Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)

Purpose: In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact. Materials and methods: Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571). Results: Genomic ALK amplification (ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n = 41] 28% [95% CI, 15 to 42]; no-ALKa [n = 860] 51% [95% CI, 47 to 54], [P 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of ALKm and MNA (P < .001). Among 571 cases with known ALKa and ALKm status, a statistically significant difference in OS was observed between cases with ALKa or clonal ALKm versus subclonal ALKm or no ALK alterations (5-year OS: ALKa [n = 19], 26% [95% CI, 10 to 47], clonal ALKm [n = 65] 33% [95% CI, 21 to 44], subclonal ALKm (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively; P = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P < .001), ALKa (HR, 2.38; P = .004), and clonal ALKm (HR, 1.77; P = .001) were independent predictors of poor outcome. Conclusion: Genetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with ALK alterations.Key Objective: High risk neuroblastoma (HR-NB) is one of the most difficult childhood cancers to cure. This study examined whether the presence of an ALK alteration (amplification or mutation) was associated with a poor prognosis in a large patient series treated on the prospective European high-risk neuroblastoma trial (HR-NBL1). Knowledge Generated: We found that ALK amplification or clonal mutation was associated with inferior prognosis in patients with HR-NB and both are independent prognostic variables on multivariate analysis. To our knowledge, this is the first study to report the highly prognostic significance of ALK amplification in HR-NB. Relevance: As ALK can be targeted therapeutically, this study convincingly argues for the introduction of ALK inhibitors for upfront management of patients with HR-NB with ALK aberrations. Importantly, the prognostic significance of ALK alterations included a subgroup of trial patients treated with the current standard of care for HR-NB including anti-GD2 immunotherapy.info:eu-repo/semantics/publishedVersio

Fibrinolysis in trauma patients: wide variability demonstrated by the Lysis Timer

Hyperfibrinolysis contributes to the pathophysiology of trauma-induced coagulopathy. At present, systematic administration of tranexamic acid (TXA) is recommended in all patients in the early phase of trauma. However, there is some debate regarding whether TXA is beneficial in all trauma patients. A rapid and accurate tool to diagnose hyperfibrinolysis may be useful for tailoring TXA treatment. We conducted a proof-of-concept study of consecutive adult trauma patients. A first blood sample was obtained at the time of pre-hospital care (T1). Patients received 1 g of TXA after T1. A second sample was obtained on arrival at the emergency unit (T2). We examined coagulation, fibrin and fibrinogen formation and degradation. Fibrinolysis was assessed by determining tissue plasminogen activator (t-PA) antigen and plasminogen activator inhibitor 1 (PAI-1) activity and global fibrinolysis capacity assay using a device developed by Hyphen BioMed: the Lysis Timer (GFC/LT). The study population consisted of 20 patients (42 ± 21 years, index of severity score 32 ± 21). Both coagulation and fibrinolysis were altered at T1. GFC/LT values exhibited hyperfibrinolysis only in five patients. Principal component analysis carried out at T1 showed two main axes of alteration. The major axis was related to coagulation, altered in all patients, while the second axis was related to fibrinolysis. GFC/LT was mainly influenced by PAI-1 activity while fibrin monomers were related to the severity of trauma. At T2, GFC/LT exhibited the marked effect of TXA on clot lysis time. In conclusion, GFC/LT demonstrated huge variation in the fibrinolytic response to trauma

Exploring Digital Transformation in Higher Education and Research via Scenarios

International audienceDigital transformation induces rapid and profound changes in higher education and research (HER). With this foresight, INRAE and Agreenium, two French public HER institutions centered on food, agriculture and the environment, explore the challenges they face in a world increasingly dependent on digital resources. Four scenarios generated via morphological analysis provide researchers, teachers and institutions a heuristic framework to anticipate risks and opportunities in terms of: platformization of research, commodification of knowledge and the ascendency of data; pressing demands to respond to planet-wide emergencies; renewed multi-stakeholder relations between civil society and the academic community; and limits on energy and raw materials devoted to digital uses

La transition numérique dans la recherche et l'enseignement supérieur à l'horizon 2040

National audiencePlateformes, réseaux sociaux, ressources en ligne, simulations, apprentissage à distance, données d’apprentissage, données massives, intelligence artificielle… la transition numérique bouleverse l’enseignement supérieur et la recherche publics. Elle modifie les contenus, les outils et méthodes pédagogiques, ainsi que le rôle des enseignants et des apprenants. Elle remodèle la recherche, ses pratiques, ses métiers et son écosystème.Pour anticiper les changements induits par la transition numérique à l’horizon 2040, INRAE et Agreenium ont commandité cette prospective. S’appuyant sur un groupe d’experts et sur une synthèse des tendances actuelles dans les sciences agronomiques, de l’environnement, de l’alimentation et vétérinaires, elle a abouti à la construction de quatre scénarios dont les enseignements sont pertinents bien au-delà de ces domaines scientifiques pour les chercheurs, enseignants, décideurs et prospectivistes. Ces scénarios éclairent les enjeux des évolutions de l’apprentissage, du partage des savoirs et des transformations des pratiques scientifiques. Ils ouvrent de nouvelles perspectives sur les relations entre la science et la société, et sur le rôle de la recherche publique face aux géants du numérique

La mythologie de l'Antiquité à la modernité

Dans une perspective diachronique et pluridisciplinaire, les contributions de ce volume se proposent d'explorer les différentes formes d’appropriation, d’adaptation ou de détournement de la mythologie, qui ont abouti d’un côté à des lectures originales des fables anciennes, de l’autre à un nouveau statut du mythe, voire à des modèles mythologiques différents. Dès l'Antiquité, la mise à distance du mythe a été une source de créativité, renouvelant les formes d’écriture et conduisant à une réorganisation du patrimoine culturel mythologique. En relation avec la polémique soulevée par Platon, les commentateurs néoplatoniciens et les mythographes de l’Antiquité tardive ont engagé un véritable débat sur le bon usage des mythes, sur lequel se sont greffés, au Moyen Âge, des discours supplémentaires, par le biais de la traduction, de la glose et de la réécriture. La réflexion médiévale sur le mythe a entraîné une adaptation de la matière mythologique ancienne, voire un détournement de son sens premier lorsque les récits mythiques païens ont été mis au service des valeurs courtoises et de la Révélation. Le discours moderne sur le mythe s’est enrichi, lui, d’autres instruments (la psychanalyse littéraire, la mythocritique…) et a permis d’avancer des interprétations inédites de l’héritage mythologique, ancien et médiéval, ainsi que de nourrir les discussions sur la nature du mythe.Che dire se un giorno le cose naturali fonti, boschi, vigne, campagna saranno assorbite dalla città e dileguate, e s’incontreranno in frasi antiche ? Ci faranno l’effeto dei theoi, delle ninfe, del sacro naturale che emerga in qualche vaso greco. Allora la semplice frase « c’era una fonte » commuoverà. C. PAVESE, Il Mestiere di vivere, M. GUGLIELMINETTI, L. NAY, C. SEGRE (éd.), Einaudi, 2000 [1990], p. 301-302. Que dire, si un jour, les choses naturelles – sources, bois, vignes, campagne – sont absorbées par la ville et escamotées, et se rencontrent dans des phrases anciennes ? Elles nous feront l’effet des theoi, des nymphes, du naturel sacré qui surgit d’un [vase] grec. Alors la simple phrase « il y avait une source » sera émouvante. C. PAVESE, Le métier de vivre, trad. de l’italien par M. ARNAUD, Paris, Gallimard, 1958, p. 357

The information system of the French Peatland Observation Service: Service National d’Observation Tourbières – a valuable tool to assess the impact of global changes on the hydrology and biogeochemistry of temperate peatlands through long term monitoring

International audienceMitigating and adapting to global changes requires a better understanding of the response of the Biosphere to these environmental variations. Human disturbances and their effects act in the long term (decades to centuries) and consequently, a similar time frame is needed to fully understand the hydrological and biogeochemical functioning of a natural system. To this end, the ‘Centre National de la Recherche Scientifique’ (CNRS) promotes and certifies long-term monitoring tools called national observation services or ‘Service National d'Observation’ (SNO) in a large range of hydrological and biogeochemical systems (e.g., cryosphere, catchments, aquifers). The SNO investigating peatlands, the SNO ‘Tourbières’, was certified in 2011 (https://www.sno-tourbieres.cnrs.fr/). Peatlands are mostly found in the high latitudes of the northern hemisphere and French peatlands are located in the southern part of this area. Thus, they are located in environmental conditions that will occur in northern peatlands in coming decades or centuries and can be considered as sentinels. The SNO Tourbières is composed of four peatlands: La Guette (lowland central France), Landemarais (lowland oceanic western France), Frasne (upland continental eastern France) and Bernadouze (upland southern France). Thirty target variables are monitored to study the hydrological and biogeochemical functioning of the sites. They are grouped into four datasets: hydrology, fluvial export of organic matter, greenhouse gas fluxes and meteorology/soil physics. The data from all sites follow a common processing chain from the sensors to the public repository. The raw data are stored on an FTP server. After operator or automatic processing, data are stored in a database, from which a web application extracts the data to make them available (https://data-snot.cnrs.fr/data-access/). Each year at least, an archive of each dataset is stored in Zenodo, with a digital object identifier (DOI) attribution (https://zenodo.org/communities/sno_tourbieres_data/)