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Selective KRAS G12C inhibitors have been developed to covalently lock the oncogene in the inactive GDP-bound state. Two of these molecules, sotorasib and adagrasib, are approved for the treatment of adult patients with KRAS G12C -mutated previously treated advanced non-small cell lung cancer. Drug treatment imposes selective pressures leading to the outgrowth of drug-resistant variants. Mass sequencing from patients’ biopsies identified a number of acquired KRAS mutations -both in cis and in trans - in resistant tumors. We demonstrate here that disease progression in vivo can also occur due to adaptive mechanisms and increased KRAS-GTP loading. Using the preclinical tool tri-complex KRAS G12C -selective covalent inhibitor, RMC-4998 (also known as RM-029), that targets the active GTP-bound (ON) state of the oncogene, we provide a proof-of-concept that the clinical stage KRAS G12C (ON) inhibitor RMC-6291 alone or in combination with KRAS G12C (OFF) drugs can be an alternative potential therapeutic strategy to circumvent resistance due to increased KRAS-GTP loading. KRAS G12C mutant selective inhibitors targeting inactive state have been approved for use in non-small cell lung cancer (NSCLC). Here, using models derived from a patient with NSCLC who progressed on sotorasib (KRAS G12C inhibitor), the authors identify increased KRAS GTP loading as an adaptive resistance mechanism which could be targeted with KRAS G12C inhibitors selective to the GTP active state.

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 .

The Gradient in Longitude of Atmospheric Constituents above the Mediterranean Basin (GLAM) airborne campaign was set up to investigate the summertime variability of gaseous pollutants, greenhouse gases, and aerosols between the western (∼3°E) and eastern (∼35°E) sections of the Mediterranean basin as well as how this connects with the impact of the Asian monsoon anticyclone on the eastern Mediterranean in the mid- to upper troposphere (∼5–10 km). GLAM falls within the framework of the Chemistry–Aerosol Mediterranean Experiment (ChArMEx) program. GLAM used the French Falcon-20 research aircraft to measure aerosols, humidity, and chemical compounds: ozone, carbon monoxide, methane, and carbon dioxide. GLAM took place between 6 and 10 August 2014, following a route from Toulouse (France) to Larnaca (Cyprus) and back again via Minorca (Spain), Lampedusa (Italy), and Heraklion (Crete, Greece). The aircraft flew at an altitude of 5 km on its outbound journey and 10 km on the return leg. GLAM also collected vertical profiles around the landing sites listed above. A combination of model outputs, chemical mapping analyses, and spaceborne and surface station measurements gathered prior to and during the campaign were used to interpret the in situ airborne measurements. The main outcome of this study is the impact of intercontinental transport on the longitudinal variability of pollutants, greenhouse gases, and aerosols at an altitude of 10 km. The eastern Mediterranean is affected by air masses from the Arabian Sea surface, and the western Mediterranean is impacted by air masses from North America (biomass burning) and West Africa (desert dust).

Background Soft-tissue sarcomas (STS) represent a heterogeneous group of rare tumors including more than 70 different histological subtypes. High throughput molecular analysis (next generation sequencing exome [NGS]) is a unique opportunity to identify driver mutations that can change the usual one-size-fits-all treatment paradigm to a patient-driven therapeutic strategy. The primary objective of the MULTISARC trial is to assess whether NGS can be conducted for a large proportion of metastatic STS participants within a reasonable time, and, secondarily to determine whether a NGS-guided therapeutic strategy improves participant’s outcome. Methods This is a randomized, multicentre, phase II/III trial inspired by the design of umbrella and biomarker-driven trials. The setting plans up to 17 investigational centres across France and the recruitment of 960 participants. Participants aged at least 18 years, with unresectable locally advanced and/or metastatic STS confirmed by the French sarcoma pathological reference network, are randomized according to 1:1 allocation ratio between the experimental arm “NGS” and the standard “No NGS”. NGS will be considered feasible if (i) NGS results are available and interpretable, and (ii) a report of exome sequencing including a clinical recommendation from a multidisciplinary tumor board is provided to investigators within 7 weeks from reception of the samples on the biopathological platform. A feasibility rate of more than 70% is expected (null hypothesis: 70% versus alternative hypothesis: 80%). In terms of care, participants randomized in “No NGS” arm and who fail treatment will be able to switch to the NGS arm at the request of the investigator. Discussion The MULTISARC trial is a prospective study designed to provide high-level evidence to support the implementation of NGS in routine clinical practice for advanced STS participants, on a large scale . Trial registration clinicaltrial.gov NCT03784014 .

Our objective was to capture subgroups of soft-tissue sarcoma (STS) using handcraft and deep radiomics approaches to understand their relationship with histopathology, gene-expression profiles, and metastatic relapse-free survival (MFS). We included all consecutive adults with newly diagnosed locally advanced STS ( N  = 225, 120 men, median age: 62 years) managed at our sarcoma reference center between 2008 and 2020, with contrast-enhanced baseline MRI. After MRI postprocessing, segmentation, and reproducibility assessment, 175 handcrafted radiomics features (h-RFs) were calculated. Convolutional autoencoder neural network (CAE) and half-supervised CAE (HSCAE) were trained in repeated cross-validation on representative contrast-enhanced slices to extract 1024 deep radiomics features (d-RFs). Gene-expression levels were calculated following RNA sequencing (RNAseq) of 110 untreated samples from the same cohort. Unsupervised classifications based on h-RFs, CAE, HSCAE, and RNAseq were built. The h-RFs, CAE, and HSCAE grouping were not associated with the transcriptomics groups but with prognostic radiological features known to correlate with lower survivals and higher grade and SARCULATOR groups (a validated prognostic clinical-histological nomogram). HSCAE and h-RF groups were also associated with MFS in multivariable Cox regressions. Combining HSCAE and transcriptomics groups significantly improved the prognostic performances compared to each group alone, according to the concordance index. The combined radiomic-transcriptomic group with worse MFS was characterized by the up-regulation of 707 genes and 292 genesets related to inflammation, hypoxia, apoptosis, and cell differentiation. Overall, subgroups of STS identified on pre-treatment MRI using handcrafted and deep radiomics were associated with meaningful clinical, histological, and radiological characteristics, and could strengthen the prognostic value of transcriptomics signatures.

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.

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.

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.

Reference 1. 1. Fourneaux B, Bourdon A, Dadone B, Lucchesi C, Daigle SR, Richard E, Laroche-Clary A, Le Loarer F, Italiano A. Identifying and targeting cancer stem cells in leiomyosarcoma: prognostic impact and role to overcome secondary resistance to PI3K/mTOR inhibition. J Hematol Oncol. 2019;12(1):11. * Article * Google Scholar Download references

The European Union’s Horizon 2020 programme has funded the SENS4ICE (Sensors for Certifiable Hybrid Architectures for Safer Aviation in Icing Environment) project [1], an innovative approach for the development and testing of new sensors for the detection of supercooled large droplets (SLD). SLD may impinge behind the protected surfaces of aircraft and therefore represents a threat to aviation safety. The newly developed sensors will be tested in combination with an indirect detection method on two aircraft, in two parallel flight programs: One on the Embraer Phenom 300 in the U.S. and one on the ATR-42 in Europe. In this framework the Deutsches Zentrum für Luft- und Raumfahrt (German Aerospace Center) is in charge of the airborne measurements and data evaluation of the microphysical properties of clouds encountered during the SENS4ICE field campaigns in February, March and April 2023. We present the instrumentation that is used in the flight experiments for the characterization of icing environments and for the validation and performance assessment of new sensors for the detection and discrimination of Appendix O and Appendix C conditions [2, 3]. Further, with partners from Centre Europeen De Recherche Et De Formation Avancee En Calcul Scientifique (CERFACS), the German Weather Service (DWD), the Italian Aerospace Research Center (CIRA) and Leading Edge Atmospherics (LEA), we present the considerations that were undertaken to find the best campaign location with highest frequency of icing occurrence on a climatological basis, taking into account the safety requirements of the aircraft. Four data sets of icing conditions based on various meteorological input data (model and observations) have been analyzed to provide an overview of the occurrence of icing. The data give a good impression on the geographical and vertical distribution of icing conditions above Europe and the Northern U.S. in general and specifically at higher altitudes (> 750 hPa or 8000ft) for the European campaign. We find enhanced icing frequencies between 1 to 5% at altitudes between 2 and 6 km even in the spring, summer and autumn months above Europe. We show highlights from selected individual cases from the North American test campaign performed in February and March 2023. The analysis gives a first impression of the extensive data set of icing conditions made available by the SENS4ICE project for sensor evaluation and for validation of satellite observations and model forecasts.