NCube/papyrus huggingface dataset:
Inhibiteurs de PARP : leur rôle potentiel en monothérapie et en combinaison en cancer du sein triple-négatif

Fourteen Canadian women die every day from breast cancer. Triple-negative breast cancer (TNBC) has a poor prognosis. Numerous efforts are made to offer these patients targeted therapies such as poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) to improve survival and minimize chemotherapy-related toxicity. It is not well understood which subset of TNBC patients will benefit from PARPi; and if different sequencing strategies of PARPi and chemotherapy can improve therapeutic efficacy and decrease toxicity.  We previously derived a 63-gene signature predicting response to PARPi with a high overall accuracy. Our objectives are 1) to evaluate the clinical implications of the 63-gene signature; and 2) to determine the optimal sequence of administration of talazoparib and carboplatin in vivo in BRCAWT TNBC. First, we evaluated the mutational frequency of the 63 genes in different clinical settings using two publically-available datatsets. Second, we compared three cohorts of orthotopic xenografts: A) talazoparib first, combined with carboplatin on day 3; carboplatin first, followed by talazoparib B) one day later; and C) seven days later.  We found that the mutational frequency was high in breast cancer subtypes of poor prognosis. Mutated luminal B patients had a lower survival than non-mutated patients. We also found that tumoral and metastatic inhibition were similar between cohorts A and B, but cohort B had less toxicity.   In conclusion, there is potential for PARPi efficacy in luminal B and poor prognosis tumors. Second, pretreatment with carboplatin may be an effective approach with less toxicity.

Keyphrases: Gene signature, Breast cancer, Triple-negative breast cancer, Chemotherapy, Targeted therapy, PARP inhibitors, Orthotopic xenograft, Metastasis, Toxicity, Combination treatment
Comparaison des effets d’une diète faible en lipides et d’une diète faible en glucides sur le profil cardiométabolique chez des sujets atteints de chylomicronémie multifactorielle : étude croisée randomisée

Multifactorial chylomicronemia syndrome (MCS) is a complex disease in which triglyceride (TG) values exceed 10 mmol/L. MCS occurs in adulthood and has a prevalence of approximately 1 in 600 adults in Quebec. Two conditions must be met to develop this disease: a genetic component (oligogenic or polygenic) as well as the presence of lifestyle risk factors (a diet high in fat and refined sugars, excessive alcohol consumption, uncontrolled diabetes or obesity). MCS is a serious health condition, as it significantly increases the risk of acute pancreatitis and can double the risk of cardiovascular disease. Currently, there are no nutritional intervention studies conducted in this population to determine the most beneficial nutritional approach. This thesis presents the results of a randomized crossover study whose objective was to evaluate the impact of a low-fat diet and a low-carbohydrate diet on the fasting and postprandial lipid profile in patients with SCD according to the presence of a rare heterozygous lipoprotein lipase (LPL) gene variant. The results of this study suggest that a low-fat diet would result in a greater reduction in TGs in subjects with a rare heterozygous variant of LPL and may ultimately help reduce the risk of acute pancreatitis in the long term.

Keyphrases: Type V, Dyslipidemia, Chylomicronemia, Hyperlipoproteinemia, Diet, Lipoprotein lipase, Pancreatitis
Effet d'un dispositif d'assistance au mouvement sur la cinématique, l'activité musculaire et la performance musicale de violonistes experts

Up to 93% of musicians are affected by playing-related musculoskeletal disorders, and particularly violinists who combine the major factors leading to these disorders: an asymmetrical and constrained posture, quasi-static weight (violin and left upper-limb) holding, quick repetitive movements, and finger pressure (onto the instrument’s neck), all leading to muscle fatigue accumulation. It is crucial to adjust violinists’ working environments to prevent muscle fatigue accumulation. Dynamic assistive support (DAS) is used in industrial settings to reduce muscle activations and thus potentially slow down fatigue development. Modifying violinists’ environmental dynamics by introducing the anti-gravitational force needed to support their left upper-limbs and instruments may perturb their movements and impair musical performance. The objective of this Masters’ project is thus to investigate motor adaptation to DAS by comparing upper-limb and neck (O1) kinematics, (O2) electromyography, and (O3) musical performance with and without DAS. Fifteen violinists were recruited from professional orchestras and graduate programs in music performance. Participants were equipped with 61 reflective markers and 11 electromyography electrodes to record kinematics and muscle activity, respectively. To quantify motor adaptation, violinists played a looped 13-second excerpt without (control), with (adaptation), and without (washout) DAS provided by a passive device (Kinova O110, Boisbriand, QC, Canada) applying an anti-gravitational force at the left elbow. All conditions were repeated one week later to test for potential savings. Nine to twelve months later, participants listened to their own audio recordings playing with and without DAS and blindly assessed their performances. Linear mixed models were used to compare DAS and no-DAS conditions’ kinematic, electromyography and musical performance data. The increase in angular error for all left degrees of freedom suggests that DAS perturbed violinists’ kinematics. The highly selective kinematic adaptation observed during the adaptation condition might have been due to the absence of auditory feedback prediction errors needed to drive motor adaptation. Indeed, musical performance with and without DAS showed no significant difference, indicating that expert violinists can maintain a high level of performance despite changes in motor output. Additionally, similarity of joint angles and muscle activities between DAS and no-DAS conditions remained strong. Finally, reduced activations of left medial deltoid and superior trapezius in assisted conditions make DAS a promising tool to limit violinists’ muscle fatigue accumulation and prevent playing-related musculoskeletal disorders.

Keyphrases: Motor adaptation, Motor control, Biomechanics, Electromyography, Mobility assistive device, Musicians’ health
Prédiction de la performance au hockey sur glace avec des évaluations de terrain

In ice hockey, the physical assessments used to date are not very specific to the task of ice hockey players and may have several limitations for predicting performance. Acceleration ability and maximum speed are highly related to player performance and only some off-ice physical assessments showed associations with these variables. Few studies have considered involvement of specific hip muscles, which are particularly solicited during the skating cycle. The data science and the use of machine learning tools have grown in recent years in the sports community. It has shown to improve prediction and has the ability to recognize complex and non-linear relationships between variables, and thus, can outperform standard statistical models and human intuition. Our main objective is the prediction of skating performance of ice hockey players with physical assessments and the use of machine learning models. We used data from physical assessment of 72 athletes who attended at the combine of the Quebec Major Junior Hockey League. We used acceleration and speed in forward and backward direction as target variables. The standard physical assessment performed on that day and isometric hip joint strength developed on its six degrees of freedom were input variables for a linear (LassoCV) and a non-linear (xgboost) model. Our machine learning models show good prediction errors by showing a mean absolute percentage error (MAPE) of less than 2.96±2.15% for the forward speed variables, while the prediction errors for acceleration and backward speed variables remain high (MAPE: > 4.46±4.15%). The broad jump and the isometric strength developed in hip flexion showed the most importance for acceleration over 5 meters (5F and 5B) and sprint over 30 meters (30F and 30B) in both skating directions. After validation of the models, coaches could use the results of these physical assessments to develop maximum forward speed performance of ice hockey players.

Keyphrases: Performance, Physical assessments, Machine learning, Prediction, Ice hockey, Skating
Caractérisation de la sénescence cellulaire durant le développement embryonnaire de l’axolotl

For several years, cellular senescence has been mainly studied as a process caused by the aging of cells and a mechanism to limit the propagation of precancerous cells. This perspective changed following the publications of Serrano and Keyes, who demonstrated the presence of senescent cells very early in the embryonic development of mice. Recently, the laboratory of Dr. Roy identified the pronephros, a transient organ which is replaced by the mesonephros (kidney counterpart in humans) at maturity, the olfactory nerve fascicles as well as the gums as areas rich in senescent cells during the development of axolotl. The evidence suggests that senescence is not only related to the aging process, but rather a physiological response which is activated by various signals present in its environment. To date, although several researchers are targeting the identification of control points for the activation of senescence, little is known about the role of senescent cells during embryonic development and how it could influence growth and morphogenesis. In the present study, we seek to identify the genes that are important in developmental senescence. The results of RNA sequencing in the axolotl pronephros have, among other things, demonstrated a significant enrichment of the PEBP1 gene which codes for a protein that acts as an inhibitor of the Raf kinase. Our findings support the idea that cellular senescence that occurs during the embryonic development of the axolotl is dependent on PEBP1 since the pharmacological inhibitor of PEBP1 (Locostatin), which blocks the interaction of PEBP1 with RAF, seems to affect the activity of senescent beta galactosidase. We suggest that PEBP1 is necessary for either the activation or the maintenance of senescence in the pronephros during embryogenesis. We further suggest that embryonic senescent is crucial for the morphogenesis of the developing organ perhaps by keeping the organ functional during the transition.

Keyphrases: axolotl, embryon, RKIP, PEBP1, RNA-seq, Development, Axolotl, Pronephros, Olfactory, Gums
Caractérisation de nouveaux modèles TDP-43/TDP-1 de Caenorhabditis elegans pour la maladie sclérose latérale amyotrophique

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive and selective loss of motor neurons. ALS is incurable and there are no effective treatments available for people living with the disease. About 90% of the cases are sporadic whereas 10% are familial, and patients usually die two to five years after symptom onset. Many gene defects are associated with ALS, including mutations in genes encoding FUS, C9orf72, SOD-1 and TDP-43 proteins. We have developed a transgenic Caenorhabditis elegans model expressing human mutant TDP-43(Q331K) in GABAergic motor neurons. We have also obtained by mutagenesis and CRISPR-Cas9 physiologically accurate models based on mutations in tdp-1, the C. elegans ortholog of TARDBP. Our objective is to characterize these models and determine if they can recapitulate key aspects of the disease such as motor deficits and age-dependent neurodegeneration causing paralysis. We believe that the TDP-1 model will reflect more precisely the physiological expression of the gene in the human disease because of its mutation in an endogenous gene, the absence of overexpression and ubiquitous protein expression. Our results show that both TDP-43 and TDP-1 models have motor deficits, synaptic transmission impairments and age-dependent neurodegeneration. However, only the TDP-43 mutation seems to have an effect on lifespan. These models provide different physiological expression of mutant proteins and thus phenotypes of varying intensity levels. They will be useful tools to elucidate new pathogenic mechanisms of ALS as well as being good candidates for drug screening and developing therapeutic strategies.

Keyphrases: TDP-43, TDP-1, C. elegans, ALS, Neurodegeneration, GABAergic motoneurons, Model
Rôle oncogénique de LMO1/2 par la dérégulation de la réplication

The acute lymphoblastic leukemia affects 30% of children with cancer. Chromosomal rearrangement implicating LMO1 or LMO2 are found in 60% of T-cell acute lymphoblastic leukemia (T-ALL) cases. Contrary to their known transcriptional role, their precise function in DNA replication is still unclear. We previously showed that LMO2 interacts with the replication complex and its aberrant expression induce DNA replication. Interestingly, preliminary data show that overexpression of LMO1 in mice lead to an increase in DNA damage at the pre-leukemic stage. Moreover, 90% of T-ALL patients present a deletion of CDKN2A/B genes, which are important regulators of senescence. In order to demonstrate the importance of the role of LMO1/2 in DNA replication, I studied the interaction between LMO2 and proteins from the replicative complex, its functional consequence as well as the induction of senescence that may result from it. Sequence analysis of yeast two-hybrid clones of interaction with LMO2 (POLD1, MCM6, PRIM1 and KAT7) identified important domains for these interactions, more specifically, a zinc finger domain in KAT7 protein. A second bioinformatic approach of gene dependency and drug sensitivities using the Depmap and CancerRX databases has revealed a specific DNA replicative stress in leukemic cell lines. Interestingly, the majority of leukemic cell lines (6 out of 7) which present a sensitivity to drug causing DNA damage expresses either LMO1 or LMO2 oncogenes. Finally, using FACS intracellular labelling, the overexpression of LMO1 and its partner SCL in thymocytes lead to an increase in p16 protein levels, a marker of senescence, at the pre-leukemic stage.  Our results revealed the impact of LMO1 and LMO2 oncogenes overexpression in T-ALL leukemia, in particular, on DNA replication. This replicative stress and the specific sensitivity of leukemic cell lines to drug causing DNA damage could therefore explain the effectiveness of certain clinical treatments against leukemia.

Keyphrases: LMO2, Leukemia
Implication de NF-κB et BMI1 dans la production de cytokines pro-inflammatoires dans un modèle de neurodégénérescence

Neurodegenerative diseases are a group of neuropathologies characterized by the progressive dysfunction of neurons and their death in the central nervous system. Among these diseases, Alzheimer's disease (AD) is the most common one. Although no aetiology has yet been identified, aging is therefore the main risk factor for AD. Thanks to several research work on aging, cellular characteristics and biochemical changes, such as senescence and inflammaging, have been associated with this phenomenon. Senescence, which is defined as a state of cell cycle arrest, could worsen neurodegenerative diseases throughout senescence associated secretory phenotypes. The involvement of the proto-oncogene BMI1 in cell cycle regulation and senescence has been demonstrated through its inhibition of the INK4/ARF locus. Additionally, BMI1 deficiency has been reported in neurons of AD patients, and it is also associated with early neurodegeneration. The NF-κB complex participates in the expression of a wide range of pro-inflammatory cytokine involved in the processes of inflammaging and cellular senescence. However, little is known about the joint involvement of BMI1 and NF-κB molecules in neurodegeneration processes. Given this context, within the framework of this master's project, we wanted to explore the combined implication of BMI1 and the canonical pathway of the NF-κB factor in the production of pro-inflammatory cytokines using in vivo and in vitro models reproducing a neurodegenerative phenotype similar to Alzheimer's disease. Our results indicate that a deficiency in BMI1 is correlated to an inactivation of the NF-κB expression both in vitro and in vivo neurones, as well as with a decrease in the expression of cytokines IL6 and IL8. Although we present results generated from unduplicated experiments, they nonetheless converge towards similar conclusions obtained in studies carried out on cancerous pathologies. Thus, our project provides additional information that could help to understand the mechanisms underlying the inflammaging phenomena in neurodegeneration.

Keyphrases: BMI1, NF-κB, Inflammaging, Neurodegeneration, Alzheimer's disease, Cellular senescence, Senescence-associated secretory phenotype (SASP)
Les défis du nouvel accord de commerce entre le Canada, les États-Unis et le Mexique (ACEUM) face à la mobilité de la main-d'œuvre professionnelle

The new United States–Mexico–Canada Agreement (USMCA) came into force the July 1 2020, introducing Annex 15-C with nine provisions regarding trade in professional services, and a new appendix on the recognition of professional qualifications. This appendix provides guidelines for the creation of future mutual recognition agreements or arrangements (MRAs) in the professional services sector. These principles raise many questions, including whether USMCA will be enough to ensure the effective implementation of future MRAs, unlike the two previous experiences of MRAs under NAFTA.   The purpose of this thesis is to advance guidelines providing key elements that must be taken into account by future negotiators of MRA-USMCA, in order to guarantee a successful implementation. Moreover, our goal is to lay the foundations on which to build a true legal system for the recognition of professional qualifications in America. This thesis stems from the idea that there is an essential interrelation between trade agreements, agreements regulating trade in professional services, professional labor mobility, and, of course, mutual recognition of professional qualifications. The development of these guidelines is inspired by the analysis of MRAs under the former NAFTA, the study of main legal frameworks of recognition in Europe and, more specifically, the content and experiences of France-Quebec MRA. This review is essential for a comprehensive understanding of the principles regarding the recognition of professional qualifications, the necessary conditions for MRAs implementation, as well as their main obstacles, advantages, and challenges. This research will allow us to present the scenario needed to arrive to an appropriate structure in future MRA-USMCA negotiations.   Our study finds that the new provisions on trade in professional services are insufficient, even though they represent a significant advancement in comparison to the old NAFTA. They constitute a starting point for the creation of stronger MRAs-USMCA. Our analysis also notes that the implementation of MRAs must be accompanied by a change of mentality regarding the possibility of integrating recognition systems between three countries with different contexts. Furthermore, MRAs will have to be conceived not only as instruments intended to establish the conditions for the recognition of professional qualifications, but also as essential tools for the construction of a global recognition system that promotes the integration of professionals into the labor market.

Keyphrases: Accord de commerce, Immigration, Canada, Mutual recognition of qualifications, Trade agreement, Trade in professional services, Labor mobility, Professional corporation, Access to employment, United States, Mexico
Précarité d’emploi et défaillances du cadre juridique : exemple de l’industrie de la restauration

This thesis focuses on the ability of Quebec labour laws to fully exert their protective role in the current context of the labour market. To explore this question in depth, we have chosen to analyze the application of the law in an industry where working conditions are often difficult and restrictive, even downright precarious, namely the restaurant industry. Specifically, this analysis focuses on the difficulties posed by the application of legal standards intended to regulate the employer-employee relationship. We look at the facets of the restaurant industry where the application of these standards is likely to fail, namely the identification of the real employer in restaurant franchises, the employee control over working hours, job security and access to unionization. This study is meant to show that, in their current form, labour laws worsen the instability that characterizes the working conditions to which employees in the restaurant industry are subjected. This thesis sheds light on the reasons why the protection enjoyed by these employees is in many cases insufficient. Although it is confined to a single sector of economic activity, this study is part of a global phenomenon in the sense that the dynamics causing the difficult working conditions in the restaurant industry affect the whole labour market.

Keyphrases: Precarious Employment, Atypical Work, Determination of the Real Employer, Work Schedule, Job Security, Unionization, Restaurant Industry
L’institutionnalisation de la scène Hip-hop underground à Montréal, ses enjeux et rapports au mainstream

This study examines the current organization of the underground Hip-hop scene in Montreal and its power relations. To understand its dynamics, tensions and competition, we investigate the complex structure of the underground scene. Approaching this research as a case study, we met the artists-rappers from the two Montreal’s collectives Kalmunity et Urban Science. We then noticed that the collectives become institutions of the underground scene. With no actual locations dedicated to Montreal's Hip-hop culture, the collectives themselves embody a symbolic space where social actors can gather and create a hub for the network of professionals within the underground scene through a system of rules and social and artistic practices. The underground scene is hinged on the main issue of visibility, organizing the social dynamics and relational logics. We observe two types of visibility : an underground and social visibility structured around the collectives, based on reputation inside a restricted group of artists, facing a mainstream and mediatic visibility, built on fame and propelled by the media. Finally, the underground artists regard power as a form of domination by the media. They refuse the media injonctions seen as extrinsic to the scene. Conversely, the collectives represent a legitimate authority for underground artists, practiced inside their restricted community, therefore coherent to their artistic practices.

Keyphrases: Hip-Hop, Rap, underground, mainstream, institution, visibility, scene, power, authority, media