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1.  PAK1 Mediates Resistance to PI3 Kinase Inhibition in Lymphomas 
The phosphatidylinositol 3-kinase pathway (PI3K) is known to play an active role in many malignancies. The role of PI3K inhibition in the treatment of lymphomas has not been fully delineated. We sought to identify a role for therapeutic PI3K inhibition across a range of B cell lymphomas.
Experimental Design
We selected three small molecule inhibitors to test in a panel of 60 cell lines that comprised diverse lymphoma types. We tested the selective PI3K inhibitor BKM120 and the dual PI3K/MTOR inhibitors BEZ235 and BGT226 in these cell lines. We applied gene expression profiling to better understand the molecular mechanisms associated with responsiveness to these drugs.
We found that higher expression of the PAK1 gene was significantly associated with resistance to all three PI3K inhibitors. Through RNA-interference mediated knock-down of the PAK1 gene, we demonstrated a dramatic increase in the sensitivity to PI3K inhibition. We further tested a small molecule inhibitor of PAK1 and found significant synergy between PI3K inhibition and PAK1 inhibition.
Thus we demonstrate that PI3K inhibition is broadly effective in lymphomas and PAK1 is a key modulator of resistance to PI3K inhibition.
PMCID: PMC3594365  PMID: 23300274
Leukemias and lymphomas; kinase and phosphatase inhibitors; diffuse large B cell lymphoma; DLBCL; Hodgkin lymphoma; Burkitt lymphoma; primary mediastinal B cell lymphoma; phosphatidylinositol 3-kinase pathway; PI3 Kinase; PI3K; PAK1; drug resistance
2.  Effects of dilemmas and aromas on performance of the Iowa Gambling Task 
Behavioural Brain Research  2010;218(1):64-72.
Males outscore females on the original version of the Iowa Gambling Task (IGT). This may be due to differential regional prefrontal cortical activation by males and females during the task. PET imagery indicates increased activation in dorsolateral (DL) prefrontal cortex (PFC) in males and in medial orbital (ORB) PFC in females. A recent study reported that females’ scores were elevated to the level of males’ by having them deliberate moral dilemmas during the IGT. This was presumably due to a relative shift in PFC activation from medial ORB PFC to DL PFC areas. In the present study, after adding new participants and combining results from previous studies we failed to find a significant effect of deliberating dilemmas prior to or during the original IGT performance. However, the typical gender effect was replicated, as was the females’ preference for cards from Deck B. The lack of dilemma-enhancement fails to support our previous suggestion of increasing activation in DL during the task. However, we investigated whether activation or ORB (also olfactory cortex) would change IGT performance. When smelling novel aromas during the IGT, males’ performance was reduced to the level of females whose performance was unchanged. This finding suggests that activation of emotional neural substrates might alter the dual cognitive (DL)/emotional (ORB) circuits that interact during decision-making.
PMCID: PMC3390743  PMID: 21074576
Changes in decision-making; Iowa Gambling Task; dilemmas; aromas; gender differences

Results 1-3 (3)