Autophagy-mediated degradation of nuclear envelope proteins during oncogene-induced senescence

Here, we report that nuclear envelope proteins are subjected to autophagic proteolysis in human cells undergoing oncogene-induced senescence. This degradation occurs in parallel with autophagy and lysosomal activity induction that accompanies the establishment of the senescence respons

Identification and caractérisation of Apollo as a new telomere protective factor

LYON-ENS Sciences (693872304) / SudocSudocFranceF

Dynamic path tracking control of a vehicle on slippery terrain

International audienceThis paper deals with accuracy and reliability for the path tracking control of a four wheel mobile robot with a double-steering system when moving at high dynamics on a slippery surface. An extended kinematic model of the robot is developed considering the effects of wheel-ground skidding. This bicycle type model is augmented to form a dynamic model that considers an actuation of the four wheels. Based on the extended kinematic model, an adaptive and predictive controller for the path tracking is developed to drive the wheels front and rear steering angles. The resulting control law is combined with a stabilization algorithm of the yaw motion which modulates the actuation torque of each four wheels, on the basis of the robot dynamic model. The global control architecture is experimentally evaluated on a wet grass slippery terrain, with speeds up to 7. m/s. Experimental results demonstrate enhancement of tracking performances in terms of stability and accuracy relative to the kinematic control. Highlights: Extended kinematic and dynamic models of a double-steered vehicle are proposed. A new adaptation dynamic sideslip observer considers the lateral slope. An adaptive and predictive double steering controller is developed. A stabilizer of the yaw motion modulates the actuation torque of each four wheels. Experiments are performed on a wet grass slippery terrain, with speeds up to 7m/s

Cibler les télomères pour forcer les cellules cancéreuses à rentrer en sénescence

Dans les cellules somatiques humaines, les télomères raccourcissent au rythme des divisions cellulaires, jusqu’à l’apparition de télomères dysfonctionnels qui induisent la sénescence ou l’apoptose selon le type cellulaire. Deux études viennent d’être publiées montrant qu’un dysfonctionnement télomérique chez la souris supprime la formation de cancers en déclenchant la sénescence. Ces résultats renforcent la notion que la sénescence est un mécanisme qui limite la prolifération tumorale et suggèrent de nouvelles stratégies thérapeutiques ciblant sélectivement certaines fonctions télomériques. Toutefois, une question importante reste sans réponse : est-ce que l’érosion des télomères limite la formation des cancers chez l’homme 

The Apollo 5' exonuclease functions together with TRF2 to protect telomeres from DNA repair

International audienc

The Apollo 5' exonuclease functions together with TRF2 to protect telomeres from DNA repair

International audienceA major issue in telomere research is to understand how the integrity of chromosome ends is preserved . The human telomeric protein TRF2 coordinates several pathways that prevent checkpoint activation and chromosome fusions. In this work, we identified hSNM1B, here named Apollo, as a novel TRF2-interacting factor. Interestingly, the N-terminal domain of Apollo is closely related to that of Artemis, a factor involved in V(D)J recombination and DNA repair. Both proteins belong to the beta-CASP metallo-beta-lactamase family of DNA caretaker proteins. Apollo appears preferentially localized at telomeres in a TRF2-dependent manner. Reduced levels of Apollo exacerbate the sensitivity of cells to TRF2 inhibition, resulting in severe growth defects and an increased number of telomere-induced DNA-damage foci and telomere fusions. Purified Apollo protein exhibits a 5'-to-3' DNA exonuclease activity. We conclude that Apollo is a novel component of the human telomeric complex and works together with TRF2 to protect chromosome termini from being recognized and processed as DNA damage. These findings unveil a previously undescribed telomere-protection mechanism involving a DNA 5'-to-3' exonuclease

Prevention of cisplatin-induced acute kidney injury: a systematic review and meta-analysis

International audienceOBJECTIVE: Cisplatin-induced acute kidney injury (CIA) is a serious adverse event that affects 20-40% of exposed patients, despite any implemented precaution to avoid it. The aim of this work was therefore to identify a relevant nephroprotective method for CIA.METHODS: We searched Pubmed, Embase, and Web of Science from 1 January 1978 to 1 June 2018, without language restriction. All studies (observational and interventional) assessing a CIA prevention method for adults receiving at least one course of cisplatin were eligible. The primary outcome was acute nephrotoxicity, as defined by the AKI-KDIGO classification (2012). The odds ratio and corresponding 95% confidence interval were used to assess the associations. We used narrative synthesis in case of heterogeneity regarding intervention, population, or outcome. When possible, a random-effects model was used to pool studies. The heterogeneity between studies was quantified (I2RESULTS: Within 4520 eligible studies, 51 articles fulfilling the selection criteria were included in the review, assessing 21 different prevention methods. A meta-analysis could only be performed on the 15 observational studies concerning magnesium supplementation (1841 patients), and showed a significant nephroprotective effect for all combined grades of CIA (OR 0.24, [0.19-0.32], I222CONCLUSIONS: While no method of prevention had so far demonstrated its indisputable efficacy, our results highlight the potential protective effect of magnesium supplementation on cisplatin-induced acute nephrotoxicity.BACKGROUND: This study is registered in PROSPERO, CRD42018090612

Impact of Tacrolimus Daily Dose Limitation in Renal Transplant Recipients Expressing CYP3A5: A Retrospective Study

The pharmacokinetic variability of tacrolimus can be partly explained by CYP3A5 activity. Our objective was to evaluate a tacrolimus sparing policy on renal graft outcome according to CYP3A5 6986A>G genetic polymorphism. This retrospective study included 1114 recipients with a median follow-up of 6.3 years. Genotyping of the 6986A>G allelic variant corresponding to CYP3A5*3 was systematically performed. One year after transplantation, tacrolimus blood trough concentration (C0) target range was 5–7 ng/mL. However, daily dose was capped to 0.10 mg/kg/day regardless of the CYP3A5 genotype. A total 208 CYP3A5*1/- patients were included. Despite a higher daily dose, CYP3A5*1/- recipients exhibited lower C0 during follow-up (p < 0.01). Multivariate analysis did not show any significant influence of CYP3A5*1/- genotype (HR = 0.70, 0.46–1.07, p = 0.10) on patient-graft survival. Glomerular Filtration Rate (GFR) decline was significantly lower for the CYP3A5*1/- group (p = 0.02). The CYP3A5*1/- genotype did not significantly impact the risk of biopsy-proven acute rejection (BPAR) (HR = 1.01, 0.68–1.49, p = 0.97) despite significantly lower C0. Based on our experience, a strategy of tacrolimus capping is associated with a better GFR evolution in CYP3A5*1/- recipients without any significant increase of BPAR incidence. Our study raised some issues about specific therapeutic tacrolimus C0 targets for CYP3A5*1/- patients and suggests to set up randomized control studies in this specific population

Hybrid-control arm construction using historical trial data for an early-phase, randomized controlled trial in metastatic colorectal cancer

Li et al. report outcomes from the atezolizumab/isatuximab arm of the phase Ib/II MORPHEUS-CRC trial in patients with metastatic colorectal cancer. In addition, the authors leverage historical control data from the phase III IMblaze370 study to provide more precise treatment effect estimates