Astrocytes reverted to a neural progenitor-like state with transforming growth factor alpha are sensitized to cancerous transformation.

International audienceGliomas, the most frequent primitive central nervous system tumors, have been suggested to originate from astrocytes or from neural progenitors/stem cells. However, the precise identity of the cells at the origin of gliomas remains a matter of debate because no pre-neoplastic state has been yet identified. Transforming growth factor (TGF)-alpha, an epidermal growth factor family member, is frequently overexpressed in the early stages of glioma progression. We previously demonstrated that prolonged exposure of astrocytes to TGF-alpha is sufficient to trigger their reversion to a neural progenitor-like state. To determine whether TGF-alpha dedifferentiating effects are associated with cancerous transforming effects, we grafted intracerebrally dedifferentiated astrocytes. We show that these cells had the same cytogenomic profile as astrocytes, survived in vivo, and did not give birth to tumors. When astrocytes dedifferentiated with TGF-alpha were submitted to oncogenic stress using gamma irradiation, they acquired cancerous properties: they were immortalized, showed cytogenomic abnormalities, and formed high-grade glioma-like tumors after brain grafting. In contrast, irradiation did not modify the lifespan of astrocytes cultivated in serum-free medium. Addition of TGF-alpha after irradiation did not promote their transformation but decreased their lifespan. These results demonstrate that reversion of mature astrocytes to an embryonic state without genomic manipulation is sufficient to sensitize them to oncogenic stress

Outcome after Surgery for Iatrogenic Acute Type A Aortic Dissection

(1) Background: Acute Stanford type A aortic dissection (TAAD) may complicate the outcome of cardiovascular procedures. Data on the outcome after surgery for iatrogenic acute TAAD is scarce. (2) Methods: The European Registry of Type A Aortic Dissection (ERTAAD) is a multicenter, retrospective study including patients who underwent surgery for acute TAAD at 18 hospitals from eight European countries. The primary outcomes were in-hospital mortality and 5-year mortality. Twenty-seven secondary outcomes were evaluated. (3) Results: Out of 3902 consecutive patients who underwent surgery for acute TAAD, 103 (2.6%) had iatrogenic TAAD. Cardiac surgery (37.8%) and percutaneous coronary intervention (36.9%) were the most frequent causes leading to iatrogenic TAAD, followed by diagnostic coronary angiography (13.6%), transcatheter aortic valve replacement (10.7%) and peripheral endovascular procedure (1.0%). In hospital mortality was 20.5% after cardiac surgery, 31.6% after percutaneous coronary intervention, 42.9% after diagnostic coronary angiography, 45.5% after transcatheter aortic valve replacement and nihil after peripheral endovascular procedure (p = 0.092), with similar 5-year mortality between different subgroups of iatrogenic TAAD (p = 0.710). Among 102 propensity score matched pairs, in-hospital mortality was significantly higher among patients with iatrogenic TAAD (30.4% vs. 15.7%, p = 0.013) compared to those with spontaneous TAAD. This finding was likely related to higher risk of postoperative heart failure (35.3% vs. 10.8%, p < 0.0001) among iatrogenic TAAD patients. Five-year mortality was comparable between patients with iatrogenic and spontaneous TAAD (46.2% vs. 39.4%, p = 0.163). (4) Conclusions: Iatrogenic origin of acute TAAD is quite uncommon but carries a significantly increased risk of in-hospital mortality compared to spontaneous TAAD

Modélisation intégrée des flux d'eau dans la ville - impacts des réseaux d'assainissement sur les écoulements souterrains

Le comportement hydrologique des bassins versants urbains est influencé par les interactions entre l'eau du sol et les réseaux d'assainissement. Ce sujet est abordé sur le plan expérimental et sur le plan de la modélisation. Ces travaux sont réalisés dans le but de consolider le modèle hydrologique distribué URBS du point de vue du fonctionnement du sous-sol urbain. L'analyse de données hydrologiques collectées sur le bassin versant du Pin Sec à Nantes montre le lien entre les niveaux piézométriques et le débit de base dans le réseau d'eau pluviale. La modélisation du sous-sol est effectuée grâce au code hydrodynamique 3D Modflow de l'USGS sur un objet élémentaire afin de tester les capacités du modèle vis-à-vis du rôle hydrologique des tranchées et du réseau d'assainissement en milieu urbain. L'étude de sensibilité du modèle a été réalisée sur l'influence du maillage, la position de la tranchée par rapport à l'écoulement et les différentes options permettant d'insérer un réseau d'assainissement. L'influence temporelle et spatiale de la tranchée a été testée par la suite avec une recharge typique de 700 mm/an

Spontaneous clearance of chronic hepatitis C virus infection in HIV positive patients, southeastern France

International audienc

Toward chronic hepatitis C eradication in HIV-positive patients, including those cirrhotic and infected with genotype 3 viruses

International audienc

Mucoadhesive Poloxamer-Based Hydrogels for the Release of HP-beta-CD-Complexed Dexamethasone in the Treatment of Buccal Diseases

International audienceOral lichen planus (OLP) is an ongoing and chronic inflammatory disease affecting the mucous membrane of the oral cavity. Currently, the treatment of choice consists in the direct application into the buccal cavity of semisolid formulations containing a corticosteroid molecule to decrease inflammatory signs and symptoms. However, this administration route has shown various disadvantages limiting its clinical use and efficacy. Indeed, the frequency of application and the incorrect use of the preparation may lead to a poor efficacy and limit the treatment compliance. Furthermore, the saliva clearance and the mechanical stress present in the buccal cavity also involve a decrease in the mucosal exposure to the drug. In this context, the design of a new pharmaceutical formulation, containing a steroidal anti-inflammatory, mucoadhesive, sprayable and exhibiting a sustained and controlled release seems to be suitable to overcome the main limitations of the existing pharmaceutical dosage forms. The present work reports the formulation, optimization and evaluation of the mucoadhesive and release properties of a poloxamer 407 thermosensitive hydrogel containing a poorly water-soluble corticosteroid, dexamethasone acetate (DMA), threaded into hydroxypropyl-beta-cyclodextrin (HP-beta-CD) molecules. Firstly, physicochemical properties were assessed to ensure suitable complexation of DMA into HP-beta-CD cavities. Then, rheological properties, in the presence and absence of various mucoadhesive agents, were determined and optimized. The hydration ratio (0.218-0.191), the poloxamer 407 (15-17 wt%) percentage and liquid-cyclodextrin state were optimized as a function of the gelation transition temperature, viscoelastic behavior and dynamic flow viscosity. Deformation and resistance properties were evaluated in the presence of various mucoadhesive compounds, being the sodium alginate and xanthan gum the most suitable to improve adhesion and mucoadhesion properties. Xanthan gum was shown as the best agent prolonging the hydrogel retention time up to 45 min. Furthermore, xanthan gum has been found as a relevant polymer matrix controlling drug release by diffusion and swelling processes in order to achieve therapeutic concentration for prolonged periods of time

Emergence of uncommon HIV-1 non-B subtypes and circulating recombinant forms and trends in transmission of antiretroviral drug resistance in patients with primary infection during the 2013-2015 period in Marseille, Southeastern France

International audiencePrimary HIV-1 infections (PHI) with non-B subtypes are increasing in developed countries while transmission of HIV-1 harboring antiretroviral resistance-associated mutations (RAMs) remains a concern. This study assessed non-B HIV-1 subtypes and RAMs prevalence among patients with PHI in university hospitals of Marseille, Southeastern France, in 2005-2015 (11 years). HIV-1 sequences were obtained by inhouse protocols from 115 patients with PHI, including 38 for the 2013-2015 period. On the basis of the phylogenetic analysis of the reverse transcriptase region, non-B subtypes were identified in 31% of these patients. They included 3 different subtypes (3A, 1C, 4F), 23 circulating recombinant forms (CRFs) (CRF02_AG, best BLAST hits being CRF 36\ₓpx and CRF30 in 7 and 1 cases, respectively), and 5 unclassified sequences (U). Non-B subtypes proportion increased significantly, particularly in 2011-2013 vs in 2005-2010 (P = .03). CRF02_AG viruses largely predominated in 2005-2013 whereas atypical strains more difficult to classify and undetermined recombinants emerged recently (2014-2015). The prevalence of protease, nucleos(t) ide reverse transcriptase, and first-generation nonnucleoside reverse transcriptase inhibitors-associated RAMs were 1.7% (World Health Organization [WHO] list, 2009/2.6% International AIDS Society [IAS] list, 2017), 5.2%/4.3%, and 5.2%/5.2%, respectively. Etravirine/rilpivirine-associated RAM (IAS) prevalence was 4.3%. Men who have sex with men (MSM) were more frequently infected with drug-resistant viruses than other patients (26% vs 7%; P = .011). The recent increase of these rare HIV-1 strains and the spread of drug-resistant HIV-1 among MSM in Southeastern France might be considered when implementing prevention strategies and starting therapies

Imbalance of the Vanin-1 Pathway in Systemic Sclerosis

International audienceSystemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and visceral organs and vascular alterations. SSc pathophysiology involves systemic inflammation and oxidative stress. Because the vanin-1 gene (vnn1) encodes an enzyme with pantetheinase activity that converts vasculoprotective pantethine into profibrotic pantothenic acid and pro-oxidant cystamine, we tested this pathway in the pathophysiology of SSc. Activation of the vanin-1/pantetheinase pathway was investigated in wild-type BALB/c mice with hypochlorous acid (HOCl)-induced SSc by ELISA and Western blotting. We then evaluated the effects of the inactivation of vnn1 on the development of fibrosis, endothelial alterations, and immunological activation in mice with HOCl- and bleomycin-induced SSc. We then explored the vanin-1/pantetheinase pathway in a cohort of patients with SSc and in controls. In wild-type mice with HOCl-induced SSc, the vanin-1/pantetheinase pathway was dysregulated, with elevation of vanin-1 activity in skin and high levels of serum pantothenic acid. Inactivation of the vnn1 gene in vnn1(-/-) mice with HOCl-induced SSc prevented the development of characteristic features of the disease, including fibrosis, immunologic abnormalities, and endothelial dysfunction. Remarkably, patients with diffuse SSc also had increased expression of vanin-1 in skin and blood and elevated levels of serum pantothenic acid that correlated with the severity of the disease. Our data demonstrate that vanin-1/pantetheinase controls fibrosis, vasculopathy, autoimmunity, and oxidative stress in SSc. The levels of vanin-1 expression and pantothenic acid determine SSc severity and can be used as markers of disease severity. More importantly, inhibition of vanin-1 can open new therapeutic approaches in SSc

Minimal clinically important difference for the EORTC QLQ-C30 and QLQ-BN20 questionnaires in glioblastoma patients using several distribution and anchor-based methods

Abstract published in Quality of Life Research, 26(Suppl 1):134:135, 2017International audienceMany researches have been conducted in the last decades on the determination of the minimal clinically important difference(MCID) for health-related quality of life (HRQOL) scores. Several methods have been proposed, generally classified in distribution oranchor-based methods. A joint use of both distribution and anchorbased approaches, using several distributions and anchors, should be recommended to study the consistency and reliability of the results. Our objective was to explore and to compare sevenapproaches from the distribution and anchor based methods of the MCID in EORTC questionnaires using a small sample size, tohighlight the advantages and disadvantages of each of them and the consistency of the results. Methods: Data from a randomized phase II clinical trial in unresectable glioblastoma patients were used. Patients completed the EORTC QLQ-C30 questionnaire and the QLQ-BN20 brain cancer module at baseline and during the treatment. Four distribution-based approaches were applied usingbaseline scores: 0.2 standard deviation (SD), 0.3 SD, 0.5 SD and the standard error of measurement. Three anchors were used: the patient rating of change (PRC), global HRQOL change (GHC) using item 30 of the QLQ-C30 and the Karnofsky performance status (PS). Correlation between HRQOL and the anchors were checked. Results: Among the 134 patients involved in this study,102 patients (76 %) had at least one HRQOL score available at baseline and were included in the analysis based on the distribution.For the distributions, the minimal and maximal MCID were (4–18) and (2–16) for the QLQ-C30 and QLQ-BN20 questionnairesrespectively. Regarding the anchor, the role functioning dimension of the QLQ-C30 questionnaire was correlated with both PS andGHC anchors (r[0.30). The MCID calculated for this dimension was 5 points for deterioration and 2 points for improvement.Conclusions: The strength of our study is the diversity of anchors explored in order to estimate the MCID (evaluated by the patienthimself and one evaluated by the clinicians), but the sample size is challenging in this context of poor prognostic disease using anchor based approaches. These results will be compared to other published results for brain cancer tumor with QLQ-BN20