The spliceosome is a therapeutic vulnerability in MYC-driven cancer.

MYC (also known as c-MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. MYC is a transcription factor, and many of its pro-tumorigenic functions have been attributed to its ability to regulate gene expression programs. Notably, oncogenic MYC activation has also been shown to increase total RNA and protein production in many tissue and disease contexts. While such increases in RNA and protein production may endow cancer cells with pro-tumour hallmarks, this increase in synthesis may also generate new or heightened burden on MYC-driven cancer cells to process these macromolecules properly. Here we discover that the spliceosome is a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene in human mammary epithelial cells, and demonstrate that BUD31 is a component of the core spliceosome required for its assembly and catalytic activity. Core spliceosomal factors (such as SF3B1 and U2AF1) associated with BUD31 are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total precursor messenger RNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Notably, genetic or pharmacological inhibition of the spliceosome in vivo impairs survival, tumorigenicity and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing, and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers.

The Role of Relationship Changes in College Students' Heavy Episodic Drinking.

OBJECTIVE: The beginning of college is a period in which increased alcohol use often coincides with greater involvement in romantic relationships. Existing literature yields inconsistent findings regarding the influence of relationship types on drinking behavior, perhaps because these studies have not accounted for recent changes in the way college students engage in dating/sexual relationships. METHODS: The present study sought to address this issue using a longitudinal study design by examining the effects of both relationship type and sexual activity on heavy episodic drinking (HED) among 1,847 college students over the course of the first 3 semesters of college. RESULTS: Results indicated that the effects of relationship type depended on whether an individual was sexually active. Nondating but sexually active students reported rates of HED comparable to students who defined themselves as casual daters. Conversely, nondating students who were not sexually active reported drinking behavior similar to those involved in exclusive relationships. Further, transitions between low- and high-risk relationship/sexual activity types were associated with corresponding changes in HED. Transitioning into a high-risk relationship was associated with significant increases in levels of HED, whereas transitioning into a low-risk relationship was associated with significant decreases in HED. CONCLUSIONS: Together, results indicate that engaging in nonexclusive dating or casual sexual relationships may play an important role in the development of problematic patterns of alcohol use during the early college years. These findings have potentially important implications both for future research and for prevention and intervention efforts targeting high-risk college drinkers.

The Comprehensive Early Drinking History Form: A Novel Measure of Early Alcohol Exposure.

BACKGROUND: Adolescent and young adult alcohol use is a major public health concern; alcohol is the most widely used substance by teenagers. It is imperative to better understand alcohol use during adolescence and early adulthood given the important changes that occur. Although numerous measures aim to capture alcohol use during this time, no existing measure gathers comprehensive information on alcohol use across these developmental stages. We developed the Comprehensive Early Drinking History Form (CEDHF), which retrospectively gathers drinking information for each year since onset of first regular use, including quantity/frequency of both regular use and periods of heaviest drinking. The CEDHF also collects information on aggregate drinking experiences between age of onset and age of first regular use. METHODS: Using a sample of young adults (ages 21 to 27) from an ongoing longitudinal study, we examined whether the CEDHF predicted both concurrent (N = 303) and future (N = 75) alcohol-related problems over and above other commonly used alcohol use measures (e.g., age of onset, age of first intoxication, Timeline Follow-Back) and current alcohol problems. RESULTS: Controlling for gender, age, and current problems, the CEDHF predicted both concurrent and future alcohol-related problems over and above these other widely used measures of alcohol exposure. CONCLUSIONS: The CEDHF may be a valuable tool when longitudinal studies are not feasible as it provides more comprehensive information than other widely used measures of early alcohol exposure. Further, this measure can provide detailed information regarding who is at highest risk for future consequences.

Age, sex, and race-varying rates of alcohol use, cannabis use, and alcohol and cannabis co-use in veterans vs. non-veterans.

BACKGROUND: Military veterans are a high-risk group for health risk behaviors, including alcohol and cannabis use. However, research on veteran vs. non-veteran rates of alcohol/cannabis use are inconsistent across studies. Further, no research has investigated veteran vs. non-veteran rates of alcohol and cannabis co-use, and few studies have tested whether demographic variables, particularly race/ethnicity, moderate group differences. Therefore, the current study tested whether 1) veteran vs. non-veterans differed in rates of alcohol use, cannabis use, and alcohol and cannabis co-use, and 2) whether demographic covariates (age, sex, race/ethnicity) moderated associations. METHODS: Data on adults (N = 706,897; 53.4% female) were derived from the 2002-2019 National Study on Drug Use and Health. Participant demographics, alcohol use frequency, drinking quantity, and cannabis use frequency were self-reported. RESULTS: Non-veterans reported higher drinking quantity, cannabis frequency, and co-use. However, being a veteran was a risk factor for heavier drinking for women, ethnic/racial minoritized participants, and adults under the age of 50. Additionally, veteran status was a risk factor for cannabis use frequency in racial/ethnic minoritized participants and women. Similarly, being a veteran was a risk factor for alcohol and cannabis co-use for racial/ethnic minoritized participants, and the buffering effect of being a Veteran on co-use was reduced for older participants and women. CONCLUSIONS: Results suggest that, at the population level, non-veterans may be heavier alcohol/cannabis users. However, moderating analyses suggested that being a veteran is a risk factor for women, racial/ethnic minoritized individuals, and younger individuals. Findings are discussed in terms of public health implications.

Contextual influences on subjective alcohol response.

Prior research demonstrates contextual influences on drug responses in both animals and humans, although studies in humans typically focus on only one aspect of context (e.g., social) and examine a limited range of subjective experiences. The current study sought to address these limitations by examining the impact of both social and physical context on the full range of subjective alcohol effects. The sample included 448 young adult social drinkers (57% male, 66.5% White) randomly assigned to consume alcohol (target blood alcohol concentration of .08 g%) or placebo in 1 of 4 contexts (solitary lab, group lab, solitary bar, group bar). Results indicated that high arousal positive (HAP) effects of alcohol (e.g., talkative, lively) were stronger in nonbar relative to bar contexts and that low arousal positive (LAP) effects (e.g., relaxed, calm) were only present in the group lab context. There were also main effects of social context such that high arousal effects (both positive and negative) were stronger in group contexts, regardless of beverage condition. These findings highlight the importance of considering context when examining alcohol effects. Studies designed to isolate pharmacological HAP effects may benefit from a nonbar setting, and studies of LAP effects might be most effective in a simulated living room or home environment, although future studies are needed to directly address this possibility. Further, studies with an explicit focus on expectancies or that need strong control for expectancies might benefit from a group context, particularly when studying high arousal effects. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Direct and indirect links between parenting styles, self-concealment (secrets), impaired control over drinking and alcohol-related outcomes.

INTRODUCTION: Self-concealment reflects uncomfortable feelings, thoughts, and information people have about themselves that they avoid telling others (Larson & Chastain, 1990). According to Larson and Chastain (1990) these secrets range from the slightly embarrassing to the very distressing with an individual's most traumatic experiences often concealed. Parental attitudes including those involving self-disclosure are thought to be expressed in their choice of parenting style (Brand, Hatzinger, Beck, & Holsboer-Trachsler, 2009). The specific aim of this investigation was to examine the direct and indirect influences of parenting styles on self-concealment, impaired control over drinking (i.e. the inability to stop drinking when intended), alcohol use (quantity/frequency), and alcohol-related problems. METHODS: A structural equation model with 419 (223 men, 196 women) university students was examined. Two and three path mediated effects were examined with the bias corrected bootstrap technique in Mplus. RESULTS: Having an authoritarian mother was directly linked to more self-concealment, while having an authoritative father was directly linked to less self-concealment. Higher levels of mother authoritarianism were indirectly linked to both increased alcohol use and alcohol-related problems through more self-concealment and more impaired control over drinking. Moreover, higher levels of father authoritativeness were indirectly linked to less alcohol use and alcohol-related problems through less self-concealment and less impaired control over drinking. CONCLUSIONS: These findings suggest that parenting styles influence vulnerabilities such as self-concealment in the impaired control over the drinking pathway to alcohol use and alcohol-related problems.