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1.  The evolutionary dynamics of variant antigen genes in Babesia reveal a history of genomic innovation underlying host–parasite interaction 
Nucleic Acids Research  2014;42(11):7113-7131.
Babesia spp. are tick-borne, intraerythrocytic hemoparasites that use antigenic variation to resist host immunity, through sequential modification of the parasite-derived variant erythrocyte surface antigen (VESA) expressed on the infected red blood cell surface. We identified the genomic processes driving antigenic diversity in genes encoding VESA (ves1) through comparative analysis within and between three Babesia species, (B. bigemina, B. divergens and B. bovis). Ves1 structure diverges rapidly after speciation, notably through the evolution of shortened forms (ves2) from 5′ ends of canonical ves1 genes. Phylogenetic analyses show that ves1 genes are transposed between loci routinely, whereas ves2 genes are not. Similarly, analysis of sequence mosaicism shows that recombination drives variation in ves1 sequences, but less so for ves2, indicating the adoption of different mechanisms for variation of the two families. Proteomic analysis of the B. bigemina PR isolate shows that two dominant VESA1 proteins are expressed in the population, whereas numerous VESA2 proteins are co-expressed, consistent with differential transcriptional regulation of each family. Hence, VESA2 proteins are abundant and previously unrecognized elements of Babesia biology, with evolutionary dynamics consistently different to those of VESA1, suggesting that their functions are distinct.
doi:10.1093/nar/gku322
PMCID: PMC4066756  PMID: 24799432
2.  RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia 
Nature genetics  2014;46(2):116-125.
The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL), is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near the breakpoints; incorporation of non-templated sequence at the junction; ~30-fold enrichment at promoters and enhancers of genes actively transcribed in B-cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single cell tracking shows that this mechanism is active throughout leukemic evolution with evidence of localized clustering and re-iterated deletions. Integration of point mutation and rearrangement data identifies ATF7IP and MGA as two new tumor suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1 lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B-cell differentiation.
doi:10.1038/ng.2874
PMCID: PMC3960636  PMID: 24413735
3.  Medication transitions and polypharmacy in older adults following acute care 
Background/objective
Medication changes at transitions of care and polypharmacy are growing concerns that adversely impact optimal drug use. We aimed to describe transitions and patterns of medication use before and 1 year after older patients were hospitalized for community-acquired pneumonia, the second-most common reason for admission in North America.
Materials and methods
This was an analysis of a population-based clinical registry of patients treated in any of the six hospitals or seven emergency departments in Edmonton, Alberta, Canada, comprising 2,105 patients 65 years and older with community-acquired pneumonia who had survived at least 1 year. The prevalence of polypharmacy (five or more unique prescription drugs), as well as new use and persistence of common drug classes were assessed.
Results
The mean age was 78 years (standard deviation 8 years), 50% were female, 62% were hospitalized, and 58% had severe pneumonia. Among the 2,105 patients, 949 (45%) were using five or more medications prior to hospitalization, increasing to 1,559 (74%) within 90 days postdischarge and remaining over 70% at 1 year. Overall, 1,690 (80%) patients newly started and 1,553 (74%) patients stopped at least one medication in the first 90 days of follow-up. The prevalence of the most common drug classes (ie, cardiovascular, alimentary/metabolism) remained stable, with the exception of anti-infective agents, whereby 25% of patients were dispensed an anti-infective agent 3 months to 1 year after hospitalization.
Conclusion
Most older patients with pneumonia are subject to polypharmacy, and almost every patient had a medication started or stopped during 1-year follow-up, with 25% using antibiotics again. The period following an episode of pneumonia represents an opportunity potentially to optimize pharmacotherapy.
Video abstract
doi:10.2147/TCRM.S58707
PMCID: PMC3964163  PMID: 24672243
polypharmacy; drug utilization; elderly; community-acquired pneumonia; pharmacoepidemiology
5.  Whole exome sequencing of adenoid cystic carcinoma 
The Journal of Clinical Investigation  2013;123(7):2965-2968.
Adenoid cystic carcinoma (ACC) is a rare malignancy that can occur in multiple organ sites and is primarily found in the salivary gland. While the identification of recurrent fusions of the MYB-NFIB genes have begun to shed light on the molecular underpinnings, little else is known about the molecular genetics of this frequently fatal cancer. We have undertaken exome sequencing in a series of 24 ACC to further delineate the genetics of the disease. We identified multiple mutated genes that, combined, implicate chromatin deregulation in half of cases. Further, mutations were identified in known cancer genes, including PIK3CA, ATM, CDKN2A, SF3B1, SUFU, TSC1, and CYLD. Mutations in NOTCH1/2 were identified in 3 cases, and we identify the negative NOTCH signaling regulator, SPEN, as a new cancer gene in ACC with mutations in 5 cases. Finally, the identification of 3 likely activating mutations in the tyrosine kinase receptor FGFR2, analogous to those reported in ovarian and endometrial carcinoma, point to potential therapeutic avenues for a subset of cases.
doi:10.1172/JCI67201
PMCID: PMC3999050  PMID: 23778141
6.  Effect of Aspirin Dose on Mortality and Cardiovascular Events in People with Diabetes: A Meta-Analysis 
Journal of General Internal Medicine  2011;26(11):1336-1344.
Objectives
Pharmacologic evidence suggests adequate antiplatelet activity in diabetic patients requires >100 mg aspirin daily, yet recent trials have used ≤100 mg daily. This meta-analysis explored the relationship between aspirin dose and prevention of cardiovascular events.
Data Sources
Six electronic databases were searched using database-appropriate terms for aspirin, diabetes, and comparative study from inception until February 2010.
Review Methods
Randomized controlled trials and cohort studies comparing aspirin to no antiplatelet therapy were included if they reported cardiovascular events as pre-specified outcomes, aspirin dose, and number of diabetic patients. Studies were stratified by daily aspirin dose (≤100 mg; 101–325 mg; >325 mg) and pooled risk ratios (RR) were calculated using random effects models. All-cause mortality was the primary outcome of interest. Cardiovascular-related mortality, myocardial infarction, and stroke were secondary outcomes.
Results
Data for diabetic patients were available from 21 studies (n = 17,522). Overall, 1,172 (15.4%) of 7,592 aspirin users and 1,520 (18.4%) of 8,269 controls died (p = 0.31). The pooled RRs were 0.89 (95% CI: 0.72–1.10; p = 0.27) from 13 studies using ≤100 mg (I2 = 64%); 0.89 (95% CI: 0.61–1.30; p = 0.55) from four studies using 101–325 mg (I2 = 83%); and 0.96 (95% CI: 0.85–1.08; p = 0.50) from eight studies using >325 mg (I2 = 0%). Aspirin use was associated with a significantly lower risk of mortality (RR: 0.82; 95% CI: 0.69–0.98; p = 0.03) in 13 secondary prevention studies (I2 = 27%), whereas aspirin use in seven primary prevention studies (I2 = 0%) was not (RR: 1.01; 95% CI 0.85–1.19; p = 0.94). A substantial amount of heterogeneity was observed amongst studies in all outcomes. Although inclusion of cohort studies was a major source of heterogeneity, stratification by study design did not reveal a significant dose-response relationship.
Conclusions/Interpretation
This summary of available data does not support an aspirin dose-response effect for prevention of cardiovascular events in diabetic patients. However, the systematic review identified an important gap in randomized controlled trial evidence for using 101–325 mg aspirin daily in diabetes.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-011-1757-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s11606-011-1757-y
PMCID: PMC3208465  PMID: 21647746
aspirin; diabetes; mortality; myocardial infarction; stroke
7.  Lung cancer and diesel exhaust: an updated critical review of the occupational epidemiology literature 
Critical Reviews in Toxicology  2012;42(7):549-598.
A recent review concluded that the evidence from epidemiology studies was indeterminate and that additional studies were required to support the diesel exhaust-lung cancer hypothesis. This updated review includes seven recent studies. Two population-based studies concluded that significant exposure-response (E-R) trends between cumulative diesel exhaust and lung cancer were unlikely to be entirely explained by bias or confounding. Those studies have quality data on life-style risk factors, but do not allow definitive conclusions because of inconsistent E-R trends, qualitative exposure estimates and exposure misclassification (insufficient latency based on job title), and selection bias from low participation rates. Non-definitive results are consistent with the larger body of population studies. An NCI/NIOSH cohort mortality and nested case-control study of non-metal miners have some surrogate-based quantitative diesel exposure estimates (including highest exposure measured as respirable elemental carbon (REC) in the workplace) and smoking histories. The authors concluded that diesel exhaust may cause lung cancer. Nonetheless, the results are non-definitive because the conclusions are based on E-R patterns where high exposures were deleted to achieve significant results, where a posteriori adjustments were made to augment results, and where inappropriate adjustments were made for the “negative confounding” effects of smoking even though current smoking was not associated with diesel exposure and therefore could not be a confounder. Three cohort studies of bus drivers and truck drivers are in effect air pollution studies without estimates of diesel exhaust exposure and so are not sufficient for assessing the lung cancer-diesel exhaust hypothesis. Results from all occupational cohort studies with quantitative estimates of exposure have limitations, including weak and inconsistent E-R associations that could be explained by bias, confounding or chance, exposure misclassification, and often inadequate latency. In sum, the weight of evidence is considered inadequate to confirm the diesel-lung cancer hypothesis.
doi:10.3109/10408444.2012.690725
PMCID: PMC3441149  PMID: 22656672
Cumulative exposure; diesel exhaust; elemental carbon; epidemiology; exposure-response; latency; lung cancer; odds ratio
8.  The landscape of cancer genes and mutational processes in breast cancer 
Nature  2012;486(7403):400-404.
All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis1, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease.
doi:10.1038/nature11017
PMCID: PMC3428862  PMID: 22722201
9.  Mutational Processes Molding the Genomes of 21 Breast Cancers 
Cell  2012;149(5-10):979-993.
Summary
All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed “kataegis,” was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed.
PaperClip
Graphical Abstract
Highlights
► The genomes of 21 breast cancers sequenced ► Multiple somatic mutational processes extracted from mutation catalogs ► Mutational processes of BRCA1/BRCA2 breast cancers are distinctive ► Localized regions of hypermutation, “kataegis,” are frequent in breast cancers
Analyses of breast cancer genomes define distinct mutational signatures that imply the existence of multiple distinct somatic mutational processes throughout the genome and reveal a remarkable phenomenon of localized hypermutation. These highly mutated regions vary in size and chromosomal location and are surprisingly frequent in cancer genomes, often colocalizing with somatic rearrangements.
doi:10.1016/j.cell.2012.04.024
PMCID: PMC3414841  PMID: 22608084
10.  Analysis of drug coverage before and after the implementation of Canada’s Common Drug Review 
Background:
Canada’s Common Drug Review was implemented to provide publicly funded drug plans (provincial and federal) with a transparent, rigorous and consistent approach for assessing the clinical effectiveness and cost-effectiveness of new drugs. We compared uptake of drug coverage across jurisdictions before and after the implementation of the Common Drug Review.
Methods:
Using the IMS Brogan formulary acceptance: monitoring and evaluation database, we identified new drug products in Canada five years before and five years after the first recommendation was made by the Common Drug Review. For each jurisdiction, we compared the proportion of drugs listed, the median time-to-listing and the agreement between the listing decisions of the drug plans and the recommendations of the Common Drug Review.
Results:
We identified 198 new drugs approved for use in Canada between May 26, 1999, and May 27, 2009, of which 53 had a recommendation from the Common Drug Review. The proportion of drugs listed decreased after the introduction of the Common Drug Review for all participating drug plans (81.1% to 71.3% overall [p ≤ 0.01 for all plans, with the exceptions of Ontario and Quebec [p = 0.07]). The change in median time-to-listing between the periods before and after the Common Drug Review varied by jurisdiction, ranging from a decrease of 691 days to an increase of 250 days. The change in median time-to-listing was not statistically significant for most jurisdictions, with the exceptions of Saskatchewan (increased, Mann–Whitney U test p = 0.01) and New Brunswick, Prince Edward Island, and Newfoundland and Labrador (all decreased, Mann–Whitney U test p < 0.01).
Interpretation:
There was a decline in the proportion of new drugs listed after the introduction of the Common Drug Review for both participating and nonparticipating jurisdictions. The introduction of the review was associated with a decreased time-to-listing for certain smaller provinces.
doi:10.1503/cmaj.110670
PMCID: PMC3225449  PMID: 22025648
11.  A Comparison of Drug Coverage in Alberta Before and After the Introduction of the National Common Drug Review Process 
Healthcare Policy  2010;6(2):e117-e144.
Objective:
The integration of the Common Drug Review (CDR) was a substantial change for Canada's public drug plans. Detailed comparisons of time-to-listing and proportion of medications covered by the province of Alberta's drug plans within the context of the CDR process have not been rigorously conducted.
Methods:
New drugs approved by Health Canada were identified five years prior to the CDR's first recommendation (May 2004) and five years after. The time-to-listing and proportion of new drugs covered on the Alberta Health and Wellness Drug Benefit List (AHWDBL) was compared between these periods. The level of agreement between CDR recommendations and coverage in Alberta was calculated using a kappa score.
Results:
Two hundred and twenty new drugs were identified and met the study eligibility criteria (118 pre-CDR, 102 post-CDR). The median time-to-listing was 312 vs. 524 days in the pre-CDR and post-CDR periods, respectively, with the difference largely driven by time from notice of compliance (NOC) to the CDR recommendation. The level of agreement between 73 drugs with CDR recommendations and coverage in Alberta was fair (kappa 0.55).
Conclusion:
Following the implementation of the CDR, the proportion of drugs covered has decreased and overall median time-to-listing of new drugs has increased in the province of Alberta. For drugs listed on the AHWDBL, the proportion of time attributable to the CDR process (NOC to CDR recommendation) was 63% of the overall time-to-listing.
PMCID: PMC3016639  PMID: 22043227
12.  Investigation into the Degree of Variability in the Solid-State Properties of Common Pharmaceutical Excipients—Anhydrous Lactose 
AAPS PharmSciTech  2010;11(4):1552-1557.
This paper reports the batch-to-batch and vendor-to-vendor variations in the solid-state characteristics of multiple batches of lactose anhydrous from each of three vendors and the subsequent impact of these differences on processability and/or functionality.
doi:10.1208/s12249-010-9527-4
PMCID: PMC3011058  PMID: 21049309
compaction; excipients; lactose; physical properties; variability
13.  Muscle Microvascular Dysfunction in Central Obesity Is Related to Muscle Insulin Insensitivity but Is Not Reversed by High-Dose Statin Treatment 
Diabetes  2009;58(5):1185-1191.
OBJECTIVE
To test the hypotheses that decreased insulin-mediated glucose disposal in muscle is associated with a reduced muscle microvascular exchange capacity (Kf) and that 6 months of high-dose statin therapy would improve microvascular function in people with central obesity.
RESEARCH DESIGN AND METHODS
We assessed skeletal muscle microvascular function, visceral fat mass, physical activity levels, fitness, and insulin sensitivity in skeletal muscle in 22 female and 17 male volunteers with central obesity whose age (mean ± SD) was 51 ± 9 years. We tested the effect of atorvastatin (40 mg daily) on muscle microvascular function in a randomized, double-blind, placebo-controlled trial lasting 6 months.
RESULTS
Kf was negatively associated with a measure of glycemia (A1C; r = −0.44, P = 0.006) and positively associated with insulin sensitivity (the ratio of insulin-stimulated glucose effectiveness, or M value, to the mean insulin concentration, or I value; r = 0.39, P = 0.02). In regression modeling, A1C, visceral fat mass, and M:I explained 38% of the variance in Kf (in a linear regression model with Kf as the outcome [R2 = 0.38, P = 0.005]). M:I was associated with Kf independently of visceral fat mass (B coefficient 3.13 [95% CI 0.22–6.02], P = 0.036). Although 6 months' treatment with atorvastatin decreased LDL cholesterol by 51% (P < 0.001) and plasma high-sensitivity C-reactive protein by 75% (P = 0.02), microvascular function was unchanged.
CONCLUSIONS
Decreased insulin-mediated glucose uptake in skeletal muscle is associated with impaired muscle microvascular exchange capacity (Kf), independently of visceral fat mass. Muscle microvascular function is not improved by 6 months of high-dose statin treatment, despite marked statin-mediated improvements in lipid metabolism and decreased inflammation.
doi:10.2337/db08-1688
PMCID: PMC2671046  PMID: 19208914
14.  The genome of the blood fluke Schistosoma mansoni 
Nature  2009;460(7253):352-358.
Schistosoma mansoni is responsible for the neglected tropical disease schistosomiasis that affects 210 million people in 76 countries. We report here analysis of the 363 megabase nuclear genome of the blood fluke. It encodes at least 11,809 genes, with an unusual intron size distribution, and novel families of micro-exon genes that undergo frequent alternate splicing. As the first sequenced flatworm, and a representative of the lophotrochozoa, it offers insights into early events in the evolution of the animals, including the development of a body pattern with bilateral symmetry, and the development of tissues into organs. Our analysis has been informed by the need to find new drug targets. The deficits in lipid metabolism that make schistosomes dependent on the host are revealed, while the identification of membrane receptors, ion channels and more than 300 proteases, provide new insights into the biology of the life cycle and novel targets. Bioinformatics approaches have identified metabolic chokepoints while a chemogenomic screen has pinpointed schistosome proteins for which existing drugs may be active. The information generated provides an invaluable resource for the research community to develop much needed new control tools for the treatment and eradication of this important and neglected disease.
doi:10.1038/nature08160
PMCID: PMC2756445  PMID: 19606141
15.  The Darkening Cloud of Diabetes 
Diabetes Care  2008;31(11):2136-2142.
OBJECTIVE—We aimed to evaluate the changes in cardiovascular-related health care utilization (drug therapies, hospitalizations) and mortality for the diabetic population during a 9-year period in Saskatchewan, Canada.
RESEARCH DESIGN AND METHODS—We identified annual diabetes prevalence rates for people aged ≥30 years between 1993 and 2001 from the administrative databases of Saskatchewan Health. Annual rates of evidence-based drug therapies (antihypertensives, ACE inhibitors, β-blockers, calcium channel blockers, 3-hydroxy-3-metaglutaryl coenzyme A reductase inhibitors [statins]), hospitalizations for cerebrovascular and cardiac events, and all-cause mortality were estimated. Rates were direct age and sex standardized using the 2001 Canadian population, and trends over time were assessed using Joinpoint regression.
RESULTS—From 1993 to 2001, diabetes prevalence increased 34% (4.7–6.5%, P < 0.001) with the highest rates in men and those aged ≥65 years. The rate of increase in diabetes prevalence appeared to slow in those aged <65 years (P < 0.01 for trend). Significant increased use of evidence-based drug therapies was observed (41% increase in antihypertensive agents, 97% increase in ACE inhibitors, 223% increase in statin therapies; all P < 0.05 for trend). During this period, both cerebrovascular and cardiac-related hospitalizations declined by 36% (9.5 vs. 6.1 per 1,000) and 19% (38.0 vs. 30.6 per 1,000) (P < 0.05 for trends), respectively, with similar reductions regardless of sex. No change in all-cause mortality was observed (17.7 vs. 17.8 deaths per 1,000; P > 0.05).
CONCLUSIONS—During our period of study, there was an increase in the utilization of evidenced-based drug therapies in people with diabetes and reductions in cardiovascular-related hospitalizations. Despite this, we observed no change in all-cause mortality.
doi:10.2337/dc08-1248
PMCID: PMC2571063  PMID: 18840767
16.  EMBL Nucleotide Sequence Database: developments in 2005 
Nucleic Acids Research  2005;34(Database issue):D10-D15.
The EMBL Nucleotide Sequence Database () at the EMBL European Bioinformatics Institute, UK, offers a comprehensive set of publicly available nucleotide sequence and annotation, freely accessible to all. Maintained in collaboration with partners DDBJ and GenBank, coverage includes whole genome sequencing project data, directly submitted sequence, sequence recorded in support of patent applications and much more. The database continues to offer submission tools, data retrieval facilities and user support. In 2005, the volume of data offered has continued to grow exponentially. In addition to the newly presented data, the database encompasses a range of new data types generated by novel technologies, offers enhanced presentation and searchability of the data and has greater integration with other data resources offered at the EBI and elsewhere. In stride with these developing data types, the database has continued to develop submission and retrieval tools to maximise the information content of submitted data and to offer the simplest possible submission routes for data producers. New developments, the submission process, data retrieval and access to support are presented in this paper, along with links to sources of further information.
doi:10.1093/nar/gkj130
PMCID: PMC1347492  PMID: 16381823

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