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ABSTRACT #28CLINICAL SCIENCESGRADUATE STUDENTPOSTER presentationPhenotypic characterization and cardiovascular outcomes of patients withfamilial hypercholesterolemiaMatt Allard 1 , Michal Martinka, Ahmad Al-Sarraf, Dan Holmes, Jiri Frohlich1Healthy Heart Prevention Clinic, St. Paul's Hospital/ Providence Health CareBackground /objectivesFamilial hypercholesterolemia (FH) is a common autosomal dominant disorder caused by loss-of-functionmutations in the low-density lipoprotein (LDL) receptor (LDL-R) or apolipoprotein B-100 (apo B) gene, orgain-of-function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in very highblood cholesterol levels and premature cardiovascular disease (CVD).To identify and phenotypically characterize patients in the Healthy Heart Prevention Clinic with FH todetermine characteristics that increase their risk of developing CVD.40MethodsPerform a chart review of the FH patients in the Prevention Clinic and use of the Cardiac Registry to determinewhich patients in this cohort developed CVD (Group 1).ResultsPreliminary work on 354 patients revealed that 72 had evidence of CVD. The average age of these patients(Group 1) is 69.7 with 58.3% being male. The 282 FH patients not found to have evidence of CVD (Group2) have an average age of 60.9 with 41.5% being male. Based upon the Dutch Lipid Clinic Network Criteria,90.3% of Group 1 was defined as having definite FH compared to 54.6% of Group 2. There were some notabledifferences in CV risk factors between the 2 groups. In the patients of Group 1 62.5% had a family history ofpremature CVD, 37.5% had history of hypertension, and 59.7% developed tendon xanthomas. In Group 251.1% had a family history of premature CVD, 18.8% had a history of hypertension, and 35.1% developedtendon xanthomas. Lastly, there is a large difference in the Lp(a) values of the two groups with Group 1 having anaverage Lp(a) value of 799.4 mg/L and Group 2 having an average Lp(a) value of 541.1 mg/L.ConclusionsDiagnosis of definite FH, older age, presence of tendon xanthomas, family history and high Lp(a) levels weremuch more prevalent in patients who developed CVD. Identifying these risk factors will allow for earlier and moreaggressive management to reduce the risk of CVD.2012 * Oral/Poster Presentations
POSTER presentationGRADUATE STUDENTBASIC SCIENCESABSTRACT #29Characterization of Stress Granules in the Coxsackievirus Type B3 InfectionGabriel Fung 1 , Chen Seng Ng 2 , Jingchun Zhang 1 , Honglin Luo 11University of British Columbia, James Hogg Research Centre, Department of Pathology andLaboratory Medicine; 2 Kyoto University, Department of Molecular GeneticsBackground /objectivesCoxsackievirus type B3 (CVB3) is a non-enveloped, positive single-stranded enterovirus that infects the heart,pleura, pancreas and liver. CVB3 infection can cause myocarditis, and its sequelae, dilated cardiomyopathy(DCM). In North America, DCM accounts for approximately 20% of heart failure and sudden death inchildren and young adults. Stress granules (SGs) are dynamic cytosolic aggregates composed of messengerribonuclearproteins (mRNPs) and target mRNAs and play an important role in mRNA storage and metabolismduring stress. SG formation has been implicated in several human diseases including viral infection,inflammation, cancer and multiple neurological diseases. We aim to elucidate the mechanism and significanceof SGs in CVB3 infection. Understanding the underlying molecular mechanisms of CVB3 replication and SGformation may aid in developing therapeutic treatments for CVB3-induced diseases.Hypothesis: CVB3-induced Stress Granule formation plays a protective role in the CVB3 infectionMethodsHeLa cells stably expressing GFP-tagged Ras-GAP SH3 domain binding protein (G3BP1), a protein involvedin the assembly of SGs, were used to monitor the formation of SGs during CVB3 infection. To explorethe potential mechanism by which CVB3 regulates SG formation, we examined protein expression ofeIF4γ(gamma), phospho-eIF2α(alpha), G3BP1, and T-cell restricted internal antigen (TIA-1), another criticalprotein that participates in SG assembly, in CVB3-infected cells. Finally, RT-PCR, immunoblot and plaqueassays were used to investigate the significance of G3BP1 by overexpressing and siRNA knockdown in HeLacells.ResultsConfocal imaging showed punctate accumulation of GFP-G3BP1 fluorescence in the cytosol at ~3 hours postinfection (hpi) and disappearance ~5 hpi, while GFP-G3BP1-Q325E mutants (cleavage resistant mutant)retained SG formation throughout CVB3 infection. By immunoblot, we showed that eIF4γ(gamma) wascleaved early after viral infection and eIF2α(alpha) became phosphorylated at ~5 hpi. Protein level of TIA-1remained unchanged while G3BP1 cleavage was observed ~5 hpi. Finally by RT-PCR, immunoblot and plaqueassay, viral replication was significantly reduced in G3BP1 overexpressing cells compared with wild-type HeLacells. Furthermore, knockdown of G3BP1 resulted in increased viral production.ConclusionsOur results suggest that translation initiation inhibition is likely the cause of SG formation during the earlyphase of CVB3 infection, however at the late stage of viral infection, disassembly occurs due to G3BP1 cleavageat amino acid Q325. Our data also suggest a protective role of G3BP1 in SGs during CVB3 infection.Oral/Poster Presentations * 2012 41
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