Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240

Glioblastoma multiforme (GBM) is the most aggressive of the astrocytic malignancies and the most common intracranial tumor in adults. Although the epidermal growth factor receptor (EGFR) is overexpressed and/or mutated in at least 50% of GBM cases and is required for tumor maintenance in animal models, EGFR inhibitors have thus far failed to deliver significant responses in GBM patients. One inherent resistance mechanism in GBM is the coactivation of multiple receptor tyrosine kinases, which generates redundancy in activation of phosphoinositide-3'-kinase (PI3K) signaling. Here we demonstrate that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is frequently phosphorylated at a conserved tyrosine residue, Y240, in GBM clinical samples. Phosphorylation of Y240 is associated with shortened overall survival and resistance to EGFR inhibitor therapy in GBM patients and plays an active role in mediating resistance to EGFR inhibition in vitro. Y240 phosphorylation can be mediated by both fibroblast growth factor receptors and SRC family kinases (SFKs) but does not affect the ability of PTEN to antagonize PI3K signaling. These findings show that, in addition to genetic loss and mutation of PTEN, its modulation by tyrosine phosphorylation has important implications for the development and treatment of GBM.

Robert Schumann e a tradução: criação poética, simultaneidade e movimento

Este trabalho examina os Escritos sobre a Música e os Músicos, do compositor alemão Robert Schumann, em especial as resenhas escritas entre 1834 e 1836, com vistas a identificar ecos das principais ideias sobre linguagem e tradução desenvolvidas na Alemanha entre o final do séc. XVIII e o início do séc. XIX. Os eixos escolhidos para construir essa ideia são os eixos do sujeito e do tempo perpassados pela noção de movimento. Do primeiro, destaca-se a ancoragem vertical, personalíssima, operada no interior do sujeito que transita de um sistema sígnico para outro, que traduz seus pensamentos, ou ainda que empreende a passagem de uma língua para outra. Do segundo, tem-se em conta a configuração desse mergulho num produto que desmantela as barreiras do tempo e, de um só golpe, contemporiza o passado e inclui o futuro.