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Alcohol hangover refers to the combination of negative mental and physical symptoms that can be experienced after an episode of alcohol consumption, typically emerging as blood alcohol concentration (BAC) approaches zero. Hangover has been associated with heavy drinking and may be relevant in the transition to alcohol use disorder (AUD). Our aim was to examine hangover prevalence and associated symptoms following intravenous alcohol self-administration (IV-ASA), and to identify possible predictors of hangover in non-dependent drinkers. Ninety-five drinkers without AUD completed an IV-ASA session. Pharmacodynamic measures of alcohol consumption included peak and average breath alcohol concentrations. Subjective measures of alcohol response included the Drug Effects Questionnaire and Biphasic Effects of Alcohol Scale. The Alcohol Hangover Scale assessed hangover symptoms from the end of the session until the following morning. 78% of participants endorsed at least one hangover symptom following IV-ASA. There was no association between hangover scores and IV-ASA measures of alcohol consumption. Additional mediation and moderation analysis revealed that self-reported intoxication was a significant mediator of the relationship between recent drinking and hangover symptoms. Hangover symptoms may be an early marker of the relationship between subjective response to alcohol and heavy drinking for those with no prior history of AUD. In particular, the effects of hangover go beyond exposure to alcohol and the individual's subjective response to this exposure is associated with their experience of hangover. Future studies should further characterize the determinants of hangover across different populations of drinkers to better understand the risk for AUD and inform prevention methods.

Carcinogenic polycyclic aromatic hydrocarbons (PAHs) were disposed directly into the Saguenay River of the St. Lawrence Estuary (SLE) by local aluminum smelters (Quebec, Canada) for 50 years (1926-1976). PAHs in the river sediments are likely etiologically related to gastrointestinal epithelial cancers observed in 7% of 156 mature (>19-year old) adult beluga found dead along the shorelines. Because DNA adduct formation provides a critical link between exposure and cancer induction, and because PAH-DNA adducts are chemically stable, we hypothesized that SLE beluga intestine would contain PAH-DNA adducts. Using an antiserum specific for DNA modified with several carcinogenic PAHs, we stained sections of paraffin-embedded intestine from 51 SLE beluga (0-63 years), 4 Cook Inlet (CI) Alaska beluga (0-26 years), and 20 beluga (0-46 years) living in Arctic areas (Eastern Beaufort Sea, Eastern Chukchi Sea, Point Lay Alaska) and aquaria, all with low PAH contamination. Stained sections showed nuclear light-to-dark pink color indicating the presence of PAH-DNA adducts concentrated in intestinal crypt epithelial lining cells. Scoring of whole tissue sections revealed higher values for the 51 SLE beluga, compared with the 20 Arctic and aquarium beluga (P = 0.003). The H-scoring system, applied to coded individual photomicrographs, confirmed that SLE beluga and CI beluga had levels of intestinal PAH-DNA adducts significantly higher than Arctic and aquarium beluga (P = 0.003 and 0.02, respectively). Furthermore, high levels of intestinal PAH-DNA adducts in four SLE beluga with gastrointestinal cancers, considered as a group, support a link of causality between PAH exposure and intestinal cancer in SLE beluga. Environ. Mol. Mutagen. 60:29-41, 2019. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Alcohol consumption is often assessed over weeks to months, but few attempts have been made to characterize alcohol consumption rates at the level of an individual drinking session. Here, we aimed to compare the rate of alcohol consumption in social drinkers at high risk for alcohol use disorder (AUD) and heavy drinkers. One hundred and sixty social drinkers and 48 heavy drinkers participated in an alcohol self-administration study. Social drinkers were classified as low risk or high risk for AUD based on sex, impulsivity, and family history of alcoholism. Participants received a priming dose of intravenous alcohol to assess alcohol-induced craving and completed a 125-minute intravenous alcohol self-administration session to assess rate of achieving a binge-level exposure (blood alcohol concentration greater than or equal to 80 mg%). There were no differences between rates of binging in high-risk and heavy drinkers (hazard ratio = 0.87; 95% CI, 0.48-1.56). Heavy drinkers reported higher levels of craving than high-risk and low-risk drinkers at baseline. However, following a priming dose of alcohol, there were no longer differences in craving between high-risk and heavy drinkers. These results indicate that high-risk social drinkers demonstrate binging behavior that is similar to heavy drinkers, which may be driven by alcohol-induced craving. Prospective studies are needed to elucidate whether these patterns of craving and consumption in high-risk social drinkers are predictive of future AUD.

Carcinogenic polycyclic aromatic hydrocarbons (PAHs) were disposed directly into the Saguenay River of the St. Lawrence Estuary (SLE) by local aluminum smelters (Quebec, Canada) for 50 years (1926-1976). PAHs in the river sediments are likely etiologically related to gastrointestinal epithelial cancers observed in 7% of 156 mature (19-year old) adult beluga found dead along the shorelines. Because DNA adduct formation provides a critical link between exposure and cancer induction, and because PAH-DNA adducts are chemically stable, we hypothesized that SLE beluga intestine would contain PAH-DNA adducts. Using an antiserum specific for DNA modified with several carcinogenic PAHs, we stained sections of paraffin-embedded intestine from 51 SLE beluga (0-63 years), 4 Cook Inlet (CI) Alaska beluga (0-26 years), and 20 beluga (0-46 years) living in Arctic areas (Eastern Beaufort Sea, Eastern Chukchi Sea, Point Lay Alaska) and aquaria, all with low PAH contamination. Stained sections showed nuclear light-to-dark pink color indicating the presence of PAH-DNA adducts concentrated in intestinal crypt epithelial lining cells. Scoring of whole tissue sections revealed higher values for the 51 SLE beluga, compared with the 20 Arctic and aquarium beluga (P = 0.003). The H-scoring system, applied to coded individual photomicrographs, confirmed that SLE beluga and CI beluga had levels of intestinal PAH-DNA adducts significantly higher than Arctic and aquarium beluga (P = 0.003 and 0.02, respectively). Furthermore, high levels of intestinal PAH-DNA adducts in four SLE beluga with gastrointestinal cancers, considered as a group, support a link of causality between PAH exposure and intestinal cancer in SLE beluga. Environ. Mol. Mutagen. 60:29-41, 2019. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Oridonin (1) has attracted considerable attention in recent years because of its unique and safe anticancer pharmacological profile. Nevertheless, it exhibits moderate to poor effects against highly aggressive cancers including triple-negative and drug-resistant breast cancer cells. Herein, we report the rational design and synthesis of novel dienone derivatives with an additional α,β-unsaturated ketone system diversely installed in the A-ring based on this class of natural scaffold that features dense functionalities and stereochemistry-rich frameworks. Efficient and regioselective enone construction strategies have been established. Meanwhile, a unique 3,7-rearrangement reaction was identified to furnish an unprecedented dienone scaffold. Intriguingly, these new analogues have been demonstrated to significantly induce apoptosis and inhibit colony formation with superior antitumor effects against aggressive and drug-resistant breast cancer cells in vitro and in vivo while also exhibiting comparable or lower toxicity to normal human mammary epithelial cells in comparison with 1.

OBJECTIVES/SPECIFIC AIMS: The current study examined hangover following IV alcohol self-administration (IV-ASA) using the Computer-Assisted Infusion System. The goal of the study was to identify predictors of hangover, including drinking history, alcohol sensitivity, family history, expectancies, and sex differences in nondependent drinkers. METHODS/STUDY POPULATION: The study sample included 89 healthy, nondependent drinkers aged 21–45 years. After a screening to exclude any medical illness or psychiatric disorders, participants completed an IV-ASA session. Each session consisted of a 25-minute priming phase, during which participants were prompted to press a button to receive individually standardized alcohol infusions, followed by a 2-hour “open bar” phase, during which they were instructed to recreate a typical drinking experience. Results from the IV-ASA included peak and average BrAC. Drinking patterns were assessed using the Alcohol Use Disorders Identification Test, which provided 3 subscales: consumption (AUDIT-C), dependence (AUDIT-D), and harmful drinking (AUDIT-H). Subjective response to alcohol was measured using the Drug Effects Questionnaire (DEQ). The Alcohol Hangover Scale (AHS) was used to assess hangover for the period between participants’ departure from the study unit and 10 am the next morning. The Alcohol Effects Questionnaire (AEFQ) is a measure which includes 40 true/false statements about how alcohol typically makes respondents feel, and was used to measure alcohol expectancies. RESULTS/ANTICIPATED RESULTS: Results showed that 78% of participants endorsed having at least 1 hangover symptom following IV-ASA. The most commonly reported items were tired, thirsty, headache, and hangover. There was no association between hangover scores and the AUDIT-C or IV-ASA. Because alcohol consumption was not related to hangover symptoms, risky drinking behavior was examined. Results indicated that participants endorsing 4 or more items on the AUDIT-D plus AUDIT-H subscales showed significantly higher average hangover scores. Linear regression analyses indicated that alcohol hangover scores were associated with DEQ items feel, high, and intoxicated. Ongoing analyses are examining additional predictors of hangover including family history, alcohol expectancies, sex differences, and other alcohol sensitivity measures. DISCUSSION/SIGNIFICANCE OF IMPACT: The results indicated that risky drinking patterns and alcohol response measures were positively associated with hangover symptoms in non-dependent drinks, while no correlation between consumption and hangover symptoms were found. Since previous research has shown than greater subjective response is associated with heavy drinking and predictive of alcohol use disorder, it is possible that hangover symptoms is a marker of this relationship. Since the role of hangover in the transition from heavy drinking to disorder still remains unclear, it will be important to characterize this relationship between alcohol sensitivity and hangover as a function of drinking patterns. This understanding may help to prevent this transition from at-risk drinking to alcohol dependent drinking.

Proliferating cells must enact a program of telomere lengthening to counteract the chromosome end replication problem. In most types of cancer cells, telomeres are maintained through the action of the ribonucleoprotein telomerase, but some cancer cells, particularly those of mesenchymal origin, utilize an alternative method of telomere repair and lengthening termed the alternative lengthening of telomeres (ALT) pathway. Since telomere maintenance is essential for tumor cell immortality, better understanding of the ALT mechanism could potentially reveal drug targets that could be used to develop novel therapies for tumors that use ALT. It has been previously observed that ALT tumors frequently carry mutations in ATRX, which partners with the protein DAXX in a chromatin remodeling complex, but how these mutations facilitate the ALT pathway is not well understood. Work in our lab identified an ALT-positive osteosarcoma cell line, identified here as OS1, in which DAXX has undergone a fusion event with the non-canonical kinesin KIFC3. We find that knockdown of the DAXX-KIFC3 fusion neither impairs ALT nor cell proliferation, suggesting that the fusion represents a loss of function. Furthermore, inducible restoration of wild-type DAXX, reversibly abrogates ALT function in this cell line. One of the hallmarks of ALT is localization of telomeres and DNA recombination machinery to nuclear PML bodies, resulting in formation of ALT- associated PML Bodies, or APBs. Thus it may be considered that changes in PML body composition represent a key aspect of the ALT mechanism. We observe that in OS1 both DAXX and ATRX fail to localize to PML bodies. This finding is consistent with the fact that the DAXX-KIFC3 fusion results in loss of a C-terminal SUMO interaction motif that normally mediates PML body interaction. Leveraging our inducible system, using biochemical and imaging approaches, we are working to define the role of DAXX in maintaining PML body composition. Citation Format: Sarah F. Clatterbuck Soper, Soyeon A. Showman, Kathryn E. Driest, Joshua J. Waterfall, Robert L. Walker, Marbin A. Pineda, Yuelin J. Zhu, Yonghong Wang, Corbin D. Ester, Sven Bilke, Paul S. Meltzer. A DAXX-KIFC3 fusion potentiates alternative lengthening of telomeres in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3467. doi:10.1158/1538-7445.AM2017-3467

The unlimited proliferative capacity of cancer cells is closely linked to maintenance of their telomeres, which shorten with each cell division in normal cells. Cancer cells are able to maintain telomere length by multiple mechanisms, including activation of telomerase and the recombination based alternative lengthening of telomeres (ALT) pathway. ALT is prevalent in osteosarcoma, with approximately 50% of osteosarcoma cases using ALT for telomere maintenance. Mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 correlate with activation of the ALT pathway in several tumor systems. While loss of ATRX is a frequent event in osteosarcoma tumors, alterations of DAXX have not been reported. We characterized the telomere maintenance mechanisms utilized by 11 osteosarcoma cell lines. Of these, 45% (5/11) were ALT positive and 45% (5/11) were telomerase positive. One cell line possessed features of both telomere maintenance mechanisms. Among ALT positive osteosarcoma cell lines, we observed frequent loss of ATRX expression (4/5) and a previously unreported translocation resulting in disruption of DAXX. The translocation abolishes recruitment of DAXX to nuclear PML bodies and prevents normal DAXX function. By reintroducing full length DAXX, we were able to suppress telomere maintenance by ALT as evidenced by multiple assays including loss of C-circles and ALT-associated PML bodies, thus demonstrating that continued DAXX deficiency is necessary for maintenance of the ALT mechanism. Suppression of ALT by DAXX reintroduction did not result in compensatory activation of telomerase. This first demonstration of ALT suppression by DAXX supports a mechanistic connection between loss of the ATRX/DAXX chromatin remodeling complex and telomere maintenance by ALT. Understanding this relationship may uncover vulnerabilities specific to ALT tumors that could potentially lead to the development of targeted therapies for diverse cancers that depend on the ALT pathway. Citation Format: Kathryn E. Driest, Joshua J. Waterfall, Robert L. Walker, Marbin A. Pineda, Ogan Abaan, Yuelin J. Zhu, Yonghong Wang, Corbin D. Ester, Sean R. Davis, Sven Bilke, Paul S. Meltzer. Reintroduction of DAXX suppresses alternative lengthening of telomeres in osteosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2717.