Hypervariabilité génotypique des mélanomes : Un défi thérapeutique

On estime à environ 5 000 le nombre annuel de nouveaux cas de mélanome en France. La proportion des formes familiales est évaluée, selon les séries, entre 5 % et 10 %. Les aspects cliniques, histologiques et biologiques de progression du mélanome sont actuellement mieux connus ; les développements technologiques récents ont, quant à eux, permis d’aborder les mécanismes moléculaires de la progression tumorale et de mettre en lumière des gènes impliqués dans cette évolution. Toutefois, des difficultés importantes persistent : il existe une grande variabilité dans l’expression de ces gènes, non seulement d’un patient à l’autre, mais aussi selon les stades de la maladie, locaux ou métastatiques ; par ailleurs, certaines des mutations retrouvées au cours du mélanome peuvent également être présentes dans des lésions bénignes (naevus). La variabilité génotypique associée au mélanome rend le ciblage thérapeutique complexe, et constitue actuellement un défi majeur en termes de traitement. Cet article, volontairement non exhaustif, insistera surtout sur les anomalies génomiques les plus étudiées, desquelles semblent naître des perspectives thérapeutiques intéressantes.Cutaneous melanoma remains a management challenge. Melanoma is the leading cause of death from skin tumors worldwide. Melanoma progression is well defined in its clinical, histopathological and biological aspects, but the molecular mechanism involved and the genetic markers associated to metastatic dissemination are only beginning to be defined. The recent development of high-throughput technologies aimed at global molecular profiling of cancer is switching on the spotlight at previously unknown candidate genes involved in melanoma. Among those genes, BRAF is one of the most supposed to be of interest and targeted therapies are ongoing in clinical trials. In familial melanoma, germline mutations in two genes, CDKN2A and CDK4, that play a pivotal role in controlling cell cycle and division. It is hope that this better understanding of the biologic features of melanoma and the mechanisms underlying tumor-induced immunosuppression will lead to efficaceous targeted therapy

Synthèse, évaluation biologique et caractérisation d'hexopyranoses fluorés

Un intérêt croissant est porté à la préparation de glucides polyfluorés. Le remplacement de fonctions hydroxyles par des atomes de fluor sur des squelettes d'hexoses pourrait permettre de découvrir de nouvelles molécules aux propriétés uniques. Les glycomimétiques fluorés sont des outils précieux pour l’étude de divers processus biochimiques. Dans nos activités de recherches visant à l’élaboration de nouvelles voies d’accès aux glucides fluorés, nous avons décrit la synthèse d’une série de galactopyranosides mono- et polyfluorés. Le défi synthétique que cela représente, associé à la rareté de certains de ces composés, nous a incités à évaluer leur profil biologique sur une protéine galactophile modèle, la PA-IL, qui est un facteur de virulence de Pseudomonas aeruginosa. Ces travaux de recherche ont porté sur la synthèse d'inhibiteurs d’intérêt pharmaceutique de faibles poids moléculaires qui contournent les inconvénients généralement associés aux oligosaccharides naturels. Seul un nombre limité de glucides fluorés ont été utilisés dans des études biologiques en raison de la difficulté inhérente à leur préparation. Cela nous a poussés à développer diverses voies de synthèse stéréosélectives de dérivés de sucres polyfluorés. Une grande diversité moléculaire a été obtenue grâce à une méthode de synthèse utilisant une approche Chiron à partir de lévoglucosan peu coûteux, processus qui est détaillé dans la présente thèse. Est décrite ici la préparation de composés fluorés dérivés d'hexopyranoses, de glycocluster, disaccharidiques, de glycopeptides et de glycoconjugué d'acide lipoïque. Des analyses structurales et des études RMN ont permis de confirmer la configuration et la conformation des molécules fluorées synthétisées. Certaines propriétés physico-chimiques comme la lipophilie ont été mesurées et l’influence de la stéréochimie relative des atomes de fluor contigus a pu être évaluée. Ces résultats mettent clairement en évidence les défis liés à la préparation de molécules organiques complexes polyhalogénées et ouvrent la voie à de nouveaux outils pertinents pour la chimie médicinale.There is a growing interest in the preparation of polyfluorinated carbohydrates. The replacement of hydroxyl groups by fluorine atoms on hexopyranoside scaffolds may allow access to the discovery of new chemical entities possessing unique properties. Fluorinated glycomimetics are invaluable tools to study various biochemical processes. As part of ongoing activities toward the preparation of fluorinated carbohydrates, the synthesis of a series of mono- and polyfluorinated galactopyranosides is described. The synthetic challenge they present combined with the scarcity of some of these compounds prompted us to evaluate their biological profile on a model galactophilic protein, PA-IL, a virulence factor from Pseudomonas aeruginosa. This research focused on the chemical synthesis of “druglike” low-molecular weight inhibitors that circumvent drawbacks typically associated with natural oligosaccharides. A limited number of fluorinated carbohydrates have been used in biological investigations because of the challenge they present. This encouraged us to develop diverse synthetic routes towards the stereoselective synthesis of polyfluorinated sugars derivatives. Hence, we report the synthesis of various heavily fluorinated compounds using a Chiron approach from inexpensive levoglucosan. A rich molecular diversity has been achieved, and herein is described the preparation of heavily fluorinated hexopyranoses derivatives, glycocluster, disaccharides, glycopeptides and lipoic acid glycoconjugate. Structural analysis and NMR studies confirm the configuration and conformation for fluorinated carbohydrate analogs, and some physicochemical properties, such as lipophilicities, have been measured and corroborated with the relative stereochemistry of multi-vicinal fluorine atoms. These results clearly highlight challenges related to the preparation of polyhalogenated complex organic molecules and pave the way to access novel medically relevant tools

Bump at the End of the Bridge: Review and Analysis of Rider Discomfort

Localized irregularities in the road profile are a well-known and persistent cause of rider discomfort when entering and exiting many bridges. This work addresses this so called “bump at the end of the bridge” problem first, through a review of relevant literature focusing on causes of the bump problem, mitigation techniques, retrofitting techniques, and special bump problems related to integral abutment bridges. Then, recognizing that approach slabs play a crucial role in the development of the bump, this problem is addressed through an investigation and comparison of approach slab designs and details utilized by various states. And, finally, the “bump at the end of the bridge” problem is addressed through dynamic analyses to ascertain the impact that various parameters of the bump geometry, road conditions, and vehicle speed have on rider discomfort. The results of the dynamic analyses indicate that the slope of the approach slab (i.e., the bump) and vehicle speed have the biggest impact on rider discomfort. Recommendations for future research are also noted

Modelado de Cadenas Cinemáticas mediante Matrices de Desplazamiento. Una alternativa al método de Denavit-Hartenberg

En este trabajo se presenta un método para el modelado de cadenas cinemáticas de robots que salva las dificultades asociadas a la elección de los sistemas de coordenadas y obtención de los parámetros de Denavit-Hartenberg. El método propuesto parte del conocimiento de la posición y orientación del extremo del robot en su configuración de reposo, para ir obteniendo en qué se transforman éstas tras los sucesivos movimientos de sus grados de libertad en secuencia descendente, desde el más alejado al más cercano a su base. Los movimientos son calculados en base a las Matrices de Desplazamiento, que permiten conocer en que se transforma un punto cuando éste es desplazado (trasladado o rotado) con respecto a un eje que no pasa por el origen. A diferencia del método de Denavit-Hartenberg, que precisa ubicar para cada eslabón el origen y las direcciones de los vectores directores de los sistemas de referencia asociados, el método basado en las Matrices de Desplazamiento precisa solo identificar el eje de cada articulación, lo que le hace más simple e intuitivo que aquel. La obtención de las Matrices de Desplazamiento y con ellas del Modelo Cinemático Directo a partir de los ejes de la articulación, puede hacerse mediante algunas simples operaciones, fácilmente programables

Universal trapping scaling on the unstable manifold for a collisionless electrostatic mode

An amplitude equation for an unstable mode in a collisionless plasma is derived from the dynamics on the two-dimensional unstable manifold of the equilibrium. The mode amplitude $\rho(t)$ decouples from the phase due to the spatial homogeneity of the equilibrium, and the resulting one-dimensional dynamics is analyzed using an expansion in $\rho$. As the linear growth rate $\gamma$ vanishes, the expansion coefficients diverge; a rescaling $\rho(t)\equiv\gamma^2\,r(\gamma t)$ of the mode amplitude absorbs these singularities and reveals that the mode electric field exhibits trapping scaling $|E_1|\sim\gamma^2$ as $\gamma\rightarrow0$. The dynamics for $r(\tau)$ depends only on the phase $e^{i\xi}$ where $d\epsilon_{{k}} /dz=|{\epsilon_{{k}}}|e^{-i\xi/2}$ is the derivative of the dielectric as $\gamma\rightarrow0$.Comment: 11 pages (Latex/RevTex), 2 figures available in hard copy from the Author ([email protected]); paper accepted by Physical Review Letter

Stereoselective synthesis of fluorinated galactopyranosides as potential molecular probes for galactophilic proteins : assessment of monofluorogalactoside–LecA interactions

The replacement of hydroxyl groups by fluorine atoms on hexopyranoside scaffolds may allow access to invaluable tools for studying various biochemical processes. As part of ongoing activities toward the preparation of fluorinated carbohydrates, a systematic investigation involving the synthesis and biological evaluation of a series of mono‐ and polyfluorinated galactopyranosides is described. Various monofluorogalactopyranosides, a trifluorinated, and a tetrafluorinated galactopyranoside have been prepared using a Chiron approach. Given the scarcity of these compounds in the literature, in addition to their synthesis, their biological profiles were evaluated. Firstly, the fluorinated compounds were investigated as antiproliferative agents using normal human and mouse cells in comparison with cancerous cells. Most of the fluorinated compounds showed no antiproliferative activity. Secondly, these carbohydrate probes were used as potential inhibitors of galactophilic lectins. The first transverse relaxation‐optimized spectroscopy (TROSY) NMR experiments were performed on these interactions, examining chemical shift perturbations of the backbone resonances of LecA, a virulence factor from Pseudomonas aeruginosa. Moreover, taking advantage of the fluorine atom, the 19F NMR resonances of the monofluorogalactopyranosides were directly monitored in the presence and absence of LecA to assess ligand binding. Lastly, these results were corroborated with the binding potencies of the monofluorinated galactopyranoside derivatives by isothermal titration calorimetry experiments. Analogues with fluorine atoms at C‐3 and C‐4 showed weaker affinities with LecA as compared to those with the fluorine atom at C‐2 or C‐6. This research has focused on the chemical synthesis of “drug‐like” low‐molecular‐weight inhibitors that circumvent drawbacks typically associated with natural oligosaccharides

Criticality in a Vlasov-Poisson system - a fermionic universality class

A model Vlasov--Poisson system is simulated close the point of marginal stability, thus assuming only the wave-particle resonant interactions are responsible for saturation, and shown to obey the power--law scaling of a second-order phase transition. The set of critical exponents analogous to those of the Ising universality class is calculated and shown to obey the Widom and Rushbrooke scaling and Josephson's hyperscaling relations at the formal dimensionality $d=5$ below the critical point at nonzero order parameter. However, the two-point correlation function does not correspond to the propagator of Euclidean quantum field theory, which is the Gaussian model for the Ising universality class. Instead it corresponds to the propagator for the fermionic {\it vector} field and to the {\it upper critical dimensionality} $d_c=2$. This suggests criticality of collisionless Vlasov-Poisson systems as representative of the {\it universality class} of critical phenomena of {\it a fermionic} quantum field description.Comment: 10 pages, 6 figures, Submitted to Phys. Rev.

Nonlinear saturation of electrostatic waves: mobile ions modify trapping scaling

The amplitude equation for an unstable electrostatic wave in a multi-species Vlasov plasma has been derived. The dynamics of the mode amplitude $\rho(t)$ is studied using an expansion in $\rho$; in particular, in the limit $\gamma\rightarrow0^+$, the singularities in the expansion coefficients are analyzed to predict the asymptotic dependence of the electric field on the linear growth rate $\gamma$. Generically $|E_k|\sim \gamma^{5/2}$, as $\gamma\rightarrow0^+$, but in the limit of infinite ion mass or for instabilities in reflection-symmetric systems due to real eigenvalues the more familiar trapping scaling $|E_k|\sim \gamma^{2}$ is predicted.Comment: 13 pages (Latex/RevTex), 4 postscript encapsulated figures which are included using the utility "uufiles". They should be automatically included with the text when it is downloaded. Figures also available in hard copy from the authors ([email protected]