NCube/papyrus huggingface dataset:
The role of MARCH1 in the B16 melanoma model

The mechanisms of cancer immunosurveillance are beginning to be understood and the concept is being supported by tremendous experimental and clinical data. While all arms of the immune system are required for maximal anti-tumor responses, the importance of CD4+ T cells in tumor eradication is now well established. However, this concept was initially problematic, as most non-hematopoietic tumors do not express MHC class II molecules at their surface, which are necessary for recognition by CD4+ T cells. It is most likely that the early response is dependent on infiltrating APCs that uptake tumor antigens and present them to CD4+ T cells via their MHC class II molecules. We thus sought to study the impact of MARCH1, an E3 ubiquitin ligase which interacts with MHC class II molecules and limits their cell surface exposure, in the context of the B16 melanoma model. Comparing wild-type mice and MARCH1-deficient mice, we posited that MARCH1-deficient mice would react poorly to the B16 tumor challenge as stabilized MHC class II expression leads to severe impairments in DCs. Our findings demonstrate that MARCH1 KO mice developped more aggressive and larger tumors than their wild-type littermates. This was seemingly due to an defective DC-mediated priming of CD4+ T cells in the lymph nodes, resulting in a significantly reduced CD4+ TIL population.

Keyphrases: MARCH1, cancer, antigen presentation, MHC class II
Transfusions de globules rouges en néonatologie et syndrome de défaillance multiviscérale aiguë

In the first few months of life, the level of hemoglobin (Hb) in the newborn normally decreases. This physiological anemia is more severe in neonates admitted to a neonatal intensive care unit (NICU), who frequently require a red blood cells (RBC) transfusion. In neonatal medicine, the indications for transfusion are controversial and practices are highly variable. To better understand those practices, we conducted the prospective study: «Epidemiology and determinants of red blood cells transfusion in a neonatal intensive care unit: a cohort study». Among the patients consecutively admitted to NICU during the study period, 13.4% received at least one RBC transfusion. Although premature babies born at less than 28 weeks gestation received the majority of transfusions (62.2%), term neonates admitted to NICU were also frequently transfused (4.9% of transfusions). The main justifications for giving a RBC transfusion were: low Hb level, underlying illness and to improve oxygen delivery. We also observed a wide range of Hb thresholds that triggered a decision to transfuse (from 62 to 137 g/L). The multiple organ dysfunction syndrome (MODS), which is defined as the simultaneous dysfunction of at least two organs or systems, is highly associated with mortality and morbidity in critically ill children. The association between MODS and transfusions is also well described in this population. Two sets of criteria of pediatric MODS are currently used in the medical literature: one by Proulx, and another by Goldstein. We did the prospective cohort study «Multiple organ dysfunction syndrome in critically ill children : clinical value of two lists of diagnostic criteria» to validate and compare the diagnostic value of those two definitions of MODS. We observed that the epidemiology of MODS varies according to which list of criteria is used: the incidence was 21.4% vs. 37.3% with Proulx and Goldstein criteria, respectively. Both sets of criteria have a good inter- and intra-rater reproducibility. The diagnostic of MODS according to Proulx criteria is associated with higher 90-days mortality (17.8% vs. 11.5%, p = 0.038). MODS is also described in neonates, using a score adapted to this population, the NEOMOD. Neonatal MODS represents an interesting outcome measure in clinical trials in neonatal transfusion medicine. However, prior to that, it needs to be better characterized.

Keyphrases: Transfusion, Érythrocytes, Diagnostic, Red blood cells, Erythrocytes, Neonates, Neonatology, Intensive care, Diagnosis, Mortality, Multiple organ dysfunction syndrome, Paediatric
Étude de l’activité cardiaque dans l’autisme adulte au repos à deux moments de la journée : hyperactivité sympathique matinale

Individuals with autistic spectrum disorder (ASD) show higher sympathetic activity of the autonomic nervous system (ANS) during wake. It is known that typically developing (TD) individuals show higher sympathetic activity in the morning compared to the evening. Studies suggest that sleep has an influence on ANS functioning. The goal of this study is to explore evening and morning ANS activity of a group of adults with ASD and a group of TD adults and to explore its relationships with subjective sleep parameters of participants. Electrocardiographic data of both groups were recorded before and after a night of sleep. Group comparisons were done on participant’s subjective sleep data and heart rate variability (HRV) in the evening and the morning. Correlations were then performed between subjective sleep measures and morning HRV parameters. Spectral analysis of the HRV showed higher sympathetic activity in the morning for the ASD group compared to the TD group. When all participants were grouped, longer nocturnal awakening and lower sleep efficiency were correlated with higher sympathetic activity in the morning. This suggest that sleep disturbances in ASD influences ANS functioning and results in higher sympathovagal balance in the morning. To our knowledge, this is the first study to investigate ANS activity of ASD adults in relation to sleep, and it may improve our understanding of the pathophysiology of this disease.

Keyphrases: Autonomic nervous system, Heart rate variability, Sleep, Autism
L’efficacité du pancréas artificiel externe durant l’exercice chez les adultes atteints de diabète de type 1

Background: Physical activity is often avoided by patients with Type 1 diabetes (T1D) despite its health benefits due to fear of its elevated hypoglycemic risk. The external artificial pancreas is a new technology that controls glucose via a closed-loop strategy of three components; a continuous glucose monitoring system (CGMS), an algorithm and an insulin pump. Studies of the artificial pancreas included physical activity sessions but were rarely designed to specifically assess its efficacy during exercise. Moreover, the precision of the CGMS can be affected by the rapidly changing blood glucose levels during exercise. Objectives: 1) To test and compare the efficacy of the two versions of the artificial pancreas, single-hormone (insulin only) and dual-hormone (insulin plus glucagon) during two types of exercise, continuous and interval, in patients with T1D. 2) To compare the performance of two CGMS, Dexcom and Enlite, at rest and during exercise. Results: 1) During single-hormone artificial pancreas in comparison to dual-hormone, 31.2% of the participants had at least one hypoglycemic episode necessitating treatment vs. 9% (p=0,02) and 24.4 ± 27.6 % of the time spent in hypoglycemia (plasma glucose < 4 mmol/l) vs. 4.4 ± 14.3% (p=0.0001), respectively. 2) The mean relative absolute differences (MARD) in reference to plasma glucose for Dexcom vs. Enlite were at rest 13.8 vs. 12.4% (p=0.53) and during exercise 22.5% vs. 20.4% (p=0.58). The comparison of mean ARD`s at rest vs. exercise were significant for Dexcom (p=0.005) and Enlite (p=0.007). Conclusions: The dual-hormone artificial pancreas was shown to be better than single-hormone at achieving hypoglycaemia-free control during exercise in adults with T1D. Dexcom and Enlite demonstrated comparable overall performances during rest and physical activity with a lower accuracy for both sensors during exercise.

Keyphrases: Type 1 diabetes, Hypoglycemia, Exercise, External artificial pancreas, Continuous glucose monitoring system
Expression de l’early growth response protein-1 (Egr-1) par le peroxyde d’hydrogène (H2O2) nécessite l’activation de l’IGF-1R, de c-Src et de PKC dans les CMLV

Increased generation of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), plays a key role in the pathophysiology of cardiovascular diseases (CVD). Excessive growth and proliferation of vascular smooth muscle cells (VSMCs) has been suggested as an important contributor of vascular dysfunction. A potential involvement of early growth response protein-1 (Egr-1), a zinc-finger transcription factor, in the development of vascular injury has been proposed. Recent studies have shown that H2O2 increases Egr-1 expression in VSMCs. However, signaling events leading to H2O2-induced Egr-1 expression are not fully understood. Therefore, this study aims to examine the signaling pathways implicated in H2O2-induced Egr-1 expression in VSMC. H2O2 increased Egr-1 expression in a time and dose-dependent fashion in A10 VSMC. Pharmacological blockade of tyrosine kinases insulin-like growth factor-1 receptor (IGF-1R) and c-Src, by AG1024 and PP2 respectively, attenuated H2O2-induced Egr-1 expression, while AG1478, an epidermal growth factor receptor (EGFR) inhibitor, and PP3, the inactive analogue of PP2, have no effect on Egr-1 expression. Pharmacological blockade of extracellular signal-regulated kinase 1/2 (ERK1/2), by UO126, and proteine kinase C (PKC), by rottlerin and rö-31-8220, decreased H2O2-induced Egr-1 expression. In summary, our results suggest that H2O2 triggers Egr-1 expression through IGF-1R, c-Src, ERK1/2 and PKC in VSMC.

Keyphrases: Egr-1, H2O2, MAPK, ERK1/2, VSMC, PKC
La fonte cornéenne post-kératoprothèse de Boston type I : épidémiologie, pathophysiologie et approche novatrice pour sa prévention

Corneal melting after implantation of a Boston keratoprosthesis (B-KPro) is a severe sight- and globe-threatening complication. While multifactorial, the final mechanism leading to corneal melting is mediated by matrix metaloproteinases (MMP). The activity of these enzymes is induced by inflammatory cytokines, mostly tumor necrosis factor alpha. The objectives of this thesis is to 1) report the epidemiologic data surrounding post-B-KPro corneal melting, 2) caracterize the content and activity of MMP, myeloperoxidase (MPO) and tissue inhibitor of metalloproteinase 1 (TIMP-1) in the tears of patients with a B-KPro and to distinguish these enzymatic profiles in accordance to the underlying ocular diagnosis and 3) to develop an ophthalmic drop of infliximab and to evaluate its in vitro characteristics. A literature review and a review of all B-KPros implanted at the CHUM allowed identification of the risk factors of corneal melting, the most important being corneal stromal nutrition and the presence of inflammation. The enzymatic profile at the ocular surface was determined through bead-based multiplex ELISA. Significant elevations of MMP-8, MMP-9 and MPO in the tears of B-KPro eyes were correlated with the type of underlying corneal pathology but not with the presence of clinically significant corneal melting. Topical infliximab 10 mg/mL remained sterile, stable and non toxic to ocular surface epithelium when prepared and used in accordance with United States Pharmacopeia recommendations. In conclusion, ocular surface inflammation is an important risk factor for corneal melting with B-KPro and therapeutic strategies to inhibit MMP should be explored in future clinical studies.

Keyphrases: Corneal melt, Keratolysis, Tumor necrosis factor alpha, Matrix metalloproteinase, Infliximab, Boston keratoprosthesis
Évaluation des facteurs influençant l’évolution clinique et l’utilisation des ressources au cours de l’hospitalisation aigue suivant une tétraplégie traumatique et leurs impacts sur la récupération fonctionnelle six mois post-lésion

Introduction and objectives: The occurrence of a spinal cord injury (SCI) causing tetraplegia is a tragic event leading to devastating consequences on the life of individuals and huge costs to our healthcare system.  Individuals who experience a traumatic SCI (TSCI) with tetraplegia require several weeks of hospitalisation in an acute care center where they are at risk of various medical complications. While factors related to the initial trauma or to the patient’s baseline characteristics are recognized to determine their clinical outcome, the impact of the perioperative management following a TSCI is still unclear. Thus, the main objective of this study is to identify factors influencing the course of acute care hospitalization in terms of clinical outcome and use of hospital resources following acute tetraplegia. Then, in order to determine clinical relevance of these factors in longer-term outcome of patients, the second objective of this project is to determine if these factors also have an impact on the functional recovery six months post injury.   Methods and results: A retrospective cohort study in a single level-1 trauma center specialized in SCI care, and a predictive prospective study were completed. Early admission to a specialized SCI center and a decreased incidence of medical complications during acute care hospitalization were found to significantly improve clinical outcomes and decrease resource utilization during acute care. Higher occurrence of medical complications and longer acute care length of stay were significant predictors of lower functional recovery (as measured by the Spinal Cord Independence Measure six-months post injury).  Conclusions: Optimization of acute care hospitalization in a specialized center may improve clinical outcomes and decrease hospital resource utilization following acute tetraplegia and thereby have a positive impact on the 6-month functional recovery. Early admission and complete perioperative management in a specialized SCI center is thus recommended following tetraplegia. This could also reduce the economic burden on our healthcare system.   Clinical applications and future directions: By highlighting the importance of high-quality care following acute SCI, this study supports current recommendations suggesting prompt transfer to a specialized acute care center following tetraplegia. Acute care management focussing on the early prevention of medical complications and optimization of recovery should be provided as early as possible following tetraplegia. Future projects working towards development of precise clinical and administrative protocols for acute SCI care will help to better regulate and define the importance of specialized centers, and to promote knowledge transfer.

Keyphrases: Spinal cord injury, specialized centers, resources utilization, clinical outcomes, functional recovery
Prédiction des enfants petits pour l’âge gestationnel par biométrie fœtale et étude de l’impact du délai échographie-accouchement

Objectives: To compare third trimester ultrasound screening methods to predict small for gestational age (SGA), and to evaluate the impact of the ultrasounddelivery interval on screening performance Methods: Data were collected from IRNPQEO/3D study: a multicenter prospective singleton cohort study in Quebec hospitals. We compared SGA prediction by the following methods: Abdominal circumference Z-score based on Hadlock (Hadlock AC), Intergrowth 21st study (Intergrowth AC) or Salomon (Salomon AC); estimated fetal weight (EFW) Z-score from Hadlock (Hadlock EFW); EFW based on customized curves from Gardosi (Gardosi EFW) and fetal growth velocity (FGVAC) based on AC between the second and the third trimester. Ultrasound-delivery intervals studied were: <4 weeks, <6 weeks and <10 weeks.  Results: 1805 patients had a third trimester ultrasound performed (median gestational age 32). Ultrasound-delivery interval was less than 4 weeks in 17% cases, less than 6 weeks in 47.5% and less than 10 weeks in 96% of cases. Areas under ROC curve (AUC) were 0.772, 0.768, 0.766, 0.765, 0.708 and 0.674 respectively for Salomon AC, Hadlock EFW, Hadlock AC, Intergrowth AC, Gardosi EFW and FGVAC. The best AUC were 0.856 for Hadlock AC, 0.824 for Hadlock AC and 0.784 for Hadlock EFW, for intervals <4, 6 and 10 weeks, respectively. At a fixed 10% false positive, best detection rates were 60.0% for Intergrowth AC, 44.3% for Hadlock AC and 42.1% for Salomon AC, for intervals <4, 6 and 10 weeks, respectively. Conclusion: Third trimester ultrasound measurements provide poor to moderate prediction for SGA. A shorter ultrasound-delivery interval provides a better prediction.

Keyphrases: RCIU, Hadlock, Small for gestational age, Ultrasound, Fetal growth, Hadlock
Facteurs de risque de mortalité des enfants à l’initiation de la thérapie de remplacement rénal aux soins intensifs

Introduction: Mortality rate associated with acute kidney injury (AKI) in pediatric intensive care units (PICU) exceeds 50%. Prior studies on renal replacement therapy (RRT) have highlighted different mortality risk factors including the presence of a multiple organ dysfunction syndrome (MODS) and fluid overload ≥ 10 to 20% before starting RRT. The aim of this study was to identify most important risk factors of 28-day mortality in patients with AKI at RRT initiation in PICU. Methods: We conducted a retrospective cohort study in a tertiary care pediatric center. All critically ill children who underwent acute continuous RRT or intermittent hemodialysis for AKI between January 1998 and December 2014 were included. A case report form was developed and specific risk factors were identified by a panel of four pediatric intensivists and two nephrologists. Risk factors analysis was made using logistic regression in SPSS and SAS software. Results: Ninety patients were included. The median age was 9 [2-14] years. The most common indication for RRT initiation was fluid overload (FO) (64.2%). The median PICU length of stay was 18.5 [8.0-31.0] days. Forty of the 90 patients (44.4%) died within 28 days after RRT initiation and forty-five (50.0%) died before PICU discharge. In a multivariate logistic regression analysis, a PELOD score ≥ 20 (OR 4.66; 95%CI 1.68-12.92) and percentage of FO ≥ 15% (OR 9.31; 95%CI 2.16-40.11) at RRT initiation were independently associated with mortality. Conclusion: This study suggests that fluid overload and severity of MODS measured by PELOD score are two risk factors of 28-day mortality in PICU patients on RRT.

Keyphrases: Hémodialyse intermittente (HDI), Acute kidney injury (AKI), Fluid overload, Intermittent hemodialysis (IHD), Multiorgan dysfunction syndrome (MODS), PELOD, Risk factor, Mortality, Pediatric intensive care unit (PICU), Renal replacement therapy (RRT)
Étude génétique et fonctionnelle des gènes de la région 14q31 associée aux maladies inflammatoires de l’intestin

Inflammatory bowel diseases, mainly comprising of ulcerative colitis (UC) and Crohn’s disease (CD), result in the chronic inflammation of the gastrointestinal tract. Genome-wide association studies have associated the 14q31 locus, including the genes galactosylceramidase (GALC) and G protein-coupled receptor 65 (GPR65), to those phenotypes. The most associated variant in this region for IBD (rs8005161; p=2,35x10-14) is correlated (r2=1) to a missense coding variant of GPR65 (rs3742704: Ile231Leu). GPR65 encodes a pH-sensing G protein-coupled receptor (GPCR). We observed that GPR65 is expressed in lymphoid and mucosal tissues as well as in immune cell lines and human primary immune cells. We also found that its expression is significantly increased in inflamed biopsies from UC patients compared to non-inflamed biopsies and biopsies from healthy controls. Upon activation by low pH, GPR65 stimulates accumulation of cAMP, formation of stress fibers and activation of the RhoA pathway. Thus GPR65 is a good candidate causal gene for the IBD pathology. Our objective, therefore, was to define pathways downstream of activation of GPR65 and to evaluate the impact GPR65*231Leu on these pathways. We used HEK 293 cells stably expressing one or the other allele of GPR65 and deficient for either Gαs/olf, Gαq/11 or Gα12/13 as it is known that Gαs/olf activates adenylyl cyclase, Gαq/11 leads to the release of intracellular Ca2+, which can also activate certain isoforms of adenylyl cyclase, and that Gα12/13 regulates actin cytoskeletal remodeling. We demonstrated that cAMP accumulation upon activation of GPR65 is, at least partly, due to the Gαs/olf pathway and only slightly or not at all to the Gαq/11 pathway. The coding variant, however, does not appear to have an effect on that pathway. In contrast, we observed that GPR65*231Leu variant reduces the GPR65-dependent stress fiber formation and inhibits the increase of filamentous actin (F-actin) content versus free globular-actin (G-actin) upon activation by low pH. Also, preliminary data showed that the stress fiber formation in HEK293 cells is due to the G12/13 pathways. In conclusion, we demonstrate that GPR65 activates both Gαs and Gα12/13, the coding variant alters the actin remodeling pathway and that GPR65 potentially has a causal role in IBD.

Keyphrases: 14q31, GPR65, GALC, AMP cyclique, genetic, G protein-coupled receptor, cyclic AMP, actin cytoskeleton, acidic pH
Effets du diabète de type 2 sur l’expression et l’activité des cytochromes P450 hépatiques et extra-hépatiques chez la souris C57BL/6 sous une diète riche en gras

Around 387 million people worldwide suffer from type 2 diabetes (T2D).  Patients with T2D often require polypharmacy, not only to ensure glycaemic control, but also to prevent and control micro- and macrovascular comorbidities associated with T2D. However, clinical practice reveals that some diabetic patients show highly variable responses to different drugs in comparison with non-diabetic patients.  Variable drug dosages and effects are observed for drugs such as clopidogrel, warfarin, cyclosporine and tacromilus. This intersubject variability in drug response in diabetic patients is an important issue as it may results in treatment failure, adverse effects or even drug toxicity. One of the underlying mechanisms suggested to explain the intersubject variability in drugs responses in diabetic patients is their modified ability to eliminate drugs through metabolism. Evidence support the association between inflammatory diseases, such as T2D, and an activity modulation of metabolism enzymes. It is known that these inflammatory processes can modulate the expression and activity of enzyme proteins, such as the cytochromes P450 (CYP450s), a major enzyme system in drug metabolism. Moreover, several organs express various CYP450s isoenzymes that may contribute to the local drug metabolism, thus influence the drugs concentration within the target organs. Therefore, the aim of this study is to assess the effects of T2D on the expression and activity of CYP450s in order to identify their responsibility in the intersubject response variability to drugs using diet-induced obesity (DIO) mice as a model.  The work carried out as part of this thesis shows that there is a modulation of the expression and activity of CYP450s isoenzymes in the DIO mouse model. Our results indicate that this modulation occurs in an isoenzyme-specific and tissue-dependent fashion. This work supports that the presence of diabetes with obesity affects hepatic and extrahepatic CYP450s, which may influence the systemic and local drug concentrations, respectively.  In a future and translational perspective, our study will lead to a better understanding of the drug elimination capacity in diabetic patients, and thus will prompt an appropriate dosage adjustment for drugs metabolized by CYP450s in diabetic patients: a step forward towards a more personalized medicine approach.

Keyphrases: Cytochromes P450, Extra-hepatic CYP450s, Type 2 diabetes, Intersubject variability, Pharmacokinetics