Combined EZH2 Inhibition and IKAROS Degradation Leads to Enhanced Antitumor Activity in Diffuse Large B-cell Lymphoma.

PURPOSE: The efficacy of EZH2 inhibition has been modest in the initial clinical exploration of diffuse large B-cell lymphoma (DLBCL), yet EZH2 inhibitors are well tolerated. Herein, we aimed to uncover genetic and pharmacologic opportunities to enhance the clinical efficacy of EZH2 inhibitors in DLBCL. EXPERIMENTAL DESIGN: We conducted a genome-wide sensitizing CRISPR/Cas9 screen with tazemetostat, a catalytic inhibitor of EZH2. The sensitizing effect of IKZF1 loss of function was then validated and leveraged for combination treatment with lenalidomide. RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing analyses were performed to elucidate transcriptomic and epigenetic changes underlying synergy. RESULTS: We identified IKZF1 knockout as the top candidate for sensitizing DLBCL cells to tazemetostat. Treating cells with tazemetostat and lenalidomide, an immunomodulatory drug that selectively degrades IKAROS and AIOLOS, phenocopied the effects of the CRISPR/Cas9 screen. The combined drug treatment triggered either cell-cycle arrest or apoptosis in a broad range of DLBCL cell lines, regardless of EZH2 mutational status. Cell-line-based xenografts also showed slower tumor growth and prolonged survival in the combination treatment group. RNA-seq analysis revealed strong upregulation of interferon signaling and antiviral immune response signatures. Gene expression of key immune response factors such as IRF7 and DDX58 were induced in cells treated with lenalidomide and tazemetostat, with a concomitant increase of H3K27 acetylation at their promoters. Furthermore, transcriptome analysis demonstrated derepression of endogenous retroviruses after combination treatment. CONCLUSIONS: Our data underscore the synergistic interplay between IKAROS degradation and EZH2 inhibition on modulating epigenetic changes and ultimately enhancing antitumor effects in DLBCL.

Attitudes and Beliefs Toward Computerized Cognitive Training in the General Population.

INTRODUCTION: In recent years, computerized cognitive training (CCT) programs have been developed commercially for widespread public consumption. Despite early enthusiasm, whether these programs enhance cognitive abilities in healthy adults is a contentious area of investigation. Given the mixed findings in the literature, researchers are beginning to investigate how beliefs and attitudes toward CCT impact motivation, expectations, and gains after cognitive training. METHOD: We collected survey data from 497 North American participants from Amazon's Mechanical Turk (MTurk). This survey asked novel questions regarding respondents' beliefs about the effectiveness of CCT for improving different domains of cognition, mood, and daily life; beliefs about whether CCT programs are supported by research; and whether impressions of CCT have improved or worsened over time. Exploratory analyses are reported descriptively, while parametric tests were used to analyze a priori hypotheses. RESULTS: Almost half of the surveyed participants had used CCT, and respondents with a self-reported psychological or neurological disorder were more likely to have used CCT platforms than participants without such conditions. Motivations for using CCT included curiosity; to improve or maintain cognition; to prevent cognitive decline; and/or for enjoyment or fun. Participants believed that CCT is somewhat effective for improving mood and cognition across a variety of domains. Greater age and fewer years of education predicted perceived effectiveness of CCT. Finally, participants largely reported unchanged opinions of CCT platforms over time. CONCLUSION: Our study suggests the need for future research regarding the general population's beliefs and attitudes toward CCT, along with knowledge translation for relevant stakeholders.

Prelimbic and infralimbic cortical inactivations attenuate contextually driven discriminative responding for reward.

The infralimbic (IL) and prelimbic (PL) cortices of the medial prefrontal cortex (mPFC) have been shown to differentially control context-dependent behavior, with the PL implicated in the expression of contextually conditioned fear and drug-seeking, and the IL in the suppression of these behaviors. However, the roles of these subregions in contextually driven natural reward-seeking remain relatively underexplored. The present study further examined the functional dichotomy within the mPFC in the contextual control over cued reward-seeking, using a contextual biconditional discrimination (CBD) task. Rats were first trained to emit a nose poke response to the presentation of an auditory stimulus (e.g., X) for the delivery of sucrose reward, and to withhold a nose poke response to the presentation of another auditory stimulus (e.g., Y) in a context-specific manner (e.g. Context A: X+, Y-; Context B: X-, Y+). Following acquisition, rats received bilateral microinjections of GABA receptor agonists (muscimol and baclofen), or saline into the IL or PL, prior to a CBD training session and a probe test (under extinction conditions). Both IL and PL inactivation resulted in robust impairment in CBD performance, indicating that both subregions are involved in the processing of appetitively motivated contextual memories in reward-seeking.