The Experts below are selected from a list of 85362 Experts worldwide ranked by ideXlab platform
David D Boehr - One of the best experts on this subject based on the ideXlab platform.
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long range interaction networks in the function and fidelity of poliovirus rna dependent rna polymerase studied by nuclear magnetic resonance
Biochemistry, 2010Co-Authors: Xiaorong Yang, Jesse L Welch, Jamie J Arnold, David D BoehrAbstract:The fidelity of the poliovirus RNA-dependent RNA polymerase (3Dpol) plays a direct role in the Genomic Evolution and pathogenesis of the virus. A single site mutation (Gly64Ser) that is remote from the catalytic center results in a higher fidelity polymerase. NMR studies with [methyl-13C]methionine-labeled protein were used to compare the solution structure and dynamics of wild-type and Gly64Ser 3Dpol. The chemical shifts for the Met6 resonance were significantly different between wild-type and Gly64Ser 3Dpol when bound in ternary complexes with RNA and incorrect, but not with correct, nucleotide, suggesting that the Gly64Ser mutation induces structural changes in the N-terminal β-strand when the enzyme is bound to incorrect but not correct nucleotide. We also observe changes in the transverse relaxation times for methionines near regions important for nucleotide and RNA binding and catalysis. Our strategy to assign the [methyl-13C]methionine resonances involved separately mutating each of the 17 methioni...
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long range interaction networks in the function and fidelity of poliovirus rna dependent rna polymerase studied by nuclear magnetic resonance
Biochemistry, 2010Co-Authors: Xiaorong Yang, Jesse L Welch, Jamie J Arnold, David D BoehrAbstract:The fidelity of the poliovirus RNA-dependent RNA polymerase (3Dpol) plays a direct role in the Genomic Evolution and pathogenesis of the virus. A single site mutation (Gly64Ser) that is remote from...
Alvin S C Wong - One of the best experts on this subject based on the ideXlab platform.
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non invasive analysis of acquired resistance to cancer therapy by sequencing of plasma dna
Nature, 2013Co-Authors: Muhammed Murtaza, Sarahjane Dawson, Dana W Y Tsui, Davina Gale, Tim Forshew, Anna M Piskorz, Christine Parkinson, Suetfeung Chin, Zoya Kingsbury, Alvin S C WongAbstract:A proof of principle study shows that by exome sequencing of cell-free circulating DNA from cancer patient plasma samples, the Genomic Evolution of metastatic cancers and the acquisition of resistance in response to therapy can be tracked over time. This proof-of-principle study shows that by sequencing cancer exomes from patient plasma samples, it is possible to track Genomic Evolution of metastatic cancers and acquisition of resistance in response to therapy. In six patients with advanced breast, lung and ovarian cancers, sequences were derived from two to five plasma samples taken during multiple courses of treatment. Mutations associated with the emergence of resistance to drugs including cisplatin, tamoxifen and gefitinib were identified. Cancers acquire resistance to systemic treatment as a result of clonal Evolution and selection1,2. Repeat biopsies to study Genomic Evolution as a result of therapy are difficult, invasive and may be confounded by intra-tumour heterogeneity3,4. Recent studies have shown that Genomic alterations in solid cancers can be characterized by massively parallel sequencing of circulating cell-free tumour DNA released from cancer cells into plasma, representing a non-invasive liquid biopsy5,6,7. Here we report sequencing of cancer exomes in serial plasma samples to track Genomic Evolution of metastatic cancers in response to therapy. Six patients with advanced breast, ovarian and lung cancers were followed over 1–2 years. For each case, exome sequencing was performed on 2–5 plasma samples (19 in total) spanning multiple courses of treatment, at selected time points when the allele fraction of tumour mutations in plasma was high, allowing improved sensitivity. For two cases, synchronous biopsies were also analysed, confirming genome-wide representation of the tumour genome in plasma. Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance. These included an activating mutation in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) following treatment with paclitaxel8; a truncating mutation in RB1 (retinoblastoma 1) following treatment with cisplatin9; a truncating mutation in MED1 (mediator complex subunit 1) following treatment with tamoxifen and trastuzumab10,11, and following subsequent treatment with lapatinib12,13, a splicing mutation in GAS6 (growth arrest-specific 6) in the same patient; and a resistance-conferring mutation in EGFR (epidermal growth factor receptor; T790M) following treatment with gefitinib14. These results establish proof of principle that exome-wide analysis of circulating tumour DNA could complement current invasive biopsy approaches to identify mutations associated with acquired drug resistance in advanced cancers. Serial analysis of cancer genomes in plasma constitutes a new paradigm for the study of clonal Evolution in human cancers.
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non invasive analysis of acquired resistance to cancer therapy by sequencing of plasma dna
Nature, 2013Co-Authors: Muhammed Murtaza, Sarahjane Dawson, Dana W Y Tsui, Davina Gale, Tim Forshew, Anna M Piskorz, Christine Parkinson, Suetfeung Chin, Zoya Kingsbury, Alvin S C WongAbstract:Cancers acquire resistance to systemic treatment as a result of clonal Evolution and selection. Repeat biopsies to study Genomic Evolution as a result of therapy are difficult, invasive and may be confounded by intra-tumour heterogeneity. Recent studies have shown that Genomic alterations in solid cancers can be characterized by massively parallel sequencing of circulating cell-free tumour DNA released from cancer cells into plasma, representing a non-invasive liquid biopsy. Here we report sequencing of cancer exomes in serial plasma samples to track Genomic Evolution of metastatic cancers in response to therapy. Six patients with advanced breast, ovarian and lung cancers were followed over 1-2 years. For each case, exome sequencing was performed on 2-5 plasma samples (19 in total) spanning multiple courses of treatment, at selected time points when the allele fraction of tumour mutations in plasma was high, allowing improved sensitivity. For two cases, synchronous biopsies were also analysed, confirming genome-wide representation of the tumour genome in plasma. Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance. These included an activating mutation in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) following treatment with paclitaxel; a truncating mutation in RB1 (retinoblastoma 1) following treatment with cisplatin; a truncating mutation in MED1 (mediator complex subunit 1) following treatment with tamoxifen and trastuzumab, and following subsequent treatment with lapatinib, a splicing mutation in GAS6 (growth arrest-specific 6) in the same patient; and a resistance-conferring mutation in EGFR (epidermal growth factor receptor; T790M) following treatment with gefitinib. These results establish proof of principle that exome-wide analysis of circulating tumour DNA could complement current invasive biopsy approaches to identify mutations associated with acquired drug resistance in advanced cancers. Serial analysis of cancer genomes in plasma constitutes a new paradigm for the study of clonal Evolution in human cancers.
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non invasive analysis of acquired resistance to cancer therapy by sequencing of plasma dna
Nature, 2013Co-Authors: Muhammed Murtaza, Sarahjane Dawson, Dana W Y Tsui, Davina Gale, Tim Forshew, Anna M Piskorz, Christine Parkinson, Suetfeung Chin, Zoya Kingsbury, Alvin S C WongAbstract:A proof of principle study shows that by exome sequencing of cell-free circulating DNA from cancer patient plasma samples, the Genomic Evolution of metastatic cancers and the acquisition of resistance in response to therapy can be tracked over time.
Xiaorong Yang - One of the best experts on this subject based on the ideXlab platform.
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long range interaction networks in the function and fidelity of poliovirus rna dependent rna polymerase studied by nuclear magnetic resonance
Biochemistry, 2010Co-Authors: Xiaorong Yang, Jesse L Welch, Jamie J Arnold, David D BoehrAbstract:The fidelity of the poliovirus RNA-dependent RNA polymerase (3Dpol) plays a direct role in the Genomic Evolution and pathogenesis of the virus. A single site mutation (Gly64Ser) that is remote from the catalytic center results in a higher fidelity polymerase. NMR studies with [methyl-13C]methionine-labeled protein were used to compare the solution structure and dynamics of wild-type and Gly64Ser 3Dpol. The chemical shifts for the Met6 resonance were significantly different between wild-type and Gly64Ser 3Dpol when bound in ternary complexes with RNA and incorrect, but not with correct, nucleotide, suggesting that the Gly64Ser mutation induces structural changes in the N-terminal β-strand when the enzyme is bound to incorrect but not correct nucleotide. We also observe changes in the transverse relaxation times for methionines near regions important for nucleotide and RNA binding and catalysis. Our strategy to assign the [methyl-13C]methionine resonances involved separately mutating each of the 17 methioni...
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long range interaction networks in the function and fidelity of poliovirus rna dependent rna polymerase studied by nuclear magnetic resonance
Biochemistry, 2010Co-Authors: Xiaorong Yang, Jesse L Welch, Jamie J Arnold, David D BoehrAbstract:The fidelity of the poliovirus RNA-dependent RNA polymerase (3Dpol) plays a direct role in the Genomic Evolution and pathogenesis of the virus. A single site mutation (Gly64Ser) that is remote from...
Eugene Skepner - One of the best experts on this subject based on the ideXlab platform.
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genomewide analysis of reassortment and Evolution of human influenza a h3n2 viruses circulating between 1968 and 2011
Journal of Virology, 2014Co-Authors: Kim B Westgeest, Theo M. Bestebroer, Colin A Russell, Xudong Lin, Monique I J Spronken, Justin Bahl, Ruud Van Beek, Eugene SkepnerAbstract:Influenza A(H3N2) viruses became widespread in humans during the 1968 H3N2 virus pandemic and have been a major cause of influenza epidemics ever since. These viruses evolve continuously by reassortment and Genomic Evolution. Antigenic drift is the cause for the need to update influenza vaccines frequently. Using two data sets that span the entire period of circulation of human influenza A(H3N2) viruses, it was shown that influenza A(H3N2) virus Evolution can be mapped to 13 antigenic clusters. Here we analyzed the full genomes of 286 influenza A(H3N2) viruses from these two data sets to investigate the Genomic Evolution and reassortment patterns. Numerous reassortment events were found, scattered over the entire period of virus circulation, but most prominently in viruses circulating between 1991 and 1998. Some of these reassortment events persisted over time, and one of these coincided with an antigenic cluster transition. Furthermore, selection pressures and nucleotide and amino acid substitution rates of all proteins were studied, including those of the recently discovered PB1-N40, PA-X, PA-N155, and PA-N182 proteins. Rates of nucleotide and amino acid substitutions were most pronounced for the hemagglutinin, neuraminidase, and PB1-F2 proteins. Selection pressures were highest in hemagglutinin, neuraminidase, matrix 1, and nonstructural protein 1. This study of genotype in relation to antigenic phenotype throughout the period of circulation of human influenza A(H3N2) viruses leads to a better understanding of the Evolution of these viruses.
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genomewide analysis of reassortment and Evolution of human influenza a h3n2 viruses circulating between 1968 and 2011
Journal of Virology, 2014Co-Authors: Kim B Westgeest, Theo M. Bestebroer, Colin A Russell, Xudong Lin, Monique I J Spronken, Justin Bahl, Ruud Van Beek, Eugene SkepnerAbstract:ABSTRACT Influenza A(H3N2) viruses became widespread in humans during the 1968 H3N2 virus pandemic and have been a major cause of influenza epidemics ever since. These viruses evolve continuously by reassortment and Genomic Evolution. Antigenic drift is the cause for the need to update influenza vaccines frequently. Using two data sets that span the entire period of circulation of human influenza A(H3N2) viruses, it was shown that influenza A(H3N2) virus Evolution can be mapped to 13 antigenic clusters. Here we analyzed the full genomes of 286 influenza A(H3N2) viruses from these two data sets to investigate the Genomic Evolution and reassortment patterns. Numerous reassortment events were found, scattered over the entire period of virus circulation, but most prominently in viruses circulating between 1991 and 1998. Some of these reassortment events persisted over time, and one of these coincided with an antigenic cluster transition. Furthermore, selection pressures and nucleotide and amino acid substitution rates of all proteins were studied, including those of the recently discovered PB1-N40, PA-X, PA-N155, and PA-N182 proteins. Rates of nucleotide and amino acid substitutions were most pronounced for the hemagglutinin, neuraminidase, and PB1-F2 proteins. Selection pressures were highest in hemagglutinin, neuraminidase, matrix 1, and nonstructural protein 1. This study of genotype in relation to antigenic phenotype throughout the period of circulation of human influenza A(H3N2) viruses leads to a better understanding of the Evolution of these viruses. IMPORTANCE Each winter, influenza virus infects approximately 5 to 15% of the world9s population, resulting in significant morbidity and mortality. Influenza A(H3N2) viruses evolve continuously by reassortment and Genomic Evolution. This leads to changes in antigenic recognition (antigenic drift) which make it necessary to update vaccines against influenza A(H3N2) viruses frequently. In this study, the relationship of genetic Evolution to antigenic change spanning the entire period of A(H3N2) virus circulation was studied for the first time. The results presented in this study contribute to a better understanding of genetic Evolution in correlation with antigenic Evolution of influenza A(H3N2) viruses.
Xudong Lin - One of the best experts on this subject based on the ideXlab platform.
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genomewide analysis of reassortment and Evolution of human influenza a h3n2 viruses circulating between 1968 and 2011
Journal of Virology, 2014Co-Authors: Kim B Westgeest, Theo M. Bestebroer, Colin A Russell, Xudong Lin, Monique I J Spronken, Justin Bahl, Ruud Van Beek, Eugene SkepnerAbstract:Influenza A(H3N2) viruses became widespread in humans during the 1968 H3N2 virus pandemic and have been a major cause of influenza epidemics ever since. These viruses evolve continuously by reassortment and Genomic Evolution. Antigenic drift is the cause for the need to update influenza vaccines frequently. Using two data sets that span the entire period of circulation of human influenza A(H3N2) viruses, it was shown that influenza A(H3N2) virus Evolution can be mapped to 13 antigenic clusters. Here we analyzed the full genomes of 286 influenza A(H3N2) viruses from these two data sets to investigate the Genomic Evolution and reassortment patterns. Numerous reassortment events were found, scattered over the entire period of virus circulation, but most prominently in viruses circulating between 1991 and 1998. Some of these reassortment events persisted over time, and one of these coincided with an antigenic cluster transition. Furthermore, selection pressures and nucleotide and amino acid substitution rates of all proteins were studied, including those of the recently discovered PB1-N40, PA-X, PA-N155, and PA-N182 proteins. Rates of nucleotide and amino acid substitutions were most pronounced for the hemagglutinin, neuraminidase, and PB1-F2 proteins. Selection pressures were highest in hemagglutinin, neuraminidase, matrix 1, and nonstructural protein 1. This study of genotype in relation to antigenic phenotype throughout the period of circulation of human influenza A(H3N2) viruses leads to a better understanding of the Evolution of these viruses.
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genomewide analysis of reassortment and Evolution of human influenza a h3n2 viruses circulating between 1968 and 2011
Journal of Virology, 2014Co-Authors: Kim B Westgeest, Theo M. Bestebroer, Colin A Russell, Xudong Lin, Monique I J Spronken, Justin Bahl, Ruud Van Beek, Eugene SkepnerAbstract:ABSTRACT Influenza A(H3N2) viruses became widespread in humans during the 1968 H3N2 virus pandemic and have been a major cause of influenza epidemics ever since. These viruses evolve continuously by reassortment and Genomic Evolution. Antigenic drift is the cause for the need to update influenza vaccines frequently. Using two data sets that span the entire period of circulation of human influenza A(H3N2) viruses, it was shown that influenza A(H3N2) virus Evolution can be mapped to 13 antigenic clusters. Here we analyzed the full genomes of 286 influenza A(H3N2) viruses from these two data sets to investigate the Genomic Evolution and reassortment patterns. Numerous reassortment events were found, scattered over the entire period of virus circulation, but most prominently in viruses circulating between 1991 and 1998. Some of these reassortment events persisted over time, and one of these coincided with an antigenic cluster transition. Furthermore, selection pressures and nucleotide and amino acid substitution rates of all proteins were studied, including those of the recently discovered PB1-N40, PA-X, PA-N155, and PA-N182 proteins. Rates of nucleotide and amino acid substitutions were most pronounced for the hemagglutinin, neuraminidase, and PB1-F2 proteins. Selection pressures were highest in hemagglutinin, neuraminidase, matrix 1, and nonstructural protein 1. This study of genotype in relation to antigenic phenotype throughout the period of circulation of human influenza A(H3N2) viruses leads to a better understanding of the Evolution of these viruses. IMPORTANCE Each winter, influenza virus infects approximately 5 to 15% of the world9s population, resulting in significant morbidity and mortality. Influenza A(H3N2) viruses evolve continuously by reassortment and Genomic Evolution. This leads to changes in antigenic recognition (antigenic drift) which make it necessary to update vaccines against influenza A(H3N2) viruses frequently. In this study, the relationship of genetic Evolution to antigenic change spanning the entire period of A(H3N2) virus circulation was studied for the first time. The results presented in this study contribute to a better understanding of genetic Evolution in correlation with antigenic Evolution of influenza A(H3N2) viruses.