3CA. Mutations were detected by sequencing, while CNGs were determined by quantitative PCR (qPCR), fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (aCGH). IC50 values for the TKIs gefitinib (Iressa) and erlotinib (Tarceva) were determined by MTS assay. For any of the seven genes tested, mutations (39/77, 50.6%), copy number gains (50/77, 64.9%) or either (65/77, 84.4%) were frequent in NSCLC lines. Mutations of EGFR (13%) and KRAS (24.7%) were frequent, while they were less frequent for the other genes. The three techniques for determining CNG were well correlated, and qPCR data were used for further analyses. CNGs were relatively frequent for EGFR and KRAS in adenocarcinomas. While mutations were largely mutually exclusive, CNGs were not. EGFR and KRAS mutant lines frequently demonstrated mutant allele specific imbalance i.e. the mutant form was usually in great excess compared to the wild type form. On a molar basis, sensitivity to gefitinib and erlotinib were highly correlated. Multivariate analyses led to the following results: 1. mEGFR and gEGFR and gHER2 were independent factors related to gefitinib sensitivity, in descending order of importance. 2. mKRAS was associated with increased in vitro resistance to gefitinib. Conclusions/Significance Our in vitro studies confirm and extend clinical observations and demonstrate the relative importance of both EGFR mutations and CNGs and HER2 CNGs in the sensitivity to TKIs.
Lung Adenocarcinoma of Never Smokers and Smokers Harbor Differential Regions of Genetic Alteration and Exhibit Different Levels of Genomic Instability
Kelsie L. Thu, Emily A. Vucic, Raj Chari, Wei Zhang, William W. Lockwood, John C. English, Rong Fu, Pei Wang, Ziding Feng, Calum E. MacAulay, Adi F. Gazdar, Stephen Lam, Wan L. Lam
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033003
Abstract: Recent evidence suggests that the observed clinical distinctions between lung tumors in smokers and never smokers (NS) extend beyond specific gene mutations, such as EGFR, EML4-ALK, and KRAS, some of which have been translated into targeted therapies. However, the molecular alterations identified thus far cannot explain all of the clinical and biological disparities observed in lung tumors of NS and smokers. To this end, we performed an unbiased genome-wide, comparative study to identify novel genomic aberrations that differ between smokers and NS. High resolution whole genome DNA copy number profiling of 69 lung adenocarcinomas from smokers (n = 39) and NS (n = 30) revealed both global and regional disparities in the tumor genomes of these two groups. We found that NS lung tumors had a greater proportion of their genomes altered than those of smokers. Moreover, copy number gains on chromosomes 5q, 7p, and 16p occurred more frequently in NS. We validated our findings in two independently generated public datasets. Our findings provide a novel line of evidence distinguishing genetic differences between smoker and NS lung tumors, namely, that the extent of segmental genomic alterations is greater in NS tumors. Collectively, our findings provide evidence that these lung tumors are globally and genetically different, which implies they are likely driven by distinct molecular mechanisms.
Software Reuse: Developers’ Experiences and Perceptions  [PDF]
William W. Agresti
Journal of Software Engineering and Applications (JSEA) , 2011, DOI: 10.4236/jsea.2011.41006
Abstract: Reusing programs and other artifacts has been shown to be an effective strategy for significant reduction of development costs. This article reports on a survey of 128 developers to explore their experiences and perceptions about using other people’s code: to what extent does the “not invented here” attitude exist? The survey was structured around a novel and simple “4A” model, which is introduced in this article: for an organization to obtain any benefits from reusing code, four conditions must obtain: availability, awareness, accessibility, and acceptability. The greatest impediments to reuse were shown to be awareness of reusable code and developers’ perceptions of its acceptability for use on their new projects. For 72% of developers, the complexity of the old code was cited as a reason that the code was not reused. The survey also included developers’ suggestions for ways to take greater advantage of existing code and related artifacts.
Finding Gaussian Curvature of Lifespan Distribution  [PDF]
William W. S. Chen
Applied Mathematics (AM) , 2014, DOI: 10.4236/am.2014.521316
Abstract: The objective of this paper is to review the lifespan model. This paper will also suggest four additional general alternative computational methods not mentioned in Kass, R.E. and Vos, P.W. [1] [2]. It is not intended to compare the four formulas to be used in computing the Gaussian curvature. Four different formulas adopted from Struik, D.J. [3] are used and labeled here as (A), (B), (C), and (D). It has been found that all four of these formulas can compute the Gaussian curvature effectively and successfully. To avoid repetition, we only presented results from formulas (B) and (D). One can more easily check other results from formulas (A) and (C).
A Note on Finding Geodesic Equation of Two Parameters Gamma Distribution  [PDF]
William W. S. Chen
Applied Mathematics (AM) , 2014, DOI: 10.4236/am.2014.521328
Abstract: Engineers commonly use the gamma distribution to describe the life span or metal fatigue of a manufactured item. In this paper, we focus on finding a geodesic equation of the two parameters gamma distribution. To find this equation, we applied both the well-known Darboux Theorem and a pair of differential equations taken from Struik [1]. The solution proposed in this note could be used as a general solution of the geodesic equation of gamma distribution. It would be interesting if we compare our results with Lauritzen’s [2].
A Study of Rock Magnetism of High-Grade Hematite Ores  [PDF]
William W. Guo
Journal of Applied Mathematics and Physics (JAMP) , 2015, DOI: 10.4236/jamp.2015.32024
Abstract:

Rock magnetism is useful in various applications. Hematite is one of the two most important carriers of magnetism in the natural world and its magnetic features were mostly studied through laboratory experiments using synthetic hematite samples. A gap exists between the magnetic behaviors of hematite contained in the natural rocks and ores and those of synthetic hematite samples. This paper presents the results of a rock magnetism study on the natural hematite ores from the Whaleback mine in the Hamersley Province in the northwest of Western Australia. It was found that high-grade hematite ores carry a much higher remanent magnetization than induced magnetization. Hematite ores with less than 0.1% magnetite appear to have an exponential correlation between the bulk susceptibility and hematite content in weight percentage, different from the commonly accepted linear relationship between the bulk susceptibility and hematite content obtained from synthetic hematite samples. The new knowledge gained from this study contributes to a better understanding of magnetic behaviors of hematite, particularly natural hematite, and hence applications to other relevant disciplines.

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