Some studies date the origins of US intercollegiate football—and, by extension, the modern game o... more Some studies date the origins of US intercollegiate football—and, by extension, the modern game of American football—back to a soccer-style game played between Princeton and Rutgers universities in 1869. This article joins with others to argue that such a narrative is misleading and goes further to clarify the significance of two “international” fixtures in 1873 and 1874, which had a formative and lasting impact on football in the United States. These games, contested between alumni from England’s Eton College and students at Yale University, and between students at Canada’s McGill University and Harvard University, combined to revolutionize the American football code. Between 1875 and 1880, previous soccer-style versions of US intercollegiate football were replaced with an imported, if somewhat modified, version of rugby football. It was the “American rugby” that arose as a result of these transnational exchanges that is the true ancestor of the gridiron game of today.
Highly Comprehensive Genomic Testing for CLL: WGS, One Key to CLL Patient Stratification
Blood, 2018
Background Chronic Lymphocytic Leukemia (CLL) is characterised by a highly heterogeneous natural ... more Background Chronic Lymphocytic Leukemia (CLL) is characterised by a highly heterogeneous natural history and treatment response. Indeed, 50% of immunoglobulin heavy chain variable region (IgHV) hypermutated patients have an excellent progression free survival (PFS) after chemoimmunotherapy. Conversely, 25% of FCR treated patients relapse within 24 months (high risk CLL). Recent studies have shown that complex karyotype with or without TP53 disruption predicts for relapse after BCL2 therapy and BTK inhibitors. However, TP53 is the only marker for which routine testing is available. Overall, nearly 80% of patients relapsing after frontline FCR do not present a known poor risk genomic marker. Additional candidate genomic predictors of poor outcome including mutations in coding regions of NOTCH1, SF3B1 and RPS15, non-coding regions of NOTCH1 and enhancer regions of PAX5, telomere length, IgHV status, and DNA Damage Repair (DDR) germline mutations including TP53 and ATM have been reporte...
Quantitative Whole Genome Analysis of Sequential Samples From Patients with B-CLL Identifies Novel Recurrent Copy Number Alterations Involving Critical B-Cell Transcription Factors
Blood, 2010
3590 Genome-wide array or sequencing analyses are powerful tools for identifying genetic aberrati... more 3590 Genome-wide array or sequencing analyses are powerful tools for identifying genetic aberrations in cancers including leukaemias. However, the majority of these aberrations are likely to be random passenger events that do not drive clonal expansion. Currently, it is unknown whether cancers are maintained by a finite set of recurrent mutations similar for each patient or whether and to what extent malignancies are ‘personalised’, and also how molecular disease drivers evolve over time in the context of clinical intervention. The answers to these questions will determine whether future treatment modalities must be tailored according to individual and dynamic cancer characteristics. We hypothesized that differential quantitative high-resolution genome-wide array analysis of sequential samples from the same patients before treatment and at subsequent relapse would have the potential to identify emerging structural abnormalities with relevance to disease progression and/or response t...
Mutational Landscape of 118 Relapsed Chronic Lymphocytic Leukemia Clinical Trial Samples; Evidence for a Multiple-Hit Profile Using Targeted Next Generation Sequencing
Blood, 2014
Background: Previous studies using next-generation sequencing (NGS) have led to the identificatio... more Background: Previous studies using next-generation sequencing (NGS) have led to the identification of a number of genes mutated frequently in CLL. Recent publications focus on the most recurrently mutated genes (TP53, SF3B1 and NOTCH1) which tend to be mutually exclusive. Large series of untreated patients have shown that these mutations have a prognostic impact. Relapse may be associated with more frequent mutational events. Further investigation of relapsed CLL genomes within a clinical trial setting using a comprehensive NGS gene panel is required. Methods: Using targeted NGS we determined the mutational spectrum of 118 refractory/relapsing CLL patients enrolled in one French and two UK prospective trials (ICLL01 from the French intergroup GCFLLC/MW-GOELAMS, NCRNCLL201, NCRNCLL202 respectively). Eighty percent of patients had an unmutated IGHV status and 21 (18%) patients carried a 17p deletion. Sequencing libraries were composed of a panel of nine recurrently mutated genes in CL...
Whole Genome Sequencing, Targeted Deep Sequencing and Copy-Number Analysis Provide a Comprehensive Picture of the Mutational Landscape of 41 Clinically Annotated CLL Cases
Blood, 2014
Background Chronic lymphocytic leukaemia (CLL) is characterised by clinical and biological hetero... more Background Chronic lymphocytic leukaemia (CLL) is characterised by clinical and biological heterogeneity. Despite significant advances in therapeutic management, CLL remains largely incurable. Current risk stratification is based on cytogenetic features (del(17p), del(11q), del(13q), +12). So far, sequencing studies in CLL have focussed predominantly on the exome. These have identified a number of genes that are recurrently mutated at low frequency such as TP53, SF3B1, ATM, NOTCH1, MYD88, and BIRC3. Apart from TP53 abnormalities, none of these are currently used to guide clinical decisions and it is unclear how they are implicated in disease pathogenesis. Methods In this study, we sought to further refine the molecular landscape of CLL using whole genome sequencing (WGS) of paired tumour and germline DNA samples from a cohort of clinically annotated patients with CLL. We sequenced a heterogeneous cohort of 41 samples (25 males, 16 females, median age 69 (range 49-94)) with a range o...
Chronic lymphocytic leukaemia (CLL) is characterised by considerable clinical and biological hete... more Chronic lymphocytic leukaemia (CLL) is characterised by considerable clinical and biological heterogeneity, with specific recurrent genomic alterations, including TP53 mutations, deletions of chromosome 17p, and IgHV mutational status, impacting on response to chemo-immunotherapy and targeted agents. Consequently, diagnostic screening for these predictive biomarkers is recommended in both national and international clinical guidelines. Current conventional methods, including fluorescent in-situ hybridisation and Sanger sequencing, exhibit shortcomings in terms of cost, speed and sensitivity, and even second-generation sequencing methods encounter technical limitations imposed by short-read lengths and bio-informatics analysis. The MinION platform from Oxford Nanopore Technologies generates exceptionally long (1-100kbp) read lengths in a short period of time and at low cost, making it a good candidate for diagnostic testing. In this paper, we present a nanopore-based CLL-specific scr...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 26, 2018
Unmutated (UM) immunoglobulin heavy chain variable region (IgHV) status or IgHV3-21 gene usage is... more Unmutated (UM) immunoglobulin heavy chain variable region (IgHV) status or IgHV3-21 gene usage is associated with poor prognosis in chronic lymphocytic leukemia (CLL) patients. Interestingly, IgHV3-21 is often co-expressed with light chain IgLV3-21, which is potentially able to trigger cell-autonomous BCR-mediated signaling. However, this light chain has never been characterized independently of the heavy chain IgHV3-21. We performed total RNA sequencing in 32 patients and investigated IgLV3-21 prognostic impact in terms of treatment-free (TFS) and overall (OS) survival in 3 other independent cohorts for a total of 813 patients. IgLV3-21 presence was tested by real-time PCR and confirmed by Sanger sequencing. Using total RNA sequencing to characterize 32 patients with high-risk CLL, we found a high frequency (28%) of IgLV3-21 rearrangements. Gene set enrichment analysis revealed that these patients express higher levels of genes responsible for ribosome biogenesis and translation in...
The 100 000 Genome Project aims to develop a diagnostics platform by introducing whole genome seq... more The 100 000 Genome Project aims to develop a diagnostics platform by introducing whole genome sequencing (WGS) into clinical practice. Samples from patients with chronic lymphocytic leukaemia were subjected to WGS. WGS detection of single nucleotide variants and insertion/deletions were validated by targeted next generation sequencing showing high concordance (96·3%), also for detection of sub-clonal variants and low-frequency TP53 variants. Copy number alteration detection was verified by fluorescent in situ hybridisation and genome-wide single nucleotide polymorphism array (concordances of 86·7% and 92·9%, respectively), confirming adequate sensitivity by WGS. Our results confirm that WGS can provide comprehensive genomic characterisation for clinical trials, drug discovery and, ultimately, precision medicine.
Despite their importance to host health and development, the communities of microorganisms associ... more Despite their importance to host health and development, the communities of microorganisms associated with humans and other animals are characterized by a large degree of unexplained variation across individual hosts. The processes that drive such inter-individual variation are not well understood. To address this, we surveyed the microbial communities associated with the intestine of the zebrafish, Danio rerio, over developmental time. We compared our observations of community composition and distribution across hosts with that predicted by a neutral assembly model, which assumes that community assembly is driven solely by chance and dispersal. We found that as hosts develop from larvae to adults, the fit of the model to observed microbial distributions decreases, suggesting that the relative importance of non-neutral processes, such as microbe-microbe interactions, active dispersal, or selection by the host, increases as hosts mature. We also observed that taxa which depart in their distributions from the neutral prediction form ecologically distinct subgroups, which are phylogenetically clustered with respect to the full metacommunity. These results demonstrate that neutral processes are sufficient to generate substantial variation in microbiota composition across individual hosts, and suggest that potentially unique or important taxa may be identified by their divergence from neutral distributions.
Philippine Studies: Historical and Ethnographic Viewpoints, 2013
Contents may not be copied or sent via email or other means to multiple sites and posted to a lis... more Contents may not be copied or sent via email or other means to multiple sites and posted to a listserv without the copyright holder's written permission. Users may download and print articles for individual, noncommercial use only. However, unless prior permission has been obtained, you may not download an entire issue of a journal, or download multiple copies of articles.
General Thomas Bender, A Nation among Nations: America's Place in World History (Hill and Wang, $... more General Thomas Bender, A Nation among Nations: America's Place in World History (Hill and Wang, $26, pbk $15) challenges the tendency among scholars of early America and the United States to avoid the use of comparative frameworks in understanding the nation's history. He shows the importance of a global context for the analysis of American history by discussing five key issues: early European journeys to the New World; the American Revolution as an example of a European war over imperial territory; the Civil War through the lens of 1848 European nation-building revolutions; late nineteenth-century territorial acquisition within the context of European imperialism; and reform-minded responses to industrialisation and urbanisation.
Objective: To assess consumer response to potential graphics, slogans, and messages for the consu... more Objective: To assess consumer response to potential graphics, slogans, and messages for the consumer interface of the MyPyramid Food Guidance System. Design: Qualitative research conducted in two phases, composed of focus groups and Web-TV testing.
Physicians Who Do and Do Not Recommend Children Get All Vaccinations
Journal of Health Communication, 2008
The objectives of this study were to determine (1) the proportion of physicians who do and do not... more The objectives of this study were to determine (1) the proportion of physicians who do and do not recommend that children receive all available vaccines and (2) physician characteristics, attitudes, and behaviors associated with not recommending children receive all vaccines. A self-administered, cross-sectional electronic survey of physicians was conducted in 2005. Analyses were restricted to pediatricians (n = 250) and family practitioners (n = 484) who indicated they see at least five pediatric patients per week. A total of 1,935 surveys were distributed, and 1,251 (65%) physicians responded. Eleven percent of the physicians included in the analysis did not recommend to parents that children receive all available vaccines. Compared with physicians who recommended all vaccines for children, physicians who did not were more likely to be family practitioners versus pediatricians (OR = 2.9, CI = 1.4-5.8), agree or be neutral versus disagree that they have some concerns about childhood immunization safety (OR = 3.1, CI = 1.8-5.2), and have <or= 3 versus >or= 8 physicians in their practice (OR = 2.0, CI = 1.1-3.7). We conclude that physician characteristics and concerns about childhood immunizations are associated with not recommending all childhood vaccines. Further investigation of physicians' concerns about vaccine safety is needed to improve health communications directed toward health care providers.
Dylan Rodríguez, Suspended Apocalypse: White Supremacy, Genocide, and the Filipino Condition (Minneapolis: University of Minnesota Press, 2010, £15.50/$25.00). Pp. xi+258. isbn 978 0 8166 5350 8
Some studies date the origins of US intercollegiate football—and, by extension, the modern game o... more Some studies date the origins of US intercollegiate football—and, by extension, the modern game of American football—back to a soccer-style game played between Princeton and Rutgers universities in 1869. This article joins with others to argue that such a narrative is misleading and goes further to clarify the significance of two “international” fixtures in 1873 and 1874, which had a formative and lasting impact on football in the United States. These games, contested between alumni from England’s Eton College and students at Yale University, and between students at Canada’s McGill University and Harvard University, combined to revolutionize the American football code. Between 1875 and 1880, previous soccer-style versions of US intercollegiate football were replaced with an imported, if somewhat modified, version of rugby football. It was the “American rugby” that arose as a result of these transnational exchanges that is the true ancestor of the gridiron game of today.
Highly Comprehensive Genomic Testing for CLL: WGS, One Key to CLL Patient Stratification
Blood, 2018
Background Chronic Lymphocytic Leukemia (CLL) is characterised by a highly heterogeneous natural ... more Background Chronic Lymphocytic Leukemia (CLL) is characterised by a highly heterogeneous natural history and treatment response. Indeed, 50% of immunoglobulin heavy chain variable region (IgHV) hypermutated patients have an excellent progression free survival (PFS) after chemoimmunotherapy. Conversely, 25% of FCR treated patients relapse within 24 months (high risk CLL). Recent studies have shown that complex karyotype with or without TP53 disruption predicts for relapse after BCL2 therapy and BTK inhibitors. However, TP53 is the only marker for which routine testing is available. Overall, nearly 80% of patients relapsing after frontline FCR do not present a known poor risk genomic marker. Additional candidate genomic predictors of poor outcome including mutations in coding regions of NOTCH1, SF3B1 and RPS15, non-coding regions of NOTCH1 and enhancer regions of PAX5, telomere length, IgHV status, and DNA Damage Repair (DDR) germline mutations including TP53 and ATM have been reporte...
Quantitative Whole Genome Analysis of Sequential Samples From Patients with B-CLL Identifies Novel Recurrent Copy Number Alterations Involving Critical B-Cell Transcription Factors
Blood, 2010
3590 Genome-wide array or sequencing analyses are powerful tools for identifying genetic aberrati... more 3590 Genome-wide array or sequencing analyses are powerful tools for identifying genetic aberrations in cancers including leukaemias. However, the majority of these aberrations are likely to be random passenger events that do not drive clonal expansion. Currently, it is unknown whether cancers are maintained by a finite set of recurrent mutations similar for each patient or whether and to what extent malignancies are ‘personalised’, and also how molecular disease drivers evolve over time in the context of clinical intervention. The answers to these questions will determine whether future treatment modalities must be tailored according to individual and dynamic cancer characteristics. We hypothesized that differential quantitative high-resolution genome-wide array analysis of sequential samples from the same patients before treatment and at subsequent relapse would have the potential to identify emerging structural abnormalities with relevance to disease progression and/or response t...
Mutational Landscape of 118 Relapsed Chronic Lymphocytic Leukemia Clinical Trial Samples; Evidence for a Multiple-Hit Profile Using Targeted Next Generation Sequencing
Blood, 2014
Background: Previous studies using next-generation sequencing (NGS) have led to the identificatio... more Background: Previous studies using next-generation sequencing (NGS) have led to the identification of a number of genes mutated frequently in CLL. Recent publications focus on the most recurrently mutated genes (TP53, SF3B1 and NOTCH1) which tend to be mutually exclusive. Large series of untreated patients have shown that these mutations have a prognostic impact. Relapse may be associated with more frequent mutational events. Further investigation of relapsed CLL genomes within a clinical trial setting using a comprehensive NGS gene panel is required. Methods: Using targeted NGS we determined the mutational spectrum of 118 refractory/relapsing CLL patients enrolled in one French and two UK prospective trials (ICLL01 from the French intergroup GCFLLC/MW-GOELAMS, NCRNCLL201, NCRNCLL202 respectively). Eighty percent of patients had an unmutated IGHV status and 21 (18%) patients carried a 17p deletion. Sequencing libraries were composed of a panel of nine recurrently mutated genes in CL...
Whole Genome Sequencing, Targeted Deep Sequencing and Copy-Number Analysis Provide a Comprehensive Picture of the Mutational Landscape of 41 Clinically Annotated CLL Cases
Blood, 2014
Background Chronic lymphocytic leukaemia (CLL) is characterised by clinical and biological hetero... more Background Chronic lymphocytic leukaemia (CLL) is characterised by clinical and biological heterogeneity. Despite significant advances in therapeutic management, CLL remains largely incurable. Current risk stratification is based on cytogenetic features (del(17p), del(11q), del(13q), +12). So far, sequencing studies in CLL have focussed predominantly on the exome. These have identified a number of genes that are recurrently mutated at low frequency such as TP53, SF3B1, ATM, NOTCH1, MYD88, and BIRC3. Apart from TP53 abnormalities, none of these are currently used to guide clinical decisions and it is unclear how they are implicated in disease pathogenesis. Methods In this study, we sought to further refine the molecular landscape of CLL using whole genome sequencing (WGS) of paired tumour and germline DNA samples from a cohort of clinically annotated patients with CLL. We sequenced a heterogeneous cohort of 41 samples (25 males, 16 females, median age 69 (range 49-94)) with a range o...
Chronic lymphocytic leukaemia (CLL) is characterised by considerable clinical and biological hete... more Chronic lymphocytic leukaemia (CLL) is characterised by considerable clinical and biological heterogeneity, with specific recurrent genomic alterations, including TP53 mutations, deletions of chromosome 17p, and IgHV mutational status, impacting on response to chemo-immunotherapy and targeted agents. Consequently, diagnostic screening for these predictive biomarkers is recommended in both national and international clinical guidelines. Current conventional methods, including fluorescent in-situ hybridisation and Sanger sequencing, exhibit shortcomings in terms of cost, speed and sensitivity, and even second-generation sequencing methods encounter technical limitations imposed by short-read lengths and bio-informatics analysis. The MinION platform from Oxford Nanopore Technologies generates exceptionally long (1-100kbp) read lengths in a short period of time and at low cost, making it a good candidate for diagnostic testing. In this paper, we present a nanopore-based CLL-specific scr...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 26, 2018
Unmutated (UM) immunoglobulin heavy chain variable region (IgHV) status or IgHV3-21 gene usage is... more Unmutated (UM) immunoglobulin heavy chain variable region (IgHV) status or IgHV3-21 gene usage is associated with poor prognosis in chronic lymphocytic leukemia (CLL) patients. Interestingly, IgHV3-21 is often co-expressed with light chain IgLV3-21, which is potentially able to trigger cell-autonomous BCR-mediated signaling. However, this light chain has never been characterized independently of the heavy chain IgHV3-21. We performed total RNA sequencing in 32 patients and investigated IgLV3-21 prognostic impact in terms of treatment-free (TFS) and overall (OS) survival in 3 other independent cohorts for a total of 813 patients. IgLV3-21 presence was tested by real-time PCR and confirmed by Sanger sequencing. Using total RNA sequencing to characterize 32 patients with high-risk CLL, we found a high frequency (28%) of IgLV3-21 rearrangements. Gene set enrichment analysis revealed that these patients express higher levels of genes responsible for ribosome biogenesis and translation in...
The 100 000 Genome Project aims to develop a diagnostics platform by introducing whole genome seq... more The 100 000 Genome Project aims to develop a diagnostics platform by introducing whole genome sequencing (WGS) into clinical practice. Samples from patients with chronic lymphocytic leukaemia were subjected to WGS. WGS detection of single nucleotide variants and insertion/deletions were validated by targeted next generation sequencing showing high concordance (96·3%), also for detection of sub-clonal variants and low-frequency TP53 variants. Copy number alteration detection was verified by fluorescent in situ hybridisation and genome-wide single nucleotide polymorphism array (concordances of 86·7% and 92·9%, respectively), confirming adequate sensitivity by WGS. Our results confirm that WGS can provide comprehensive genomic characterisation for clinical trials, drug discovery and, ultimately, precision medicine.
Despite their importance to host health and development, the communities of microorganisms associ... more Despite their importance to host health and development, the communities of microorganisms associated with humans and other animals are characterized by a large degree of unexplained variation across individual hosts. The processes that drive such inter-individual variation are not well understood. To address this, we surveyed the microbial communities associated with the intestine of the zebrafish, Danio rerio, over developmental time. We compared our observations of community composition and distribution across hosts with that predicted by a neutral assembly model, which assumes that community assembly is driven solely by chance and dispersal. We found that as hosts develop from larvae to adults, the fit of the model to observed microbial distributions decreases, suggesting that the relative importance of non-neutral processes, such as microbe-microbe interactions, active dispersal, or selection by the host, increases as hosts mature. We also observed that taxa which depart in their distributions from the neutral prediction form ecologically distinct subgroups, which are phylogenetically clustered with respect to the full metacommunity. These results demonstrate that neutral processes are sufficient to generate substantial variation in microbiota composition across individual hosts, and suggest that potentially unique or important taxa may be identified by their divergence from neutral distributions.
Philippine Studies: Historical and Ethnographic Viewpoints, 2013
Contents may not be copied or sent via email or other means to multiple sites and posted to a lis... more Contents may not be copied or sent via email or other means to multiple sites and posted to a listserv without the copyright holder's written permission. Users may download and print articles for individual, noncommercial use only. However, unless prior permission has been obtained, you may not download an entire issue of a journal, or download multiple copies of articles.
General Thomas Bender, A Nation among Nations: America's Place in World History (Hill and Wang, $... more General Thomas Bender, A Nation among Nations: America's Place in World History (Hill and Wang, $26, pbk $15) challenges the tendency among scholars of early America and the United States to avoid the use of comparative frameworks in understanding the nation's history. He shows the importance of a global context for the analysis of American history by discussing five key issues: early European journeys to the New World; the American Revolution as an example of a European war over imperial territory; the Civil War through the lens of 1848 European nation-building revolutions; late nineteenth-century territorial acquisition within the context of European imperialism; and reform-minded responses to industrialisation and urbanisation.
Objective: To assess consumer response to potential graphics, slogans, and messages for the consu... more Objective: To assess consumer response to potential graphics, slogans, and messages for the consumer interface of the MyPyramid Food Guidance System. Design: Qualitative research conducted in two phases, composed of focus groups and Web-TV testing.
Physicians Who Do and Do Not Recommend Children Get All Vaccinations
Journal of Health Communication, 2008
The objectives of this study were to determine (1) the proportion of physicians who do and do not... more The objectives of this study were to determine (1) the proportion of physicians who do and do not recommend that children receive all available vaccines and (2) physician characteristics, attitudes, and behaviors associated with not recommending children receive all vaccines. A self-administered, cross-sectional electronic survey of physicians was conducted in 2005. Analyses were restricted to pediatricians (n = 250) and family practitioners (n = 484) who indicated they see at least five pediatric patients per week. A total of 1,935 surveys were distributed, and 1,251 (65%) physicians responded. Eleven percent of the physicians included in the analysis did not recommend to parents that children receive all available vaccines. Compared with physicians who recommended all vaccines for children, physicians who did not were more likely to be family practitioners versus pediatricians (OR = 2.9, CI = 1.4-5.8), agree or be neutral versus disagree that they have some concerns about childhood immunization safety (OR = 3.1, CI = 1.8-5.2), and have <or= 3 versus >or= 8 physicians in their practice (OR = 2.0, CI = 1.1-3.7). We conclude that physician characteristics and concerns about childhood immunizations are associated with not recommending all childhood vaccines. Further investigation of physicians' concerns about vaccine safety is needed to improve health communications directed toward health care providers.
Dylan Rodríguez, Suspended Apocalypse: White Supremacy, Genocide, and the Filipino Condition (Minneapolis: University of Minnesota Press, 2010, £15.50/$25.00). Pp. xi+258. isbn 978 0 8166 5350 8
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