Inhibition sélective des «vraies» et «pseudo»-cholinestérases du rectus de grenouille

Summary The hydrolysis of acetylcholine chloride (0.01M) by frog's rectus extracts, is inhibited by low concentrations of 3318 CT (CI-50 3.2×10^–7) and high concentrations of D.F.P. (CI-50 1.3×10^–5). Inversely, the hydrolysis of butyrylcholine perchlorate is inhibited by low concentrations of D.F.P. (CI-50 3×10^–9) and high concentrations of 3318 CT (CI-50 3×10^–4). Both are inhibited by similar concentrations of neostigmine (CI-50 1.1×10^–7 and 1.5×10^–7). Frog's rectus thus contains true and pseudo-cholinesterases. The inhibitions produced by D.F.P. added to the muscle itself (and not the extract) correlates well with the potentiation of the corresponding ester. Sensitization to AcCh and to BuCh appears to be specifically related to the inhibition of Ac ChE for the former ester, of XChE for the second one.     

Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma

Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.