12 results on '"Seiser, Eric L."'
Search Results
2. A Cytogenetically Characterized, Genome-Anchored 10-Mb BAC Set and CGH Array for the Domestic Dog
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Thomas, Rachael, Duke, Shannon E., Bloom, Stephanie K., Breen, Tessa E., Young, Andrea C., Feiste, Erika, Seiser, Eric L., Tsai, Pei-Chien, Langford, Cordelia F., Ellis, Peter, Karlsson, Elinor K., Lindblad-Toh, Kerstin, and Breen, Matthew
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- 2007
3. FLT3 mutations in canine acute lymphocytic leukemia
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Seiser Eric L, Small George W, Suter Steven E, Thomas Rachael, Breen Matthew, and Richards Kristy L
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background FMS-like tyrosine kinase 3 (FLT3) is a commonly mutated protein in a variety of human acute leukemias. Mutations leading to constitutively active FLT3, including internal tandem duplications of the juxtamembrane domain (ITD), result in continuous cellular proliferation, resistance to apoptotic cell death, and a poorer prognosis. A better understanding of the molecular consequences of FLT3 activation would allow improved therapeutic strategies in these patients. Canine lymphoproliferative diseases, including lymphoma and acute leukemias, share evolutionarily conserved chromosomal aberrations and exhibit conserved mutations within key oncogenes when compared to their human counterparts. A small percentage of canine acute lymphocytic leukemias (ALL) also exhibit FLT3 ITD mutations. Methods We molecularly characterized FLT3 mutations in two dogs and one cell line, by DNA sequencing, gene expression analysis via quantitative real-time PCR, and sensitivity to the FLT3 inhibitor lestaurtinib via in vitro proliferation assays. FLT 3 and downstream mediators of FLT3 activation were assessed by Western blotting. Results The canine B-cell leukemia cell line, GL-1, and neoplastic cells from 2/7 dogs diagnosed cytologically with ALL were found to have FLT3 ITD mutations and FLT3 mRNA up-regulation. Lestaurtinib, a small molecule FLT3 inhibitor, significantly inhibited the growth of GL-1 cells, while not affecting the growth of two other canine lymphoid cell lines without the FLT3 mutation. Finally, western blots were used to confirm the conserved downstream mediators of FLT3 activating mutations. Conclusions These results show that ALL and FLT3 biology is conserved between canine and human patients, supporting the notion that canine ALL, in conjunction with the GL-1 cell line, will be useful in the development of a relevant large animal model to aid in the study of human FLT3 mutant leukemias.
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- 2011
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4. Functional
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Seiser, Eric L., Rzyman, Witold, Auman, Todd, Etheridge, Amy S., Mirza, Osman, Jassem, Jacek, Jantus-Lewintre, Eloisa, Owzar, Kouros, Paré-Brunet, Laia, Innocenti, Federico, Jiang, Chen, Zhang, Wei, Dziadziuszko, Rafal, Camps, Carlos, Crona, Daniel, Hirsch, Fred R., and Glubb, Dylan M.
- Abstract
BACKGROUND: We propose that single-nucleotide polymorphisms (SNPs) in genes of the vascular endothelial growth factor pathway of angiogenesis will associate with survival in non-small-cell lung cancer (NSCLC) patients. METHODS: Fifty-three SNPs in vascular endothelial growth factor-pathway genes were genotyped in 150 European stage I-III NSCLC patients and tested for associations with patient survival. Replication was performed in an independent cohort of 142 European stage I-III patients. Reporter gene assays were used to assess the effects of SNPs on transcriptional activity. RESULTS: In the initial cohort, five SNPs associated (q < 0.05) with relapse-free survival (RFS). The minor alleles of intronic FLT1 SNPs, rs7996030 and rs9582036, associated with reduced RFS (hazard ratio [HR] = 1.67 [95% confidence interval, CI, 1.22-2.29] and HR = 1.51 [95% CI, 1.14-2.01], respectively) and reduced transcriptional activity. The minor alleles of intronic KRAS SNPs, rs12813551 and rs10505980, associated with increased RFS (HR = 0.64 [0.46-0.87] and HR = 0.64 [0.47-0.87], respectively), and the minor allelic variant of rs12813551 also reduced transcriptional activity. Lastly, the minor allele of the intronic KRAS SNP rs10842513 associated with reduced RFS (HR = 1.65 [95% CI, 1.16-2.37]). Analysis of the functional variants suggests they are located in transcriptional enhancer elements. The negative effect of rs9582036 on RFS was confirmed in the replication cohort (HR = 1.69 [0.99-2.89], p = 0.028), and the association was significant in pooled analysis of both cohorts (HR = 1.67 [1.21-2.30], p = 0.0001). CONCLUSIONS: The functional FLT1 variant rs9582036 is a prognostic determinant of recurrence in stage I-III NSCLC. Its predictive value should be tested in the adjuvant setting of stage I-III NSCLC.
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- 2015
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5. Functional FLT1 genetic variation is a prognostic factor for recurrence in stage I-III non-small cell lung cancer
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Universitat Politècnica de València. Escuela Técnica Superior de Ingeniería Agronómica y del Medio Natural - Escola Tècnica Superior d'Enginyeria Agronòmica i del Medi Natural, Glubb, Dylan M, Pare-Brunet, Laia, Jantus Lewintre, Eloisa, Jiang, Chen, Crona, Daniel, Etheridge, Amy S., Mirza, Osman, Zhang, Wei, Seiser, Eric L., Rzyman, Witold, Jassem, Jacek, Auman, Todd, Hirsch, Fred R, Owzar, Kouros, Camps, Carlos, Dziadziuszko, Rafal, Innocenti, Federico, Universitat Politècnica de València. Escuela Técnica Superior de Ingeniería Agronómica y del Medio Natural - Escola Tècnica Superior d'Enginyeria Agronòmica i del Medi Natural, Glubb, Dylan M, Pare-Brunet, Laia, Jantus Lewintre, Eloisa, Jiang, Chen, Crona, Daniel, Etheridge, Amy S., Mirza, Osman, Zhang, Wei, Seiser, Eric L., Rzyman, Witold, Jassem, Jacek, Auman, Todd, Hirsch, Fred R, Owzar, Kouros, Camps, Carlos, Dziadziuszko, Rafal, and Innocenti, Federico
- Abstract
Acceso abierto en: http://dx.doi.org/10.1097/JTO.0000000000000549, Background: We propose that single-nucleotide polymorphisms (SNPs) in genes of the vascular endothelial growth factor pathway of angiogenesis will associate with survival in non-small-cell lung cancer (NSCLC) patients. Methods: Fifty-three SNPs in vascular endothelial growth factor-pathway genes were genotyped in 150 European stage I-III NSCLC patients and tested for associations with patient survival. Replication was performed in an independent cohort of 142 European stage I-III patients. Reporter gene assays were used to assess the effects of SNPs on transcriptional activity. Results: In the initial cohort, five SNPs associated (q < 0.05) with relapse-free survival (RFS). The minor alleles of intronic FLT1 SNPs, rs7996030 and rs9582036, associated with reduced RFS (hazard ratio [HR] = 1.67 [95% confidence interval, CI, 1.22-2.29] and HR = 1.51 [95% CI, 1.14-2.01], respectively) and reduced transcriptional activity. The minor alleles of intronic KRAS SNPs, rs12813551 and rs10505980, associated with increased RFS (HR = 0.64 [0.46-0.87] and HR = 0.64 [0.47-0.87], respectively), and the minor allelic variant of rs12813551 also reduced transcriptional activity. Lastly, the minor allele of the intronic KRAS SNP rs10842513 associated with reduced RFS (HR = 1.65 [95% CI, 1.16-2.37]). Analysis of the functional variants suggests they are located in transcriptional enhancer elements. The negative effect of rs9582036 on RFS was confirmed in the replication cohort (HR = 1.69 [0.99-2.89], p = 0.028), and the association was significant in pooled analysis of both cohorts (HR = 1.67 [1.21-2.30], p = 0.0001). Conclusions: The functional FLT1 variant rs9582036 is a prognostic determinant of recurrence in stage I-III NSCLC. Its predictive value should be tested in the adjuvant setting of stage I-III NSCLC.
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- 2015
6. Hidden Markov Model-Based CNV Detection Algorithms for Illumina Genotyping Microarrays
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Seiser, Eric L., primary and Innocenti, Federico, additional
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- 2014
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7. Refining tumor-associated aneuploidy through 'genomic recoding' of recurrent DNA copy number aberrations in 150 canine non-Hodgkin lymphomas
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Thomas, Rachael, Seiser, Eric L., Motsinger-Reif, Alison, Borst, Luke, Valli, Victor E., Kelley, Kathryn, Suter, Steven E., Argyle, David, Burgess, Kristine, Bell, Jerold, Lindblad-Toh, Kerstin, Modiano, Jaime F., Breen, Matthew, Thomas, Rachael, Seiser, Eric L., Motsinger-Reif, Alison, Borst, Luke, Valli, Victor E., Kelley, Kathryn, Suter, Steven E., Argyle, David, Burgess, Kristine, Bell, Jerold, Lindblad-Toh, Kerstin, Modiano, Jaime F., and Breen, Matthew
- Abstract
Identification of the genomic regions most intimately associated with non-Hodgkin lymphoma (NHL) pathogenesis is confounded by the genetic heterogeneity of human populations. We hypothesize that the restricted genetic variation of purebred dogs, combined with the contrasting architecture of the human and canine karyotypes, will increase the penetrance of fundamental NHL-associated chromosomal aberrations in both species. We surveyed non-random aneuploidy in 150 canine NHL cases, revealing limited genomic instability compared to their human counterparts and no evidence for CDKN2A/B deletion in canine B-cell NHL. 'Genomic recoding' of canine NHL data into a 'virtual human' chromosome format showed remarkably few regions of copy number aberration (CNA) shared between both species, restricted to regions of dog chromosomes 13 and 31, and human chromosomes 8 and 21. Our data suggest that gene discovery in NHL may be enhanced through comparative studies exploiting the less complex association between CNAs and tumor pathogenesis in canine patients.
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- 2011
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8. Refining tumor-associated aneuploidy through ‘genomic recoding’ of recurrent DNA copy number aberrations in 150 canine non-Hodgkin lymphomas
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Thomas, Rachael, primary, Seiser, Eric L., additional, Motsinger-Reif, Alison, additional, Borst, Luke, additional, Valli, Victor E., additional, Kelley, Kathryn, additional, Suter, Steven E., additional, Argyle, David, additional, Burgess, Kristine, additional, Bell, Jerold, additional, Lindblad-toh, Kerstin, additional, Modiano, Jaime F., additional, and Breen, Matthew, additional
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- 2011
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9. FLT3 mutations in canine acute lymphocytic leukemia
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Suter, Steven E, primary, Small, George W, additional, Seiser, Eric L, additional, Thomas, Rachael, additional, Breen, Matthew, additional, and Richards, Kristy L, additional
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- 2011
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10. Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin
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Zhou, Kaixin, Yee, Sook Wah, Seiser, Eric L, van Leeuwen, Nienke, Tavendale, Roger, Bennett, Amanda J, Groves, Christopher J, Coleman, Ruth L, van der Heijden, Amber A, Beulens, Joline W, de Keyser, Catherine E, Zaharenko, Linda, Rotroff, Daniel M, Out, Mattijs, Jablonski, Kathleen A, Chen, Ling, Javorský, Martin, Židzik, Jozef, Levin, Albert M, Williams, L Keoki, Dujic, Tanja, Semiz, Sabina, Kubo, Michiaki, Chien, Huan-Chieh, Maeda, Shiro, Witte, John S, Wu, Longyang, Tkáč, Ivan, Kooy, Adriaan, van Schaik, Ron H N, Stehouwer, Coen D A, Logie, Lisa, Sutherland, Calum, Klovins, Janis, Pirags, Valdis, Hofman, Albert, Stricker, Bruno H, Motsinger-Reif, Alison A, Wagner, Michael J, Innocenti, Federico, Hart, Leen M 't, Holman, Rury R, McCarthy, Mark I, Hedderson, Monique M, Palmer, Colin N A, Florez, Jose C, Giacomini, Kathleen M, and Pearson, Ewan R
- Abstract
Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10−14) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.
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- 2016
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11. Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin
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Innocenti, Federico, Groves, Christopher J., Stricker, Bruno H., Motsinger-Reif, Alison A., Van Schaik, Ron H.N., Yee, Sook Wah, Witte, John S., Van Leeuwen, Nienke, Levin, Albert M., Palmer, Colin N.A., Seiser, Eric L., Holman, Rury R., Maeda, Shiro, Wagner, Michael J., Stehouwer, Coen D.A., Hofman, Albert, Giacomini, Kathleen M., Keoki Williams, McCarthy, Mark I., Bennett, Amanda J., Kooy, Adriaan, Out, Mattijs, Dujic, Tanja, Klovins, Janis, Wu, Longyang, Logie, Lisa, Hart, Leen M., Beulens, Joline W., Zidzik, Jozef, Florez, Jose C., Jablonski, Kathleen A., Pirags, Valdis, Zaharenko, Linda, Hedderson, Monique M., De Keyser, Catherine E., Sutherland, Calum, Chien, Huan-Chieh, Pearson, Ewan R., Tká, Ivan, Chen, Ling, Javorský, Martin, Van Der Heijden, Amber A., Semiz, Sabina, Tavendale, Roger, Kubo, Michiaki, Zhou, Kaixin, Coleman, Ruth L., and Rotroff, Daniel M.
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endocrine system diseases ,nutritional and metabolic diseases ,3. Good health - Abstract
Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (p=6.6×10−14) greater metformin-induced in haemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 is the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.
12. Hidden Markov Model-Based CNV Detection Algorithms for Illumina Genotyping Microarrays.
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Seiser EL and Innocenti F
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Somatic alterations in DNA copy number have been well studied in numerous malignancies, yet the role of germline DNA copy number variation in cancer is still emerging. Genotyping microarrays generate allele-specific signal intensities to determine genotype, but may also be used to infer DNA copy number using additional computational approaches. Numerous tools have been developed to analyze Illumina genotype microarray data for copy number variant (CNV) discovery, although commonly utilized algorithms freely available to the public employ approaches based upon the use of hidden Markov models (HMMs). QuantiSNP, PennCNV, and GenoCN utilize HMMs with six copy number states but vary in how transition and emission probabilities are calculated. Performance of these CNV detection algorithms has been shown to be variable between both genotyping platforms and data sets, although HMM approaches generally outperform other current methods. Low sensitivity is prevalent with HMM-based algorithms, suggesting the need for continued improvement in CNV detection methodologies.
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- 2015
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