Régulation de la lipoprotéine lipase macrophagique dans l'hypercholestérolémie familiale et le diabète de type 2

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal

Targeting Insulin and Insulin-Like Growth Factor Pathways in Epithelial Ovarian Cancer

Ovarian cancer is the most lethal of all gynecological malignancies, due in part to the diagnosis at an advanced stage caused by the lack of specific signs and symptoms and the absence of reliable tests for screening and early detection. Most patients will respond initially to treatment but about 70% of them will suffer a recurrence. Therefore, new therapeutic modalities are urgently needed to overcome chemoresistance observed in ovarian cancer patients. Evidence accumulates suggesting that the insulin/insulin growth factor (IGF) pathways could act as a good therapeutic target in several cancers, including ovarian cancer. In this paper, we will focus on the role of insulin/IGF in ovarian cancer tumorigenesis and treatment

Comparison of peak flow velocity through the left ventricular outflow tract and effective orifice area indexed to body surface area in Golden Retriever puppies to predict development of subaortic stenosis in adult dogs.

Objective — To evaluate the usefulness of Doppler-derived peak flow velocity through the left ventricular outflow tract (LVOT Vmax) and effective orifice area indexed to body surface area (EOAi) in puppies to predict development of subaortic stenosis (SAS) in the same dogs as adults. Design — Prospective, longitudinal, observational study. Animals — 38 Golden Retrievers. Procedures — Cardiac auscultation and echocardiography were performed on 2- to 6-monthold puppies, then repeated at 12 to 18 months. Subaortic stenosis was diagnosed when LVOT Vmax was = 2.3 m/s in adult dogs with left basilar systolic murmurs. Results—All puppies with EOAi < 1.46 cm2/m2 had SAS as adults. All adults with EOAi <1.29 cm2/m2 had SAS. An LVOT Vmax > 2.3 m/s in puppyhood was 63% sensitive and 100% specific for SAS in adulthood. In puppies, LVOT Vmax was more strongly associated with a future diagnosis of SAS (area under the curve [AUC], 0.89) than was EOAi (AUC, 0.80). In puppies, the combination of LVOT Vmax and EOAi yielded slightly higher sensitivity (69%) and specificity (100%) for adult SAS than did LVOT Vmax alone. In unaffected and affected dogs, LVOT Vmax increased significantly from puppyhood to adulthood but EOAi did not. Conclusions and Clinical Relevance — In Golden Retriever puppies, LVOT Vmax > 2.3 m/s and EOAi < 1.46 cm2/m2 were both associated with a diagnosis of SAS at adulthood. The combination of these 2 criteria may result in higher sensitivity for SAS screening. Unlike LVOT Vmax, EOAi did not change during growth in either unaffected Golden Retrievers or those with SAS. (J Am Vet Med Assoc 2014;245:1367–1374

Une formation complémentaire et appliquée : un besoin pour la relève en recherche interventionnelle en santé des populations

La recherche interventionnelle en santé des populations (RISP) est un champ de recherche émergeant et distinct, qui appelle à la rencontre des milieux scientifiques et de pratique de santé publique. Or, la formation académique traditionnelle universitaire, qui repose sur des ancrages disciplinaires spécifiques, est insuffisante pour outiller adéquatement les nouveaux chercheurs en RISP. Dans ce commentaire, nous soutenons l’idée que la RISP nécessite la mise en œuvre d’un éventail de compétences et de connaissances distinctes, qui sont plus aisément acquises et développées à travers une formation complémentaire et appliquée. En nous appuyant sur notre expérience comme boursiers du Programme stratégique de formation 4P, nous avons identifié les éléments qui ont contribué à préparer notre carrière de futurs et nouveaux chercheurs en RISP. Nous croyons que les programmes de formation complémentaires et appliqués, tels que le Programme 4P, représentent une stratégie prometteuse pour former et soutenir la relève en RISP dans son rôle d’amélioration de la santé des populations.Population Health Intervention Research (PHIR) is an emerging and distinct field that combines scientific research and public health practice. However, traditional academic training in research, which is founded on specific disciplinary orientations, does not sufficiently inform and prepare new PHIR researchers. In this commentary, we advance the idea that PHIR requires a broader range of competencies and knowledge that must be developed through a complementary and applied training program. Drawing on our experience as 4P Strategic Training Program fellows, we identified key elements of the program that have helped prepare us in our careers as future and new PHIR researchers. We believe that complementary and applied training programs such as the 4P Program are a promising strategy in training and supporting the next generation of PHIR researchers in their efforts to improve population health

Reproducibility of CRISPR-Cas9 methods for generation of conditional mouse alleles: A multi-center evaluation

Background CRISPR-Cas9 gene-editing technology has facilitated the generation of knockout mice, providing an alternative to cumbersome and time-consuming traditional embryonic stem cell-based methods. An earlier study reported up to 16% efficiency in generating conditional knockout (cKO or floxed) alleles by microinjection of 2 single guide RNAs (sgRNA) and 2 single-stranded oligonucleotides as donors (referred herein as “two-donor floxing” method). Results We re-evaluate the two-donor method from a consortium of 20 laboratories across the world. The dataset constitutes 56 genetic loci, 17,887 zygotes, and 1718 live-born mice, of which only 15 (0.87%) mice contain cKO alleles. We subject the dataset to statistical analyses and a machine learning algorithm, which reveals that none of the factors analyzed was predictive for the success of this method. We test some of the newer methods that use one-donor DNA on 18 loci for which the two-donor approach failed to produce cKO alleles. We find that the one-donor methods are 10- to 20-fold more efficient than the two-donor approach. Conclusion We propose that the two-donor method lacks efficiency because it relies on two simultaneous recombination events in cis, an outcome that is dwarfed by pervasive accompanying undesired editing events. The methods that use one-donor DNA are fairly efficient as they rely on only one recombination event, and the probability of correct insertion of the donor cassette without unanticipated mutational events is much higher. Therefore, one-donor methods offer higher efficiencies for the routine generation of cKO animal models.This work was supported by the National Collaborative Research Infrastructure (NCRIS) via the Australian Phenomics Network (APN) (to Gaetan Burgio and Paul Thomas), by an Institutional Development Award (PI: Shelley Smith) P20GM103471 (to CBG, RMQ, DWH, JDE, and RR), by NIGMS 1P30GM110768-01 and P30CA036727 (as part of support to University of Nebraska Mouse Genome Engineering and DNA Sequencing Cores), the British Heart Foundation FS12-57, FS12/57/29717, and CH/13/2/30154 and the program grant RG/15/12/31616 (to Kathryn Hentges and Bernard Keavney), the Wellcome Trust grants 107849/Z/ 15/Z, 097820/Z11/B, and 105610/Z/14/Z, the Medical Research Council MR/ N029992/1 (to DB and CBL), the National BioResource Project of Ministry of Education, Culture, Sports, Science and Technology/Japan Agency for Medical Research and Development (MEXT/AMED), Japan, the Canadian Institutes of Health Research MOP#142452 (MCB and LJM). LJM is a member of the Research Centre of the McGill University Health Centre which is supported in part by FQRS. Dr. William Thompson was supported by the Indiana Clinical and Translational Sciences Institute, funded in part by grant #UL1 TR001108 from the National Institute of Health (NIH), National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award. KC Kent Lloyd is supported by the NIH (UM1OD023221), and work contributed by staff from the UC Davis Mouse Biology Program (MBP) is supported by a grant from the American College of Laboratory Animal Medicine. The work contributed from Xiande Liu, Chad Smith, Eric Jonasch, Xuesong Zhang, and Jan ParkerThornburg is supported by the NIH under the award number P30CA16672 (XL, CS, EJ, XZ, JPT) and R50CA211121 (JPT). Joseph Miano is supported by the NIH under the award number HL138987. R Sedlacek was supported by LM2015040 (Czech Centre for Phenogenomics), CZ.1.05/1.1.00/02.0109 (BIOCEV), and CZ.1.05/2.1.00/19.0395 by the Ministry of Education, Youth and Sports (MEYS) and by Academy of Sciences of the Czech Republic (RVO 68378050). David Ray was supported by a Wellcome Trust Investigator (107849/Z/15/Z) and the Medical Research Council (MR/P011853/1 and MR/P023576/) grants. Andrew Loudon was supported by a Wellcome Trust Investigator (107849/Z/15/Z), Biotechnology and Biological Sciences Research Council (BB/N015584/1), Medical Research Council (MR/P023576/1). The work contributed from Gloria Lopez-Castejon is supported by the Wellcome Trust (104192/Z/14/Z) and the Royal Society. Pilar Alcaide was supported by the NIH (HL 123658). The work contributed from Surinder K. Batra is supported by the NIH under the award number P01 CA217798

Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation

International audienceAnterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). Mouse AGR2 deletion increases intestinal inflammation and promotes the development of inflammatory bowel disease (IBD). Although these biological effects are well established, the underlying molecular mechanisms of AGR2 function toward inflammation remain poorly defined. Here, using a protein-protein interaction screen to identify cellular regulators of AGR2 dimerization, we unveiled specific enhancers, including TMED2, and inhibitors of AGR2 dimerization, that control AGR2 functions. We demonstrate that modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro-inflammatory phenotypes, through either autophagy-dependent processes or secretion of AGR2, respectively. We also demonstrate that in IBD and specifically in Crohn's disease, the levels of AGR2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. Our study demonstrates that AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. The latter might represent systemic alarm signals for pro-inflammatory responses