Mechanism of melanoma cells selective apoptosis induced by a photoactive NADPH analogue

Melanoma is one of the most lethal cancers when it reaches a metastatic stage. Despite the spectacular achievements of targeted therapies (BRAF inhibitors) or immuno-therapies (anti-CTLA4 or anti-PD1), most patients with melanoma will need additional treatments. Here we used a photoactive NADPH analogue called NS1 to induce cell death by inhibition of NADPH oxidases NOX in melanoma cells, including melanoma cells isolated from patients. In contrast, healthy melanocytes growth was unaffected by NS1 treatment. NS1 established an early Endoplasmic Reticulum stress by the early release of calcium mediated by (a) calcium-dependent redox-sensitive ion channel(s). These events initiated autophagy and apoptosis in all tested melanoma cells independently of their mutational status. The autophagy promoted by NS1 was incomplete. The autophagic flux was blocked at late stage events, consistent with the accumulation of p62, and a close localization of LC3 with NS1 associated with NS1 inhibition of NOX1 in autophagosomes. This hypothesis of a specific incomplete autophagy and apoptosis driven by NS1 was comforted by the use of siRNAs and pharmacological inhibitors blocking different processes. This study highlights the potential therapeutic interest of NS1 inducing cell death by triggering a selective ER stress and incomplete autophagy in melanoma cells harbouring wt and BRAF mutation

Enterovirus Migration Patterns between France and Tunisia

International audienceThe enterovirus (EV) types echovirus (E-) 5, E-9, and E-18, and coxsackievirus (CV-) A9 are infrequently reported in human diseases and their epidemiologic features are poorly defined. Virus transmission patterns between countries have been estimated with phyloge-netic data derived from the 1D/VP1 and 3CD gene sequences of a sample of 74 strains obtained in France (2000-2012) and Tunisia (2011-2013) and from the publicly available sequences. The EV types (E-5, E-9, and E-18) exhibited a lower worldwide genetic diversity (respective number of genogroups: 4, 5, and 3) in comparison to CV-A9 (n = 10). The phylo-genetic trees estimated with both 1D/VP1 and 3CD sequence data showed variations in the number of co-circulating lineages over the last 20 years among the four EV types. Despite the low number of genogroups in E-18, the virus exhibited the highest number of recombi-nant 3CD lineages (n = 10) versus 4 (E-5) to 8 (E-9). The phylogenies provided evidence of multiple transportation events between France and Tunisia involving E-5, E-9, E-18, and CV-A9 strains. Virus spread events between France and 17 other countries in five continents had high probabilities of occurrence as those between Tunisia and two European countries other than France. All transportation events were supported by BF values > 10. Inferring the source of virus transmission from phylogenetic data may provide insights into the patterns of sporadic and epidemic diseases caused by EVs

Aortic stenosis and transthyretin cardiac amyloidosis: the chicken or the egg?

International audienceBackground Aortic stenosis (AS) and transthyretin cardiac amyloidosis (TTR-CA) are both frequent in elderly. The combination of these two diseases has never been investigated. Aims To describe patients with concomitant AS and TTR-CA. Methods Six cardiologic French centres identified retrospectively cases of patients with severe or moderate AS associated with TTR-CA hospitalized during the last 6 years. Results Sixteen patients were included. Mean +/- SD age was 79 +/- 6 years, 81% were men. Sixty per cent were NYHA III-IV, 31% had carpal tunnel syndrome, and 56% had atrial fibrillation. Median (Q1; Q4) NT-proBNP was 4382 ( 2425; 4730) pg/mL and 91% had elevated cardiac troponin level. Eighty-eight per cent had severe AS (n = 14/16), of whom 86% (n = 12) had low-gradient AS. Mean +/- SD interventricular septum thickness was 18 +/- 4 mm. Mean left ventricular ejection fraction and global LS were 50 +/- 13% and -7 +/- 4%, respectively. Diagnosis of TTR-CAwas histologically proven in 38%, and was based on strong cardiac uptake of the tracer at biphosphonate scintigraphy in the rest. Eighty-one per cent had wild-type TTR-CA (n = 13), one had mutated Val122l and 19% did not had genetic test (n = 3). Valve replacement was surgical in 63% and via transcatheter in 13%. Median follow-up in survivors was 33 (16; 65) months. Mortality was of 44% (n = 7) during the whole follow-up period. Conclusions Combination of AS and TTR-CA may occur in elderly patients particularly those with a low-flow low-gradient AS pattern and carries bad prognosis. Diagnosis of TTR-CA in AS is relevant to discuss specific treatment and management

Disparities in particulate matter (PM10) origins and oxidative potential at a city scale (Grenoble, France) – Part 2: Sources of PM10 oxidative potential using multiple linear regression analysis and the predictive applicability of multilayer perceptron neural network analysis

International audienceThe oxidative potential (OP) of particulate matter (PM) measures PM capability to potentially cause anti-oxidant imbalance. Due to the wide range and complex mixture of species in particulates, little is known about the pollution sources most strongly contributing to OP. A 1-year sampling of PM10 (particles with an aerodynamic diameter below 10) was performed over different sites in a medium-sized city (Grenoble, France). An enhanced fine-scale apportionment of PM10 sources, based on the chemical composition, was performed using the positive matrix factorization (PMF) method and reported in a companion paper (Borlaza et al., 2020). OP was assessed as the ability of PM10 to generate reactive oxygen species (ROS) using three different acellular assays: dithiothreitol (DTT), ascorbic acid (AA), and 2,7-dichlorofluorescein (DCFH) assays. Using multiple linear regression (MLR), the OP contributions of the sources identified by PMF were estimated. Conversely, since atmospheric processes are usually non-linear in nature, artificial neural network (ANN) techniques, which employ non-linear models, could further improve estimates. Hence, the multilayer perceptron analysis (MLP), an ANN-based model, was additionally used to model OP based on PMF-resolved sources as well. This study presents the spatiotemporal variabilities of OP activity with influences by season-specific sources, site typology and specific local features, and assay sensitivity. Overall, both MLR and MLP effectively captured the evolution of OP. The primary traffic and biomass burning sources were the strongest drivers of OP in the Grenoble basin. There is also a clear redistribution of source-specific impacts when using OP instead of mass concentration, underlining the importance of PM redox activity for the identification of potential sources of PM toxicity. Finally, the MLP generally offered improvements in OP prediction, especially for sites where synergistic and/or antagonistic effects between sources are prominent, supporting the value of using ANN-based models to account for the non-linear dynamics behind the atmospheric processes affecting OP of PM10

Disparities in particulate matter (PM₁₀) origins and oxidative potential at a city scale (Grenoble, France) – Part 1: Source apportionment at three neighbouring sites

International audienceA fine-scale source apportionment of PM10 was conducted in three different urban sites (background, hyper-center, and peri-urban) within 15 km of the city in Grenoble, France using Positive Matrix Factorization (PMF 5.0) on measured chemical species from collected filters (24 h) from February 2017 to March 2018. To improve the PMF solution, several new organic tracers (3-MBTCA, pinic acid, phthalic acid, MSA, and cellulose) were additionally used in order to identify sources that are commonly unresolved by classic PMF methodologies. An 11-factor solution was obtained in all sites, including commonly identified sources from primary traffic (13 %), nitrate-rich (17 %), sulfate-rich (17 %), industrial (1 %), biomass burning (22 %), aged sea salt (4 %), sea/road salt (3 %), and mineral dust (7 %), and the newly found sources from primary biogenic (4 %), secondary biogenic oxidation (10 %), and MSA-rich (3 %). Generally, the chemical species exhibiting similar temporal trends and strong correlations showed uniformly distributed emission sources in the Grenoble basin. The improved PMF model was able to obtain and differentiate chemical profiles of specific sources even at high proximity of receptor locations, confirming its applicability in a fine-scale resolution. In order to test the similarities between the PMF-resolved sources, the Pearson distance and standardized identity distance (PD-SID) of the factors in each site were compared. The PD-SID metric determined whether a given source is homogeneous (i.e., with similar chemical profiles) or heterogeneous over the three sites, thereby allowing better discrimination of localized characteristics of specific sources. Overall, the addition of the new tracers allowed the identification of substantial sources (especially in the SOA fraction) that would not have been identified or possibly mixed with other factors, resulting in an enhanced resolution and sound source profile of urban air quality at a city scale