Published by Elsevier Ltd. All rights reserved.”
“Proteasome inhibition

is a novel treatment for several hematological malignancies. However, resistance to the proteasome inhibitor bortezomib (BTZ, Velcade) is an emerging clinical impediment. Mutations in the beta 5 subunit of the proteasome, the primary target of BTZ, have been associated with drug resistance. However, the exact mechanism by which these mutations contribute to BTZ resistance, is still largely unknown. Toward this end, we here developed BTZ-resistant multiple myeloma (8226) and acute lymphoblastic leukemia (CCRF-CEM) cell line models by exposure to stepwise increasing concentrations of BTZ. Characterization click here of the various BTZ-resistant cells revealed upregulation of mutant beta 5 subunit of the proteasome. These newly identified beta 5-subunit mutations, along with previously described mutations, formed a mutation cluster region in the BTZ-binding pocket of the beta 5 subunit, that of the S1 specificity pocket in particular. Moreover,

we provide the first evidence that the mechanism underlying BTZ resistance in these tumor cells is impaired binding of BTZ to the mutant beta 5 subunit of the WH-4-023 nmr proteasome. We propose that proteasome subunit overexpression is an essential compensatory mechanism for the impaired catalytic activity of these mutant proteasomes. Our findings further suggest that second-generation proteasome inhibitors that target the alpha 7 subunit of the proteasome can overcome DAPT supplier this drug resistance modality. Leukemia (2012) 26, 757-768; doi:10.1038/leu.2011.256; published online 23 September 2011″
“We attempted to formulate a model of quality of life (QoL) in chronic stage of schizophrenia with 72 patients by including key variables, i.e., psychopathology, insight, executive functioning, and side effects, proposed to be its significant predictors in previous studies. We applied the structural equation modelling (SEM) method to simultaneously test a number of possible hypotheses

concerning the inter-relations among the predictors of QoL in schizophrenia patients by formulating possible models and examining their levels of fitness. Our most fit model (X(2)=2.106, df=4, P=0.716; CFI=1.000; TLI=1.213: RMSEA=0.000, LO=0.000, HI=0.132) showed that the severity of psychopathology not only directly causes poor QoL but also by adversely affecting insight. On the other hand, executive function may not be affected significantly by psychopathology, but executive function still plays an important role in determining the QoL not only directly, but also indirectly by influencing self-evaluation of side-effects. Impaired insight and executive function caused by severe level of psychopathology contribute to an increased reporting of side-effects, resulting in cumulative dysfunction in daily life for patients with chronic schizophrenia.