Élargir les mandats de responsabilité sociale à la recherche biomédicale dans les facultés canadiennes

Background: Social accountability (SA), as defined by Boelen and Heck, is the obligation of medical schools to address the needs of communities through education, research and service activities. While SA is embedded within health profession education frameworks in medicine, they are rarely taught within graduate-level (MSc/PhD) education. Methods: As these programs train future medical researchers, we invited first-year graduate students enrolled in a mandatory professionalism class at our institution (n = 111) to complete a survey on their perceptions of the importance of SA in their research, training, and future careers. Results: Over 80% (n = 87) of respondents agreed that SA is relevant and felt committed to integrating it into their future research activities, only a limited number of students felt confident and/or supported in their abilities to integrate SA into their research. Conclusions: Specific SA training in graduate education is necessary for students to effectively incorporate elements of SA into their research, and as such support the SA mandates of their training institutions. We posit that awareness of SA principles formalizes the professional standards for biomedical researchers and is thus foundational for developing a professionalism curriculum in graduate education programs in medicine. We propose an expansion of the World Health Organization (WHO) partnership pentagon to include partners within the research ecosystem (funding partners, certification bodies) that collaborate with biomedical researchers to make research socially accountable.Contexte : La responsabilité sociale (RS), telle que définie par Boelen et Heck, est l'obligation pour les facultés de médecine de répondre aux besoins des communautés par l’entremise de l'éducation, de la recherche et des activités de service. Bien que la responsabilité sociale soit intégrée dans les cadres de formation des professionnels de santé en médecine, elle est rarement enseignée au niveau des études supérieures (MSc/PhD). Méthodes : Étant donné que ces programmes forment les futurs chercheurs médicaux, nous avons invité les étudiants de première année inscrits à un cours obligatoire sur le professionnalisme dans notre établissement (n = 111) à participer à une enquête sur leurs perceptions de l'importance de la RS dans leur recherche, leur formation et leur future carrière. Résultats : Plus de 80 % (n = 87) des répondants ont reconnu la pertinence de la RS et se sont engagés à l'intégrer dans leurs futures activités de recherche, mais seul un nombre limité d'étudiants se sont sentis confiants et/ou soutenus dans leurs capacités à intégrer la RS dans leur recherche. Conclusions : Une formation propre à la RS dans le cadre des études supérieures est nécessaire pour que les étudiants puissent intégrer efficacement des éléments de la RS dans leur recherche, et ainsi promouvoir les mandats de RS de leurs établissements de formation. Nous estimons que la sensibilisation aux principes de la RS formalise les normes professionnelles des chercheurs biomédicaux et qu'elle est donc fondamentale pour l'élaboration d'un programme de professionnalisme dans les programmes d'études supérieures en médecine. Nous proposons d'élargir le pentagone du partenariat de l'Organisation mondiale de la santé (OMS) pour y inclure les partenaires de l'écosystème de la recherche (partenaires financiers, organismes de certification) qui collaborent avec les chercheurs biomédicaux pour rendre la recherche socialement responsable

Pre-B cell to macrophage transdifferentiation without significant promoter DNA methylation changes

Transcription factor-induced lineage reprogramming or transdifferentiation experiments are essential for understanding the plasticity of differentiated cells. These experiments helped to define the specific role of transcription factors in conferring cell identity and played a key role in the development of the regenerative medicine field. We here investigated the acquisition of DNA methylation changes during C/EBPα-induced pre-B cell to macrophage transdifferentiation. Unexpectedly, cell lineage conversion occurred without significant changes in DNA methylation not only in key B cell- and macrophage-specific genes but also throughout the entire set of genes differentially methylated between the two parental cell types. In contrast, active and repressive histone modification marks changed according to the expression levels of these genes. We also demonstrated that C/EBPα and RNA Pol II are associated with the methylated promoters of macrophage-specific genes in reprogrammed macrophages without inducing methylation changes. Our findings not only provide insights about the extent and hierarchy of epigenetic events in pre-B cell to macrophage transdifferentiation but also show an important difference to reprogramming towards pluripotency where promoter DNA demethylation plays a pivotal role

Expression of CCAAT/Enhancer Binding Protein Beta in Muscle Satellite Cells Inhibits Myogenesis in Cancer Cachexia.

Cancer cachexia is a paraneoplastic syndrome that causes profound weight loss and muscle mass atrophy and is estimated to be the cause of up to 30% of cancer deaths. Though the exact cause is unknown, patients with cancer cachexia have increased muscle protein catabolism. In healthy muscle, injury activates skeletal muscle stem cells, called satellite cells, to differentiate and promote regeneration. Here, we provide evidence that this mechanism is inhibited in cancer cachexia due to persistent expression of CCAAT/Enhancer Binding Protein beta (C/EBPβ) in muscle myoblasts. C/EBPβ is a bzip transcription factor that is expressed in muscle satellite cells and is normally downregulated upon differentiation. However, in myoblasts exposed to a cachectic milieu, C/EBPβ expression remains elevated, despite activation to differentiate, resulting in the inhibition of myogenin expression and myogenesis. In vivo, cancer cachexia results in increased number of Pax7+ cells that also express C/EBPβ and the inhibition of normal repair mechanisms. Loss of C/EBPβ expression in primary myoblasts rescues differentiation under cachectic conditions without restoring myotube size, indicating that C/EBPβ is an important inhibitor of myogenesis in cancer cachexia

Angiotensin 1-7 increases fiber cross sectional area and force in juvenile mouse skeletal muscle

Recent studies reported that in skeletal muscle angiotensin 1-7 (Ang 1-7), via its receptor Mas (MasR), prevents the atrophy induced by angiotensin II and by cast immobilization; it also improves muscle integrity and function in the mdx mouse, a muscular dystrophy model. The objectives of this study were to document i) the extent of the Ang 1-7's hypertrophic effect in terms of muscle mass and muscle fiber cross sectional area (CSA), ii) how Ang 1-7 affects muscle contractile function in terms of twitch and tetanic force, force-frequency relationship, and iii) whether the effect involves MasR. Wild type and MasR deficient (MasR(-/-)) mice were treated with Ang 1-7 (100 ng/kg body weight·min using an osmotic pump) for 4 or 16 weeks. Ang 1-7 significantly increased skeletal muscle/body weight ratio of soleus, tibialis and gastrocnemius, but not of EDL. It significantly increased fiber cross sectional area in the order of type I>IIA>IIB. In EDL and soleus muscles, it significantly increased twitch and tetanic force while causing a shift in the force-frequency relationship toward lower stimulation frequencies. It had no effect on fiber type composition. None of the Ang 1-7 effects observed in wild type mice were observed in MasR(-/-) muscles. It caused a transient increase in phosphorylated Akt and 4EBP proteins while having no effect on the phosphorylation of S6, MuRF-1 and atrogin-1 and a decrease in PAX7 expression in satellite cells. This is the first study demonstrating the hypertrophic effects of Ang 1-7 in normal muscle acting via its MasR

Transcription Factor Smad3 Is Required for the Inhibition of Adipogenesis by Retinoic Acid*

The process of adipocyte differentiation is driven by a highly coordinated cascade of transcriptional events that results in the development of the mature adipocyte and in lipid accumulation. One of the early events of differentiation is the up-regulation of CCAAT/enhancer-binding protein β (C/EBPβ) expression. C/EBPβ then acts to up-regulate the expression of adipogenic factors such as C/EBPα, which control the late stage of adipogenesis. Retinoic acid (RA) is a potent inhibitor of adipogenesis, and its action appears to block C/EBPβ transcriptional potential early during differentiation. Using preadipocytes and mesenchymal stem cell models, we show that RA specifically blocks the occupancy of C/EBPβ of the Cebpa promoter, thereby abrogating the differentiation process. RA does not act directly on C/EBPβ but rather stimulates the expression of the transforming growth factor β-effector protein Smad3, which can interact with C/EBPβ via its Mad homology 1 domain and can interfere with C/EBPβ DNA binding. The RA-induced increase in Smad3 expression results in increased cytoplasmic and nuclear Smad3, an important event as ectopic expression of Smad3 in preadipocytes in the absence of RA treatment only modestly inhibits adipogenesis and C/EBPβ DNA binding, suggesting that Smad3 alone is not sufficient to completely recapitulate the effects of retinoic acid treatment during differentiation. However, in the absence of Smad3, RA is not able to inhibit adipocyte differentiation or to elicit a decrease in C/EBPβ DNA occupancy suggesting that Smad3 is necessary to convey the inhibitory effects of retinoic acid during adipogenesis

Conditioned medium from human cancers stimulate C/EBPβ expression in myoblasts.

<p><b>(A)</b> C2C12 myoblasts were incubated with conditioned medium from indicated human cancers or unconditioned medium (UM) mixed 1:1 with fresh myoblast medium for 48 hours. C/EBPβ expression was assessed by western blot. β-actin is a loading control. <b>(B)</b><i>Cebpb</i> mRNA expression in myoblasts treated with PC-3 medium or unconditioned medium for 48 hours. *p<0.05, n = 5. <b>(C)</b><i>Il1b</i> expression in SKOV3 and PC-3 cancer cells. *p<0.05, n = 5.</p

Glucocorticoid-stimulated preadipocyte differentiation is mediated through acetylation of C/EBPβ by GCN5

Preadipocyte differentiation in culture is driven by an insulin and cAMP dependant transcriptional cascade which induces the bzip transcription factors C/EBPβ and C/EBPδ. We have previously shown that glucocorticoid treatment, which strongly potentiates this differentiation pathway, stimulates the titration of the corepressor histone deacetylase 1 (HDAC1) from C/EBPβ. This results in a dramatic enhancement of C/EBPβ-dependent transcription from the C/EBPα promoter, concomitant with potentiation of preadipocyte differentiation. Here, we show that C/EBPβ is acetylated by GCN5 and PCAF within a cluster of lysine residues between amino acids 98–102 and that this acetylation is strongly induced by glucocorticoid treatment. Arginine substitution of the lysine residues within the acetylation motif of C/EBPβ prevented acetylation and blocked the ability of glucocorticoids to enhance C/EBPβ-directed transcription and to potentiate C/EBPβ-dependent preadipocyte differentiation. Moreover, acetylation of C/EBPβ appeared to directly interfere with the interaction of HDAC1 with C/EBPβ, suggesting that PCAF/GCN5-dependent acetylation of C/EBPβ serves as an important molecular switch in determining the transcriptional regulatory potential of this transcription factor