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INTRODUCTION: DLL3, an atypical Notch ligand, is expressed in SCLC tumors but is not detectable in normal adult tissues. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate containing a DLL3-targeting antibody tethered to a cytotoxic agent pyrrolobenzodiazepine by means of a protease-cleavable linker. The efficacy and safety of Rova-T compared with topotecan as second-line therapy in patients with SCLC expressing high levels of DLL3 (DLL3-high) was evaluated. METHODS: The TAHOE study was an open-label, two-to-one randomized, phase 3 study comparing Rova-T with topotecan as second-line therapy in DLL3-high advanced or metastatic SCLC. Rova-T (0.3 mg/kg) was administered intravenously on day 1 of a 42-day cycle for two cycles, with two additional cycles available to patients who met protocol-defined criteria for continued dosing. Topotecan (1.5 mg/m2) was administered intravenously on days 1 to 5 of a 21-day cycle. The primary end point was overall survival (OS). RESULTS: Patients randomized to Rova-T (n = 296) and topotecan (n = 148) were included in the efficacy analyses. The median age was 64 years, and 77% had the extensive disease at initial diagnosis. The median OS (95% confidence interval) was 6.3 months (5.6-7.3) in the Rova-T arm and 8.6 months (7.7-10.1) in the topotecan arm (hazard ratio, 1.46 [95% confidence interval: 1.17-1.82]). An independent data monitoring committee recommended that enrollment be discontinued because of the shorter OS observed with Rova-T compared with topotecan. Safety profiles for both drugs were consistent with previous reports. CONCLUSIONS: Compared with topotecan, which is the current standard second-line chemotherapy, Rova-T exhibited an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC. A considerable unmet therapeutic need remains in this population. ispartof: JOURNAL OF THORACIC ONCOLOGY vol:16 issue:9 pages:1547-1558 ispartof: location:United States status: published

In this study we apply electron tomography of dislocations to quartz with a view to assess whether the von Mises-Taylor criterion is satisfied or violated in a deformed crystal of quartz. We propose a method to perform electron tomography with few projected images which allows extension of this technique to beam-sensitive materials such as quartz. The 3D characterization of the dislocation microstructure allows the evaluation of contributions to dislocation mobility with no ambiguity. From the geometrical characteristics of the dislocations and their Burgers vectors, we show how to identify the non-zero components of the strain tensor. We show that in the quartz grain investigated, the von-Mises-Taylor criterion is satisfied thanks to the climb of 〈c + a〉 dislocations. The TEM national facility in Lille (France) is supported by the Conseil Regional du Nord-Pas de Calais, the European Regional Development Fund (ERDF), and the Institut National des Sciences de l’Univers (INSU, CNRS). This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program under grant agreement 787198 – TimeMan. We thank A.K. Kronenberg and an anonymous reviewer for constructive comments.

The viscoplastic behavior of polycrystalline Mg$_2$SiO$_4$ wadsleyite aggregates, a major high pressure phase of the mantle transition zone of the Earth (depth range: 410 -- 520 km), is obtained by properly bridging several scale transition models. At the very fine nanometric scale corresponding to the disloca-tion core structure, the behavior of thermally activated plastic slip is modeled for strain-rates relevant for laboratory experimental conditions, at high pressure and for a wide range of temperatures, based on the Peierls-Nabarro-Galerkin model. Corresponding single slip reference resolved shear stresses and associated constitutive equations are deduced from Orowan's equation in order to describe the average viscoplastic behavior at the grain scale, for the easiest slip systems. These data have been implemented in two grain-polycrystal scale transition models, a mean-field one (the recent Fully-Optimized Second-Order Viscoplastic Self-Consistent scheme of [44]) allowing rapid evaluation of the effective viscosity of polycrystalline aggregates , and a full-field (FFT based [45] [33]) method allowing investigating stress and strain-rate localization in typical microstructures and heterogeneous activation of slip systems within grains. Calculations have been performed at pressure and temperatures relevant for in-situ conditions. Results are in very good agreement with available mechanical tests conducted at strain-rates typical for laboratory experiments., Comment: Comptes Rendus M\'ecanique, Elsevier Masson, In press

One main concern in climate science is to reduce uncertainties on sea level predictions. In particular,these uncertainties depend on the quantification of the mass losses of polar ice caps including Greenlandice sheet. Iceberg calving at Greenland glaciers accounts for up to half of ice losses at glacier termini.Some icebergs detaching from Greenland glaciers have the height of the glacier and are thin so unstableand capsize exerting a force on the glacier front which generates a seismic wave recorded at stationsin Greenland and further away. These seismic signals have been recorded for the last twenty-five yearsby the permanent stations. The number of such events has increased and the spatial distribution hasevolved. What is the evolution of the volume of capsizing icebergs ?Field data on capsizing icebergs are lacking, except for seismic data. Indeed, the database of seismicsignals gives continuous information about iceberg capsize events: we aim to extract information fromthese data. The characteristics of seismic signals depend on the iceberg volume and the whole dynamicof the capsizing iceberg [2]. The global aim of this work is to calculate the volum of capsizing icebergs.To do this, we compare recorded seismic signals to synthetic seismic signals calculated using a modelof iceberg capsize. Therefore, we solve an inverse problem to obtain information on the dynamic of thecapsize and in particular an estimation of the volume of the iceberg.Iceberg capsize dynamics depends on complex phenomena: iceberg-water interactions, iceberg-glacierfriction, glacier-sea floor friction, elasto-viscoplastic deformation of ice. Solving directly fluid flow, solidmotion, and contact equations even in two dimensions is very costly and can hardly be used to generatecatalogs and to solve inverse problem. Therefore, a simplified mechanical model of a capsizing icebergin water has been developed based on few assumptions. The proposed model, named SAFIM (semi-analytical floating iceberg model) accounts for sea hydrodynamics only through hydrostatic pressure,pressure drag, and added mass, and it has been validated based on a separate state-of-the-art Compu-tational Fluid Dynamics code which can handle free surface and arbitrary iceberg configurations. Theerror on the horizontal force exerted by the fluid on the iceberg capsizing in open ocean (with no contactwith the glacier) calculated with SAFIM goes from 4% to 20%, and the drag coefficient that minimizesthis error goes from 1 to 3, depending on the aspect ratio of the iceberg., Une des questions principales en sciences du climat est l'amélioration de la précision des prédictions du niveau des océans. En particulier, les incertitudes dépendent de la quantification de la perte de masse des calottes polaires comme celle du Groenland. Le détachement d'icebergs au front des glaciers du Groenland représente jusqu'à la moitié des pertes de masses aux terminus de ces glaciers. Certains icebergs qui se détachent des glaciers du Groenland ont la même hauteur que le terminus du glacier, sont fins donc instables et se retournent proche du glacier. Ils exercent ainsi une force sur le glacier qui crée un signal sismique enregistré sur des stations situées au Groenland ou plus loin. Le nombre d'évènements de ce type a augmenté et la distribution spatiale de ces évènements a évoluée [1]. Qu'en est-il de l'évolution du volume de ces icebergs qui se retournent ? Les données de terrain sur ces évènements sont rares, à l'exception des données sismiques qui donnent des informations continues sur les évènements de retournement d'icebergs. Les caractéristiques du signal sismique dépendent du volume de l'iceberg et de toute la dynamique du retournement [2]. Le but ultime de ce travail est de calculer les volumes des icebergs qui se retournent. Pour ce faire, nous comparons des signaux sismiques enregistrés à des signaux sismiques synthétiques obtenus à l'aide d'un modèle mécanique de retournement d'iceberg [3]. Ainsi, nous résolvons un problème inverse pour obtenir des informations sur la dynamique du retournement et une estimation du volume des icebergs [4]. Nous nous intéressons, dans cet article, à la modélisation mécanique du retournement d'un iceberg. La dynamique du retournement d’un iceberg dépend de phénomènes complexes : les interactions entre l’iceberg, l’eau et le glacier, le frottement entre le glacier et le lit rocheux, la déformation élasto-viscoplastique de la glace. Résoudre les équations de la mécanique des fluides, du mouvement solide et les équations de contacts solides est très coûteux, même en deux dimensions, et peu adapté à la génération d’un catalogue pour résoudre un problème inverse. Ainsi, un modèle mécanique simplifié de retournement d’iceberg dans l’eau a été développé sous quelques hypothèses. Le modèle proposé, nommé SAFIM (modèle semi-analytique d’un iceberg flottant) tient compte de la dynamique des fluides via la pressionhydrostatique, une pression de traînée et des masses ajoutées. Ce modèle SAFIM a été validé à partird’un modèle de mécanique des fluides numérique ISIS-CFD qui résoud la dynamique d’un fluide à surface libre en interaction avec un solide. L’erreur sur la force horizontale du fluide sur l’iceberg qui se retourne dans un océan infini (sans contact avec le glacier) calculée avec SAFIM est de l’ordre de 4% à 20%, et le coefficient de traînée qui minimise cette erreur varie entre 1 et 3, en fonction du rapport d’aspect de l’iceberg.

Colloque avec actes et comité de lecture. Internationale.; International audience; To validate mean- and full-field micromechanical models, we have performed elastic strain measurements using several diffraction techniques (neutrons,transmission and reflexion under synchrotron radiation, and laboratory X-ray) during which the specimen was tensile deformed in-situ. Application has been performed on a duplex steel (ferrite and austenite) as an example of two-phase high-strength polycrystals. The uncertainty and relevance of the different measurements will be discussed and compared with simulations based on an elasto-viscoplastic self-consistent model.

International audience; From the mechanical point of view, polycrystalline materials have to be considered asa specific class of composites. They are composed of many grains, with grains sizeranging from nm to cm scales. Grains are generally assembled in a random way, i.e.their size, shape, and lattice orientation do not depend on the size, shape, and orientationof the surrounding grains (figure 1). Therefore, the microstructure of polycrystalscan hardly be described exactly. Most of the time, one can only access a statisticalcharacterization of grain arrangement e.g. with the help of cross-correlation functions.In the Euler orientation space, microstructure description is generally limited tothe distribution of crystal lattice orientations (Orientation Distribution Function, ODF,or crystallographic texture).

International audience; The strongly anisotropic rheology of olivine polycrystals, associated to their microstructure, constitutes a key feature affecting the dynamics of the Earth's upper mantle. High pressure deformation experiments carried out on olivine single crystals under synchrotron radiation, together with estimations of lattice friction based on first-principle calculations, show a transition from easy [100] to easy [001] slips as pressure and temperature (thus depth) increases. We input these data at the slip system level into the second-order extension of the self-consistent scheme to assess microstructure evolution along a typical flow pattern beneath an oceanic spreading center

The strongly anisotropic rheology of olivine polycrystals, associated to their microstructure, constitutes a key feature affecting the dynamics of the Earth's upper mantle. High pressure deformation experiments carried out on olivine single crystals under synchrotron radiation, together with estimations of lattice friction based on first-principle calculations, show a transition from easy [100] to easy [001] slips as pressure and temperature (thus depth) increases. We input these data at the slip system level into the second-order extension of the self-consistent scheme to assess microstructure evolution along a typical flow pattern beneath an oceanic spreading center

The Earth’s upper mantle is known to exhibit elastic anisotropy, which is common-ly attributed to the presence of Lattice Preferred Orientations (LPO). Such anisotropy is revealed in recordings of seismic waves that travel through the mantle with speeds that depend on propagation and/or polarization direction. The development of LPO is due to the plastic deformation of mantle minerals associated with large-scale convec-tive flow. Both olivine and pyroxene crystals exhibit an orthorhombic structure and have only a few slip systems available for dislocation creep. This leads to very high viscoplastic anisotropy at the grain scale, so that an upper mantle region with strong seismic anisotropy (i.e., pronounced LPO) may also exhibit a large effective viscoplas-tic anisotropy which may manifest itself as differences in effective viscosities of up to one or two orders of magnitude depending on the loading direction. This may have a large influence on the flow in (at least) some regions of the mantle [CHR 87], as was also shown for the flow of ice in ice sheets [MAN 97], but the topic has received little attention [BLA 07]. The key of this issue is to understand the link between single crys-tal rheology, microstructure (in particular LPO) and associated polycrystal behavior,e.g. as attempted for polar ices [CAS 08b].

Plastie deformation of ice monocrystal is essentially due to dislocation glide in basal planes. Glide on other slip systems or eventually climb of basal dislocations limits the strain rate of polycrystalline ice. In polar ice sheets, a preferred c-axis orientation develops with strain, and induces and strong viscoplastie anisotropy. A ViscoPlastic Self-consistent (VPSC) approach is used for predicting mechanical behavior of polycrystalline ice and texture development. Results are compared to those of the uniform stress model (lower bound) and uniform strain rate model (upper bound). In these models, ice crystals are assumed to deform by basal, prismatic, and pyramidal slip. The slip system resistance of a grain in-situ is determined from the mechanical behavior (deterrnined experimentally) of strongly anisotropic polycrystalline samples.According to the VPSC model, the behavior of a grain in-situ is closed to that of an isolated monocrystal. This model perfectly reproduces the experimental behavior of anisotropic polycrystals. When polycrystalline ice is deformed by hard glide, the strain rate direction is very sensitive to the direction of the applied stress. Such deformation conditions should appear near the ice divide of ice sheets. In the upper layer of ice sheets (grain growth zone), the VPSC model gives a good estimation of texture development. In the deeper ice, rotation recrystallization has a significant influence on texture development. Mechanical tests in cold rooms indicate a tendency to a quasi-newtonien behavior under very low stress conditions., La déformation plastique du monocristaI de glace se produit essentiellement par glissement de dislocations dans les plans de base. Le glissement sur d'autres systèmes ou une éventuelle montée de dislocations basales limite la vitesse de déformation de la glace polycristalline. Dans les glaces des calottes polaires, une orientation préferentielle des axes c se développe au cours de la déformation, induisant une forte anisotropie viscoplastique. Un modèle auto-cohérent viscoplastique (VPSC) est utilisé pour calculer le comportement mécanique de la glace polycristalline et le développement des textures. Les résultats sont comparés à ceux du modèle à contraintes uniformes (borne inférieure) et à déformations uniformes (borne supérieure). Dans les modèles, il est supposé que le monocristal de glace se déforme par glissement basal, prismatique, et pyramidal. La résistance des systèmes de glissement d'un grain in-situ est déterminée à partir de résultats d'essais mécaniques sur des échantillons polycristallins fortement anisotropes. D'après le modèle VPSC, le comportement d'un grain in-situ est semblable à celui d'un monocristal isolé. Ce modèle reproduit parfaitement le comportement expérimental des glaces polycristallines anisotropes. Lorsqu'un polycristal est déformé de telle manière à ce que le glissement basal soit difficilement activé, la direction de la vitesse de déformation est très sensible à la direction de la contrainte, appliquée. De telles conditions de déformation devraient se retrouver dans le voisinage des dômes des calottes polaires. Dans les couches de surface des calottes polaires (zone de grossissement de grains), le modèle VPSC permet d'obtenir une bonne estimation du développement des textures. Dans les glaces plus profondes, on montre que la recristallisation par rotation a une influence significative sur le développement des textures. Une série d'essais mécaniques en laboratoire indique une tendance au comportement newtonien sous de très faibles contraintes.