Patterns of genomic change in residual disease after neoadjuvant chemotherapy for estrogen receptor-positive and HER2-negative breast cancer

Background: Treatment of patients with residual disease after neoadjuvant chemotherapy for breast cancer is an unmet clinical need. We hypothesised that tumour subclones showing expansion in residual disease after chemotherapy would contain mutations conferring drug resistance. Methods: We studied oestrogen receptor and/or progesterone receptor-positive, HER2-negative tumours from 42 patients in the EORTC 10994/BIG 00-01 trial who failed to achieve a pathological complete response. Genes commonly mutated in breast cancer were sequenced in pre and post-treatment samples. Results: Oncogenic driver mutations were commonest in PIK3CA (38% of tumours), GATA3 (29%), CDH1 (17%), TP53 (17%) and CBFB (12%); and amplification was commonest for CCND1 (26% of tumours) and FGFR1 (26%). The variant allele fraction frequently changed after treatment, indicating that subclones had expanded and contracted, but there were changes in both directions for all of the commonly mutated genes. Conclusions: We found no evidence that expansion of clones containing recurrent oncogenic driver mutations is responsible for resistance to neoadjuvant chemotherapy. The persistence of classic oncogenic mutations in pathways for which targeted therapies are now available highlights their importance as drug targets in patients who have failed chemotherapy but provides no support for a direct role of driver oncogenes in resistance to chemotherapy. ClinicalTrials.gov: EORTC 10994/BIG 1-00 Trial registration number NCT00017095.SCOPUS: ar.jDecretOANoAutActifinfo:eu-repo/semantics/publishe

Apprendre les métiers du care en France et en Allemagne au-delà des assignations de genre. Une approche ethnographique par les capabilities

International audienc

Inwiefern erweitert die Ausbildung zu Care-Berufen die Freiheit der Berufswahl in der Île de France und in Nordrhein-Westfalen?

La théorie des effets sociétaux des politiques d’éducation sur l’organisation industrielle a prévalu dans la recherche française des années 1970 à nos jours sous l’impulsion de l’école d’Aix menée par les chercheurs du Lest François Sellier, Marc Maurice et Jean-Jacques Silvestre (1982). Les métiers du soin et de l’aide à l’enfant et à la personne âgée dépendante appris sous statut scolaire en Allemagne et en apprentissage en France témoignent de l’effet négatif de l’apprentissage sur le parcours des jeunes apprentis.The theory of societal effects of the education policies on the industrial organisation prevails in the french research from the seventieth to today at the instigation oft he researcher oft he labor Lest Franços Sellier, Marc Maurice and Jean-Jacques Silvestre (1982). The profession of the care to children and old people wich is as pupills in Germany and apprentice in France learns gives evidence to an negative effect on the educational path of the young apprentice.Die Theorie der gesellschaftlichen Effekten der Bildungspolitiken auf die Industrieorganisation vorherrschte in der französische Forschung von den siebziger Jahren bis heute unter der Schwung der von Forschern des Lestlaboratorium geleiteten Schule von Aix François Sellier, Marc Maurice und Jean-Jacques Silvestre (1982). Die Pflege- und Hilfsberufe zur Kinder und Alten, die in Deutschland in Berufskollegs und in Frankreich als Lehrling ausgebildet sind beweisen einen negativen Effekt auf der Bildungslaufbahn der jungen Lehrlingen

Wilfried Nippel, Liberté antique, liberté moderne. Les fondements de la démocratie, de l’Antiquité à nos jours

La démocratie athénienne, sans théorie ni intention missionnaire, tient lieu de cas particulier dans le monde grec. Or ce système politique, mis au point dans le cadre d’états de petite taille – selon les critères modernes – a fasciné la postérité jusqu’à nos jours, tantôt comme un repoussoir (l’ochlocratie, tyrannie de la majorité tant redoutée) tantôt comme un modèle exemplaire d’autodétermination collective dépassant nettement toutes les formes de démocraties indirectes et représentatives...

Wilfried Nippel, Liberté antique, liberté moderne. Les fondements de la démocratie, de l’Antiquité à nos jours

La démocratie athénienne, sans théorie ni intention missionnaire, tient lieu de cas particulier dans le monde grec. Or ce système politique, mis au point dans le cadre d’états de petite taille – selon les critères modernes – a fasciné la postérité jusqu’à nos jours, tantôt comme un repoussoir (l’ochlocratie, tyrannie de la majorité tant redoutée) tantôt comme un modèle exemplaire d’autodétermination collective dépassant nettement toutes les formes de démocraties indirectes et représentatives...

Data from Sentis et al. (2015) for main publication

Functional response data provided by Arnaud Sentis and colleagues (https://doi.org/10.1111/gcb.12931). “Daphnia_density” is the initial prey number; “Daphnia_eaten” is the number of eaten prey individuals after the experiment. Please see the original publication by Sentis et al. (2015, https://doi.org/10.1111/gcb.12931) for details and also cite their paper if using these data! These data appear only in the main publication (D1) published in MEE

Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRASG12D-driven Pancreatic TumorigenesisSummary

Background & Aims: Transforming growth factor beta (TGFβ) acts either as a tumor suppressor or as an oncogene, depending on the cellular context and time of activation. TGFβ activates the canonical SMAD pathway through its interaction with the serine/threonine kinase type I and II heterotetrameric receptors. Previous studies investigating TGFβ-mediated signaling in the pancreas relied either on loss-of-function approaches or on ligand overexpression, and its effects on acinar cells have so far remained elusive. Methods: We developed a transgenic mouse model allowing tamoxifen-inducible and Cre-mediated conditional activation of a constitutively active type I TGFβ receptor (TβRICA) in the pancreatic acinar compartment. Results: We observed that TβRICA expression induced acinar-to-ductal metaplasia (ADM) reprogramming, eventually facilitating the onset of KRASG12D-induced pre-cancerous pancreatic intraepithelial neoplasia. This phenotype was characterized by the cellular activation of apoptosis and dedifferentiation, two hallmarks of ADM, whereas at the molecular level, we evidenced a modulation in the expression of transcription factors such as Hnf1β, Sox9, and Hes1. Conclusions: We demonstrate that TGFβ pathway activation plays a crucial role in pancreatic tumor initiation through its capacity to induce ADM, providing a favorable environment for KRASG12D-dependent carcinogenesis. Such findings are highly relevant for the development of early detection markers and of potentially novel treatments for pancreatic cancer patients. Keywords: Pancreas, Cancer, TGFβ, Acinar-to-Ductal Metaplasia, KRASG12