ALK2 inhibitors display beneficial effects in preclinical models of <i>ACVR1</i> mutant diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brainstem tumour, with a quarter of patients harbouring somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2. Despite being an amenable drug target, little has been done to-date to systematically evaluate the role of ACVR1 in DIPG, nor to screen currently available inhibitors in patient-derived tumour models. Here we show the dependence of DIPG cells on the mutant receptor, and the preclinical efficacy of two distinct chemotypes of ALK2 inhibitor in vitro and in vivo. We demonstrate the pyrazolo[1,5-a]pyrimidine LDN-193189 and the pyridine LDN-214117 to be orally bioavailable and well-tolerated, with good brain penetration. Treatment of immunodeprived mice bearing orthotopic xenografts of H3.3K27M, ACVR1R206H mutant HSJD-DIPG-007 cells with 25 mg/kg LDN-193189 or LDN-214117 for 28 days extended survival compared with vehicle controls. Development of ALK2 inhibitors with improved potency, selectivity and advantageous pharmacokinetic properties may play an important role in therapy for DIPG patients

Germline bi-allelic <i>SH2B3/LNK</i> alteration predisposes to a neonatal juvenile myelomonocytic leukemia-like disorder

Juvenile myelomonocytic leukemia (JMML) is a rare, generally aggressive myeloproliferative neoplasm affecting young children. It is characterized by granulomonocytic expansion, with monocytosis infiltrating peripheral tissues. JMML is initiated by mutations upregulating RAS signaling. Approximately 10% of cases remain without an identified driver event. Exome sequencing of 2 unrelated cases of familial JMML of unknown genetics and analysis of the French JMML cohort identified 11 patients with variants in SH2B3, encoding LNK, a negative regulator of the JAK-STAT pathway. All variants were absent from healthy population databases, and mutation spectrum was consistent with a loss of function of the LNK protein. A stoploss variant was shown to affect both protein synthesis and stability. The other variants were either truncating or missense, the latter affecting the SH2 domain that interacts with activated JAK. Of the 11 patients, 8 from 5 families inherited pathogenic bi-allelic SH2B3 germline variants from their unaffected heterozygous parents. These children represent half of the cases with no identified causal mutation in the French cohort. They displayed typical clinical and hematological JMML features with neonatal onset and marked thrombocytopenia. They were characterized by absence of additional genetic alterations and a hypomethylated DNA profile with fetal characteristics. All patients showed partial or complete spontaneous clinical resolution. However, progression to thrombocythemia and immunity-related pathologies may be of concern later in life. Bi-allelic SH2B3 germline mutations thus define a new condition predisposing to a JMML-like disorder, suggesting that the JAK pathway deregulation is capable of initiating JMML, and opening new therapeutic options

Effect of Digital Elevation Model Resolution on the Simulation of the Snow Cover Evolution in the High Atlas

International audienceThe snow melt from the High Atlas represents a crucial water resource for crop irrigation in the semiarid regions of Morocco. Recent studies have used assimilation of snow cover area data from high-resolution optical sensors to compute the snow water equivalent and snow melt in other mountain regions. These techniques however require large model ensembles, and therefore it is a challenge to determine the adequate model resolution that yields accurate results with reasonable computation time. Here we study the sensitivity of an energy balance model to the resolution of the model grid for a pilot catchment in the High Atlas. We used a time series of 8-m resolution snow cover area maps with an average revisit time of 7.5 days to evaluate the model results. The digital elevation model was generated from Pléiades stereo images and resampled from 8 to 30, 90, 250, 500, and 1,000 m. The results indicate that the model performs well from 8 to 250 m but the agreement with observations drops at 500 m. This is because significant features of the topography were too smoothed out to properly characterize the spatial variability of meteorological forcing, including solar radiation. We conclude that a resolution of 250 m might be sufficient in this area. This result is consistent with the shape of the semivariogram of the topographic slope, suggesting that this semivariogram analysis could be used to transpose our conclusion to other study regions

Parallel machines scheduling problem subject to transportation delays constraints

International audienc

Resolution of the parallel machines scheduling problem with preemption and transportation delays

International audienc

Performance of temperature and radiation index models for point-scale snow water equivalent (SWE) simulations in the Moroccan High Atlas Mountains

International audienc

Preemptive Scheduling with jobs transportation

International audienc

Linkages between snow cover, temperature and rainfall and the North Atlantic Oscillation over Morocco

Snowpack significantly contributes to water resources in North Africa. The objective of this work was to analyze the impact of the North Atlantic Oscillation (NAO) on rainfall and temperature in Morocco at a sub-seasonal scale and to evaluate, for the first time, linkages between the NAO and snow cover area (SCA) derived from remote sensing observations. For this purpose, we analyzed daily SCA products (2000-2013) from the MODIS sensor, meteorological data from 37 stations (1993-2011), NCEP re-analysis of surface air temperature and rainfall rate, and a monthly NAO index. The linear linkages sought using simple correlation analysis demonstrated that negative (positive) NAO (1) is associated with enhanced (reduced) rainfall in December and February for the northern part of the country; (2) occurs with above-normal (below-normal) temperature and, in contrast with rainfall, the correlation persists far inland and late in the season. These results highlight a possible competing influence of NAO on the snowpack dynamic through rainfall and temperature. Indeed, negative (positive) NAO tends to favor earlier (later) melting and lesser (greater) SCA in spring (April-May) through milder temperatures. Results have direct implications for seasonal forecast of SCA in Morocco