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Background Whole exome sequencing and RNA sequencing (WES/RNASeq) should now be implemented in the clinical practice in order to increase access to optimal care for cancer patients. Providing results to Tumour Boards in a relevant time frame—that is, compatible with the clinical pathway—is crucial. Assessing the feasibility of this implementation in the French care system is the primary objective of the Multipli study, as one of the four pilot projects of the national France Genomic Medicine 2025 (FGM 2025) plan. The Multipli study encompasses two innovative trials which will be driven in around 2400 patients suffering from a soft-tissue sarcoma (Multisarc) or a metastatic colorectal carcinoma (Acompli). Methods Prior to launching the FGM 2025 cancer pilot study itself, the performance of the Multipli genomic workflow has been evaluated through each step, from the samples collection to the Molecular Tumour Board (MTB) report. Two Multipli-assigned INCa-labelled molecular genetics centres, the CEA-CNRGH sequencing platform and the Institut Bergonie’s Bioinformatics Platform were involved in a multicentric study. The duration of each step of the genomic workflow was monitored and bottlenecks were identified. Results Thirty barriers which could affect the quality of the samples, sequencing results and the duration of each step of the genomic pathway were identified and mastered. The global turnaround time from the sample reception to the MTB report was of 44 calendar days. Conclusion Our results demonstrate the feasibility of tumour genomic analysis by WES/RNASeq within a time frame compatible with the current cancer patient care. Lessons learnt from the Multipli WES/RNASeq Platforms Workflow Study will constitute guidelines for the forthcoming Multipli study and more broadly for the future clinical routine practice in the first two France Genomic Medicine 2025 platforms.

Introduction. Lymph node metastasis is determinant in the prognosis and treatment of endometrioid endometrial cancer (EEC) but the risk–benefit balance of surgical lymph node staging remains controversial. Objective. Describe the pathways associated with lymph node metastases in EEC detected by whole RNA sequencing. Methods. RNA-sequencing was performed on a retrospective series of 30 non-metastatic EEC. N+ and N− patients were matched for tumoral size, tumoral grade and myometrial invasion. Results. Twenty-eight EECs were analyzable (16 N+ and 12 N−). Bioinformatics Unsupervised analysis revealed three patterns of expression, enriched in N+, mix of N+/N− and enriched in N−, respectively. The cluster with only N+ patient overexpressed extra cellular matrix, epithelial to mesenchymal and smooth muscle contraction pathways with respect to the N− profile. Differential expression analysis between N+ and N− was used to generate a 54-genes signature with an 87% accuracy. Conclusion. RNA-expression analysis provides a basis to develop a gene expression-based signature that could pre-operatively predict lymph node invasion.

International audience

Background Leiomyosarcoma (LMS) is one of the most frequent soft tissue sarcoma subtypes and is characterized by a consistent deregulation of the PI3K/mTOR pathway. Cancer stem cells (CSCs) have been poorly studied in soft tissue sarcomas. In this study, we aimed to evaluate the association between CSCs, the outcome of LMS patients, and the resistance to PI3K/mTOR pathway inhibition. Methods We investigated the relationships between aldehyde dehydrogenase 1 (ALDH1) expression, a cancer stem cell marker, and the outcome of LMS patients in two independent cohorts. We assessed the impact of CSCs in resistance to PI3K/mTOR pathway inhibition using LMS cell lines, a xenograft mouse model, and human tumor samples. Results We found that enhanced ALDH1 activity is a hallmark of LMS stem cells and is an independent prognostic factor. We also identified that secondary resistance to PI3K/mTOR pathway inhibition was associated with the expansion of LMS CSCs. Interestingly, we found that EZH2 inhibition, a catalytic component of polycomb repressive complex which plays a critical role in stem cell maintenance, restored sensitivity to PI3K/mTOR pathway inhibition. Importantly, we confirmed the clinical relevance of our findings by analyzing tumor samples from patients who showed secondary resistance after treatment with a PI3Kα inhibitor. Conclusions Altogether, our findings suggest that CSCs have a strong impact on the outcome of patients with LMS and that combining PI3K/mTOR and EZH2 inhibitors may represent a promising strategy in this setting. Electronic supplementary material The online version of this article (10.1186/s13045-018-0694-1) contains supplementary material, which is available to authorized users.

Background Inhibition of ChK1 appears as a promising strategy for selectively potentiate the efficacy of chemotherapeutic agents in G1 checkpoint-defective tumor cells such as those that lack functional p53 protein. The p53 pathway is commonly dysregulated in soft-tissue sarcomas (STS) through mutations affecting TP53 or MDM2 amplification. GDC-0575 is a selective ATP-competitive inhibitor of CHK1. Methods We have performed a systematic screening of a panel of 10 STS cell lines by combining the treatment of GDC-0575 with chemotherapy. Cell proliferation, cell death and cell cycle analysis were evaluated with high throughput assay. In vivo experiments were carried out by using TP53-mutated and TP53 wild-type patient-derived xenograft models of STS. Clinical activity of GDC-0575 combined with chemotherapy in patients with TP53-mutated and TP53 wild-type STS was also assessed. Results We found that GDC-0575 abrogated DNA damage-induced S and G2–M checkpoints, exacerbated DNA double-strand breaks and induced apoptosis in STS cells. Moreover, we observed a synergistic or additive effect of GDC-0575 together with gemcitabine in vitro and in vivo in TP53-proficient but not TP53-deficient sarcoma models. In a phase I study of GDC-0575 in combination with gemcitabine, two patients with metastatic TP53-mutated STS had an exceptional, long-lasting response despite administration of a very low dose of gemcitabine whereas one patient with wild-type TP53 STS had no clinical benefit. Genetic profiling of samples from a patient displaying secondary resistance after 1 year showed loss of one preexisting loss-of-function mutation in the helical domain of DNA2. Conclusion We provide the first preclinical and clinical evidence that potentiation of chemotherapy activity with a CHK1 inhibitor is a promising strategy in TP53-deficient STS and deserves further investigation in the phase II setting.

Lothon, Marie et al., © 2014 Author(s). Due to the major role of the sun in heating the earth's surface, the atmospheric planetary boundary layer over land is inherently marked by a diurnal cycle. The afternoon transition, the period of the day that connects the daytime dry convective boundary layer to the night-time stable boundary layer, still has a number of unanswered scientific questions. This phase of the diurnal cycle is challenging from both modelling and observational perspectives: it is transitory, most of the forcings are small or null and the turbulence regime changes from fully convective, close to homogeneous and isotropic, toward a more heterogeneous and intermittent state. These issues motivated the BLLAST (Boundary-Layer Late Afternoon and Sunset Turbulence) field campaign that was conducted from 14 June to 8 July 2011 in southern France, in an area of complex and heterogeneous terrain. A wide range of instrumented platforms including full-size aircraft, remotely piloted aircraft systems, remote-sensing instruments, radiosoundings, tethered balloons, surface flux stations and various meteorological towers were deployed over different surface types. The boundary layer, from the earth's surface to the free troposphere, was probed during the entire day, with a focus and intense observation periods that were conducted from midday until sunset. The BLLAST field campaign also provided an opportunity to test innovative measurement systems, such as new miniaturized sensors, and a new technique for frequent radiosoundings of the low troposphere. Twelve fair weather days displaying various meteorological conditions were extensively documented during the field experiment. The boundary-layer growth varied from one day to another depending on many contributions including stability, advection, subsidence, the state of the previous day's residual layer, as well as local, meso-or synoptic scale conditions. Ground-based measurements combined with tethered-balloon and airborne observations captured the turbulence decay from the surface throughout the whole boundary layer and documented the evolution of the turbulence characteristic length scales during the transition period. Closely integrated with the field experiment, numerical studies are now underway with a complete hierarchy of models to support the data interpretation and improve the model representations., The BLLAST field experiment was made possible thanks to the contribution of several institutions and supports: INSU-CNRS (Institut National des Sciences de l’Univers, Centre national de la Recherche Scientifique, LEFE-IMAGO program), Météo-France, Observatoire Midi-Pyrénées (University of Toulouse), EUFAR (EUropean Facility for Airborne Research) BLLATE-1&2, COST ES0802 (European Cooperation in the field of Scientific and Technical) and the Spanish MINECO projects CGL2009–08609, CGL2012–37416–C04–03, CGL2012–37416– C04–02 and CGL2011-13477-E

The Fennec climate programme aims to improve understanding of the Saharan climate system through a synergy of observations and modelling. We present a description of the Fennec airborne observations during 2011 and 2012 over the remote Sahara (Mauritania and Mali) and the advances in the understanding of mineral dust and boundary layer processes they have provided. Aircraft instrumentation aboard the UK FAAM BAe146 and French SAFIRE (Service des Avions Français Instrumentés pour la Recherche en Environnement) Falcon 20 is described, with specific focus on instrumentation specially developed for and relevant to Saharan meteorology and dust. Flight locations, aims and associated meteorology are described. Examples and applications of aircraft measurements from the Fennec flights are presented, highlighting new scientific results delivered using a synergy of different instruments and aircraft. These include (1) the first airborne measurement of dust particles sizes of up to 300 microns and associated dust fluxes in the Saharan atmospheric boundary layer (SABL), (2) dust uplift from the breakdown of the nocturnal low-level jet before becoming visible in SEVIRI (Spinning Enhanced Visible Infra-Red Imager) satellite imagery, (3) vertical profiles of the unique vertical structure of turbulent fluxes in the SABL, (4) in situ observations of processes in SABL clouds showing dust acting as cloud condensation nuclei (CCN) and ice nuclei (IN) at −15 °C, (5) dual-aircraft observations of the SABL dynamics, thermodynamics and composition in the Saharan heat low region (SHL), (6) airborne observations of a dust storm associated with a cold pool (haboob) issued from deep convection over the Atlas Mountains, (7) the first airborne chemical composition measurements of dust in the SHL region with differing composition, sources (determined using Lagrangian backward trajectory calculations) and absorption properties between 2011 and 2012, (8) coincident ozone and dust surface area measurements suggest coarser particles provide a route for ozone depletion, (9) discrepancies between airborne coarse-mode size distributions and AERONET (AERosol Robotic NETwork) sunphotometer retrievals under light dust loadings. These results provide insights into boundary layer and dust processes in the SHL region – a region of substantial global climatic importance.

International audience; The PLANET System was used for real-time satellite data transmission during the HAIC-HIWC Darwin field campaign (January to March 2014). The basic system was initially providing aircraft tracking, chat, weather text messages (METAR, TAF, etc.), and aeronautical information (NOTAMs) in a standalone application. In the framework of the HAIC project, many improvements were made in order to fulfill requirements of the onboard and ground science teams for the field campaign. The aim of this paper is to present the main improvements of the system that were implemented for the Darwin field campaign. New features of the system are related to the hardware component, the communication protocol, weather and tracking display, geomarkers on the map, and image processing and compression before onboard transfer.

Background: Soft tissue sarcomas are a heterogeneous group of malignant tumors including more than 70 histological subtypes. We have recently demonstrated that dual targeting of PI3K/mTOR pathway is associated with significant anti-tumor activity in in vitro and in vivo models of leiomyosarcoma (LMS), one of the most frequent sarcoma subtype. Secondary resistance limits the efficacy of all targeted therapies. We have developed and characterized resistance models to a dual PI3K/mTOR inhibitor in order to describe underlying resistance mechanisms and develop alternative strategies. Methods: To develop in vitro BEZ-235 (dual PI3K/mTOR inhibitor) resistance models, 3 LMS and 1 myxofibrosarcoma cell lines were exposed to increasing doses of BEZ-235 several months. To characterize the resistance models, sensitivity to BEZ-235 was assessed by MTT assay and Annexin V-PI staining. To test in vivo the resistance models, effects of BEZ-235 treatment were observed in mice with subcutaneous cell line-derived xenograft tumors for 3 weeks. The transcriptome profile of sensitive and resistant tumors to BEZ-235 was analyzed by using RNA-seq. Results: After prolonged exposure of cell lines to BEZ-235, we obtained secondary resistant cell lines characterized by an IC50 value 5- to 21-fold higher than parental sensitive cells. Resistant cells were also significantly less sensitive to BEZ-235-induced apoptosis than parental cells. We confirmed the resistance patterns in vivo with a significantly higher anti-tumor effect of BEZ235 in sensitive cell-line derived xenograft group compared with resistant cell-line derived xenograft group. Deep transcriptome profiling indicated overexpression of stem cells related genes in resistant cells as well as a modification of the cellular metabolism. By using 1) RNAi-mediated suppression of pyruvate carboxylase (PC), a potential key player in our resistance models and 2) hallmarks of CSC like CD133 and enhanced aldehyde dehydrogenase (ALDH) activity, we confirmed that resistant tumors were characterized by a significantly higher proportion of cancer stem cells and by a metabolic shift with a strong deregulation of glucose metabolism. Conclusions: Selection of CSC subpopulation and metabolism shift play a crucial role in secondary resistance to dual PI3K/mTOR inhibition in sarcoma. Strategies assessing anti-CSC agents to suppress acquired resistance may have major implications to improve efficacy of dual PI3K/mTOR targeting in human malignancies. Citation Format: Benjamin Fourneaux, Aurélien Bourdon, Vanessa Chaire, Carlo Lucchesi, Marie Karanian, Raphael Pineau, Audrey Laroche, Antoine Italiano. Mechanisms of secondary resistance to dual PI3K/mTOR inhibition in sarcomas with complex genetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4106. doi:10.1158/1538-7445.AM2017-4106

National audience

International audience; GreenIT has emerged as a discipline concerned with the optimization of software solutions with regards to their energy consumption. In this domain, most of the state-of-the-art solutions concentrate on coarse-grained approaches to monitor the energy consumption of a device or a process. However, none of the existing solutions addresses in-process energy monitoring to provide in-depth analysis of a process energy consumption. In this paper, we therefore report on a fine-grained runtime energy monitoring framework we developed to help developers to diagnose energy hotspots with a better accuracy than the state-of-the-art. Concretely, our approach adopts a 2-layer architecture including OS-level and process-level energy monitoring. OS-level energy monitoring estimates the energy consumption of processes according to different hardware devices (CPU, network card). Process-level energy monitoring focuses on Java-based applications and builds on OS-level energy monitoring to provide an estimation of energy consumption at the granularity of classes and methods. We argue that this per-method analysis of energy consumption provides better insights to the application in order to identify potential energy hotspots. In particular, our preliminary validation demonstrates that we can monitor energy hotspots of Jetty web servers and monitor their variations under stress scenarios.

GreenIT has emerged as a discipline concerned with the optimization of software solutions with regards to energy consumption. In this domain, most of the state-of-the-art solutions concentrate on coarse-grained approaches to monitor the energy consumption of a device or a process. However, none of the existing solutions addresses in-process energy monitoring to provide in-depth analysis of a process energy consumption. In this paper, we therefore report on a fine-grained real-time energy monitoring framework we developed to diagnose energy leaks with a better accuracy than the state-of-the-art. Concretely, our approach adopts a 2-layer architecture including OS-level and process-level energy monitoring. OS-level energy monitoring estimates the energy consumption of processes according to different hardware devices (CPU, network, memory). Process-level energy monitoring focuses on Java-based applications and builds on OS-level energy monitoring to provide an estimation of energy consumption at the granularity of classes and methods. We argue that this per-method analysis of energy consumption provides better insights to the application in order to identify potential energy leaks. In particular, our preliminary validation demonstrates that we can diagnose energy hotspots of Jetty application servers and monitor their variations when stressing web applications.; L'informatique verte a émergé comme une discipline qui s'intéresse à l'optimisation des solutions logicielles en ce qui concerne la consommation d'énergie. Dans ce domaine, la plupart des solutions de l'état de l'art se concentre sur des approches à gros grains pour contrôler la consommation énergétique d'un matériel ou un processus. Toutefois, aucune des solutions existantes gère la surveillance au niveau processus afin de fournir une analyse en profondeur de la consommation énergétique d'un processus. Dans ce papier, nous proposons un canevas logiciel à grain fin pour surveiller en temps réel la consommation énergétique des applications, et pour diagnostiquer les fuites d'énergie avec une meilleure précision que l'état de l'art. En particulier, notre approche adopte une architecture à 2 couches, une au niveau du système d'exploitation et le suivi de l'énergie au niveau des processus. La couche de surveillance de l'énergie au niveau de l'OS estime la consommation énergétique au niveau du processus selon différents périphériques matériels (processeur, réseau, mémoire). La couche de surveillance de l'énergie au niveau des processus se concentre sur les applications Java et s'appuie sur la couche OS pour fournir une estimation de la consommation d'énergie à la granularité des classes et méthodes. Nous soutenons que cette analyse au niveau des méthodes de la consommation énergétique fournit un meilleur aperçu de l'application afin d'identifier les fuites énergétiques potentielles. En particulier, nos expériences démontrent que nous pouvons diagnostiquer les hotspots énergétique des serveurs d'application Jetty et de surveiller leurs variations lorsque nous mettons sous pression les applications web.

As part of the EUREC4A (Elucidating the role of cloud–circulation coupling in climate) field campaign, which took place in January and February 2020 over the western tropical Atlantic near Barbados, the French SAFIRE ATR42 research aircraft (ATR) conducted 19 flights in the lower troposphere. Each flight followed a common flight pattern that sampled the atmosphere around the cloud base level, at different heights of the subcloud layer, near the sea surface and in the lower free troposphere. The aircraft's payload included a backscatter lidar and a Doppler cloud radar that were both horizontally oriented; a Doppler cloud radar looking upward; microphysical probes; a cavity ring-down spectrometer for water isotopes; a multiwavelength radiometer; a visible camera; and multiple meteorological sensors, including fast rate sensors for turbulence measurements. With this instrumentation, the ATR characterized the macrophysical and microphysical properties of trade-wind clouds together with their thermodynamical, turbulent and radiative environment. This paper presents the airborne operations, the flight segmentation, the instrumentation, the data processing and the EUREC4A datasets produced from the ATR measurements. It shows that the ATR measurements of humidity, wind and cloud base cloud fraction measured with different techniques and samplings are internally consistent; that meteorological measurements are consistent with estimates from dropsondes launched from an overflying aircraft (the High Altitude and LOng Range Research Aircraft, HALO); and that water-isotopic measurements are well correlated with data from the Barbados Cloud Observatory. This consistency demonstrates the robustness of the ATR measurements of humidity, wind, cloud base cloud fraction and water-isotopic composition during EUREC4A. It also confirms that through their repeated flight patterns, the ATR and HALO measurements provided a statistically consistent sampling of trade-wind clouds and of their environment. The ATR datasets are freely available at the locations specified in Table 11.

International audience; Energy consumption by information and communication technologies (ICT) has been growing rapidly over recent years. Comparable to the civil aviation domain, the research community now considers ICT energy consumption as a major concern. Several studies report that energy consumption is an issue during all steps of a computer's life, from hardware assemblage, to usage, and dismantling. Research in the area of Green IT has proposed various approaches to save energy at the hardware and software levels. In the context of software, this challenge requires identification of new development methodologies that can help reduce the energy footprint. To tackle this challenge, we propose PowerAPI, a tool to quantify this energy consumption, by providing an application programming interface (API) that monitors, in real-time, the energy consumed at the granularity of a system process.