Brain activation covaries with reported criminal behaviors when making risky choices: A fuzzy-trace theory approach.

Criminal behavior has been associated with abnormal neural activity when people experience risks and rewards or exercise inhibition. However, neural substrates of mental representations that underlie criminal and noncriminal risk-taking in adulthood have received scant attention. We take a new approach, applying fuzzy-trace theory, to examine neural substrates of risk preferences and criminality. We extend ideas about gist (simple meaning) and verbatim (precise risk-reward tradeoffs) representations used to explain adolescent risk-taking to uncover neural correlates of developmentally inappropriate adult risk-taking. We tested predictions using a risky-choice framing task completed in the MRI scanner, and examined neural covariation with self-reported criminal and noncriminal risk-taking. As predicted, risk-taking was correlated with a behavioral pattern of risk preferences called "reverse framing" (preferring sure losses over a risky option and a risky option over sure gains, the opposite of typical framing biases) that has been linked to risky behavior in adolescents and is rarely observed in nondisordered adults. Experimental manipulations confirmed processing interpretations of typical framing (gist-based) and reverse-framing (verbatim-based) risk preferences. In the brain, covariation with criminal and noncriminal risk-taking was observed predominantly when subjects made reverse-framing choices. Noncriminal risk-taking behavior was associated with emotional reactivity (amygdala) and reward motivation (striatal) areas, whereas criminal behavior was associated with greater activation in temporal and parietal cortices, their junction, and insula. When subjects made more developmentally typical framing choices, reflecting nonpreferred gist processing, activation in dorsolateral prefrontal cortex covaried with criminal risk-taking, which may reflect cognitive effort to process gist while inhibiting preferred verbatim processing. (PsycINFO Database Record

Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma.

Multiple myeloma cells secrete more disulfide bond-rich proteins than any other mammalian cell. Thus, inhibition of protein disulfide isomerases (PDI) required for protein folding in the endoplasmic reticulum (ER) should increase ER stress beyond repair in this incurable cancer. Here, we report the mechanistically unbiased discovery of a novel PDI-inhibiting compound with antimyeloma activity. We screened a 30,355 small-molecule library using a multilayered multiple myeloma cell-based cytotoxicity assay that modeled disease niche, normal liver, kidney, and bone marrow. CCF642, a bone marrow-sparing compound, exhibited a submicromolar IC50 in 10 of 10 multiple myeloma cell lines. An active biotinylated analog of CCF642 defined binding to the PDI isoenzymes A1, A3, and A4 in MM cells. In vitro, CCF642 inhibited PDI reductase activity about 100-fold more potently than the structurally distinct established inhibitors PACMA 31 and LOC14. Computational modeling suggested a novel covalent binding mode in active-site CGHCK motifs. Remarkably, without any further chemistry optimization, CCF642 displayed potent efficacy in an aggressive syngeneic mouse model of multiple myeloma and prolonged the lifespan of C57BL/KaLwRij mice engrafted with 5TGM1-luc myeloma, an effect comparable to the first-line multiple myeloma therapeutic bortezomib. Consistent with PDI inhibition, CCF642 caused acute ER stress in multiple myeloma cells accompanied by apoptosis-inducing calcium release. Overall, our results provide an illustration of the utility of simple in vivo simulations as part of a drug discovery effort, along with a sound preclinical rationale to develop a new small-molecule therapeutic to treat multiple myeloma. Cancer Res; 76(11); 3340-50. ©2016 AACR.