A Transversal Approach Combining In Silico, In Vitro and In Vivo Models to Describe the Metabolism of the Receptor Interacting Protein 1 Kinase Inhibitor Sibiriline

International audienceSibiriline is a novel drug inhibiting receptor-interacting protein 1 kinase (RIPK1) and necroptosis, a regulated form of cell death involved in several disease models. In this study, we aimed to investigate the metabolic fate of sibiriline in a cross-sectional manner using an in silico prediction, coupled with in vitro and in vivo experiments. In silico predictions were performed using GLORYx and Biotransformer 3.0 freeware; in vitro incubation was performed on differentiated human HepaRG cells, and in vivo experiments including a pharmacokinetic study were performed on mice treated with sibiriline. HepaRG culture supernatants and mice plasma samples were analyzed with ultra-high-performance liquid chromatography, coupled with tandem mass spectrometry (LC-HRMS/MS). The molecular networking bioinformatics tool applied to LC-HRMS/MS data allowed us to visualize the sibiriline metabolism kinetics. Overall, 14 metabolites, mostly produced by Phase II transformations (glucuronidation and sulfation) were identified. These data provide initial reassurance regarding the toxicology of this new RIPK1 inhibitor, although further studies are required

Impact of creative art therapy on fatigue and quality of life in patients treated for localized breast cancer: A randomized study

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Tracking Light-Induced Electron Transfer towards O2 in a Hybrid Photoredox-Laccase System

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Spatially-consistent Feature Matching and Learning for Heritage Image Analysis

International audienceProgress in the digitization of cultural assets leads to online databases that become too large for a human to analyze. Moreover, some analyses might be challenging, even for experts. In this paper, we explore two applications of computer vision to analyze historical data: watermark recognition and one-shot repeated pattern detection in artwork collections. Both problems present computer vision challenges which we believe to be representative of the ones encountered in cultural heritage applications: limited supervision is available, the tasks are fine-grained recognition, and the data comes in several different modalities. Both applications are also highly practical, as recognizing watermarks makes it possible to date and locate documents, while detecting repeated patterns allows exploring visual links between artworks. We demonstrate on both tasks the benefits of relying on deep mid-level features. More precisely, we define an image similarity score based on geometric verification of mid-level features and show how spatial consistency can be used to fine-tune out-of-the-box features for the target dataset with weak or no supervision. This paper relates and extends our previous works. Our code and data are available at \url{http://imagine.enpc.fr/~shenx/HisImgAnalysis/}

Core-binding factor acute myeloid leukemia in first relapse: a retrospective study from the French AML Intergroup

International audienceAlthough core-binding factor-acute myeloid leukemia (CBF-AML) (t[8;21] or inv[16]/t[16;16]) represents a favorable cytogenetic AML subgroup, 30% to 40% of these patients relapse after standard intensive chemotherapy. The encouraging results of gemtuzumab ozogamicin (GO) in newly diagnosed AML, and particularly in CBF-AML, incited us to retrospectively investigate the impact of GO-based salvage in these patients. We retrospectively analyzed the outcome of 145 patients with CBF-AML (59 t[8;21], 86 inv[16]/t[16;16]) in first relapse. As salvage, 48 patients received GO-based chemotherapy and 97 patients received conventional chemotherapy. Median age was 43 years (range, 16-76). Median first complete remission duration was 12.1 months (range, 2.1-93.6). Overall, second complete remission (CR2) rate was 88%. With a median follow-up from relapse of 3.5 years, the estimated 5-year disease-free survival (DFS) was 50% and 5-year overall survival (OS) was 51%. Older age and shorter first complete remission duration was associated with a shorter OS. Patients treated with GO had similar CR2 rate but significantly higher 5-year DFS (68% vs 42%; P = .05) and OS (65% vs 44%; P = .02). In multivariate analysis, GO salvage was still associated with a significant benefit in DFS and OS. In the 78 patients who received allogeneic hematopoietic stem cell transplantation in CR2, GO before transplant significantly improved posttransplant DFS and OS without excess of treatment-related mortality

Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study

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In Adults with Ph-Negative Acute Lymphoblastic Leukemia (ALL), Age-Adapted Chemotherapy Intensity and MRD-Driven Transplant Indication Significantly Reduces Treatment-Related Mortality (TRM) and Improves Overall Survival - Results from the Graall-2014 Trial

International audienceBackground During the 2005-2014 period, the GRAALL conducted the GRAALL-2005 trial in patients (pts) with Philadelphia chromosome (Ph)-negative ALL aged 18-59y. In this trial, all pts received a pediatric-inspired chemotherapy, whatever their age. Post-hoc analysis revealed an unacceptable TRM in pts aged 45-59y (Huguet et al. J Clin Oncol 2018; 36:2514-23). Allogeneic hematopoietic stem cell transplantation (HSCT) was offered in first complete remission (CR) to most CR pts, defined at high-risk (HR) by at least one baseline clinical or biological HR factor (CNS involvement, complex karyotype [≥5 abns.], low hypodiploidy/near triploidy, poor early blast clearance, late CR, as well as WBC ≥ 30x109/L, lack of CD10 expression, KMT2A rearrangement or TCF3::PBX1 fusion for B-cell precursor [BCP] ALL). Minimal residual disease (MRD) response was not considered for HSCT indication at that time.In the next GRAALL-2014 trial conducted in a similar population, we introduced two major changes in the treatment strategy. First, chemotherapy intensity (steroids, anthracycline and L-asparaginase) was reduced in pts aged 45-59y to decrease excessive TRM. Secondly, the indication for HSCT was modified, relying on IG/TR MRD response only (post-induction MRD ≥10-3 and/or post-consolidation MRD ≥10-4) while not on any former baseline HR criterion. Here, we compare the outcomes of the two trials, focusing on the impact of these two major evolutions.Patients & Methods A total of 743 pts treated in the GRAALL-2014 trial between 2015 and 2020 were compared to the 787 pts from the historical GRAALL-2005 trial, in terms of CR and induction death rates, rate of HSCT in CR1, cumulative incidence of TRM (CITRM) and relapse (CIR), relapse-free (RFS) and overall (OS) survival. It should be noted that two nested Phase 2 trials were introduced by amendment during the GRAALL-2014 course (in 2017 and 2018, respectively), aiming to evaluate post-remission addition of nelarabine and blinatumomab in 87 T-ALL and 94 BCP-ALL selected pts, respectively.Results Main patient characteristics, including age, gender, BCP/T-ALL, WBC, and historical baseline HR features, did not significantly differ between the two trial cohorts, even if CNS disease at diagnosis was more frequent in the 2014 cohort (12 vs 7%, p= 0.001).Outcome comparisons are shown in Table 1. Overall, the induction death rate was significantly reduced in the GRAALL-2014 (3 vs 6%, p= 0.005). As expected, this was only observed in pts aged 44-59y (3 vs 11%, p= 0.001), in whom dose-intensity reduction also translated into a higher need for second induction course (9 vs 5%, p= 0.05) eventually resulting in a higher CR rate (92 vs 86%, p= 0.05). Due to the newly introduced MRD-based stratification, the rate of pts with HSCT indication was markedly reduced (30 vs 65%, p<0.001), especially in pts aged 18-44y (21 vs 40%, p<0001). Consequently, the rate of pts transplanted in CR1 dropped down from 38 to 23% (p<0.001).The GRAALL-2014 strategy also yielded a significant reduction in CITRM (5 vs 11% at 3 years; p<0.001; Figure 1B) after CR achievement. This reduction was more pronounced in pts aged 45-59y (7 vs 17%, p<0.001 compared to 4 vs 8%, p= 0.02 in 18-44y pts). This was associated with an increased CIR (35% vs 28% at 3 years; p= 0.01), with more late relapses as depicted in Figure 1A. Even if the resulting RFS was similar in both cohorts (59 vs 62% at 3 years; p= 0.77), OS was significantly longer in the GRAALL-2014 (71 vs 64%; p= 0.002) (Figure 1C) likely due to better post-relapse outcomes. When censoring those GRAALL-2014 pts who received nelarabine or blinatumomab in CR1, observations were basically unchanged, even if the difference in CIR was even more marked.Finally, using a 3-month RFS landmark in the 211 GRAALL-2014 pts eligible for HSCT in CR1 based on their poor early MRD response, HSCT significantly prolonged RFS (HR= 0.46 [95% CI, 0.27-0.78]; p= 0.004).Conclusions In adults with Ph-negative ALL enrolled in the GRAALL-2014, age-adapted chemotherapy intensity and MRD-driven indication for HSCT significantly reduced induction and post-remission TRM. This translated into a prolonged OS, indicating that this strategy was safe, despite a higher incidence of late relapses. Newly available salvage options along with HSCT in CR2 might also have played a role

Littérature comparée et correspondance des arts

« Dans l’évolution la plus récente, les frontières entre les genres artistiques fluent les unes dans les autres, ou plus précisément : leurs lignes de démarcation s’effrangent. » Dans la lignée de cette réflexion d’Adorno, la notion de correspondance des arts et la notion de correspondance entre la littérature et les arts, héritières du romantisme allemand, gagnent à être explorées par la littérature comparée de façon neuve. Il revient à la littérature comparée, placée sous le signe de l’interdisciplinarité et du décloisonnement, d’être un précipité de questions pour une nouvelle poétique des arts. Les interrogations soumises au travail collectif sont nombreuses : Quelle est l’origine de l’intensification croissante de la correspondance entre la littérature et les arts ? En quoi la correspondance des arts pose-t-elle la question des limites du langage et engage-t-elle une redéfinition de la légitimité et de la fonction de la littérature et des arts ? Comment un art, un artiste ou une œuvre artistique sont-ils pris en charge par la littérature de plusieurs pays qui se ressourcent à leur contact ? Le but de la correspondance des arts est-il seulement esthétique ou aussi éthique ? Ce volume se compose de quatre sections qui mettent en correspondance la littérature comparée avec les différents domaines artistiques : la musique, pour la première partie ; les arts visuels pour la deuxième et la troisième partie (peinture, sculpture, puis danse, photographie et cinéma) ; et enfin, pour la quatrième partie, ce que l’on peut appeler, à la suite des romantiques allemands, « la ronde des arts »

L’homme et sa diversité

Qu’est-ce que l’anthropologie biologique ? Science des interactions entre l'homme et son milieu, l'anthropologie biologique aborde les grands questionnements actuels sur notre espèce : Comment l'homme s'adapte-t-il aux changements rapides de mode de vie et d'alimentation ? Quelle est l'influence des migrations sur l'évolution des flux géniques ? À quelles modifications morphologiques ou physiologiques éventuelles du corps humain assiste-t-on à l'heure actuelle ? Des spécialistes issus des différents domaines concernés confrontent ici leurs points de vue, et ouvrent de nouvelles perspectives de recherche