No cytotoxic effect of

nutlin-3 was detected in ALL cells with either p53-mutant or -null phenotype. In wt-p53 ALL cells, there was a significant positive correlation between MDM2 expression levels and sensitivity to nutlin-3. Nutlin-3-induced cell death was mediated by p53-induced activation of proapoptotic proteins and by p53-induced repression of the anti-apoptotic protein Epoxomicin solubility dmso survivin. As p53 function is inhibited by MDM2 in chemoresistant, MDM2-overexpressing ALL cells, potent killing of these cells by nutlin-3 suggests that this agent may be a novel therapeutic for refractory ALL.”
“We investigated the activity of ITF2357, a novel histone deacetylase inhibitor (HDACi) with antitumor activity, on cells carrying the JAK2(V617F) mutation obtained from polycythemia vera (PV) and essential thrombocythemia ( ET) patients as well as the HEL cell line. The clonogenic activity of JAK2(V617F) mutated cells was inhibited by low concentrations of ITF2357

(IC(50) 0.001-0.01 mu M), 100- to 250-fold lower than required to inhibit growth of normal or tumor cells lacking this mutation. Under these conditions, ITF2357 allowed a seven fold increase in the outgrowth of unmutated over mutated colonies. By western blotting we showed that in HEL cells, ITF2357 led to the disappearance of total and phosphorylated JAK2(V617F) BLZ945 cost as well as pSTAT5 and pSTAT3, but it did not affect the wild-type JAK2 or STAT proteins in the control K562 cell line. By real-time PCR, we showed that, upon exposure to ITF2357, JAK2(V617F) mRNA was not modified in granulocytes from PV patients while the expression of the PRV-1 gene, a known target of JAK2, was rapidly downmodulated. Altogether, the data presented suggest that ITF2357 inhibits proliferation of cells bearing the JAK2(V617F) mutation through a specific downmodulation of the JAK2(V617F) protein and inhibition of its downstream signaling.”
“The role of the cerebellum has been increasingly recognized not only in motor control but in sensory, cognitive and emotional learning and regulation. Purkinje cells, being

the sole output from the cerebellar Tryptophan synthase cortex, occupy an integrative position in this network. Plasticity at this level is known to critically involve calcium signaling. In the last few years, electrophysiological study of genetically engineered mice has demonstrated the topical role of several genes encoding calcium-binding proteins (calretinin, calbindin, parvalbumin). Specific inactivation of these genes results in the emergence of a fast network oscillation (ca. 160 Hz) throughout the cerebellar cortex in alert animals, associated with ataxia. This oscillation is produced by synchronization of Purkinje cells along the parallel fiber beam. It behaves as an electrophysiological arrest rhythm, being blocked by sensorimotor stimulation. Pharmacological manipulations showed that the oscillation is blocked by GABA(A) and NMDA antagonists as well as gap junction blockers.