To identify biobehavioral mechanisms underlying excessive reward consumption, reward valuation-effort (RV-E) assessments should (a) parallel measures in basic science to permit translation from preclinical to clinical studies; (b) quantify constructs dimensionally from healthy to disease states; and (c) hold relevance across different diagnostic categories. To address these aims, we developed a progressive ratio (PR) task whereby RV-E is measured as breakpoint when participants worked for access to playing a game. We evaluated test-retest reliability of breakpoint and convergent and discriminant validity of interpretations of this score against an established PR task for food. In Study 1, female undergraduates (N = 71; 33% racial minority; 28% ethnic minority) completed the game and food tasks in fasted and fed states. In Study 2, women (N = 189; 29% racial minority; 27% ethnic minority) with eating disorders (n = 158) were compared to controls (n = 31) on tasks. Game task breakpoint demonstrated excellent test-retest reliability, intraclass correlation coefficient (ICC) = .91, 95% CI [.80, -.96], over 2 weeks and convergent validity with the fasted food task (r = .51, p < .001). Consistent with animal models, breakpoint was lower in fed compared to fasted states across tasks, B (SE) = 321.01 (552.40), p < .001. Finally, the game task demonstrated discriminant validity from measurement of satiation. In Study 2, women with eating disorders demonstrated higher breakpoint on both tasks compared to controls, and game PR task breakpoint decreased from a fasted to fed state. The game PR task offers a novel approach for translating results from animal models of RV-E into testable hypotheses in nonclinical and clinical samples. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Objective: Suicide attempts and self-injurious behaviors (SIBs) are known to be elevated among people with bulimia nervosa (BN). The aim of the current study was to examine the Interpersonal-Psychological Theory of Suicide (IPTS) as a framework for understanding, assessing, and mitigating suicidal behavior among women with BN. The IPTS suggests that for individuals to enact lethal suicide attempts, they must have both the desire to die (consisting of thwarted belongingness and perceived burdensomeness) as well as the capability to die (often acquired through repeated exposure to provocative or painful experiences).Method: Two-hundred and four women with eating disorders, the majority of whom met criteria for a current DSM-IV diagnosis of BN, completed measures from which proxies for IPTS variables were formed. Bivariate correlations and multiple regressions tested main effects and interactions of study variables. Tests of the difference between dependent correlations probed differential associations between study variables and suicidal ideation versus suicidal behavior.Results and Conclusions: Results yielded considerable but not unalloyed support for the theory, with desire to die variables (particularly perceived burdensomeness) more strongly associating with suicidal ideation than behavior, and the opposite holding true regarding capability. These findings suggest that the IPTS may provide a useful framework for understanding, assessing, and mitigating suicide risk among individuals with BN.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. β-Catenin (CTNNB1)-mutated HCC represents 30% of cases of the disease with no precision therapeutics available. Using chemical libraries derived from clinical multi-kinase inhibitor (KI) scaffolds, we screened HCC organoids to identify WNTinib, a KI with exquisite selectivity in CTNNB1-mutated human and murine models, including patient samples. Multiomic and target engagement analyses, combined with rescue experiments and in vitro and in vivo efficacy studies, revealed that WNTinib is superior to clinical KIs and inhibits KIT/mitogen-activated protein kinase (MAPK) signaling at multiple nodes. Moreover, we demonstrate that reduced engagement on BRAF and p38α kinases by WNTinib relative to several multi-KIs is necessary to avoid compensatory feedback signaling-providing a durable and selective transcriptional repression of mutant β-catenin/Wnt targets through nuclear translocation of the EZH2 transcriptional repressor. Our studies uncover a previously unknown mechanism to harness the KIT/MAPK/EZH2 pathway to potently and selectively antagonize CTNNB1-mutant HCC with an unprecedented wide therapeutic index.