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Search Results: 1 - 10 of 221095 matches for " Todd C Skaar "
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Whole Genome Amplification of DNA for Genotyping Pharmacogenetics Candidate Genes
Santosh Philips,Steffi Oesterreich,Todd C. Skaar
Frontiers in Pharmacology , 2012, DOI: 10.3389/fphar.2012.00054
Abstract: Whole genome amplification (WGA) technologies can be used to amplify genomic DNA when only small amounts of DNA are available. The Multiple Displacement Amplification Phi polymerase based amplification has been shown to accurately amplify DNA for a variety of genotyping assays; however, it has not been tested for genotyping many of the clinically relevant genes important for pharmacogenetic studies, such as the cytochrome P450 genes, that are typically difficult to genotype due to multiple pseudogenes, copy number variations, and high similarity to other related genes. We evaluated whole genome amplified samples for Taqman? genotyping of SNPs in a variety of pharmacogenetic genes. In 24 DNA samples from the Coriell human diversity panel, the call rates, and concordance between amplified (~200-fold amplification) and unamplified samples was 100% for two SNPs in CYP2D6 and one in ESR1. In samples from a breast cancer clinical trial (Trial 1), we compared the genotyping results in samples before and after WGA for three SNPs in CYP2D6, one SNP in CYP2C19, one SNP in CYP19A1, two SNPs in ESR1, and two SNPs in ESR2. The concordance rates were all >97%. Finally, we compared the allele frequencies of 143 SNPs determined in Trial 1 (whole genome amplified DNA) to the allele frequencies determined in unamplified DNA samples from a separate trial (Trial 2) that enrolled a similar population. The call rates and allele frequencies between the two trials were 98 and 99.7%, respectively. We conclude that the whole genome amplified DNA is suitable for Taqman? genotyping for a wide variety of pharmacogenetically relevant SNPs.
The role of single nucleotide polymorphisms in breast cancer metastasis
James M Rae, Todd C Skaar, Susan G Hilsenbeck, Steffi Oesterreich
Breast Cancer Research , 2008, DOI: 10.1186/bcr1842
Abstract: Modern genetics has been applied to many aspects of breast cancer. For example, it is well established that inherited mutations in BCRA1 and BCRA2 can predispose women to this disease, as well as to ovarian cancer [1]. Changes in other genes, such as p53, PTEN, or CHEK2, are also associated with increased risk of breast cancer. Recent genome-wide association studies have led to the identification of numerous polymorphisms associated with increased risk for breast cancer, with FGFR2 being one of the top candidate genes [2,3]. Also, numerous ongoing studies are being carried out to understand whether there is a heritable genetic contribution to therapeutic responses in breast cancer patients [4]. Because of the importance of metastasis in the prognosis of breast cancer patients, it is important to determine whether germ line polymorphisms also play a role in breast cancer metastasis. Indeed, there is a paucity of data from microarray and other studies to fully explain breast cancer metastasis from tumor somatic cell evolution, thus opening the question of whether germline polymorphisms could contribute to breast cancer metastasis.Recent studies in mice indicate that inherited genetic backgrounds can influence metastatic potential. The elucidation of the causal genetic variants in these models may lead to the identification of important metastasis genes and heritable genetic variants that predispose humans to breast cancer metastasis. Using the MMTV-PyMT transgenic mouse model, which develops mammary tumors with 100% penetrance, Hunter and colleagues [5] have shown that the incidence of pulmonary metastasis was influenced by the mouse genetic background. They found that the AKR and FVB stains show high metastatic efficiency, while two others (DBA and NZB) show low rates of metastasis. Quantitative trait genetic mapping analysis identified a probable metastasis efficiency locus (Mtes1) on mouse chromosome 19 in a 10 Mb region orthologous to human chromosome 11q12-13. Al
A modulated empirical Bayes model for identifying topological and temporal estrogen receptor α regulatory networks in breast cancer
Changyu Shen, Yiwen Huang, Yunlong Liu, Guohua Wang, Yuming Zhao, Zhiping Wang, Mingxiang Teng, Yadong Wang, David A Flockhart, Todd C Skaar, Pearlly Yan, Kenneth P Nephew, Tim HM Huang, Lang Li
BMC Systems Biology , 2011, DOI: 10.1186/1752-0509-5-67
Abstract: We developed a modulated empirical Bayes model, and constructed a novel topological and temporal transcription factor (TF) regulatory network in MCF7 breast cancer cell line upon stimulation by 17β-estradiol stimulation. In the network, significant TF genomic hubs were identified including ER-alpha and AP-1; significant non-genomic hubs include ZFP161, TFDP1, NRF1, TFAP2A, EGR1, E2F1, and PITX2. Although the early and late networks were distinct (<5% overlap of ERα target genes between the 4 and 24 h time points), all nine hubs were significantly represented in both networks. In MCF7 cells with acquired resistance to tamoxifen, the ERα regulatory network was unresponsive to 17β-estradiol stimulation. The significant loss of hormone responsiveness was associated with marked epigenomic changes, including hyper- or hypo-methylation of promoter CpG islands and repressive histone methylations.We identified a number of estrogen regulated target genes and established estrogen-regulated network that distinguishes the genomic and non-genomic actions of estrogen receptor. Many gene targets of this network were not active anymore in anti-estrogen resistant cell lines, possibly because their DNA methylation and histone acetylation patterns have changed.Estrogens regulate diverse physiological processes in reproductive tissues and in mammary, cardiovascular, bone, liver, and brain tissues [1]. The most potent and dominant estrogen in human is 17β-estradiol (E2). The biological effects of estrogens are mediated primarily through estrogen receptors α and β (ER-α and -β), ligand-inducible transcription factors of the nuclear receptor superfamily. Estrogens control multiple functions in hormone-responsive breast cancer cells [2], and ERα, in particular, plays a major role in the etiology of the disease, serving as a major prognostic marker and therapeutic target in breast cancer management [2].Binding of hormone to receptor facilitates both genomic and non-genomic ERα activities to
Genetic variation in DNA-repair pathways and response to radiochemotherapy in esophageal adenocarcinoma: a retrospective cohort study of the Eastern Cooperative Oncology Group
Harry H Yoon, Paul J Catalano, Kathleen M Murphy, Todd C Skaar, Santosh Philips, Mark Powell, Elizabeth A Montgomery, Michael J Hafez, Steven M Offer, Geoffrey Liu, Stephen J Meltzer, Xifeng Wu, Arlene A Forastiere, Al B Benson, Lawrence R Kleinberg, Michael K Gibson
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-176
Abstract: Eighty-one eligible treatment-na?ve subjects with newly diagnosed resectable esophageal adenocarcinoma received radiotherapy (45 Gy) concurrent with cisplatin-based chemotherapy, with planned subsequent surgical resection. The primary endpoint was pCR, defined as complete absence of tumor in the surgical specimen after radiochemotherapy. Using germline DNA from 60 subjects, we examined the base-excision repair SNP, XRCC1 Arg399Gln, and 4 other SNPs in nucleotide excision (XPD Lys751Gln and Asp312Asn, ERCC1 3' flank) and double-stranded break (XRCC2 5' flank) repair pathways, and correlated genotype with pCR rate. Paired tumor tissue was used to estimate the frequency of allelic imbalance at the XRCC1 SNP.The variant allele of the XRCC1 SNP (399Gln) was detected in 52% of subjects. Only 6% of subjects with the variant allele experienced a pCR, compared to 28% of subjects without the variant allele (odds ratio 5.37 for failing to achieve pCR, p = 0.062). Allelic imbalance at this locus was found in only 10% of informative subjects, suggesting that germline genotype may reflect tumor genotype at this locus. No significant association with pCR was noted for other SNPs.Assessed for the first time in a prospective, interventional trial cohort of esophageal adenocarcinoma, XRCC1 399Gln was associated with resistance to radiochemotherapy. Further investigation of this genetic variation is warranted in larger cohorts. In addition, these data indicate that germline genotype may serve as a surrogate for tumor genotype at this locus.Esophageal adenocarcinoma (EAC) is one of the fastest rising cancers in the West, particularly among white men[1]. Survival remains poor despite experimentation with numerous cytotoxic agents and therapeutic approaches, as well as improvements in diagnostic, surgical, and radiation technique[2]. In the U.S., a widely used standard to attempt to cure locally advanced disease, which is a common stage at presentation, is to provide concurrent radiochem
Nuclear receptor coregulator SNP discovery and impact on breast cancer risk
Ryan J Hartmaier, Sandrine Tchatchou, Alexandra S Richter, Jay Wang, Sean E McGuire, Todd C Skaar, Jimmy M Rae, Kari Hemminki, Christian Sutter, Nina Ditsch, Peter Bugert, Bernhard HF Weber, Dieter Niederacher, Norbert Arnold, Raymonda Varon-Mateeva, Barbara Wappenschmidt, Rita K Schmutzler, Alfons Meindl, Claus R Bartram, Barbara Burwinkel, Steffi Oesterreich
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-438
Abstract: The identification of novel SNPs was accomplished by sequencing the coding regions of these genes in 96 apparently normal individuals (48 Caucasian Americans, 48 African Americans). To assess their association with breast cancer risk, five SNPs were genotyped in 1218 familial BRCA1/2-mutation negative breast cancer cases and 1509 controls (rs1804645, rs6094752, rs2230782, rs2076546, rs2229840).Through our resequencing effort, we identified 74 novel SNPs (30 in NCoR, 32 in SMRT, 10 in SRC-3, and 2 in SRC-1). Of these, 8 were found with minor allele frequency (MAF) >5% illustrating the large amount of genetic diversity yet to be discovered. The previously shown protective effect of rs2230782 in SRC-3 was strengthened (OR = 0.45 [0.21-0.98], p = 0.04). No significant associations were found with the other SNPs genotyped.This data illustrates the importance of coregulators, especially SRC-3, in breast cancer development and suggests that more focused studies, including functional analyses, should be conducted.Nuclear receptors are critical for proper development and function of many physiological pathways including lipid metabolism, inflammation, and cell growth [1-3]. Over the past 25 years, it has become clear that nuclear receptors are also critical for the onset and progression of many diseases, including cancer. In breast cancer, for example, estrogen receptor-α (ERα) is expressed and drives tumor growth in approximately 2/3 of cases. However, only recently it has been appreciated that proper nuclear receptor function is absolutely dependent on the interaction with coregulator proteins [4]. These proteins couple nuclear receptors with RNA polymerase II and chromatin remodeling machinery to either activate (coactivators) or repress (corepressors) nuclear receptor mediated gene transcription. And because a single or a subset of coregulators can simultaneously regulate multiple cellular processes through multiple nuclear receptors, they have been classified as 'master
Genome-Wide Discovery of Drug-Dependent Human Liver Regulatory Elements
Robin P. Smith equal contributor,Walter L. Eckalbar equal contributor,Kari M. Morrissey,Marcelo R. Luizon,Thomas J. Hoffmann,Xuefeng Sun,Stacy L. Jones,Shelley Force Aldred,Anuradha Ramamoorthy,Zeruesenay Desta,Yunlong Liu,Todd C. Skaar,Nathan D. Trinklein,Kathleen M. Giacomini,Nadav Ahituv
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004648
Abstract: Inter-individual variation in gene regulatory elements is hypothesized to play a causative role in adverse drug reactions and reduced drug activity. However, relatively little is known about the location and function of drug-dependent elements. To uncover drug-associated elements in a genome-wide manner, we performed RNA-seq and ChIP-seq using antibodies against the pregnane X receptor (PXR) and three active regulatory marks (p300, H3K4me1, H3K27ac) on primary human hepatocytes treated with rifampin or vehicle control. Rifampin and PXR were chosen since they are part of the CYP3A4 pathway, which is known to account for the metabolism of more than 50% of all prescribed drugs. We selected 227 proximal promoters for genes with rifampin-dependent expression or nearby PXR/p300 occupancy sites and assayed their ability to induce luciferase in rifampin-treated HepG2 cells, finding only 10 (4.4%) that exhibited drug-dependent activity. As this result suggested a role for distal enhancer modules, we searched more broadly to identify 1,297 genomic regions bearing a conditional PXR occupancy as well as all three active regulatory marks. These regions are enriched near genes that function in the metabolism of xenobiotics, specifically members of the cytochrome P450 family. We performed enhancer assays in rifampin-treated HepG2 cells for 42 of these sequences as well as 7 sequences that overlap linkage-disequilibrium blocks defined by lead SNPs from pharmacogenomic GWAS studies, revealing 15/42 and 4/7 to be functional enhancers, respectively. A common African haplotype in one of these enhancers in the GSTA locus was found to exhibit potential rifampin hypersensitivity. Combined, our results further suggest that enhancers are the predominant targets of rifampin-induced PXR activation, provide a genome-wide catalog of PXR targets and serve as a model for the identification of drug-responsive regulatory elements.
RGxE: An R Program for Genotype x Environment Interaction Analysis  [PDF]
Mahendra Dia, Todd C. Wehner, Consuelo Arellano
American Journal of Plant Sciences (AJPS) , 2017, DOI: 10.4236/ajps.2017.87116
Abstract: Genotype x environmental interaction (GxE) can lead to differences in performance of genotypes over environments. GxE analysis can be used to analyze the stability of genotypes and the value of test locations. We developed an Rlanguage program (RGxE) that computes univariate stability statistics, descriptive statistics, pooled ANOVA, genotype F ratio across location and environment, cluster analysis for location, and location correlation with average location performance. Univariate stability statistics calculated are regression slope (bi), deviation from regression (S2d), Shukla’s variance (σi2), S square Wricke’s ecovalence (Wi), and Kang’s yield stability (YSi). RGxE is free and intended for use by scientists studying performance of polygenic or quantitative traits over multiple environments. In the present paper we provide the RGxE program and its components along with an example input data and outputs. Additionally, the RGxE program along with associated files is also available on GitHub at https://github.com/mahendra1/RGxE,


and http://cuke.hort.ncsu.edu/cucurbit/wehner/software.html.

Judicial reform in Argentina, Chile and Uruguay Un análisis de las reformas judiciales de Argentina, Chile y Uruguay
América Latina Hoy , 2010,
Abstract: This article is about judicial reform in the Southern Cone in the 1990s. It shows that for Argentina and Chile, procedural c Este artículo trata sobre las reformas judiciales en Sudamérica, durante los a os 90. Muestra que tanto en el caso de la Argentina como en el de Chile, las reformas a los códigos de procedimiento estuvieron motivadas por tres factores centrales, vinculados con el doble pro-ceso de democratización y liberalización económica: i) la preocupación con la violación de dere-chos humanos que provenía de los pasados regímenes autoritarios; ii) el deseo de crear ambientes legales estables tanto para los derechos de propiedad como para la inversión extranjera; y iii) la preocupación pública en torno a tasas de criminalidad cada vez más altas. Las reformas consti-tucionales que afectaron a las Cortes Supremas tanto en la Argentina como en Chile estuvieron vinculadas por razones estrictamente auto-interesadas. En última instancia, estas reformas fue-ron el resultado de compromisos políticos entre la izquierda y la derecha en respuesta a parti-culares eventos nacionales. En Uruguay, los frustrados intentos por desarrollar reformas en el código de procedimientos criminales y en el ámbito de la Corte Suprema pueden atribuirse a una combinación de falta de voluntad política, la carencia de apoyo a las mismas reformas judi-ciales, y una falta de recursos económicos. Notablemente, el análisis muestra que en ninguno de los tres países examinados las agencias internacionales han jugado un rol significativo a la hora de promover reformas u ofrecer asistencia financiera o técnica en favor de los cambios en los códigos de procedimiento o en la organización de las Cortes Supremas. Ello sugiere que estos dos tipos de reformas judiciales en el Cono Sur han sido motivados, ante todo, a partir de deman-das nacionales, y no a partir de una presión internacional –lo que muestra una diferencia impor-tante en el contexto de reformas que distinguió a estos tres países latinoamericanos–, y el que se dio en otros países de la región.
Does Judicial Independence explain Post-transitional Justice? Puede la independencia judicial explicar la justicia postransicional?
América Latina Hoy , 2012,
Abstract: Post-transitional justice in Latin America started in the Southern Cone in the mid-1990s and gradually spread to a number of countries which are seeking to address the human rights violations committed during the authoritarian regimes that dominated the continent from 1970s to the early 1990s. To distinguish trials at the time of transition from trials that take place years into the consolidation phase, this article develops a theoretical framework that explains variations in the propensity to prosecute the military for gross human rights violations (i.e., the number of trials) across time and across countries. The main argument presented here is that constitutional reforms have made Latin American judges more prone to prosecute the military for past human right violations because judges now enjoy more independence from powerful Executives and the hierarchy of the judicial system has loosened, making lower court judges less dependent on their superiors. As a result, judges, especially those sympathetic to a human rights agenda, can push prosecutions more forcefully than they could before. La justicia postransicional se inició en el Cono Sur de América Latina a mediados de la década de 1990 y gradualmente se ha expandido a otros países que buscan afrontar violaciones de derechos humanos cometidas durante los regímenes autoritarios que dominaron el continente desde la década de 1970 hasta inicios de la década de 1990. Para diferenciar los juicios de la transición de los juicios que se llevaron a cabo a os después durante la fase de consolidación democrática, este artículo desarrolla un marco teórico que explica las variaciones en la tendencia a juzgar a los militares por graves violaciones de derechos humanos (por ejemplo, el número de juicios) a lo largo del tiempo y entre países. El argumento principal que aquí se presenta es que las reformas constitucionales han hecho que los jueces latinoamericanos sean más propensos a perseguir a los militares por violaciones de derechos humanos porque los jueces ahora poseen más independencia del Poder Ejecutivo y, además, porque la jerarquía del sistema judicial se ha suavizado, haciendo que los jueces de primeras instancias sean menos dependientes de sus superiores. Como resultado, los jueces –especialmente aquellos afines a la agenda de los derechos humanos– pueden promover procesos judiciales con más energía que antes.
Negative refraction: A tutorial
Johannes Skaar
Physics , 2010,
Abstract: The concepts of negative refractive index and near-field imaging are explained in the form of a tutorial.
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