EBNA1 inhibitors have potent and selective antitumor activity in xenograft models of Epstein-Barr virus-associated gastric cancer.

BACKGROUND AND AIMS: Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is the most common EBV-associated cancer and accounts for ~ 10% of all gastric cancers (GC). Epstein-Barr virus nuclear antigen 1 (EBNA1), which is critical for the replication and maintenance of the EBV latent genome, is consistently expressed in all EBVaGC tumors. We previously developed small molecule inhibitors of EBNA1. In this study, we investigated the efficacy and selectivity of an EBNA1 inhibitor in cell-based and animal xenograft models of EBV-positive and EBV-negative gastric carcinoma. METHODS: We tested the potency of an EBNA1 inhibitor, VK-1727, in vitro and in xenograft studies, using EBV-positive (SNU719 and YCCEL1) and EBV-negative (AGS and MKN74) GC cell lines. After treatment, we analyzed cell viability, proliferation, and RNA expression of EBV genes by RT-qPCR. RESULTS: Treatment with VK-1727 selectively inhibits cell cycle progression and proliferation in vitro. In animal studies, treatment with an EBNA1 inhibitor resulted in a significant dose-dependent decrease in tumor growth in EBVaGC xenograft models, but not in EBV-negative GC xenograft studies. Gene expression analysis revealed that short term treatment in cell culture tended towards viral gene activation, while long-term treatment in animal xenografts showed a significant decrease in viral gene expression. CONCLUSIONS: EBNA1 inhibitors are potent and selective inhibitors of cell growth in tissue culture and animal models of EBV-positive GC. Long-term treatment with EBNA1 inhibitors may lead to loss of EBV in mouse xenografts. These results suggest that pharmacological targeting of EBNA1 may be an effective strategy to treat patients with EBVaGC.

Association of work-related and leisure-time physical activity with workplace food purchases, dietary quality, and health of hospital employees.

BACKGROUND: While leisure-time physical activity (PA) has been associated with reduced risk of cardiometabolic disease, less is known about the relationship between work-related PA and health. Work-related PA is often not a chosen behavior and may be associated with lower socioeconomic status and less control over job-related activities. This study examined whether high work-related PA and leisure-time PA reported by hospital employees were associated with healthier dietary intake and reductions in cardiometabolic risk. METHODS: This was a cross-sectional analysis of 602 hospital employees who used workplace cafeterias and completed the baseline visit for a health promotion study in 2016-2018. Participants completed the International Physical Activity Questionnaire and clinical measures of weight, blood pressure, HbA1c, and lipids. Healthy Eating Index (HEI) scores were calculated from two 24-h dietary recalls, and a Healthy Purchasing Score was calculated based on healthfulness of workplace food/beverage purchases. Regression analyses examined Healthy Purchasing Score, HEI, and obesity, hypertension, hyperlipidemia, and diabetes/prediabetes by quartile of work-related PA, leisure-time PA, and sedentary time. RESULTS: Participants' mean age was 43.6 years (SD = 12.2), 79.4% were female, and 81.1% were white. In total, 30.3% had obesity, 20.6% had hypertension, 26.6% had prediabetes/diabetes, and 32.1% had hyperlipidemia. Median leisure-time PA was 12.0 (IQR: 3.3, 28.0) and median work-related PA was 14.0 (IQR: 0.0, 51.1) MET-hours/week. Higher leisure-time PA was associated with higher workplace Healthy Purchasing Score and HEI (p's < 0.01) and lower prevalence of obesity, diabetes/prediabetes, and hyperlipidemia (p's < 0.05). Work-related PA was not associated with Healthy Purchasing Score, HEI, or cardiometabolic risk factors. Increased sedentary time was associated with lower HEI (p = 0.02) but was not associated with the workplace Healthy Purchasing Score. CONCLUSIONS: Employees with high work-related PA did not have associated reductions in cardiometabolic risk or have healthier dietary intake as did employees reporting high leisure-time PA. Workplace wellness programs should promote leisure-time PA and healthy food choices for all employees, but programs may need to be customized and made more accessible to meet the unique needs of employees who are physically active at work. TRIAL REGISTRATION: This trial was prospectively registered with clinicaltrials.gov (Identifier: NCT02660086) on January 21, 2016. The first participant was enrolled on September 16, 2016.

The association of impulsivity with effects of the ChooseWell 365 workplace nudge intervention on diet and weight.

Impulsivity is associated with unhealthy food choices. Nudge interventions in the food environment may be particularly helpful for individuals with high impulsivity. To examine if trait, choice, and action impulsivity were associated with the effectiveness of a workplace-based nudge intervention to improve diet and weight. This was a planned secondary analysis of 487 participants of ChooseWell 365, a randomized controlled trial that tested a 12-month nudge intervention to improve cafeteria purchases among hospital employees. Trait impulsivity was measured with the Barratt Impulsiveness Scale. Choice and action impulsivity were assessed with delay discounting and response inhibition tasks, respectively. Tertiles were generated for each measure. Multivariable regression models examined the association of impulsivity with cafeteria purchases [Healthy Purchasing Score (HPS)] over 12 months, dietary intake [Healthy Eating Index-2015 (HEI) score], and body mass index (BMI) measured at 12 months. Interaction terms tested differences in intervention effect by level of impulsivity. Participants with higher trait (p = .02) and choice (p < .001) impulsivity had lower baseline HPS than those with lower impulsivity. Employees of all impulsivity levels increased healthy eating, but higher trait impulsivity was associated with smaller increase in HPS over 12 months (p = .03). In the highest action impulsivity tertile, 12-month BMI increased less for intervention vs. control participants (0.3 vs. 0.5 kg/m2; p-interaction = .04). There were no interaction effects for trait or choice impulsivity. A workplace nudge intervention improved food choices among employees of all impulsivity levels and attenuated weight gain in those with higher action impulsivity.

Impulsivity is an individual trait characterized by the tendency to make quick or rash decisions. High impulsivity is associated with less healthy food choices and poorer health outcomes, including obesity. "Nudges", which are small interventions that steer people towards healthy choices without removing other options, may be particularly helpful for individuals with high impulsivity. Our study tested whether trait impulsivity (i.e., impulsive personality tendencies), choice impulsivity (i.e., preference for immediate vs. later rewards), and action impulsivity (i.e., low behavioral inhibition) were associated with the effectiveness of a workplace nudge intervention to increase healthy food choices and slow weight gain among hospital employees. We found that higher trait and choice impulsivity were associated with less healthy food purchases in the study population at baseline, but employees of all levels of impulsivity improved their food purchases in response to the intervention. The intervention may have helped slow weight gain in individuals with high action impulsivity.

Identification of Mubritinib (TAK 165) as an inhibitor of KSHV driven primary effusion lymphoma via disruption of mitochondrial OXPHOS metabolism.

KSHV-associated cancers have poor prognoses and lack therapeutics that selectively target viral gene functions. We developed a screening campaign to identify known drugs that could be repurposed for the treatment of KSHV-associated cancers. We focused on primary effusion lymphoma (PEL), which has particularly poor treatment outcomes. We developed a luciferase reporter assay to test the ability of drugs to inhibit DNA binding of the KSHV LANA DNA binding domain (DBD). In parallel, we screened drugs for selective inhibition of a KSHV+ PEL cells. While potent hits were identified in each assay, only one hit, Mubritinib, was found to score in both assays. Mubritinib caused PEL cells to undergo cell cycle arrest with accumulation of sub-G1 population and Annexin V. Mubritinib inhibited LANA binding to KSHV terminal repeat (TR) DNA in KSHV+ PEL cells, but did not lead to KSHV lytic cycle reactivation. Mubritinib was originally identified as a receptor tyrosine kinase (RTK) inhibitor selective for HER2/ErbB2. But recent studies have revealed that Mubritinib can also inhibit the electron transport chain (ETC) complex at nanomolar concentrations. We found that other related ETC complex inhibitors (Rotenone and Deguelin) exhibited PEL cell growth inhibition while RTK inhibitors failed. Seahorse analysis demonstrated that Mubritinib selectively inhibits the maximal oxygen consumption (OCR) in PEL cells and metabolomics revealed changes in ATP/ADP and ATP/AMP ratios. These findings indicate that PEL cells are selectively sensitive to ETC complex inhibitors and provide a rationale for repurposing Mubritinib for selective treatment of PEL.

Association of Worksite Food Purchases and Employees' Overall Dietary Quality and Health.

INTRODUCTION: Most Americans spend half their waking hours at work and consume food acquired there. The hypothesis was that the healthfulness of worksite food purchases was associated with employees' overall diet and health. METHODS: Participants were 602 hospital employees who regularly used worksite cafeterias and enrolled in a health promotion study in 2016-2018. All cafeterias used traffic-light labels (green=healthy, yellow=less healthy, red=unhealthy). A Healthy Purchasing Score was calculated for each participant by summing weighted proportions of cafeteria items purchased over a 3-month observation period (red=0, yellow=0.5, green=1; range, 0-1). Healthy Eating Index scores (range, 0-100) were calculated based on two 24-hour dietary recalls. BMI, blood pressure, and HbA1c were measured. Hypertension and prediabetes/diabetes diagnoses were determined by self-reported and clinical data. Regression analyses examined dietary quality and diagnoses by tertile of Healthy Purchasing Score (T1=least healthy purchases, T3=most healthy), adjusting for demographics. All data were collected before the start of the intervention and were analyzed in 2018. RESULTS: Mean age was 43.6 years (SD=12.2), 79% were female, and 81% were white. Mean BMI was 28.3 kg/m2 (SD=6.5); 21% had hypertension, and 27% had prediabetes/diabetes. Mean Healthy Eating Index was 60.4 (SD=12.5); mean Healthy Purchasing Score was 0.66 (SD=0.15). Healthier purchases were associated with healthier Healthy Eating Index scores (T1=55.6, T2=61.0, T3=64.5, p<0.001) and lower obesity prevalence (T1=38%, T2=29%, T3=24%, p<0.001); similar patterns were observed for hypertension and prediabetes/diabetes. CONCLUSIONS: Worksite food purchases were associated with overall dietary quality and cardiometabolic risk. Interventions to increase healthfulness of food choices at work may improve employees' health.