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Varma S.,HiThru Analytics LLC | Simpson B.,University of Mississippi Medical Center | Kim M.,King's College London | Riveros C.,University of Newcastle | And 12 more authors.
Alzheimer's and Dementia | Year: 2016

Introduction: Recently, quantitative metabolomics identified a panel of 10 plasma lipids that were highly predictive of conversion to Alzheimer's disease (AD) in cognitively normal older individuals (n = 28, area under the curve [AUC] = 0.92, sensitivity/specificity of 90%/90%). Methods: Quantitative targeted metabolomics in serum using an identical method as in the index study. Results: We failed to replicate these findings in a substantially larger study from two independent cohorts-the Baltimore Longitudinal Study of Aging ([BLSA], n = 93, AUC = 0.642, sensitivity/specificity of 51.6%/65.7%) and the Age, Gene/Environment Susceptibility-Reykjavik Study ([AGES-RS], n = 100, AUC = 0.395, sensitivity/specificity of 47.0%/36.0%). In analyses applying machine learning methods to all 187 metabolite concentrations assayed, we find a modest signal in the BLSA with distinct metabolites associated with the preclinical and symptomatic stages of AD, whereas the same methods gave poor classification accuracies in the AGES-RS samples. Discussion: We believe that ours is the largest blood biomarker study of preclinical AD to date. These findings underscore the importance of large-scale independent validation of index findings from biomarker studies with relatively small sample sizes. © 2016.


PubMed | U.S. National Institute on Aging, University of Newcastle, HiThru Analytics LLC, Biocrates Life Sciences and 4 more.
Type: Journal Article | Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association | Year: 2016

Recently, quantitative metabolomics identified a panel of 10 plasma lipids that were highly predictive of conversion to Alzheimers disease (AD) in cognitively normal older individuals (n=28, area under the curve [AUC]=0.92, sensitivity/specificity of 90%/90%).Quantitative targeted metabolomics in serum using an identical method as in the index study.We failed to replicate these findings in a substantially larger study from two independent cohorts-the Baltimore Longitudinal Study of Aging ([BLSA], n=93, AUC=0.642, sensitivity/specificity of 51.6%/65.7%) and the Age, Gene/Environment Susceptibility-Reykjavik Study ([AGES-RS], n=100, AUC=0.395, sensitivity/specificity of 47.0%/36.0%). In analyses applying machine learning methods to all 187 metabolite concentrations assayed, we find a modest signal in the BLSA with distinct metabolites associated with the preclinical and symptomatic stages of AD, whereas the same methods gave poor classification accuracies in the AGES-RS samples.We believe that ours is the largest blood biomarker study of preclinical AD to date. These findings underscore the importance of large-scale independent validation of index findings from biomarker studies with relatively small sample sizes.


Steel C.,National Institute of Allergy and Infectious Diseases | Varma S.,National Institute of Allergy and Infectious Diseases | Varma S.,HiThru Analytics LLC | Nutman T.B.,National Institute of Allergy and Infectious Diseases
PLoS Neglected Tropical Diseases | Year: 2012

Background: Human filarial infection is characterized by downregulated parasite-antigen specific T cell responses but distinct differences exist between patients with longstanding infection (endemics) and those who acquired infection through temporary residency or visits to filarial-endemic regions (expatriates). Methods and Findings: To characterize mechanisms underlying differences in T cells, analysis of global gene expression using human spotted microarrays was conducted on CD4 + and CD8 + T cells from microfilaremic Loa loa-infected endemic and expatriate patients. Assessment of unstimulated cells showed overexpression of genes linked to inflammation and caspase-associated cell death, particularly in endemics, and enrichment of the Th1/Th2 canonical pathway in endemic CD4 + cells. However, pathways within CD8 + unstimulated cells were most significantly enriched in both patient groups. Antigen (Ag)-driven gene expression was assessed to microfilarial Ag (MfAg) and to the nonparasite Ag streptolysin O (SLO). For MfAg-driven cells, the number of genes differing significantly from unstimulated cells was greater in endemics compared to expatriates (p<0.0001). Functional analysis showed a differential increase in genes associated with NFkB (both groups) and caspase activation (endemics). While the expatriate response to MfAg was primarily a CD4 + pro-inflammatory one, the endemic response included CD4 + and CD8 + cells and was linked to insulin signaling, histone complexes, and ubiquitination. Unlike the enrichment of canonical pathways in CD8 + unstimulated cells, both groups showed pathway enrichment in CD4 + cells to MfAg. Contrasting with the divergent responses to MfAg seen between endemics and expatriates, the CD4 + response to SLO was similar; however, CD8 + cells differed strongly in the nature and numbers (156 [endemics] vs 36 [expatriates]) of genes with differential expression. Conclusions: These data suggest several important pathways are responsible for the different outcomes seen among filarial-infected patients with varying levels of chronicity and imply an important role for CD8 + cells in some of the global changes seen with lifelong exposure.


Sousa F.G.,U.S. National Cancer Institute | Sousa F.G.,Federal University of Mato Grosso do Sul | Matuo R.,U.S. National Cancer Institute | Matuo R.,Federal University of Mato Grosso do Sul | And 11 more authors.
DNA Repair | Year: 2015

Loss of function of DNA repair (DNAR) genes is associated with genomic instability and cancer predisposition; it also makes cancer cells reliant on a reduced set of DNAR pathways to resist DNA-targeted therapy, which remains the core of the anticancer armamentarium. Because the landscape of DNAR defects across numerous types of cancers and its relation with drug activity have not been systematically examined, we took advantage of the unique drug and genomic databases of the US National Cancer Institute cancer cell lines (the NCI-60) to characterize 260 DNAR genes with respect to deleterious mutations and expression down-regulation; 169 genes exhibited a total of 549 function-affecting alterations, with 39 of them scoring as putative knockouts across 31 cell lines. Those mutations were compared to tumor samples from 12 studies of The Cancer Genome Atlas (TCGA) and The Cancer Cell Line Encyclopedia (CCLE). Based on this compendium of alterations, we determined which DNAR genomic alterations predicted drug response for 20,195 compounds present in the NCI-60 drug database. Among 242 DNA damaging agents, 202 showed associations with at least one DNAR genomic signature. In addition to SLFN11, the Fanconi anemia-scaffolding gene SLX4 (FANCP/BTBD12) stood out among the genes most significantly related with DNA synthesis and topoisomerase inhibitors. Depletion and complementation experiments validated the causal relationship between SLX4 defects and sensitivity to raltitrexed and cytarabine in addition to camptothecin. Therefore, we propose new rational uses for existing anticancer drugs based on a comprehensive analysis of DNAR genomic parameters. © 2015.


Reinhold W.C.,U.S. National Cancer Institute | Reinhold W.C.,U.S. National Institutes of Health | Sunshine M.,U.S. National Cancer Institute | Sunshine M.,SRA International, Inc. | And 9 more authors.
Cancer Research | Year: 2012

High-throughput and high-content databases are increasingly important resources in molecular medicine, systems biology, and pharmacology. However, the information usually resides in unwieldy databases, limiting ready data analysis and integration. One resource that offers substantial potential for improvement in this regard is the NCI-60 cell line database compiled by the U.S. National Cancer Institute, which has been extensively characterized across numerous genomic and pharmacologic response platforms. In this report, we introduce a CellMiner (http://discover.nci.nih.gov/cellminer/) web application designed to improve the use of this extensive database. CellMiner tools allowed rapid data retrieval of transcripts for 22,379 genes and 360 microRNAs along with activity reports for 20,503 chemical compounds including 102 drugs approved by the U.S. Food and Drug Administration. Converting these differential levels into quantitative patterns across the NCI-60 clarified data organization and cross-comparisons using a novel pattern match tool. Data queries for potential relationships among parameters can be conducted in an iterative manner specific to user interests and expertise. Examples of the in silico discovery process afforded by CellMiner were provided for multidrug resistance analyses and doxorubicin activity; identification of colon-specific genes, microRNAs, and drugs; microRNAs related to the miR-17-92 cluster; and drug identification patterns matched to erlotinib, gefitinib, afatinib, and lapatinib. CellMiner greatly broadens applications of the extensive NCI-60 database for discovery by creating web-based processes that are rapid, flexible, and readily applied by users without bioinformatics expertise. ©2012 AACR.


Reinhold W.C.,U.S. National Institutes of Health | Varma S.,U.S. National Institutes of Health | Varma S.,HiThru Analytics LLC | Sousa F.,U.S. National Institutes of Health | And 11 more authors.
PLoS ONE | Year: 2014

Exome sequencing provides unprecedented insights into cancer biology and pharmacological response. Here we assess these two parameters for the NCI-60, which is among the richest genomic and pharmacological publicly available cancer cell line databases. Homozygous genetic variants that putatively affect protein function were identified in 1,199 genes (approximately 6% of all genes). Variants that are either enriched or depleted compared to non-cancerous genomes, and thus may be influential in cancer progression and differential drug response were identified for 2,546 genes. Potential gene knockouts are made available. Assessment of cell line response to 19,940 compounds, including 110 FDA-approved drugs, reveals ≈80-fold range in resistance versus sensitivity response across cell lines. 103,422 gene variants were significantly correlated with at least one compound (at p<0.0002). These include genes of known pharmacological importance such as IGF1R, BRAF, RAD52, MTOR, STAT2 and TSC2 as well as a large number of candidate genes such as NOM1, TLL2, and XDH. We introduce two new web-based CellMiner applications that enable exploration of variant-to-compound relationships for a broad range of researchers, especially those without bioinformatics support. The first tool, "Genetic variant versus drug visualization", provides a visualization of significant correlations between drug activity-gene variant combinations. Examples are given for the known vemurafenib-BRAF, and novel ifosfamide-RAD52 pairings. The second, "Genetic variant summation" allows an assessment of cumulative genetic variations for up to 150 combined genes together; and is designed to identify the variant burden for molecular pathways or functional grouping of genes. An example of its use is provided for the EGFR-ERBB2 pathway gene variant data and the identification of correlated EGFR, ERBB2, MTOR, BRAF, MEK and ERK inhibitors. The new tools are implemented as an updated web-based CellMiner version, for which the present publication serves as a compendium. © 2014 Reinhold et al.


Gillet J.-P.,U.S. National Institutes of Health | Varma S.,HiThru Analytics LLC | Gottesman M.M.,U.S. National Institutes of Health
Journal of the National Cancer Institute | Year: 2013

Although advances in genomics during the last decade have opened new avenues for translational research and allowed the direct evaluation of clinical samples, there is still a need for reliable preclinical models to test therapeutic strategies. Human cancer-derived cell lines are the most widely used models to study the biology of cancer and to test hypotheses to improve the efficacy of cancer treatment. Since the development of the first cancer cell line, the clinical relevance of these models has been continuously questioned. Based upon recent studies that have fueled the debate, we review the major events in the development of the in vitro models and the emergence of new technologies that have revealed important issues and limitations concerning human cancer cell lines as models. All cancer cell lines do not have equal value as tumor models. Some have been successful, whereas others have failed. However, the success stories should not obscure the growing body of data that motivates us to develop new in vitro preclinical models that would substantially increase the success rate of new in vitro-assessed cancer treatments. © 2013 The Author.


Varma S.,U.S. National Institutes of Health | Varma S.,HiThru Analytics LLC | Pommier Y.,U.S. National Institutes of Health | Sunshine M.,U.S. National Institutes of Health | And 3 more authors.
PLoS ONE | Year: 2014

Array-based comparative genomic hybridization (aCGH) is a powerful technique for detecting gene copy number variation. It is generally considered to be robust and convenient since it measures DNA rather than RNA. In the current study, we combine copy number estimates from four different platforms (Agilent 44 K, NimbleGen 385 K, Affymetrix 500 K and Illumina Human1Mv1-C) to compute a reliable, high-resolution, easy to understand output for the measure of copy number changes in the 60 cancer cells of the NCI-DTP (the NCI-60). We then relate the results to gene expression. We explain how to access that database using our CellMiner web-tool and provide an example of the ease of comparison with transcript expression, whole exome sequencing, microRNA expression and response to 20,000 drugs and other chemical compounds. We then demonstrate how the data can be analyzed integratively with transcript expression data for the whole genome (26,065 genes). Comparison of copy number and expression levels shows an overall medium high correlation (median r = 0.247), with significantly higher correlations (median r = 0.408) for the known tumor suppressor genes. That observation is consistent with the hypothesis that gene loss is an important mechanism for tumor suppressor inactivation. An integrated analysis of concurrent DNA copy number and gene expression change is presented. Limiting attention to focal DNA gains or losses, we identify and reveal novel candidate tumor suppressors with matching alterations in transcript level.


Reinhold W.C.,U.S. National Institutes of Health | Sunshine M.,U.S. National Institutes of Health | Sunshine M.,Research Applications Corporation | Varma S.,U.S. National Institutes of Health | And 4 more authors.
Clinical Cancer Research | Year: 2015

The NCI-60 cancer cell line panel provides a premier model for data integration, and systems pharmacology being the largest publicly available database of anticancer drug activity, genomic, molecular, and phenotypic data. It comprises gene expression (25,722 transcripts), microRNAs (360 miRNAs), whole-genome DNA copy number (23,413 genes), whole-exome sequencing (variants for 16,568 genes), protein levels (94 genes), and cytotoxic activity (20,861 compounds). Included are 158 FDA-approved drugs and 79 that are in clinical trials. To improve data accessibility to bioinformaticists and non-bioinformaticists alike, we have developed the CellMiner web-based tools. Here, we describe the newest CellMiner version, including integration of novel databases and tools associated with whole-exome sequencing and protein expression, and review the tools. Included are (i) "Cell line signature" for DNA, RNA, protein, and drugs; (ii) "Cross correlations" for up to 150 input genes, microRNAs, and compounds in a single query; (iii) "Pattern comparison" to identify connections among drugs, gene expression, genomic variants, microRNA, and protein expressions; (iv) "Geneticvariation versus drug visualization" to identify potential new drug: gene DNA variant relationships; and (v) "Genetic variant summation" designed to provide a synopsis of mutational burden on any pathway or gene group for up to 150 genes. Together, these tools allow users to flexibly query the NCI-60 data for potential relationships between genomic, molecular, and pharmacologic parameters in a manner specific to the user's area of expertise. Examples for both gain- (RAS) and loss-of-function (PTEN) alterations are provided. © 2015 American Association for Cancer Research.


Reinhold W.C.,U.S. National Institutes of Health | Varma S.,U.S. National Institutes of Health | Varma S.,HiThru Analytics LLC | Rajapakse V.N.,U.S. National Institutes of Health | And 6 more authors.
Human Genetics | Year: 2014

The current convergence of molecular and pharmacological data provides unprecedented opportunities to gain insights into the relationships between the two types of data. Multiple forms of large-scale molecular data, including but not limited to gene and microRNA transcript expression, DNA somatic and germline variations from next-generation DNA and RNA sequencing, and DNA copy number from array comparative genomic hybridization are all potentially informative when one attempts to recognize the panoply of potentially influential events both for cancer progression and therapeutic outcome. Concurrently, there has also been a substantial expansion of the pharmacological data being accrued in a systematic fashion. For cancer cell lines, the National Cancer Institute cell line panel (NCI-60), the Cancer Cell Line Encyclopedia (CCLE), and the collaborative Genomics of Drug Sensitivity in Cancer (GDSC) databases all provide subsets of these forms of data. For the patient-derived data, The Cancer Genome Atlas (TCGA) provides analogous forms of genomic information along with treatment histories. Integration of these data in turn relies on the fields of statistics and statistical learning. Multiple algorithmic approaches may be chosen, depending on the data being considered, and the nature of the question being asked. Combining these algorithms with prior biological knowledge, the results of molecular biological studies, and the consideration of genes as pathways or functional groups provides both the challenge and the potential of the field. The ultimate goal is to provide a paradigm shift in the way that drugs are selected to provide a more targeted and efficacious outcome for the patient. © 2014, Springer-Verlag Berlin Heidelberg (outside the USA).

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