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Background: Ex vivo confocal microscopy using fusion mode and digital staining (EVCM) scans unfixed fresh tissue and produces rapidly digitally stained images of very similar quality to classical pathology. We investigated whether EVCM could represent an alternative to the standard histological examination of the pretherapeutic basal cell carcinoma (BCC) punch biopsies. Objectives: The objective of the study was to assess diagnostic accuracy of EVCM versus traditional histopathological examination for diagnosing and subtyping clinically suspicious lesions of BCC in 3-mm fresh and nonfixed punch biopsies. Methods: In this prospective monocentric observational study, patients with clinically suspected BCC were consecutively enrolled. Punch biopsies were imaged using EVCM and subsequently processed for standard histologic examination (gold standard). EVCM images were examined by a dermatopathologist blinded to clinical aspect of the lesion and histopathological results. Concordance between the EVCM and histology analysis was calculated with Cohen’s kappa (κ) statistic. Results: Sixty-six patients were recruited, and 106 biopsies were analyzed. EVCM correctly diagnosed 70/73 BCCs and 31/33 non-BCC lesions, corresponding to a sensitivity of 96% and a specificity of 94% (positive predictive value = 97%, negative predictive value = 91%). The EVCM assessment led to over-staging and under-staging of BCC subtypes in 5% and 11% of cases, respectively. It led to over-staging and under-staging of BCC depths in 5% and 15%, respectively. The kappa coefficient for concordance was 0.78 (95% confidence interval [CI]: 0.69–0.88) when considering BCC subtypes and 0.81 (95% CI: 0.72–0.90) when considering BCC depths. Conclusions: These results render EVCM as a promising option for “real-time” pretreatment evaluation of clinically suspected BCC lesions. Further larger randomized studies are needed to assess the efficiency of EVCM versus standard care in patients with clinically suspected BCC.

Parallel black box optimization consists in estimating the optimum of a function using $\lambda$ parallel evaluations of $f$. Averaging the $\mu$ best individuals among the $\lambda$ evaluations is known to provide better estimates of the optimum of a function than just picking up the best. In continuous domains, this averaging is typically just based on (possibly weighted) arithmetic means. Previous theoretical results were based on quadratic objective functions. In this paper, we extend the results to a wide class of functions, containing three times continuously differentiable functions with unique optimum. We prove formal rate of convergences and show they are indeed better than pure random search asymptotically in $\lambda$. We validate our theoretical findings with experiments on some standard black box functions.

International audience; Many solid materials contain nanoparticles to enhance their functionalities. The question of whether they may release nanoparticles at different moments of their life cycle is raised. Lifecycle includes waste management. There is therefore a need to determine the fate of nanoparticles when the materials they are incorporated in are incinerated. The present study aims at shedding light on these issues. In this context, three real-life wastes selected for their specific compositions were combusted in a lab-scale furnace under incineration conditions. The first two wastes contained nanoparticles, namely silica and titanium dioxide. The third waste was purposely nanoparticle free. In addition, the waste containing titanium dioxide did contain chlorine and the nanoparticle-free material was partly made of sulfur. Disposal of halogen and sulfur-containing garbage implies an incineration temperature of 1100 °C. This complex waste composition was seen as an opportunity to assess possible interactions between nanoparticles and hazardous elements such as chlorine and sulfur during the combustion. Most of the analyses were supported by electronic microscopy imaging after having sampled particles in the fumes and in the bottom ashes. Eventually, three mechanistic scenarios were drawn from these experiments. Focus was made on the evolution of the nanostructure. It was observed to be preserved for the first waste. It disappeared both from the aerosol and the residue for the second waste. The third material, though not initially nanostructured, led to the formation of a nanostructure in the aerosol.

International audience; The previous survey of the French CaRPE project has shown a lack of information and showed the interest to assess the residual exposure to these particles. This paper presents the results of various sampling operations and emission analyses of plasma spraying equipment. For this purpose, different areas have been targeted, such as at the level of the emissions channeled upstream and downstream of the filtration system, at the workstation level as well as fugitive emissions. Various measurements were carried out: real-time particle size distribution, mass concentration of total suspended dust, heavy metals, sampling characterization by EDX/ MET, etc. The metallic aerosol is mainly composed of nanometric structures. The number concentration is particularly high (between 108 and 109 particles/cm3) downstream the filtration system. Measurements upstream and downstream of the filtration system have made it possible to determine its efficiency, which is greater than 90%. The mass concentration downstream of the filter is ~2.6 mg/m3 while the number concentration remains above 106 particles/cm3. Some recommendations were then derived. Very great vigilance is therefore recommended in order to protect the operator, since we must remember that we are in the presence of a very high concentration of metallic and nanostructured particles.

Choosing the right selection rate is a long standing issue in evolutionary computation. In the continuous unconstrained case, we prove mathematically that a single parent \(\mu =1\) leads to a sub-optimal simple regret in the case of the sphere function. We provide a theoretically-based selection rate \(\mu /\lambda \) that leads to better progress rates. With our choice of selection rate, we get a provable regret of order \(O(\lambda ^{-1})\) which has to be compared with \(O(\lambda ^{-2/d})\) in the case where \(\mu =1\). We complete our study with experiments to confirm our theoretical claims.

Characterization of the exposition to nanoparticles and nano-objects at workplaces is a huge technical challenge. Workplace exposure during short durations is particularly difficult to detect due to the low performances of the samplers. This article proposes a solution allowing for characterizing emissions at workplaces and presents the results obtained from a nanomaterials exposure measurement campaign performed on six different process lines (PLs) distributed all over Europe. By using our Short Time Sampling (STS) approach, the emitted nanomaterials are characterized in terms of their number concentration, size, shape and chemical composition. The background noise without any production activity is first measured for each PL and then it is distinguished from the emitted nanomaterials during production. The PLs yield different nanomaterial emission levels: the PL using the extrusion of polymer composites shows high emission whereas the PL dealing with the electrospinning of polyamide nanofibers shows the least i.e. no significant change in the background noise during the process and no detectable nanofiber emission either. The nanomaterials get emitted in the form of nanoparticles or submicronic fibers, or their agglomerates and aggregates i.e. Nano Objects, Agglomerates and Aggregates (NOAA). By the developed technique, 9 out of 37 of the studied steps have been shown to exhibit exposures to nanoparticles and nano-objects. For nanosafety measures, the energetic processes like spraying, extrusion, transport and cleaning activities of the nanomaterials in the powder form require most attention.

International audience; Background: The cyclin-dependent kinases (CDKs) CDK2 and CDK4 are involved in regulation of cell-cycle progression, and psoriasis is characterized by hyperproliferation of basal epidermal cells. CDK inhibitory proteins (CKIs) such as p16INK 4A (p16) bind CDK4/6 kinases and prevent their interaction with D-type cyclins. CKIs such as p21Cip1 (p21) and p27Kip1 (p27) associate with CDK-cyclin complexes and prevent their activation.Objectives: To gain insight into the molecular implication of CDK2 and CDK4 kinases in psoriasis, we sought to characterize expression of these kinases and associated cyclins, as well as of CKIs, and addressed the status of CDK2 and CDK4 activity in human psoriatic epidermis.Methods: A cohort of 24 patients with psoriasis participated in the study. Biopsies were removed from a chronic plaque and from nonlesional skin. CDK2, CDK4, cyclin D1, cyclin E and CKI protein expression was assessed by immunoblotting, immunohistochemistry and immunofluorescence. CDK4 and CDK2 mRNA expression was determined by real-time polymerase chain reaction. Specific kinase activities of CDK2 and CDK4 were evaluated using fluorescent peptide biosensors.Results: CDK2-cyclin E expression and activity were significantly increased in psoriatic epidermis compared with uninvolved adjacent skin. In contrast, CDK4-cyclin D1 activity was inhibited, although its expression was increased in psoriatic epidermis and its transcription slightly inhibited. p27 expression was reduced, while p16 and p21 expression was induced in psoriatic epidermis.Conclusions: Epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations are not associated with changes in CDK transcription and instead involve post-translational control mediated by decreased expression of p27 and p16 overexpression, respectively. What's already known about this topic? Cyclin-dependent kinases (CDKs) are involved in cell-cycle progression. The levels of cyclin partners and CDK inhibitors regulate their activity. Psoriasis is a chronic T-cell-driven inflammatory skin disease characterized by hyperproliferation of basal epidermal cells. What does this study add? Thanks to fluorescent peptide biosensors, this study demonstrates that epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations involve post-translational control mediated by decreased expression of p27, and p16 overexpression, respectively. What is the translational message? CDK2 and CDK4 are involved in regulation of cell-cycle progression, and psoriasis is characterized by hyperproliferation of basal epidermal cells. Epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations are not associated with changes in CDK transcription and instead involve post-translational control mediated by decreased expression of p27 and p16 overexpression, respectively. Pharmacological modulation of CDK2 and CDK4 may constitute a promising therapeutic strategy.

Les GRK2/3 forment une sous-famille de kinases (GRK ou G protein-coupled receptor kinase) associees aux recepteurs couples aux proteines G. Elles jouent un role dans la desensibilisation de ces recepteurs et modulent la signalisation cellulaire en phosphorylant des substrats impliques dans l’inflammation et la proliferation cellulaires. L’objectif de notre etude a ete d’evaluer l’expression et la transcription des GRK2/3 dans l’epiderme psoriasique. Des biopsies ont ete realisees en peau saine et lesee chez neuf malades atteints de psoriasis moderes a severes. L’expression des proteines d’interet a ete evaluee par immunofluorescence, microscopie confocale et Western-Blot epidermique. L’etude de la transcription a ete faite par qPCR epidermique. Il existait une diminution des GRK2 et GRK3 dans le cytoplasme (respectivement (46,3 ± 8,2) % et (57,5 ± 8,6) %, n = 3) et dans le noyau (respectivement (49,4 ± 10,4) % et (44,5 ± 10,4) %, n = 3). Les formes phosphorylees de la GRK2 etaient egalement diminuees dans l’epiderme psoriasique. Les analyses par blot ont confirme ces resultats. Il existait en revanche une induction de la transcription de GRK2 (2,33 ± 0,43, n = 3) et de GRK3 (2,83 ± 0,36, n = 3). La diminution de l’expression des GRK2/3 pourrait etre associee a une augmentation de l’activite des RCPG dans l’epiderme psoriasique et jouer un role dans la modulation des voies de signalisation GRK-dependantes.

International audience; Melanoma and Merkel cell carcinoma are two aggressive skin malignancies with high disease-related mortality and increasing incidence rates. Currently, invasive tumor tissue biopsy is the gold standard for their diagnosis, and no reliable easily accessible biomarker is available to monitor patients with melanoma or Merkel cell carcinoma during the disease course. In these last years, liquid biopsy has emerged as a candidate approach to overcome this limit and to identify biomarkers for early cancer diagnosis, prognosis, therapeutic response prediction, and patient follow-up. Liquid biopsy is a blood-based non-invasive procedure that allows the sequential analysis of circulating tumor cells, circulating cell-free and tumor DNA, and extracellular vesicles. These innovative biosources show similar features as the primary tumor from where they originated and represent an alternative to invasive solid tumor biopsy. In this review, the biology and technical challenges linked to the detection and analysis of the different circulating candidate biomarkers for melanoma and Merkel cell carcinoma are discussed as well as their clinical relevance.

Introduction Le projet Sport-UV est une collaboration entre physiciens et dermatologues menee en 3 etapes :. – evaluer le risque solaire chez les sportifs - modelisation du risque et etude des comportements ; – sensibilisation de cette cible ; – etude interventionnelle. Nous presentons ici les resultats de la modelisation des doses d’ultraviolets (UV) erythemales (DE) et de vitamine D (DD) synthetisee par des sujets pratiquant du sport en plein air dans 3 villes, Paris, Marseille et Brest. Materiel et methodes Les modelisations des DE et DD ont ete calculees a partir des donnees climatologiques et des contenus d’ozone en France. Les calculs ont pris en compte : periodes, jours/heures d’exposition, angles d’exposition de la peau, phototypes, surface cutanee exposee et nebulosite. Resultats Pendant les journees d’ete, en situations de ciel clair, les DE a midi peuvent atteindre des valeurs superieures a 800 Jm−2. Ces quantites sont suffisantes pour le developpement d’un erytheme chez des individus de phototype V (DE > 600 Jm−2) en moins d’une heure. Les doses maximales cumulees pendant toute la journee ont varie entre 4,6 a 5,5 kJm−2 selon les variabilites naturelles de la couche d’ozone. Pour les 3 villes etudiees, les DE calculees etaient superieures a 10 SED, 8 mois sur 12. Marseille presente des quantites de rayonnement UV significativement plus elevees que celles observees a Paris ou Brest. Ces doses sont calculees pour des surfaces a l’horizontale. Sur une surface a 30°, le sujet recoit 89 % de rayonnement UV ; sur une surface a 60°, elle tombe a 63 %. Les nuages impactent la quantite d’UV selon le type et le taux de couverture. Nos simulations ont montre des attenuations > 60 %. Pour atteindre la synthese de 1000 UI de vit D pour un individu de phototype II avec exposition du visage, des mains et des bras, le temps varie entre 30 min (debut mars et fin septembre) a Discussion Nos resultats montrent que l’ensemble du territoire national est soumis a une irradiation UV relativement homogene, quel que soit le phototype. Pour les 3 villes etudiees, les DE calculees etaient importantes et comparables tout au long de l’annee, a l’exception de la periode novembre–fevrier. En raison des consequences clinicobiologiques de l’exposition UV, ces donnees doivent etre connues des sportifs et des professionnels exposes. En ce qui concerne la synthese epidermique de vitamine D, les quantites de rayonnement UV sont suffisantes et compatibles avec une duree d’exposition quotidienne realiste de mai a septembre. Conclusion Cette modelisation du risque est la 1ere etape du projet Sport-UV et montre la complexite des calculs et des parametres impliques. L’etude des comportements, en cours dans differents sports pratiques en plein air, permettra de mieux cibler les populations les plus « a risque » au sein des sportifs, avant realisation d’une etude interventionnelle.

Nanotechnology is said to be the industry of the 21st century. The production of nanoproducts keeps growing at a rapid pace. Consequently, the need to anticipate how to deal with these products at each step of their life cycle is more and more necessary. Nanowaste management including product incineration is to be investigated to assess the impact it could have both on human health and the environment. The growing number of registrations of nanoscale substances (R-Nano in France) clearly demonstrates that the amount of nanowaste to be processed in waste treatment plants will increase in years to come. Though to date French and European regulations relative to nanowaste management do not exist, recommendations may at least be delivered to minimize possible impact on the environment and human health. Data on nanowaste incineration are still scarce. This motivates to better understand the phenomena at stake. Little is known yet about nanowaste incineration and the ensuing fate of nanoparticles. In addition, literature is scarce. In this context, the Nanowet project supported by the ADEME agency was set up to complement the existing studies. It focuses on the treatment of halogenand sulfur- containing nanowaste by elevated temperature incineration (1100°C). The objective is threefold, namely to assess the influence of (i) high temperature on the whole process (ii) the effect of the presence of acid gases in the fumes on particle emission and (iii) the effect of the wet scrubber technology installed in the waste treatment plant on nanoparticle capture efficiency. Three polymer wastes were selected and characterized for this project: two of these wastes contained nanofillers (silica and titanium dioxide) in addition with sulfur and chlorine. A lab scale horizontal tubular furnace operating with a temperature of 1100°C was utilized at INERIS nanosafety laboratory for the Nanowet experiments. Criteria relative to combustion requirements when incinerating products were carefully checked. Four series of experiments were carried out. The first three implied the incineration of each waste one after the other. The last series involved the incineration of a mix of the three wastes. It should be noted that at least four incineration experiments were carried out for each series. Eventually, the obtained results make it possible determining the fate of the nanoparticles and the impact of the mix of the three wastes on nanoparticle release.

Nanotechnology is said to be the industry of the 21st century. The production of nanoproducts keeps growing at a rapid pace. In November 2016 in France, the 4th annual declaration on imported, distributed and manufactured nanoscale substances reported a total number of registrations four times that of year 2013. Consequently, the need to anticipate how to deal with these products at each step of their life cycle is more and more necessary. Nanowaste management including product incineration is to be investigated to assess the impact it could have both on human health and the environment. The growing number of registrations of nanoscale substances clearly demonstrates that the amount of nanowaste to be processed in waste treatment plant will increase in years to come. Though to date French and European regulations relative to nanowaste management do not exist, recommendations may at least be delivered to minimize possible impact on the environment and human health. Data on nanowaste incineration are still scarce, which motivates considering this question to better understand the phenomena at stake...

Most dustiness studies do not measure dust release over long durations, nor do they characterize the effect of dust release on bulk powders. In this study, we tested the dustiness of two different samples of silicon carbide (SiC) powders (referred to as F220 and F320) over six hours using a vortex shaker. Additionally, we characterized the bulk sample for change in shape and size distribution due to the testing. Both powders release respirable fractions of dust particles but differ in their dust generation behavior. The numbers of released respirable particles for powder F220 are more than two times higher than those of powder F320. The dust generation mechanism might include the release of aerosols due to the attrition of particles owing to inter-particle and particle-wall impaction. This study emphasizes the need for long duration dustiness tests for hard materials like SiC and characterization for change in bulk material properties due to dust generation and release. Furthermore, the results can aid in selecting the bulk material for long-term applications based on dustiness.

Type I interferonopathies are a group of Mendelian disorders characterized by a common physiopathology: the up-regulation of type I interferons. To date, interferonopathies include Aicardi-Goutieres syndrome, familial chilblain lupus, spondyenchondromatosis, PRoteasome-associated auto-inflammatory syndrome (PRAAS) and Singleton-Merten syndrome. These diseases present phenotypic overlap including cutaneous features like chilblain lupus, that can be inaugural or present within the first months of life. This novel set of inborn errors of immunity is evolving rapidly, with recognition of new diseases and genes. Recent and improved understanding of the physiopathology of overexpression of type I interferons has allowed the development of targeted therapies, currently being evaluated, like Janus-kinases or reverse transcriptase inhibitors.

Resume Introduction Le lymphœdeme massif localise (LML) est une tumeur benigne des tissus mous qui survient chez les malades atteints d’obesite morbide et qui prend le plus souvent l’aspect d’une volumineuse masse isolee. Observation Nous rapportons le cas d’une femme de 39 ans hospitalisee pour une pemphigoide bulleuse evoluant depuis 3 semaines et souffrant d’obesite morbide. A l’examen, il existait un lymphœdeme chronique bilateral des membres inferieurs et des LML multiples dont la taille avait progressivement augmente au cours des dix dernieres annees. On trouvait une volumineuse tumeur appendue au creux inguinal gauche et deux autres tumeurs de taille plus reduite siegeant sur la face posterieure des cuisses. Une exerese chirurgicale de la masse inguinale etait effectuee apres reduction ponderale. Discussion Le LML est une tumeur benigne dont l’exerese est cependant souhaitable chaque fois que cela est possible, car une evolution a long terme vers un angiosarcome a ete rapportee dans 13 % des cas. Cette tumeur, dont l’association a une pemphigoide bulleuse semble ici fortuite, est probablement secondaire a une obstruction prolongee des canaux lymphatiques par un exces important de tissu adipeux.