Angiotensin II and growth factors in the pathogenesis of diabetic nephropathy

Angiotensin II and growth factors in the pathogenesis of diabetic nephropathy. The renin-angiotensin system (RAS) and growth factors mediate structural and functional changes during the course of diabetic nephropathy (DN). Studies in humans and experimental models with DN suggest their involvement in the development and progression of DN. Activation of renal tissue RAS and increased expression of growth factors have been demonstrated at early stages of the disease. Angiotensin II and growth factors alter renal hemodynamics and exert trophic changes in renal cells that eventually result in fibrosis through direct mechanisms or through the release of other mediators. Their effects are likely modulated by metabolic changes including high glucose and free fatty acids. While blockade of the RAS ameliorates DN in humans, such evidence for blockade of growth factors is still lacking. It is likely that susceptibility to the development of DN and therapeutic efficacy are modulated by genetic polymorphisms in components of the RAS and growth factors including their receptors and other target molecules. Approaches to understand the intricate relationship between these systems and the mechanism(s) by which they alter capillary permeability and result in structural changes are areas of fruitful investigation

Sestrin2 as a Novel Biomarker and Therapeutic Target for Various Diseases

Sestrin2 (SESN2), a highly conserved stress-inducible metabolic protein, is known to repress reactive oxygen species (ROS) and provide cytoprotection against various noxious stimuli including genotoxic and oxidative stress, endoplasmic reticulum (ER) stress, and hypoxia. Studies demonstrate that the upregulation of Sestrin2 under conditions of oxidative stress augments autophagy-directed degradation of Kelch-like ECH-associated protein 1 (Keap1), which targets and breaks down nuclear erythroid-related factor 2 (Nrf2), a key regulator of various antioxidant genes. Moreover, ER stress and hypoxia are shown to induce Sestrins, which ultimately reduce cellular ROS levels. Sestrin2 also plays a pivotal role in metabolic regulation through activation of the key energy sensor AMP-dependent protein kinase (AMPK) and inhibition of mammalian target of rapamycin complex 1 (mTORC1). Other downstream effects of Sestrins include autophagy activation, antiapoptotic effects in normal cells, and proapoptotic effects in cancer cells. As perturbations in the aforementioned pathways are well documented in multiple diseases, Sestrin2 might serve as a potential therapeutic target for various diseases. Thus, the aim of this review is to discuss the upstream regulators and the downstream effectors of Sestrins and to highlight the significance of Sestrin2 as a biomarker and a therapeutic target in diseases such as metabolic disorders, cardiovascular and neurodegenerative diseases, and cancer.This publication was made possible by a NPRP award [NPRP8-1750-3-360] from the Qatar National Research Fund (a member of The Qatar Foundation). The statements made herein are solely the responsibility of the authors

Matched and mismatched unrelated donor compared to autologous stem cell transplantation for acute myeloid leukemia in first complete remission : a retrospective, propensity score-weighted analysis from the ALWP of the EBMT

Background: Optimal post-remission strategy for patients with acute myeloid leukemia (AML) is matter of intense debate. Recent reports have shown stronger anti-leukemic activity but similar survival for allogeneic stem cell transplantation (allo-HSCT) from matched sibling donor compared to autologous transplantation (auto-HSCT); however, there is scarcity of literature confronting auto-HSCT with allo-HSCT from unrelated donor (UD-HSCT), especially mismatched UD-HSCT. Methods: We retrospectively compared outcome of allogeneic transplantation from matched (10/10 UD-HSCT) or mismatched at a single HLA-locus unrelated donor (9/10 UD-HSCT) to autologous transplantation in patients with AML in first complete remission (CR1). A total of 2879 patients were included; 1202 patients received auto-HSCT, 1302 10/10 UD-HSCT, and 375 9/10 UD-HSCT. A propensity score-weighted analysis was conducted to control for disease risk imbalances between the groups. Results: Matched 10/10 UD-HSCT was associated with the best leukemia-free survival (10/10 UD-HSCT vs auto-HSCT: HR 0.7, rho = 0.0016). Leukemia-free survival was not statistically different between auto-HSCT and 9/10 UD-HSCT (9/10 UD-HSCT vs auto-HSCT: HR 0.8, rho = 0.2). Overall survival was similar across the groups (10/10 UD-HSCT vs auto-HSCT: HR 0.98, rho = 0.84; 9/10 UD-HSCT vs auto-HSCT: HR 1.1, rho = 0.49). Notably, in intermediate-risk patients, OS was significantly worse for 9/10 UD-HSCT (9/10 UD-HSCT vs auto-HSCT: HR 1.6, rho = 0.049), while it did not differ between auto-HSCT and 10/10 UD-HSCT (HR 0.95, rho = 0.88). In favorable risk patients, auto-HSCT resulted in 3-year LFS and OS rates of 59 and 78 %, respectively. Conclusions: Our findings suggest that in AML patients in CR1 lacking an HLA-matched sibling donor, 10/10 UD-HSCT significantly improves LFS, but this advantage does not translate in better OS compared to auto-HSCT. In intermediate-risk patients lacking a fully HLA-matched donor, auto-HSCT should be considered as a valid option, as better survival appears to be provided by auto-HSCT compared to mismatched UD-HSCT. Finally, auto-HSCT provided an encouraging outcome in patients with favorable risk AML.Peer reviewe

Nox4 Mediates Renal Cell Carcinoma Cell Invasion through Hypoxia-Induced Interleukin 6- and 8- Production

Inflammatory cytokines are detected in the plasma of patients with renal cell carcinoma (RCC) and are associated with poor prognosis. However, the primary cell type involved in producing inflammatory cytokines and the biological significance in RCC remain unknown. Inflammation is associated with oxidative stress, upregulation of hypoxia inducible factor 1-alpha, and production of pro-inflammatory gene products. Solid tumors are often heterogeneous in oxygen tension together suggesting that hypoxia may play a role in inflammatory processes in RCC. Epithelial cells have been implicated in cytokine release, although the stimuli to release and molecular mechanisms by which they are released remain unclear. AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status and a role for AMPK in the regulation of cell inflammatory processes has recently been demonstrated.We have identified for the first time that interleukin-6 and interleukin-8 (IL-6 and IL-8) are secreted solely from RCC cells exposed to hypoxia. Furthermore, we demonstrate that the NADPH oxidase isoform, Nox4, play a key role in hypoxia-induced IL-6 and IL-8 production in RCC. Finally, we have characterized that enhanced levels of IL-6 and IL-8 result in RCC cell invasion and that activation of AMPK reduces Nox4 expression, IL-6 and IL-8 production, and RCC cell invasion.Together, our data identify novel mechanisms by which AMPK and Nox4 may be linked to inflammation-induced RCC metastasis and that pharmacological activation of AMPK and/or antioxidants targeting Nox4 may represent a relevant therapeutic intervention to reduce IL-6- and IL-8-induced inflammation and cell invasion in RCC

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Évaluation intermédiaire du programme structurel européen objectif 5b concernant la Bretagne (période 1994-1999)

Les politiques structurelles de l'Union européenne relevant de l'objectif 5b sont des politiques régionales visant au développement et à l'ajustement structurel des zones rurales. Le programme structurel 5b, baptisé "Morgane" en Bretagne, a pour objectif de lutter contre les pertes d'emploi et de population dans les zones jugées fragiles. Son objectif ultime est la lutte contre la désertification, son outil essentiel est le développement économique. Le programme "Morgane II" porte sur la période 1994-1999. Le travail réalisé consiste en une évaluation à mi-parcours des réalisations et de l'état d'avancement. Il s'agit d'analyser la pertinence du programme et de l'articulation enjeux-objectifs-actions, et de porter un jugement in itinere sur l'efficacité à attendre, en fin du programme, des actions mises en œuvre. Outre une analyse globale de l'état d'avancement de l'ensemble du programme, des analyses approfondies sont menées concernant les actions touchant à l'activité agricole, à la mise en valeur de la forêt, à la qualité de l'environnement et du cadre de vie, au développement des entreprises industrielles, et à l'emploi et à la formation. Cette évaluation intermédiaire donne lieu à des recommandations relatives à la poursuite du programme, à l'articulation des actions, à l'instruction et au suivi des opérations, et conduit à une réflexion sur la dynamique du programme

Évaluation intermédiaire du programme structurel européen objectif 5b concernant la Bretagne (période 1994-1999) : rapport final

Les politiques structurelles de l'Union européenne relevant de l'objectif 5b sont des politiques régionales visant au développement et à l'ajustement structurel des zones rurales. Le programme structurel 5b, baptisé "Morgane" en Bretagne, a pour objectif de lutter contre les pertes d'emploi et de population dans les zones jugées fragiles. Son objectif ultime est la lutte contre la désertification, son outil essentiel est le développement économique. Le programme "Morgane II" porte sur la période 1994-1999. Le travail réalisé consiste en une évaluation à mi-parcours des réalisations et de l'état d'avancement. Il s'agit d'analyser la pertinence du programme et de l'articulation enjeux-objectifs-actions, et de porter un jugement in itinere sur l'efficacité à attendre, en fin du programme, des actions mises en œuvre. Outre une analyse globale de l'état d'avancement de l'ensemble du programme, des analyses approfondies sont menées concernant les actions touchant à l'activité agricole, à la mise en valeur de la forêt, à la qualité de l'environnement et du cadre de vie, au développement des entreprises industrielles, et à l'emploi et à la formation. Cette évaluation intermédiaire donne lieu à des recommandations relatives à la poursuite du programme, à l'articulation des actions, à l'instruction et au suivi des opérations, et conduit à une réflexion sur la dynamique du programme