Alterations in Glutathione Levels and Apoptotic Regulators Are Associated with Acquisition of Arsenic Trioxide Resistance in Multiple Myeloma

Arsenic trioxide (ATO) has been tested in relapsed/refractory multiple myeloma with limited success. In order to better understand drug mechanism and resistance pathways in myeloma we generated an ATO-resistant cell line, 8226/S-ATOR05, with an IC50 that is 2–3-fold higher than control cell lines and significantly higher than clinically achievable concentrations. Interestingly we found two parallel pathways governing resistance to ATO in 8226/S-ATOR05, and the relevance of these pathways appears to be linked to the concentration of ATO used. We found changes in the expression of Bcl-2 family proteins Bfl-1 and Noxa as well as an increase in cellular glutathione (GSH) levels. At low, clinically achievable concentrations, resistance was primarily associated with an increase in expression of the anti-apoptotic protein Bfl-1 and a decrease in expression of the pro-apoptotic protein Noxa. However, as the concentration of ATO increased, elevated levels of intracellular GSH in 8226/S-ATOR05 became the primary mechanism of ATO resistance. Removal of arsenic selection resulted in a loss of the resistance phenotype, with cells becoming sensitive to high concentrations of ATO within 7 days following drug removal, indicating changes associated with high level resistance (elevated GSH) are dependent upon the presence of arsenic. Conversely, not until 50 days without arsenic did cells once again become sensitive to clinically relevant doses of ATO, coinciding with a decrease in the expression of Bfl-1. In addition we found cross-resistance to melphalan and doxorubicin in 8226/S-ATOR05, suggesting ATO-resistance pathways may also be involved in resistance to other chemotherapeutic agents used in the treatment of multiple myeloma.

Occupational therapists' attitudes toward homosexuality

Two hundred and eighty-five occupational therapists were surveyed to determine their general attitudes toward homosexuality, and whether certain demographic variables and means of exposure affected these attitudes. Attitudes ranged from neutral to positive. Those demographic variables that did affect respondents' attitudes were: sexual orientation, gender, and educational level. Those respondents who identified themselves as homosexual or bisexual had more positive attitudes than those who were heterosexual. Female respondents had more positive attitudes than male respondents and those respondents who held a Master's degree had more positive attitudes than those who held a Bachelor's degree. It was determined that respondents who had a family member or friend who was gay had more positive attitudes than those who did not. An unexpected finding was that respondents who had received adequate information about homosexuality in their occupational therapy curriculum had more negative attitudes than those who did not receive adequate information. It was therefore concluded that those occupational therapists who had not been provided with adequate information on homosexuality in their occupational therapy curriculum but had more positive attitudes toward homosexuality, were older and had more years of experience in occupational therapy. ^