Biomedical Physiology and Kinesiology, Department of

Receive updates for this collection

Polymorphisms in Stromal Genes and Susceptibility to Serous Epithelial Ovarian Cancer: A Report from the Ovarian Cancer Association Consortium

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2011
Abstract: 

Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among Caucasians were estimated with odds ratios (OR) among 397 cases and 920 controls in two U.S.-based studies (discovery set), 436 cases and 1,098 controls in Australia (replication set 1) and a consortium of 15 studies comprising 1,668 cases and 4,249 controls (replication set 2). The discovery set and replication set 1 (833 cases and 2,013 controls) showed statistically homogeneous (Pheterogeneity≥0.48) decreased risks of sEOC at four variants: DCN rs3138165, rs13312816 and rs516115, and LUM rs17018765 (OR = 0.6 to 0.9; Ptrend = 0.001 to 0.03). Results from replication set 2 were statistically homogeneous (Pheterogeneity≥0.13) and associated with increased risks at DCN rs3138165 and rs13312816, and LUM rs17018765: all ORs = 1.2; Ptrend≤0.02. The ORs at the four variants were statistically heterogeneous across all 18 studies (Pheterogeneity≤0.03), which precluded combining. In post-hoc analyses, interactions were observed between each variant and recruitment period (Pinteraction≤0.003), age at diagnosis (Pinteraction = 0.04), and year of diagnosis (Pinteraction = 0.05) in the five studies with available information (1,044 cases, 2,469 controls). We conclude that variants in DCN and LUM are not directly associated with sEOC, and that confirmation of possible effect modification of the variants by non-genetic factors is required.

Document type: 
Article
File(s): 

GWAS of Follicular Lymphoma Reveals Allelic Heterogeneity at 6p21.32 and Suggests Shared Genetic Susceptibility with Diffuse Large B-cell Lymphoma

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2011
Abstract: 

Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL–associated locus on 6p21.32, rs2647012 (ORcombined = 0.64, Pcombined = 2×10−21) located 962 bp away from rs10484561 (r2<0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012:ORadjusted = 0.70, Padjusted = 4×10−12; rs10484561:ORadjusted = 1.64, Padjusted = 5×10−15). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL–associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (ORcombined = 1.36, Pcombined = 1.4×10−7). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.

Document type: 
Article
File(s): 

Genetic Variation in Healthy Oldest-Old

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2009-08-14
Abstract: 

Individuals who live to 85 and beyond without developing major age-related diseases may achieve this, in part, by lacking disease susceptibility factors, or by possessing resistance factors that enhance their ability to avoid disease and prolong lifespan. Healthy aging is a complex phenotype likely to be affected by both genetic and environmental factors. We sequenced 24 candidate healthy aging genes in DNA samples from 47 healthy individuals aged eighty-five years or older (the ‘oldest-old’), to characterize genetic variation that is present in this exceptional group. These healthy seniors were never diagnosed with cancer, cardiovascular disease, pulmonary disease, diabetes, or Alzheimer disease. We re-sequenced all exons, intron-exon boundaries and selected conserved non-coding sequences of candidate genes involved in aging-related processes, including dietary restriction (PPARG, PPARGC1A, SIRT1, SIRT3, UCP2, UCP3), metabolism (IGF1R, APOB, SCD), autophagy (BECN1, FRAP1), stem cell activation (NOTCH1, DLL1), tumor suppression (TP53, CDKN2A, ING1), DNA methylation (TRDMT1, DNMT3A, DNMT3B) Progeria syndromes (LMNA, ZMPSTE24, KL) and stress response (CRYAB, HSPB2). We detected 935 variants, including 848 single nucleotide polymorphisms (SNPs) and 87 insertion or deletions; 41% (385) were not recorded in dbSNP. This study is the first to present a comprehensive analysis of genetic variation in aging-related candidate genes in healthy oldest-old. These variants and especially our novel polymorphisms are valuable resources to test for genetic association in models of disease susceptibility or resistance. In addition, we propose an innovative tagSNP selection strategy that combines variants identified through gene re-sequencing- and HapMap-derived SNPs.

Document type: 
Article
File(s): 

A Direct Assessment of “Obesogenic” Built Environments: Challenges and Recommendations

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2011
Abstract: 

This paper outlines the challenges faced during direct built environment (BE) assessments of 42 Canadian communities of various income and urbanization levels. In addition, we recommend options for overcoming such challenges during BE community assessments. Direct BE assessments were performed utilizing two distinct audit methods: (1) modified version of Irvine-Minnesota Inventory in which a paper version of an audit tool was used to assess BE features and (2) a Physical Activity and Nutrition Features audit tool, where the presence and positions of all environmental features of interest were recorded using a Global-Positioning-System (GPS) unit. This paper responds to the call for the need of creators and users of environmental audit tools to share experiences regarding the usability of tools for BE assessments. The outlined BE assessment challenges plus recommendations for overcoming them can help improve and refine the existing audit tools and aid researchers in future assessments of the BE.

Document type: 
Article

The Neuroinflammatory Response in ALS: The Roles of Microglia and T Cells

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2012
Abstract: 

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by upper and lower motoneuron death. Mutations in the gene for superoxide dismutase 1 (SOD1) cause a familial form of ALS and have been used to develop transgenic mice which overexpress human mutant SOD1 (mSOD) and these mice exhibit a motoneuron disease which is pathologically and phenotypically similar to ALS. Neuroinflammation is a pathological hallmark of many neurodegenerative diseases including ALS and is typified by the activation and proliferation of microglia and the infiltration of T cells into the brain and spinal cord. Although the neuroinflammatory response has been considered a consequence of neuronal dysfunction and death, evidence indicates that manipulation of this response can alter disease progression. Previously viewed as deleterious to neuronal survival, recent reports suggest a trophic role for activated microglia in the mSOD mouse during the early stages of disease that is dependent on instructive signals from infiltrating T cells. However, at advanced stages of disease, activated microglia acquire increased neurotoxic potential, warranting further investigation into factors capable of skewing microglial activation towards a neurotrophic phenotype as a means of therapeutic intervention in ALS.

Document type: 
Article

A Cross-Sectional Analysis of the Association between Physical Activity and Visceral Adipose Tissue Accumulation in a Multiethnic Cohort

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2012
Abstract: 

Higher levels of VAT at the same body size and lower levels of physical activity (PA) have been reported in persons of Chinese and South Asian origin compared to European origin. The purpose of this study was to test the hypothesis that higher levels of VAT in persons of Chinese and South Asian origin versus European origin are associated with lower levels of PA. Chinese, European, and South Asian participants were assessed for sociodemographics, obesity-related measures, anthropometrics, and PA. Bivariate correlations, analysis of covariance, and regression models were used to explore ethnic differences in PA and the role of PA in explaining obesity-related measures. We observed ethnic differences in both body fat distribution and PA. Chinese and South Asians had higher amounts of VAT at a given BMI but lower amounts of moderate PA, vigorous PA, and moderate-to-vigorous PA (MVPA). Furthermore, we found ethnic-specific differences in the associations between body fat distribution and PA with only Europeans showing a consistent negative relationship between body fat distribution and PA. When ethnic differences in PA were taken into account, there were no longer any differences in VAT between the Chinese and European groups, while VAT remained higher in South Asians than Europeans.

Document type: 
Article
File(s): 

Genetic Variation in the NBS1, MRE11, RAD50 and BLM Genes and Susceptibility to Non-Hodgkin Lymphoma

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2009
Abstract: 

Background: Translocations are hallmarks of non-Hodgkin lymphoma (NHL) genomes. Becauselymphoid cell development processes require the creation and repair of double stranded breaks, itis not surprising that disruption of this type of DNA repair can cause cancer. The members of theMRE11-RAD50-NBS1 (MRN) complex and BLM have central roles in maintenance of DNA integrity.Severe mutations in any of these genes cause genetic disorders, some of which are characterizedby increased risk of lymphoma.Methods: We surveyed the genetic variation in these genes in constitutional DNA of NHLpatients by means of gene re-sequencing, then conducted genetic association tests for susceptibilityto NHL in a population-based collection of 797 NHL cases and 793 controls.Results: 114 SNPs were discovered in our sequenced samples, 61% of which were novel and notpreviously reported in dbSNP. Although four variants, two in RAD50 and two in NBS1, showedassociation results suggestive of an effect on NHL, they were not significant after correction formultiple tests.Conclusion: These results suggest an influence of RAD50 and NBS1 on susceptibility to diffuselarge B-cell lymphoma and marginal zone lymphoma. Larger association and functional studies couldconfirm such a role.

Document type: 
Article

Canadian Optically-Guided Approach for Oral Lesions Surgical (COOLS) Trial: Study Protocol for a Randomized Controlled Trial

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2011
Abstract: 

Background: Oral cancer is a major health problem worldwide. The 5-year survival rate ranges from 30-60%, andhas remained unchanged in the past few decades. This is mainly due to late diagnosis and high recurrence of thedisease. Of the patients who receive treatment, up to one third suffer from a recurrence or a second primarytumor. It is apparent that one major cause of disease recurrence is clinically unrecognized field changes whichextend beyond the visible tumor boundary. We have previously developed an approach using fluorescencevisualization (FV) technology to improve the recognition of the field at risk surrounding a visible oral cancer thatneeds to be removed and preliminary results have shown a significant reduction in recurrence rates.Method/Design: This paper describes the study design of a randomized, multi-centre, double blind, controlledsurgical trial, the COOLS trial. Nine institutions across Canada will recruit a total of 400 patients with oral severedysplasia or carcinoma in situ (N = 160) and invasive squamous cell carcinoma (N = 240). Patients will be stratifiedby participating institution and histology grade and randomized equally into FV-guided surgery (experimental arm)or white light-guided surgery (control arm). The primary endpoint is a composite of recurrence at or 1 cm withinthe previous surgery site with 1) the same or higher grade histology compared to the initial diagnosis (i.e., thediagnosis used for randomization); or 2) further treatment due to the presence of severe dysplasia or higherdegree of change at follow-up. This is the first randomized, multi-centre trial to validate the effectiveness of the FVguidedsurgery.Discussion: In this paper we described the strategies, novelty, and challenges of this unique trial involving asurgical approach guided by the FV technology. The success of the trial requires training, coordination, and qualityassurance across multiple sites within Canada. The COOLS trial, an example of translational research, may result inreduced recurrence rates following surgical treatment of early-stage oral cancer with significant impacts on survival,morbidity, patients’ quality of life and the cost to the health care system.Trial Registration: Clinicaltrials.gov NCT01039298

Document type: 
Article

Development of a Biomechanical Energy Harvester

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2009
Abstract: 

Background: Biomechanical energy harvesting–generating electricity from people during dailyactivities–is a promising alternative to batteries for powering increasingly sophisticated portabledevices. We recently developed a wearable knee-mounted energy harvesting device that generatedelectricity during human walking. In this methods-focused paper, we explain the physiologicalprinciples that guided our design process and present a detailed description of our device designwith an emphasis on new analyses.Methods: Effectively harvesting energy from walking requires a small lightweight device thatefficiently converts intermittent, bi-directional, low speed and high torque mechanical power toelectricity, and selectively engages power generation to assist muscles in performing negativemechanical work. To achieve this, our device used a one-way clutch to transmit only kneeextension motions, a spur gear transmission to amplify the angular speed, a brushless DC rotarymagnetic generator to convert the mechanical power into electrical power, a control system todetermine when to open and close the power generation circuit based on measurements of kneeangle, and a customized orthopaedic knee brace to distribute the device reaction torque over alarge leg surface area.Results: The device selectively engaged power generation towards the end of swing extension,assisting knee flexor muscles by producing substantial flexion torque (6.4 Nm), and efficientlyconverted the input mechanical power into electricity (54.6%). Consequently, six subjects walkingat 1.5 m/s generated 4.8 ± 0.8 W of electrical power with only a 5.0 ± 21 W increase in metaboliccost.Conclusion: Biomechanical energy harvesting is capable of generating substantial amounts ofelectrical power from walking with little additional user effort making future versions of thistechnology particularly promising for charging portable medical devices.

Document type: 
Article

A Randomized Controlled Trial of an Extensive Lifestyle Management Intervention (ELMI) Following Cardiac Rehabilitation: Study Design and Baseline Data

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2002
Abstract: 

Background: Cardiac rehabilitation programs (CRP) represent comprehensive interventions thatare typically limited to four months. Following completion of CRP, it appears that risk factors andlifestyle behaviours may deteriorate. The Extensive Lifestyle Management Intervention (ELMI)Following Cardiac Rehabilitation trial will investigate the benefits of a randomized intervention toprevent these adverse changes.Methods: Patients with ischemic heart disease (IHD) were randomized following a standard CRPto the ELMI or to usual care. The ELMI program is a case-managed intervention aimed atindividualizing risk factor and lifestyle management based on current treatment guidelines. Theprogram consists of cardiac rehabilitation sessions, telephone follow-up and risk factor and lifestylecounselling sessions. Health professionals work with participants using behavioural counselling andcommunications with participants' family physicians. Usual care participants return to their familyphysicians' care, and come to the study clinic only to undergo annual outcomes assessment. Theprimary outcome is change in IHD global risk after four years. Secondary outcomes includecombined cardiovascular events, health care utilization, lifestyle adherence, quality of life and riskfactors.Results: Over 28 months, 302 men and women were randomized. This represented 29% of thetotal population screened. The average age of study participants is 64 years, 18% are women, 53%have had a previous myocardial infarction, 73% have undergone previous revascularization and 20%have diabetes mellitus. Ischemic heart disease risk factors for the entire cohort improvedsignificantly after subjects had gone through previous CRPs. Baseline risk factors, lifestylebehaviours and medications were similar between the groups.

Document type: 
Article