Attractive and repulsive cracks in a heterogeneous material

We study experimentally the paths of an assembly of cracks growing in interaction in a heterogeneous two-dimensional elastic brittle material submitted to uniaxial stress. For a given initial crack assembly geometry, we observe two types of crack path. The first one corresponds to a repulsion followed by an attraction on one end of the crack and a tip to tip attraction on the other end. The second one corresponds to a pure attraction. Only one of the crack path type is observed in a given sample. Thus, selection between the two types appears as a statistical collective process.Comment: soumis \`a JSTA

Propagation d'ondes sonores dans des empilements granulaires non-cohésifs

Propagation of sound waves in cohesionless granular packings presents original and complex behaviors due to the divided nature of those materials. They behave as disordered and nonlinear media. Our study is original because we use photoelastic cylinders. By means of a fast camera, we visualize the deformation field associated to the sound wave propagation. First we are interested in the simplest granular packing : a one-dimensional array of cylinders in contact. We carry out an experimental investigation concerning the propagation of an acoustic pulse, in both cases where the pulse amplitude is small (linear wave), or large (nonlinear waves), compared to the static confining force applied to the chain. In the first case, we prove the prominent role played by the imperfections of the contacts on the sound celerity. We also show that the pulse damping mainly originates from dry friction. In the case of very large amplitude, the initial pulse breaks down into a wave train of decreasing amplitudes, with a width comprised between 3 and 4 grains and a supersonic speed. This speed, in units of the bulk sound celerity, depends only on the ratio of the amplitude to the static confining pressure. These observations are interpreted by generalizing the results of Nesterenko. Finally , we address the case of the two-dimensional packings. Linear sound waves propagate through the static force chains and their velocities increase with the static force in the chain. However they are always smaller than in the one-dimensional case. It suggests that the wave behavior along the force chain is affected by the lateral contacts of the chain.La propagation d'ondes sonores dans des empilements granulaires présente des comportements originaux et mal-élucidés liés à l'aspect divisé de ces matériaux. Ceux-ci se comportent notamment comme des milieux désordonnés et non-linéaires. Notre étude est originale car nous employons des grains photoélastiques. Couplés à une caméra rapide, nous visualisons le champ de déformation associé à la propagation de l'onde sonore. Nous abordons d'abord le cas de l'empilement le plus simple : une chaîne unidimensionnelle de grains cylindriques en contact. Nous étudions la propagation d'impulsions sonores dans les deux cas où leurs amplitudes sont petites (régime linéaire) ou grandes (régime non-linéaire) devant la force de confinement statique appliquée à la chaîne. Dans le premier cas, nous observons l'effet des imperfections de surface des grains sur la vitesse des ondes. Nous constatons aussi que la dissipation est essentiellement due au frottement solide. Pour les grandes amplitudes, l'impulsion initiale se décompose en un train de pics d'amplitudes décroissantes, de largeurs comprises entre 3 et 4 grains et de vitesses supersoniques. La vitesse du pic principal, adimensionnée par la vitesse du son linéaire, ne dépend que du rapport entre l'amplitude de l'onde et la force statique. Ces observations sont interprétées en généralisant les résultats de Nesterenko. Nous présentons ensuite le cas des empilements bidimensionnels. Les ondes linéaires se propagent dans les chaînes de forces et leurs vitesses croient avec la force statique. Elles restent cependant toujours inférieures à celles mesurées à 1D. Cela suggère que la dynamique de l'onde le long d'une chaîne de force est influencée par les contacts latéraux à cette chaîne de force

Propagation d'ondes sonores dans des empilements granulaires non-cohésifs (visualisation par photoélasticité)

Cette thèse est consacrée à l étude de la propagation d ondes sonores dans des empilements granulaires non-cohésifs. Ces milieux se comportent comme des milieux désordonnés et non-linéaires. Notre étude est originale car nous employons des grains photoélastiques et cylindriques. En utilisant une caméra rapide, nous visualisons le champ de déformation associé à la propagation de l onde sonore et nous testons une alternative à la loi de contact propre aux sphères. Nous abordons d abord le cas de l empilement le plus simple : une chaîne unidimensionnelle de cylindres. Nous étudions la propagation d impulsions sonores dans les deux cas ou leurs amplitudes sont petites (régime linéaire) ou grandes (régime non-linéaire) devant la force de confinement statique appliquée à la chaîne. Dans le premier cas, nous observons l effet des imperfections de surface des grains sur la vitesse des ondes. Nous constatons aussi que la dissipation est essentiellement due au frottement solide. Pour les grandes amplitudes, l impulsion initiale se décompose en un train de pics d amplitudes décroissantes, de largeurs comprises entre 3 et 4 grains et de vitesse supersonique. Celle-ci, adimensionnée par la vitesse du son linéaire, ne dépend que du rapport entre l amplitude de l onde et la force statique. Ces observations sont interprétées en généralisant les résultats de Nesterenko. Nous présentons ensuite le cas des empilements bidimensionnels. Les ondes linéaires se propagent dans les chaînes de forces et leurs vitesses croient avec la force statique. Elles restent cependant toujours inférieures à celles mesurées à 1D, ce qui démontre le rôle joué par les contacts latéraux de la chaîne.This work is devoted to sound wave propagation in cohesion less granular packings. Such media are disordered and display nonlinear properties. Our study is original because we use photoelastic cylinders. By means of a fast camera, we visualize the deformation field associated to the sound wave propagation in the granular media. Moreover, we probe a contact law different from that of spherical grains. Firstly we are interested to the simplest granular packing : a one-dimensional array of cylinders in contact. We conduct an experimental investigation concerning the propagation of an acoustic pulse, in both cases where the pulse amplitude is small (linear wave), or large (nonlinear waves), compared to the static confining force applied to the array. In the first case, we prove the prominent role played by the imperfections of the contacts on the sound celerity. We also show that the pulse damping mainly originates in dry friction. In the case of very large amplitude, the initial pulse breaks down in a waves train of decreasing amplitudes, with a width comprised between 3 and 4 grains and with supersonic speed. This speed, in units of sound celerity, depend only on the ratio of the amplitude and the static confining pressure. These observations are interpreted by generalizing the results of Nesterenko. At last, we address the case of the two-dimensional packings. Linear sound waves propagate through the static force chains and their velocities increase with the static force in the chain. However they are always smaller than in the one-dimensional case, what proves the role played by the lateral contacts of the chain.NICE-BU Sciences (060882101) / SudocSudocFranceF

Work fluctuations in a nematic liquid crystal]{Work fluctuations in a nematic liquid crystal

to be published in JSTAT: theory and experimentsInternational audienceThe orientation fluctuations of the director of a liquid crystal are measured, by a sensitive polarization interferometer, close to the Fréedericksz transition, which is a second order transition driven by an electric field. Using mean field theory, we define the work injected into the system by a change of the electric field and we calibrate it using Fluctuation-Dissipation Theorem. We show that the work fluctuations satisfy the Transient Fluctuation Theorem. An analytical justification of this result is given. The open problems for the out of equilibrium case are finally discussed

Real-life efficacy and predictors of response to immunotherapy in pituitary tumors: a cohort study

International audienceAbstract Objective After temozolomide failure, no evidence-based treatment is available for pituitary carcinomas (PCs) and aggressive pituitary tumors (APTs). To date, only 12 cases treated with immune-checkpoint inhibitors (ICIs) have been published, showing encouraging efficacy. Predictive factors of response are lacking. Here, we aimed to assess the real-life efficacy and predictors of response to ICIs in PCs and APTs. Design and methods This study is a multicentric, retrospective, observational cohort study, including all PCs and APTs treated with ICIs in France up to March 2022. PD-L1 immunohistochemistry and CD8+ T cell infiltration were evaluated centrally. Results Six PCs (four corticotroph and two lactotroph) and nine APTs (five corticotroph and four lactotroph) were included. The real-life efficacy of ICIs was lower than previously published data. Three corticotroph tumors (33.3%) showed partial response, one (11.1%) stable disease, while five (55.6%) progressed. One lactotroph tumor (16.7%) showed partial response, one (16.7%) stable disease, while four (66.7%) progressed. PCs responded far better than APTs, with 4/6 PCs showing partial response compared to 0/9 APTs. Corticotroph tumors responded slightly better than lactotroph tumors. In the four responsive corticotroph tumors, PD-L1 staining was negative and CD8+ T cell infiltration attained a maximum of 1% in the tumor center. Conclusions Confirmation of the presence or absence of metastases is necessary before starting ICIs. After temozolomide failure, ICIs appear as a good therapeutic option for PCs, especially for corticotroph carcinomas. Negative PD-L1 staining and very low CD8+ T cell infiltration in the tumor center should not preclude ICI administration in corticotroph carcinomas. Significance statement This is the first study to assess the real-life efficacy of ICIs in pituitary carcinomas (PCs) and aggressive pituitary tumors. We also assessed potential predictors of response and are the first to assess the predictive value of CD8+ cell infiltration. We identified the tumor type as a major predictor, ICIs proving far more effective in treating PCs. Our study provides evidence that ICIs are a good option after temozolomide failure for PCs (four of six responded), especially for corticotroph carcinomas (three of four responded). We also provide evidence that negative PD-L1 staining and very low CD8+ cell infiltration in the tumor center should not preclude ICI administration in corticotroph carcinomas. Moreover, our findings point toward the need to systematically perform extension workup before starting ICIs

Association of Energy Expenditure and Efficacy in Metastatic Renal Cell Carcinoma Patients Treated with Nivolumab

Background: Nivolumab improved patients’ survival in metastatic renal cell carcinoma (mRCC). We aimed to evaluate resting energy expenditure (REE) (i.e., patients’ basal metabolism) to predict efficacy. Methods: We conducted a monocentric, observational study of mRCC patients receiving nivolumab between October 2015 and May 2020. REE was measured prior to initiating immunotherapy using indirect calorimetry to determine hypo, normo and hypermetabolism. Primary endpoint was 6-month, progression-free survival (PFS), and secondary endpoints were response rate, PFS and overall survival (OS). Results: Of the 51 consecutive patients, 15 (29%) were hypermetabolic, 24 (47%) normometabolic, and 12 (24%) hypometabolic. The 6-month PFS was 15% for hypermetabolic patients and 65% for non-hypermetabolic patients (p p = 0.01). Disease progression was noted as the best response in 73% of hypermetabolic patients and 26% of non-hypermetabolic patients (p = 0.02). Median PFS was 2.8 and 8.7 months (p p = 0.13) in the hypermetabolic and non-hypermetabolic groups, respectively. Conclusions: Our study identifies an association between mRCC patients’ energy expenditure and nivolumab efficacy. The measurement of REE by indirect calorimetry in routine practice could help identify patients at risk of nivolumab failure

Nivolumab, nivolumab–ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial

International audienceBackground: We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab-ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups.Methods: This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab-ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab-ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab-ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment.Findings: Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab-ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6-18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16-45) of 42 patients with nivolumab and 16 (39%; 24-55) of 41 patients with nivolumab-ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25-1·56]). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20-70) of 16 patients with nivolumab and nine (50% 26-74) of 18 patients with nivolumab-ipilimumab (OR 0·78 [95% CI 0·20-3·01]). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33-67) of 36 patients with a VEGFR-TKI and 19 (51%; 34-68) of 37 patients with nivolumab-ipilimumab (OR 0·95 [95% CI 0·38-2·37]). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1-72) of five patients who received nivolumab-ipilimumab. The most common treatment-related grade 3-4 adverse events were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab-ipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab-ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab-ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib.Interpretation: We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma