Autophagy, tissue repair, and fibrosis: a delicate balance

Tissue repair and fibrosis, an abnormal form of repair, occur in most human organs in response to injury or inflammation. Fibroblasts play a major role in the normal repair process by differentiating into myofibroblasts that synthesize extracellular matrix (ECM) components and favor tissue remodeling to reestablish normal function and integrity. However, their persistent accumulation at the site of injury is a hallmark of fibrosis. Autophagy is a catabolic process that occurs in eukaryotic cells as a stress response to allow cell survival and maintenance of cellular homeostasis by degrading and recycling intracellular components. Recent advances identify autophagy as an important regulator of myofibroblast differentiation, tissue remodeling, and fibrogenesis. In this mini-review, we provide an overview of the interactions between autophagy, ECM, and fibrosis, and emphasize the molecular mechanisms involved in myofibroblast differentiation. We also describe the emerging concept of secretory autophagy as a new avenue for intercellular communication at the site of tissue injury and repair

Étude de la matière organique dissoute provenant de la décharge d'eau souterraine d'une flèche de sable en milieu côtier

RÉSUMÉ: L'est du Canada est sujet à une augmentation du niveau de la mer depuis la fin de l'Holocène. Cette augmentation est principalement associée à un ajustement isostatique et a provoqué des transgressions marines, lesquelles ont généré une submersion de la végétation terrigène établie le long de la côte nord-est de l'Amérique du Nord. Au fil du temps, la matière organique (MO) terrigène associée à cette végétation côtière est susceptible de former des horizons composés d'anciens sols organiques appelés paléosols. Ces paléosols sont souvent enfouis sous des sédiments côtiers tels que le sable et les galets, lesquels ont une perméabilité élevée qui permet l'advection d'eau dans les sédiments et les paléosols. Par conséquent, les paléosols peuvent constituer une source de vieille MO terrigène pour l'océan côtier et sont donc susceptibles d'influencer sa biogéochimie à une échelle locale, voir régionale, en affectant non seulement les bilans carbone, mais également les processus biogéochimiques en cours dans le système. La présente étude se concentre sur la dynamique tidale des flux de matière organique dissoute (DOM) mobilisée à partir d'un paléosol localisé sous les sédiments d'une flèche de sable située dans la Baie-des-Chaleurs (QC, Canada). Les trois principaux objectifs consistent à : 1) déterminer les débits de décharge d'eau souterraine provenant de la flèche en utilisant la loi de Darcy ainsi que la mesure de l'activité en 222Rn dans la zone de décharge ; 2) estimer les flux de C organique dissous (COD) du système en utilisant les concentrations en DOC mesurées dans la zone de décharge et les débits de décharge calculés ; et 3) caractériser la MOD de la zone de décharge et des sources environnantes potentielles à partir de leur signature optique (absorbance et fluorescence) afin de déterminer les sources possibles de MOD pour le système. Les résultats de l'analyse hydrologique obtenus en appliquant la loi de Darcy montrent une forte variation des flux de décharge d'eau souterraine, avec des valeurs passant de 0 cm·j-1 à marée haute à 106 cm·j-1 à marée descendante. Le suivi de l'activité en 222Rn dans la zone de décharge a permis d'établir que la contribution des eaux riches en 222Rn aux débits de décharge d'eau souterraine obtenus selon la loi de Darcy varie de 13 à 31 %. Les résultats de l'analyse du 222Rn suggèrent également la présence de deux cellules distinctes d'eau souterraine qui proviennent toutes deux de la recirculation d'eau de mer dans la flèche de sable et illustrent la complexité de la relation entre la variation du niveau de marée et la décharge des eaux souterraines. Les flux de COD provenant de la décharge d'eau souterraine sont estimés à 391,3 (± 100,2) et 360,0 (± 423,5) mmol C·j-1·m-1 en 2018 et 2019, respectivement. Bien qu'il demeure encore difficile d'établir le lien en les flux de MOD et la présence du paléosol sous la flèche de sable, les résultats démontrent une nette différence entre les propriétés optiques de la MOD de la zone de décharge et celles des sources environnantes potentielles. En effet, l'analyse optique de la MOD de la zone de décharge révèle un fort caractère terrigène, une haute aromaticité et un important degré d'humification, suggérant ainsi que la présence du paléosol influence les caractéristiques optiques de la MOD dans la zone de décharge. Les résultats soulignent le rôle complexe des paléosols localisés en zone intertidale sur les flux de MOD et les caractéristiques optiques de l'océan côtier, et ils soulignent la nécessité de mieux quantifier l'impact des systèmes côtiers transgressifs sur les bilans de carbone régionaux et locaux. -- Mot(s) clé(s) en français : Décharge d'eau souterraine, Matière organique dissoute, Transgression marine, Paléosol, Océan côtier. -- ABSTRACT: Since the Late Holocene, eastern Canada has been subjected to a sea-level rise that is mainly associated with post-glacial rebound. This rise has caused marine transgressions and thus submersion of terrigenous vegetation along the northeastern coast of North America. Over time, terrigenous organic matter (OM) from coastal vegetation is likely to form horizons of old organic soils, which are commonly known as paleosols. These paleosols are often buried under coastal sediments such as sands that have a high permeability and allow water in the sediments to advect through the paleosols. Therefore, paleosols can be a source of terrigenous OM to subterranean estuaries (STE). Here, we focused on the tidal dynamics of dissolved organic matter (DOM) fluxes mobilized from the paleosol of a sand spit located in Chaleur Bay (Québec, Canada). We estimated volumetric submarine groundwater discharge (SGD) fluxes using Darcy's law and radon-222 (222Rn), and we determined associated dissolved organic carbon (DOC) fluxes exported to receiving water. We also focused on the characterization of SGD-derived DOM based on the absorbance and fluorescence of the colored dissolved organic matter (CDOM). A multivariate data analysis was realized to better understand DOM sources. Results from Darcy's law show a wide range of SGD fluxes, reaching 106 cm·d-1 during the ebb tide. The contribution of 222Rn-rich groundwaters to total discharge rates determined using Darcy's law ranged between 13 and 31%. Furthermore, analysis of 222Rn activity in the discharge zone suggested the presence of two different cells of recirculated saline groundwater in the sand spit and illustrates the complex relationship between tidal oscillation and SGD. Results indicated mean potential SGD-derived DOC fluxes of 60.7 (± 15.5) and 55.8 (± 36.5) mol C·yr-1 in 2018 and 2019, respectively. The optical analysis of DOM from the discharge zone revealed an important old terrigenous component to the DOM pool. Our findings revealed a clear difference between the optical properties of DOM from the discharge zone and the endmembers. Furthermore, these findings demonstrate the complex role of the paleosol as a source of organic carbon to the coastal ocean and highlight the need to better quantify the impact of transgressive coastal systems on regional and local carbon budgets. -- Mot(s) clé(s) en anglais : Submarine Groundwater Discharge, Dissolved Organic Matter, Marine Transgression, Paleosol, Coastal Ocean

The use of personalized medicine for patient selection for renal transplantation: Physicians' views on the clinical and ethical implications

<p>Abstract</p> <p>Background</p> <p>The overwhelming scarcity of organs within renal transplantation forces researchers and transplantation teams to seek new ways to increase efficacy. One of the possibilities is the use of personalized medicine, an approach based on quantifiable and scientific factors that determine the global immunological risk of rejection for each patient. Although this approach can improve the efficacy of transplantations, it also poses a number of ethical questions.</p> <p>Methods</p> <p>The qualitative research involved 22 semi-structured interviews with nephrologists involved in renal transplantation, with the goal of determining the professionals' views about calculating the global immunological risk and the attendant ethical issues.</p> <p>Results</p> <p>The results demonstrate a general acceptance of this approach amongst the participants in the study. Knowledge of each patient's immunological risk could improve treatment and the post-graft follow-up. On the other hand, the possibility that patients might be excluded from transplantation poses a significant ethical issue. This approach is not seen as something entirely new, given the fact that medicine is increasingly scientific and evidence-based. Although renal transplantation incorporates scientific data, these physicians believe that there should always be a place for clinical judgment and the physician-patient relationship.</p> <p>Conclusions</p> <p>The participants see the benefits of including the calculation of the global immunological risk within transplantation. Such data, being more precise and rigorous, could be of help in their clinical work. However, in spite of the use of such scientific data, a place must be retained for the clinical judgment that allows a physician to make decisions based on medical data, professional expertise and knowledge of the patient. To act in the best interests of the patient is key to whether the calculation of the global immunological risk is employed.</p

Ferrite recrystallization and austenite formation during annealing of cold-rolled advanced high-strength steels: In situ synchrotron X-ray diffraction and modeling

Ferrite recrystallization and austenite formation occurring during annealing of cold-rolled advanced high-strength steels are key mechanisms as they largely determine the final microstructure and mechanical properties. However, the influence of processing parameters on these mechanisms and their interactions is still not fully understood. This is particularly the case for Dual-Phase steels having an initial cold-rolled microstructure con-sisting of ferrite and martensite before annealing, which were scarcely investigated compared to ferrite-pearlite initial microstructures. In situ synchrotron X-ray diffraction experiments together with post-mortem metallo-graphic analysis allowed clarifying both ferrite recrystallization and austenite formation during annealing of a ferrite-martensite initial microstructure depending on the process parameters of the annealing cycle. Results showed a major influence of recrystallization state on austenite formation, leading to an unexpected effect of heating rate on austenite formation kinetics. A modeling approach was undertaken to rationalize the influence of heating rate on austenite formation by taking into account the bi-phased ferrite-martensite initial microstructure and the effect of ferrite recrystallization state

Blasts in context:the impact of the immune environment on acute myeloid leukemia prognosis and treatment

Acute myeloid leukemia (AML) is a cancer that originates from the bone marrow (BM). Under physiological conditions, the bone marrow supports the homeostasis of immune cells and hosts memory lymphoid cells. In this review, we summarize our present understanding of the role of the immune microenvironment on healthy bone marrow and on the development of AML, with a focus on T cells and other lymphoid cells. The types and function of different immune cells involved in the AML microenvironment as well as their putative role in the onset of disease and response to treatment are presented. We also describe how the immune context predicts the response to immunotherapy in AML and how these therapies modulate the immune status of the bone marrow. Finally, we focus on allogeneic stem cell transplantation and summarize the current understanding of the immune environment in the post-transplant bone marrow, the factors associated with immune escape and relevant strategies to prevent and treat relapse.</p

Autophagy drives fibroblast senescence through MTORC2 regulation

Sustained macroautophagy/autophagy favors the differentiation of fibroblasts into myofibroblasts. Cellular senescence, another means of responding to long-term cellular stress, has also been linked to myofibroblast differentiation and fibrosis. Here, we evaluate the relationship between senescence and myofibroblast differentiation in the context of sustained autophagy. We analyzed markers of cell cycle arrest/senescence in fibroblasts in vitro, where autophagy was triggered by serum starvation (SS). Autophagic fibroblasts expressed the senescence biomarkers CDKN1A/p21 and CDKN2A/p16 and exhibited increased senescenceassociated GLB1/beta-galactosidase activity. Inhibition of autophagy in serum-starved fibroblasts with 3-methyladenine, LY294002, or ATG7 (autophagy related 7) silencing prevented the expression of senescence-associated markers. Similarly, suppressing MTORC2 activation using rapamycin or by silencing RICTOR also prevented senescence hallmarks. Immunofluorescence microscopy showed that senescence and myofibroblast differentiation were induced in different cells, suggesting mutually exclusive activation of senescence and myofibroblast differentiation. Reactive oxygen species (ROS) are known inducers of senescence and exposing fibroblasts to ROS scavengers decreased ROS production during SS, inhibited autophagy, and significantly reduced the expression of senescence and myofibroblast differentiation markers. ROS scavengers also curbed the AKT1 phosphorylation at Ser473, an MTORC2 target, establishing the importance of ROS in fuelling MTORC2 activation. Inhibition of senescence by shRNA to TP53/p53 and shRNA CDKN2A/p16 increased myofibroblast differentiation, suggesting a negative feedback loop of senescence on autophagy-induced myofibroblast differentiation. Collectively, our results identify ROS as central inducers of MTORC2 activation during chronic autophagy, which in turn fuels senescence activation and myofibroblast differentiation in distinct cellular subpopulations

Characterization of three new serous epithelial ovarian cancer cell lines

<p>Abstract</p> <p>Background</p> <p>Cell lines constitute a powerful model to study cancer, and here we describe three new epithelial ovarian cancer (EOC) cell lines derived from poorly differentiated serous solid tumors (TOV-1946, and TOV-2223G), as well as the matched ascites for one case (OV-1946).</p> <p>Methods</p> <p>In addition to growth parameters, the cell lines were characterized for anchorage independent growth, migration and invasion potential, ability to form spheroids and xenografts in SCID mice.</p> <p>Results</p> <p>While all cell lines were capable of anchorage independent growth, only the TOV-1946 and OV-1946 cell lines were able to form spheroid and produce tumors. Profiling of keratins, p53 and Her2 protein expression was assessed by immunohistochemistry and western blot analyses. Somatic <it>TP53 </it>mutations were found in all cell lines, with TOV-1946 and OV-1946 harboring the same mutation, and none harbored the commonly observed somatic mutations in <it>BRAF</it>, <it>KRAS </it>or germline BRCA1/2 mutations found to recur in the French Canadian population. Conventional cytogenetics and spectral karyotype (SKY) analyses revealed complex karyotypes often observed in ovarian disease.</p> <p>Conclusion</p> <p>This is the first report of the establishment of matched EOC cell lines derived from both solid tumor and ascites of the same patient.</p