The Epstein–Barr virus lytic cycle activator Zta interacts with methylated ZRE in the promoter of host target gene egr1

Activation of the host gene egr1 is essential for the lytic replication of Epstein–Barr virus (EBV). egr1 is activated by Zta (BZLF1, ZEBRA). Zta interacts directly with DNA through a series of closely related Zta-response elements (ZREs). Here we dissect the mechanism used by Zta to interact with the egr1 promoter and identify a weak interaction with egr1ZRE that is dependent on the distal part of egr1ZRE. Furthermore, we demonstrate that the ability of Zta to interact with egr1ZRE is enhanced at least tenfold by methylation. The ability of Zta to transactivate a reporter construct driven by the egr1 promoter can be enhanced by methylation. As the ability of Zta to interact with a methylated ZRE in the EBV genome correlates with its ability to activate the expression of the endogenous viral gene BRLF1, this suggests that Zta may also have the capability to overturn epigenetic control of egr1

Recruitment and Activation of Pancreatic Stellate Cells from the Bone Marrow in Pancreatic Cancer: A Model of Tumor-Host Interaction

BACKGROUND AND AIMS: Chronic pancreatitis and pancreatic cancer are characterised by extensive stellate cell mediated fibrosis, and current therapeutic development includes targeting pancreatic cancer stroma and tumor-host interactions. Recent evidence has suggested that circulating bone marrow derived stem cells (BMDC) contribute to solid organs. We aimed to define the role of circulating haematopoietic cells in the normal and diseased pancreas. METHODS: Whole bone marrow was harvested from male β-actin-EGFP donor mice and transplanted into irradiated female recipient C57/BL6 mice. Chronic pancreatitis was induced with repeat injections of caerulein, while carcinogenesis was induced with an intrapancreatic injection of dimethylbenzanthracene (DMBA). Phenotype of engrafted donor-derived cells within the pancreas was assessed by immunohistochemistry, immunofluorescence and in situ hybridisation. RESULTS: GFP positive cells were visible in the exocrine pancreatic epithelia from 3 months post transplantation. These exhibited acinar morphology and were positive for amylase and peanut agglutinin. Mice administered caerulein developed chronic pancreatitis while DMBA mice exhibited precursor lesions and pancreatic cancer. No acinar cells were identified to be donor-derived upon cessation of cerulein treatment, however rare occurrences of bone marrow-derived acinar cells were observed during pancreatic regeneration. Increased recruitment of BMDC was observed within the desmoplastic stroma, contributing to the activated pancreatic stellate cell (PaSC) population in both diseases. Expression of stellate cell markers CELSR3, PBX1 and GFAP was observed in BMD cancer-associated PaSCs, however cancer-associated, but not pancreatitis-associated BMD PaSCs, expressed the cancer PaSC specific marker CELSR3. CONCLUSIONS: This study demonstrates that BMDC can incorporate into the pancreas and adopt the differentiated state of the exocrine compartment. BMDC that contribute to the activated PaSC population in chronic pancreatitis and pancreatic cancer have different phenotypes, and may play important roles in these diseases. Further, bone marrow transplantation may provide a useful model for the study of tumor-host interactions in cancer and pancreatitis

AVI-7288 for Marburg Virus in Nonhuman Primates and Humans

BACKGROUND: AVI-7288 is a phosphorodiamidate morpholino oligomer with positive charges that targets the viral messenger RNA that encodes Marburg virus (MARV) nucleoprotein. Its safety in humans is undetermined. METHODS: We assessed the efficacy of AVI-7288 in a series of studies involving a lethal challenge with MARV in nonhuman primates. The safety of AVI-7288 was evaluated in a randomized, multiple-ascending-dose study in which 40 healthy humans (8 humans per dose group) received 14 once-daily infusions of AVI-7288 (1 mg, 4 mg, 8 mg, 12 mg, or 16 mg per kilogram of body weight) or placebo, in a 3: 1 ratio. We estimated the protective dose in humans by comparing pharmacokinetic variables in infected nonhuman primates, uninfected nonhuman primates, and uninfected humans. RESULTS: Survival in infected nonhuman primates was dose-dependent, with survival rates of 0%, 30%, 59%, 87%, 100%, and 100% among monkeys treated with 0 mg, 3.75 mg, 7.5 mg, 15 mg, 20 mg, and 30 mg of AVI-7288 per kilogram, respectively (P < 0.001 with the use of the log-rank test for the comparison of survival across groups). No safety concern was identified at doses up to 16 mg per kilogram per day in humans. No serious adverse events were reported. Drug exposure (the area under the curve) was dose-dependent in both nonhuman primates and humans; drug clearance was independent of dose but was higher in nonhuman primates than in humans. The protective dose in humans was initially estimated, on the basis of exposure, to be 9.6 mg per kilogram per day (95% confidence interval, 6.6 to 12.5) for 14 days. Monte Carlo simulations supported a dose of 11 mg per kilogram per day to match the geometric mean protective exposure in nonhuman primates. CONCLUSIONS: This study shows that, on the basis of efficacy in nonhuman primates and pharmacokinetic data in humans, AVI-7288 has potential as postexposure prophylaxis for MARV infection in humans

Children Residing in Low-Income Households Like a Variety of Vegetables

Child vegetable intake falls far below the minimum recommended levels. Knowing which vegetables children may like help those responsible for providing vegetables to children to improve intake. The objective of this study was to measure vegetable liking for a wide variety of vegetables by a racially and ethnically diverse population of 9&ndash;12-year old children from low-income families. Children rated their liking of 35 vegetables using a 10-point hedonic scale. We tabulated the number of children that found each vegetable acceptable (ratings of &lsquo;okay&rsquo; or above) and the number that found each vegetable unacceptable (ratings below &lsquo;okay&rsquo;). More than 50% of children who had tried a vegetable considered it acceptable. A large majority of the vegetables had mean ratings in the acceptable range. Corn was the most liked vegetable, closely followed by potatoes, lettuce, and carrots. Artichoke had the lowest mean liking, followed by onion and beets. We found children liked a wide variety of vegetables which offers counter evidence to the commonly held perception that children do not like vegetables

Testing the Effectiveness of In-Home Behavioral Economics Strategies to Increase Vegetable Intake, Liking, and Variety Among Children Residing in Households That Receive Food Assistance

ABSTRACT Objective: To test the effectiveness of behavioral economics strategies for increasing vegetable intake, variety, and liking among children residing in homes receiving food assistance. Design: A randomized controlled trial with data collected at baseline, once weekly for 6 weeks, and at study conclusion. Setting: Family homes. Participants: Families with a child (9-12 years) will be recruited through community organizations and randomly assigned to an intervention (n ¼ 36) or control (n ¼ 10) group. Intervention: The intervention group will incorporate a new behavioral economics strategy during home dinner meal occasions each week for 6 weeks. Strategies are simple and low-cost. Main Outcome Measure(s): The primary dependent variable will be child&apos;s dinner meal vegetable consumption based on weekly reports by caregivers. Fixed independent variables will include the strategy and week of strategy implementation. Secondary dependent variables will include vegetable liking and variety of vegetables consumed based on data collected at baseline and study conclusion. Analysis: Mean vegetable intake for each strategy across families will be compared using a mixed-model analysis of variance with a random effect for child. In additionally, overall mean changes in vegetable consumption, variety, and liking will be compared between intervention and control groups. Key Words: vegetable, behavioral economics, low-income, children, protocol (J Nutr Educ Behav. 2015;47:e1-e9.) Accepted December 18, 2014. INTRODUCTION Childhood obesity remains a significant public health concern in the US, especially among populations with low socioeconomic status. 1,2 Although the direct relationship between vegetable intake and weight status among children remains unclear, replacing high energy-dense foods with vegetables has the potential to lower dietary energy intake, thereby reducing the risk of obesity. 3 According to National Health and Nutrition Examination Survey (NHANES) data (2007)(2008), approximately 95% of children aged of 9-13 years do not meet the dietary recommendation for total daily vegetable intake. 5 Although programs such as the National School Lunch Program address the issue of availability in schools, additional efforts are necessary to encourage vegetable selection and consumption among children at home. The relatively new field of behavioral economics is proposed as a means to improve dietary behavior based on the effectiveness of small, environmental changes known as nudges to alter choice behavior. Nudges are made by someone with control over the choice environment