Targeting matriptase in breast cancer abrogates tumour progression via impairment of stromal-epithelial growth factor signalling.

Matriptase is an epithelia-specific membrane-anchored serine protease that has received considerable attention in recent years because of its consistent dysregulation in human epithelial tumours, including breast cancer. Mice with reduced levels of matriptase display a significant delay in oncogene-induced mammary tumour formation and blunted tumour growth. The abated tumour growth is associated with a decrease in cancer cell proliferation. Here we demonstrate by genetic deletion and silencing that the proliferation impairment in matriptase-deficient breast cancer cells is caused by their inability to initiate activation of the c-Met signalling pathway in response to fibroblast-secreted pro-HGF. Similarly, inhibition of matriptase catalytic activity using a selective small-molecule inhibitor abrogates the activation of c-Met, Gab1 and AKT, in response to pro-HGF, which functionally leads to attenuated proliferation in breast carcinoma cells. We conclude that matriptase is critically involved in breast cancer progression and represents a potential therapeutic target in breast cancer

Matriptase regulates c-Met mediated proliferation and invasion in inflammatory breast cancer.

The poor prognosis for patients with inflammatory breast cancer (IBC) compared to patients with other types of breast cancers emphasizes the need to better understand the molecular underpinnings of this disease with the goal of developing effective targeted therapeutics. Dysregulation of matriptase expression, an epithelial-specific member of the type II transmembrane serine protease family, has been demonstrated in many different cancer types. To date, no studies have assessed the expression and potential pro-oncogenic role of matriptase in IBC. We examined the functional relationship between matriptase and the HGF/c-MET signaling pathway in the IBC cell lines SUM149 and SUM190, and in IBC patient samples. Matriptase and c-Met proteins are localized on the surface membrane of IBC cells and their expression is strongly correlated in infiltrating cancer cells and in the cancer cells of lymphatic emboli in patient samples. Abrogation of matriptase expression by silencing with RNAi or inhibition of matriptase proteolytic activity with a synthetic inhibitor impairs the conversion of inactive pro-HGF to active HGF and subsequent c-Met-mediated signaling, leading to efficient impairment of proliferation and invasion of IBC cells. These data show the potential of matriptase inhibitors as a novel targeted therapy for IBC, and lay the groundwork for the development and testing of such drugs

Diastereoselective synthesis of phosphite triesters and phosphorothioates

The diastereoselective synthesis of phosphite triesters and related phosphorothioate triesters and diesters has been investigated, with the goal of synthesizing diastereomerically pure DNA phosphorothioates.Towards this end, the elaboration of a new heterobicyclic structure, imidazo-oxazaphosphorine such as 56, is reported. This unstable intermediate led to the highly diastereoselective synthesis of simple phosphite triesters upon reaction with various alcohols.Two new types of sterically hindered chiral oxazaphosphorinanes 135 and 146 were then synthesized from cholesterol and camphor respectively. These structures, derived from $gamma$-aminoalcohols possessing a tertiary alcohol function, could be isolated and characterized. They revealed very reactive in acidic conditions and led to rearrangements.Finally, oxazaphosphorinane 188 derived from 1,2-O-isopropylidene-D-xylofuranose, was synthesized and characterized. The introduction of a participating group adjacent to the leaving phosphorothioate group led to the fast release of the phosphorothioate moiety. This new chiral auxiliary was successfully used as a precursor in the diastereoselective synthesis of a T-T phosphorothioate dimer, in a diastereomeric ratio of 28.5:1.* ftn*Please refer to dissertation for diagrams

An Automatic Choice of Simple Geometric Shapes for Modelling Terrain Diffraction Phenomena

When predicting diffraction path loss using a 2-dimensional Digital Terrain Model (D.T.M.), the terrain profile is often simulated by a cascaded arrangement of canonical shapes as the perfectly absorbing half plane (or knife-edge), the wedge and the cylinder. It is often difficult to choose among all the diffraction models, that use these simple geometric shapes, the model that best suits to a given link. In this paper, an original algorithm, which makes an automatic choice of the suitable shape of a given diffracting obstacle, is described. This algorithm is then applied to CELAR (Centre d’Electronique de l’Armement) radio links at a frequency of 2.4 GHz

Comparaison de différents modèles de diffraction dans la bande UHF

International audienc

Taking-and-merging games as rewrite games

This work is a contribution to the study of rewrite games. Positions are finite words, and the possible moves are defined by a finite number of local rewriting rules. We introduce and investigate taking-and-merging games, that is, where each rule is of the form a^k->epsilon. We give sufficient conditions for a game to be such that the losing positions (resp. the positions with a given Grundy value) form a regular language or a context-free language. We formulate several related open questions in parallel with the famous conjecture of Guy about the periodicity of the Grundy function of octal games. Finally we show that more general rewrite games quickly lead to undecidable problems. Namely, it is undecidable whether there exists a winning position in a given regular language, even if we restrict to games where each move strictly reduces the length of the current position. We formulate several related open questions in parallel with the famous conjecture of Guy about the periodicity of the Grundy function of octal games

A Propagation Model Based on Diffraction by Multiple Rounded Obstacles using a Digital Terrain Model compared with Models using Obstacles of other Shapes

In the prediction of ground wave propagation loss over irregular terrain, knife-edge (Fresnel-Kirchhoff theory) or wedge (Uniform Theory of Diffraction (U.T.D.)) diffraction is used to predict signal attenuation. But, most of the time, the obstacles encountered along the propagation path are not sharp but look like smooth hills. So, in order to get a better approach of the terrain obstacles, we have developed a model based on multiple diffraction by cylindrical obstacles. This model is applied in the frequency range 1 GHz – 20 GHz using a 2-dimensional Digital Terrain Model (D.T.M) containing altimetry and planimetry information. It uses a maximum of 3 prevalent rounded obstacles. First, the formulation used for single cylinder diffraction is done. Then, the original algorithm to find the radius of curvature of the cylinders, as well as the diffraction path, are described. Finally, this model is applied to a terrain profile extracted from the D.T.M. and containing a prevalent smooth obstacle. The predicted results are compared with measured data obtained by CELAR (Centre d’Electronique de l’Armement) and with models using obstacles of other shapes at a frequency of 2.4 GHz

Taking-and-merging games as rewrite games

This work is a contribution to the study of rewrite games. Positions are finite words, and the possible moves are defined by a finite number of local rewriting rules{u_i→v_i}: a move consists in the substitution of one occurrence of u_i by v_i, for some i. We introduce and investigate taking-and-merging games, that is, where each rule is of the form a^k→ε. We give sufficient conditions for a game to be such that the losing positions (resp. the positions with a given Grundy value) form a regular language or a context-free language. We formulate several related open questions in parallel with the famous conjecture of Guy about the periodicity of the Grundy function of octal games.Finally we show that more general rewrite games quickly leadt o undecidable problems. Namely, it is undecidable whether there exists a winning position in a given regular language, even if we restrict to games where each move strictly reduces the length of the current positio

Wedge Angle Influence on UTD Diffraction in Prediction of Propagation Path Loss for a Digital Terrain Model

International audienceWhen applying Uniform Theory of Diffraction (U.T.D.) on the problem of predicting path loss using a 2-dimensional Digital Terrain Model (D.T.M.), this terrain can be simplified using a treatment procedure based on Fast Fourier Transform (F.F.T.) . This simplification reduces calculation time but also changes the wedge angle used as obstacle. In order to show the influence of the terrain simplification on the propagation path loss computation, a study of the variation of the wedge angle is done using an idealized terrain profile and applied to a CELAR (Centre d’Electronique de l’Armement) radio link extracted from a D.T.M