Nectin-4: a new prognostic biomarker for efficient therapeutic targeting of primary and metastatic triple-negative breast cancer

International audienceBackground: Triple-negative breast cancers (TNBCs) are associated with a poor prognosis. In contrast to other molecular sub-types, they have no identified specific target and chemotherapy remains the only available systemic treatment. The adhesion molecule nectin-4 represents a new potential therapeutic target in different cancer models. Here, we have tested the prognos-tic value of nectin-4 expression and assessed the therapeutic efficiency of an anti-nectin 4 antibody drug conjugate (ADC) on localised and metastatic TNBC in vitro and in vivo. Materials and methods: We analysed nectin-4/PVRL4 mRNA expression in 5673 invasive breast cancers and searched for correlations with clinicopathological features including metastasis-free survival (MFS). Immunohistochemistry was carried out in 61 TNBCs and in samples of primary TNBC Patient-Derived Xenografts (PDXs). An anti-nectin-4 antibody eligible for ADC was produced and tested in vitro and in vivo in localised and metastatic TNBC PDXs. Results: High nectin-4/PVRL4 mRNA expression was associated with poor-prognosis features including the TN and basal sub-types. High PVRL4 mRNA expression showed independent negative prognostic value for MFS in multivariate analysis in TNBCs. Nectin-4 protein expression was not detected in adult healthy tissues including mammary tissue. Membranous protein expression was found in 62% of TNBCs, with strong correlation with mRNA expression. We developed an ADC (N41mab-vcMMAE) comprising a human anti-nectin-4 monoclonal antibody conjugated to monomethyl auristatin-E (MMAE). In vitro, this ADC bound to nectin-4 with high affinity and specificity and induced its internalisation as well as dose-dependent cytotoxicity on nectin-4-expressing breast cancer cell lines. In vivo, this ADC induced rapid, complete and durable responses on nectin-4-positive xenograft TNBC samples including primary tumours, metastatic lesions, and local relapses; efficiency was dependent on both the dose and the nectin-4 tumour expression level. Conclusion: Nectin-4 is both a new promising prognostic biomarker and specific therapeutic target for ADC in the very limited armamentarium against TNBC

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Étude des agrégats de sélénium en phase vapeur en fonction de leur taille. II. Structure électronique des chaînes de sélénium dans l'approximation des liaisons fortes et par une méthode « self-consistent » du type CNDO

The molecular orbital calculation of selenium chains Sen (n = 2 to 10) is carried out in the framework of the Hückel model for σ bands and in the CNDO self-consistent approximation. The ionization energies and the binding energy calculated for a chain are compared with the experimental values. The electronic structure of energy levels is compared with the results reported in the literature.Le calcul des orbitales moléculaires des chaînes de sélénium Se n (n = 2 à 10) est effectué dans le cadre du modèle de Hückel pour les liaisons σ ainsi que dans l'approximation self-consistent du type CNDO. Les énergies d'ionisation ainsi que l'énergie par liaison dans une chaîne sont comparées aux valeurs expérimentales. La structure électronique des niveaux d'énergie est comparée aux résultats de la littérature

Low-energy cluster beam deposition : do you need it ?

Physical and chemical properties of films prepared by Low-Energy Cluster Beam Deposition (LECBD) are presented, discussed and compared to those of films obtained by other conventional deposition techniques. LECBD films are formed by the stacking of individual grains corresponding roughly to the incident free clusters. This original structure suggests that LECBD is promising for technological and theoretical applications. Film properties strongly related to the mean grain size can be controlled with this original technique. This work shows several examples showing the assets of LECBD : ultrathin sintered films, high surface-volume ratio or continuous ultrathin films, new structures of metallic deposits. Used as a tool to obtain experimental data to study fractal 2D models or to elaborate deposits to study quantum size effects, this deposition technique would be original, efficient and sometimes essential in many research areas