Abstract Despite extensive genomic exploration, the mechanisms that initiate malignancy remain obscure. We addressed this issue by studying how chronic liver diseases progress to hepatocellular carcinoma (HCC). We focused our studies on the role of p62/SQSTM1, whose accumulation is a hallmark of premalignant liver disease. Using mice, we found that hepatocyte-specific p62 ablation inhibits HCC development in four distinct models, with strongest effect exerted in etiologies involving mTORC1 activation. Forced p62 expression in autophagy-competent livers suffices for HCC induction. Amongst p62 activities including aggregate formation, binding ubiquitinated proteins, mTORC1 stimulation and transcription factor activation, most critical is the NRF2 pathway, which is mutationally activated in 14% of human HCCs. We propose that environmentally-induced p62-dependent NRF2 signaling is a key early event inHCC pathogenesis that together with mTORC1 promotes survival and expansion of superoxide-accumulating HCC-initiating cells. Indeed, high p62 expression in preneoplastic human liver predicts rapid HCC recurrence after curative ablation. Citation Format: Michael Karin. p62/SQSTM1 accumulation links chronic tissue damage to malignant progression in liver and pancreas. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA08.
Cancers often arise as the end stage of inflammation in adults, but not in children. As such there is a complex interplay between host immune cells during neoplastic development, with both an ability to promote cancer and limit or eliminate it, most often complicit with the host. In humans, defining inflammation and the presence of inflammatory cells within or surrounding the tumor is a critical aspect of modern pathology. Groups defining staging for neoplasms are strongly encouraged to assess and incorporate measures of the presence of apoptosis, autophagy, and necrosis and also the nature and quality of the immune infiltrate. Both environmental and genetic factors enhance the risk of cigarette smoking, Helicobacter pylori, hepatitis B/C, human papilloma virus, solar irradiation, asbestos, pancreatitis, or other causes of chronic inflammation. Identifying suitable genetic polymorphisms in cytokines, cytokine receptors, and Toll-like receptors among other immune response genes is also seen as high value as genomic sequencing becomes less expensive. Animal models that incorporate and assess not only the genetic anlagen but also the inflammatory cells and the presence of microbial pathogens and damage-associated molecular pattern molecules are necessary. Identifying micro-RNAs involved in regulating the response to damage or injury are seen as highly promising. Although no therapeutic strategies to prevent or treat cancers based on insights into inflammatory pathways are currently approved for the common epithelial malignancies, there remains substantial interest in agents targeting COX2 or PPARgamma, ethyl pyruvate and steroids, and several novel agents on the horizon.
Achieving Change Across Sectors: Integrating Research, Policy, and Practice (C. D. Economos) The 2013 Active Living Research (ALR) Annual Conference brought together a network of individuals from research, policy, and practice to exchange data, experiences, and aspirations toward building a more active-friendly national landscape. There were evidence generators, evidence users, and those who do a bit of both. Primarily a generator, I also find myself at the intersection when called upon to inform policy or to implement evidence-based practice. My own approach to research has become more interdisciplinary and participatory to generate evidence that is inclusive and relevant to policy debates, so the conference theme created a comfortable atmosphere for me. The rich dialogue among attendees exemplified the commitment of many to uphold our individual roles, varied at times throughout our careers, in designing and implementing evidence-based public health strategies and policies to promote effective and sustained action. What becomes exceedingly clear when sectors are brought together is that the system is interdependent—evidence informs policy development and practice, and evaluating policy implementation and practice-based interventions generates new evidence. The cycle is continuous. Public health has several health priorities that require thoughtful and careful collaborations between researchers, practitioners, and policymakers across many sectors. Perhaps most pressing is the fact that we have an obesity epidemic caused by environments and policies that encourage overconsuming and underexpending energy. The urgency of addressing the epidemic compels a variety of policy-related actions that reach far and deep within the population. To maximize impact, these actions must be feasible, synergistic, cost-effective, free of unintended adverse consequences, and based on the best available evidence. From the perspective of an evidence generator, the following questions are contemplated on a regular basis: What is the status of the evidence? How do we go forward in the absence of complete evidence? What types of studies are required to fill the gaps and expand the evidence base? What are the disciplines that would enrich a research study? Who should participate in the research process? How do we communicate useful results to people who can use them? From the perspective of a policymaker or practitioner (or evidence user), the questions begin once a body of evidence exists: How can the data be combined and compiled to inform decision makers and stakeholders about the value and importance of evidence and how it could inform a particular policy decision? What type of methods should be used to evaluate the impact of new policy implementation? To address these questions and others, the Institute of Medicine’s Bridging the Evidence Gap report explains how various forms of evidence are used in evidence-based public health decision making. A closer look at the types of evidence and how it’s used in policymaking illustrates the range of information often taken into account by policymakers and suggests an expanded role for evidence generators. For example, when conducting a controlled trial in a community with multilevel outcomes, it is important to pay attention to the knowledge, ideas and interests, and opinions and views of the community as well as costs and resources used. A variety of distinct pieces of evidence (quantitative and qualitative) and sources of knowledge have meaning and can ultimately inform policy. This generally makes the results more meaningful for the community and their representatives. Different types of evidence can be merged with specific capacities, such as an individual’s skills, experience, and participation in networks, to influence the adoption and adaptation of evidence in practice. At the organizational levels, capacity is often visible leadership, Christina D. Economos, PhD, is at Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts. James F. Sallis, PhD, is with Active Living Research, University of California, San Diego, San Diego, California. NiCole R. Keith, PhD, is at the Department of Kinesiology, Indiana UniversityPurdue University, Indianapolis, Indiana. Jimmy Newkirk, BS, is with the National Physical Activity Society, Coats, North Carolina.
No abstract is provided for this article.
The design of communities and transportation systems is strongly related to nonmotorized transportation (NMT) behavior; however, the effect of environmental policy variables on total physical activity is not clear. Because large proportions of people in the United States live in the sprawling and exclusively residential environments associated with low levels of walking for transport, land use and transportation policies may already be having a substantial, although generally undocumented, impact on public health. Professionals from numerous fields are concerned that we have built our communities so that it is difficult, and in many cases dangerous, to walk or bike, and have thus engineered physical activity out of our daily lives. There is a public health imperative to evaluate environmental and policy variables and their associations with NMT, recreational physical activity, and total physical activity. The results of such studies can inform efforts to alter the environments in which people live their daily lives so as to promote population shifts in physical activity and improve transportation systems. Conducting and applying research on environmental correlates of NMT and physical activity will require collaboration among researchers from a wide range of professions.
Creating more physical activity–supportive built environments is recommended by the World Health Organization for controlling noncommunicable diseases. The IPEN (International Physical Activity and Environment Network) Adult Study was undertaken to provide international evidence on associations of built environments with physical activity and weight status in 12 countries on 5 continents ( n > 14,000). This article presents reanalyzed data from eight primary papers to identify patterns of findings across studies. Neighborhood environment attributes, whether measured objectively or by self-report, were strongly related to all physical activity outcomes (accelerometer-assessed total physical activity, reported walking for transport and leisure) and meaningfully related to overweight/obesity. Multivariable indexes of built environment variables were more strongly related to most outcomes than were single-environment variables. Designing activity-supportive built environments should be a higher international health priority. Results provide evidence in support of global initiatives to increase physical activity and control noncommunicable diseases while achieving sustainable development goals.
To examine the relationship between parental behaviors and physical activity and fitness in elementary school-aged children.Cross-sectional survey of students and parents.Seven public elementary schools in a suburban southern California city.One hundred forty-eight fourth-grade girls and 149 fourth-grade boys and their parents. Eighty-four percent were white.None.Children's physical activity was indicated by self-report, data obtained from a monitor (accelerometer), and results of the mile run/walk. Multiple regression analysis, controlling for ethnicity and body mass index, was conducted separately for girls and boys to explain variation in child activity and fitness. Parents' reported physical activity was not associated with child activity or fitness. However, availability of transportation by parents to sport and fitness activities was significant (or nearly so) in two regressions for boys and in one regression for girls. Parents who played with their children had more active boys, based on self-report, but verbal encouragement to be active was not significant in any model.The parental role as gatekeeper of access to activity and sport facilities deserves further study.
