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HANOVER, NH - Pre-school age children who are exposed to child-targeted fast-food advertising on television are considerably more likely to consume fast-food products, according to a recent Dartmouth-led study published in the journal Public Health Nutrition. According to the Federal Trade Commission, the greatest exposure to food advertising in the US for children aged 2-11 years comes from fast-food restaurant chains. In 2009, the fast-food industry spent more than $580 million on child-targeted marketing, with television being the predominant medium. "In general, children's consumption of fast food is associated with increased intakes of calories, fat and sugar, making fast-food consumption an important risk factor for obesity and other health problems," says Madeline Dalton, PhD, lead author on the study, who is a professor of pediatrics at Dartmouth's Geisel School of Medicine and a researcher at the Dartmouth-Hitchcock Norris Cotton Cancer Center. "We also know that dietary practices that are formed early in life are carried throughout adolescence and adulthood." Funded by the National Institutes of Health, the study is the first research conducted in a community setting to demonstrate a significant positive association between child-directed fast-food TV ads and increased consumption of fast food among children of pre-school age. "Most parents won't be surprised by the study's findings since they probably know this from observing their own children, and the results are also consistent with food marketing influences that have been observed in highly controlled laboratory settings," Dalton says. "I think what's significant about this study is we're using scientific methods we've developed over the past two decades to measure media and advertising exposure in an objective way, so that the findings are generalizable to real life and we're able to control for influences that we know are important--like parents' fast-food consumption and the overall amount of TV that children watch," she says. In the nine-month study, the research team recruited a total of 548 parents who had a pre-school age child (average of 4.4 years) to complete a written survey during their visits to pediatric and women, infant, and children clinics in Southern New Hampshire. Parents reported their child's viewing time, channels watched, and fast-food consumption during the past week. Their responses were combined with a list of fast-food commercials that were aired on kids' TV channels during that same period to calculate the children's exposure to child-targeted TV ads from three fast-food restaurant chains: McDonald's, Subway, and Wendy's. -- 43 percent of the preschoolers ate food from these restaurants during the past week; a similar percentage (41 percent) had been exposed to the TV ads. --Moderate or high exposure to TV ads increased the likelihood of consuming the fast food by about 30 percent. --Importantly, this association was independent of the overall number of hours of TV the children watched, the frequency with which their parents ate fast food, and other factors like socioeconomic status. --McDonald's accounted for nearly three-quarters of the TV commercials and an even greater proportion (79 percent) of the children's fast-food consumption. According to Dalton, the findings are particularly concerning because children under six years of age can't distinguish between advertisements and programs when they're watching TV--which makes them very vulnerable to persuasive messaging. "These data provide empirical evidence in support of policy recommendations to limit child-directed fast-food marketing on TV," Dalton says. Meghan Longacre, PhD, a study co-author and assistant professor of biomedical data sciences at Geisel, adds, "An important part of the take-home message for parents is that there are preschool channels that don't feature fast-food advertising, and to the extent that they can direct their child's viewing to those channels exclusively, they themselves can protect their children from that exposure." While Dalton considers the findings to be "very significant," she says more research needs to be done to inform national policy around child-targeted fast-food marketing practices. "The biggest limitation of our study is that it's cross-sectional, so we're talking about association, not causality," she explains. "The next step is a longitudinal study, which will also allow us to collect and analyze data on things like the actual food choices children make and even more precise estimates of their viewing time per channel." This research was funded by the National Institutes of Health, grant number R01HD071021. Co-authors on the study include: Linda Titus, PhD, Kristy Hendricks, PhD, Keith Drake, PhD, Lauren Cleveland, MS, from the Geisel School of Medicine, and Jennifer Harris, PhD, MBA, from the Rudd Center for Food Policy and Obesity at the University of Connecticut. Founded in 1797, the Geisel School of Medicine at Dartmouth strives to improve the lives of the communities it serves through excellence in learning, discovery, and healing. The Geisel School of Medicine is renowned for its leadership in medical education, health care policy and delivery science, biomedical research, global health, and in creating innovations that improve lives worldwide. As one of America's leading medical schools, Dartmouth's Geisel School of Medicine is committed to training new generations of diverse leaders who will help solve our most vexing challenges in health care.


Compton D.A.,Norris Cotton Cancer Center
Current Opinion in Cell Biology | Year: 2011

Accurate chromosome segregation during cell division is essential for genome integrity. Errors in chromosome segregation are irreversible and lead to a state of aneuploidy where the number of chromosomes in a cell or organism is not a multiple of the haploid number of chromosomes. Aneuploidy reduces fecundity and is a frequent cause of inherited birth defects. In addition, aneuploidy is very common in solid tumors where it is associated with poor patient prognosis. Recent work has revealed the most common pathways by which chromosomes mis-segregate leading to aneuploidy. Moreover, answers to the key question of how cells respond to aneuploidy are beginning to emerge. © 2010 Elsevier Ltd.


Ceeraz S.,Norris Cotton Cancer Center | Nowak E.C.,Norris Cotton Cancer Center | Noelle R.J.,Norris Cotton Cancer Center | Noelle R.J.,King's College London
Trends in Immunology | Year: 2013

Fine-tuning the immune response and maintaining tolerance to self-antigens involves a complex network of co-stimulatory and co-inhibitory molecules. The recent FDA approval of ipilimumab, a monoclonal antibody blocking cytotoxic T lymphocyte antigen (CTLA)-4, demonstrates the impact of checkpoint regulators in disease. This is reinforced by ongoing clinical trials targeting not only CTLA-4, but also the programmed death (PD)-1 and B7-H4 pathways in various disease states. Recently, two new B7 family inhibitory ligands, V-domain Ig suppressor of T cell activation (VISTA) and B7-H6 were identified. Here, we review recent understanding of B7 family members and their concerted regulation of the immune response to either self or foreign pathogens. We also discuss clinical developments in targeting these pathways in different disease settings, and introduce VISTA as a putative therapeutic target. © 2013 Elsevier Ltd.


Kaur M.,Dartmouth College | Cole M.D.,Norris Cotton Cancer Center
Cancer Research | Year: 2013

The control of normal cell growth is a balance between stimulatory and inhibitory signals. MYC is a pleiotropic transcription factor that both activates and represses a broad range of target genes and is indispensable for cell growth. Whereas much is known about gene activation by MYC, there is no established mechanism for the majority of MYC-repressed genes. We report that MYC transcriptionally activates the PTEN tumor suppressor in normal cells to inactivate the phosphoinositide 3-kinase (PI3K) pathway, thus suppressing AKT activation. Suppression of AKT enhances the activity of the EZH2 histone methyltransferase, a subunit of the epigenetic repressor Polycomb Repressive Complex 2 (PRC2), while simultaneously stabilizing the protein. MYC-mediated enhancement in EZH2 protein level and activity results in local and genome-wide elevation in the repressive H3K27me3 histone modification, leading to widespread gene repression including feedback autoregulation of the MYC gene itself. Depletion of either PTEN or EZH2 and inhibition of the PI3K/AKT pathway leads to gene derepression. Importantly, expression of a phospho-defective EZH2 mutant is sufficient to recapitulate nearly half of all MYC-mediated gene repression. We present a novel epigenetic model for MYC-mediated gene repression and propose that PTEN and MYC exist in homeostatic balance to control normal growth, which is disrupted in cancer cells. © 2012 AACR.


Kisselev A.F.,Norris Cotton Cancer Center | Groettrup M.,University of Konstanz
Current Opinion in Chemical Biology | Year: 2014

Specialized variants of the constitutive 20S proteasome in the immune system like the immunoproteasomes and the thymoproteasome contain active site-bearing subunits which differ in their cleavage priorities and substrate binding pockets. The immunoproteasome plays a crucial role in antigen processing and for the differentiation of pro-inflammatory T helper cells which are involved in the pathogenesis of autoimmunity. Selective inhibitors of the immunoproteasome and constitutive proteasome have recently been generated which interfere with the development and progression of autoimmune diseases. Here we describe these inhibitors and their therapeutic potential as predicted from preclinical models. © 2014 Elsevier Ltd.


Kisselev A.F.,Norris Cotton Cancer Center | Van Der Linden W.A.,Leiden University | Overkleeft H.S.,Leiden University
Chemistry and Biology | Year: 2012

Proteasomes are large, multisubunit proteolytic complexes presenting multiple targets for therapeutic intervention. The 26S proteasome consists of a 20S proteolytic core and one or two 19S regulatory particles. The 20S core contains three types of active sites. Many structurally diverse inhibitors of these active sites, both natural product and synthetic, have been discovered in the last two decades. One, bortezomib, is used clinically for treatment of multiple myeloma, mantle cell lymphoma, and acute allograft rejection. Five more recently developed proteasome inhibitors are in trials for treatment of myeloma and other cancers. Proteasome inhibitors also have activity in animal models of autoimmune and inflammatory diseases, reperfusion injury, promote bone and hair growth, and can potentially be used as anti-infectives. In addition, inhibitors of ATPases and deubiquitinases of 19S regulatory particles have been discovered in the last decade. © 2012 Elsevier Ltd All rights reserved.


Kettenbach A.N.,Norris Cotton Cancer Center | Rush J.,Cell Signaling Technology Inc. | Gerber S.A.,Norris Cotton Cancer Center
Nature Protocols | Year: 2011

In the analysis of biological systems, it is of interest to identify the components of the system and to monitor their changes in abundance under different conditions. The AQUA (for 'absolute quantification') method allows sensitive and specific targeted quantification of protein and post-translational modifications in complex protein mixtures using stable isotopeg-labeled peptides as internal standards. Each AQUA experiment is composed of two stages: method development and application to a biological scenario. In the method development stage, peptides from the protein of interest are chosen and then synthesized with stable isotopes such as 13C, 2H or 15N. The abundance of these internal standards and their endogenous counterparts can be measured by mass spectrometry with selected reaction monitoring or selected ion monitoring methods. Once an AQUA method is established, it can be rapidly applied to a wide range of biological samples, from tissue culture cells to human plasma and tissue. After AQUA peptide synthesis, the development, optimization and application of AQUA analyses to a specific biological problem can be achieved in ∼1 week. Here we demonstrate the usefulness of this method by monitoring both Polo-like kinase 1 (Plk1) protein abundance in multiple lung cancer cell lines and the extent of Plk1 activation loop phosphorylation (pThr-210) during release from S phase. © 2011 Nature America, Inc. All rights reserved.


Rolland S.G.,Norris Cotton Cancer Center | Conradt B.,Norris Cotton Cancer Center
Current Opinion in Cell Biology | Year: 2010

Mitochondria are highly dynamic organelles that constantly fuse and divide. Dynamin-related GTPases are the core components of the machineries that mediate mitochondrial fusion and fission. The role and regulation of these machineries are currently under intense investigation. Recently, members of the BCL2 family of proteins, conserved regulators of apoptosis, have been implicated in the regulation of mitochondrial dynamics. Here, we review the functions of mitochondrial fusion and fission in apoptotic and nonapoptotic cells and how members of the BCL2 family of proteins regulate these functions. © 2010 Elsevier Ltd.


Miller T.W.,Norris Cotton Cancer Center
Clinical Cancer Research | Year: 2014

Low estrogen receptor (ER) levels in breast tumors are associated with poorer response to antiestrogen therapy. Finn and colleagues identify low ER levels as a biomarker predicting benefit from the addition of the EGFR/HER2 dual inhibitor lapatinib to an antiestrogen treatment regimen in patients with metastatic ER+/HER2- breast cancer. © 2014 American Association for Cancer Research.


Sempere L.F.,Norris Cotton Cancer Center
Expert Review of Molecular Diagnostics | Year: 2011

The promise of personalized medicine is highly dependent on the identification of biomarkers that inform diagnostic decisions and treatment options, as well as on the accurate, rapid and cost-effective detection and interpretation of these biomarkers. miRNAs, which are short noncoding regulatory RNAs, are rapidly emerging as a novel class of biomarkers with a unique set of biological and chemical properties that makes them very appealing candidates for theranostic applications in cancer. Since the utility of some protein-encoding gene biomarkers is already exploited in routine clinical practice, it will be important to identify areas in which miRNAs provide complementary or superior information to these existing (and other translational) biomarkers to enhance the diagnostic, prognostic and predictive power of molecular characterization of tumors. In this article, the challenges and opportunities for integration of miRNA-based assays in the clinical toolkit to improve care and management of patients afflicted with solid tumors will be discussed. © 2011 Lorenzo F Sempere.

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