Thrombospondin-1 interactions regulate eicosanoid metabolism and signaling in cancer-related inflammation.

The metabolism of arachidonic acid and other polyunsaturated fatty acids produces eicosanoids, a family of biologically active lipids that are implicated in homeostasis and in several pathologies that involve inflammation. Inflammatory processes mediated by eicosanoids promote carcinogenesis by exerting direct effects on cancer cells and by affecting the tumor microenvironment. Therefore, understanding how eicosanoids mediate cancer progression may lead to better approaches and chemopreventive strategies for the treatment of cancer. The matricellular protein thrombospondin-1 is involved in processes that profoundly regulate inflammatory pathways that contribute to carcinogenesis and metastatic spread. This review focuses on interactions of thrombospondin-1 and eicosanoids in the microenvironment that promote carcinogenesis and how the microenvironment can be targeted for cancer prevention to increase curative responses of cancer patients.

The Dietary Supplement Label Database: Recent Developments and Applications.

Objective: To describe the history, key features, recent enhancements, and common applications of the Dietary Supplement Label Database (DSLD). Background and History: Although many Americans use dietary supplements, databases of dietary supplements sold in the United States have not been widely available. The DSLD, an easily accessible public-use database was created in 2008 to provide information on dietary supplement composition for use by researchers and consumers. Rationale: Accessing current information easily and quickly is crucial for documenting exposures to dietary supplements because they contain nutrients and other bioactive ingredients that may have beneficial or adverse effects on human health. This manuscript details recent developments with the DSLD to achieve this goal and provides examples of how the DSLD has been used. Recent Developments: With periodic updates to track changes in product composition and capture new products entering the market, the DSLD currently contains more than 71,000 dietary supplement labels. Following usability testing with consumer and researcher user groups completed in 2016, improvements to the DSLD interface were made. As of 2017, both a desktop and mobile device version are now available. Since its inception in 2008, the use of the DSLD has included research, exposure monitoring, and other purposes by users in the public and private sectors. Future Directions: Further refinement of the user interface and search features to facilitate ease of use for stakeholders is planned. Conclusions: The DSLD can be used to track changes in product composition and capture new products entering the market. With over 71,000 DS labels it is a unique resource that policymakers, researchers, clinicians, and consumers may find valuable for multiple applications.

Green Cancer Prevention and Beyond.

The concept of green chemoprevention was introduced in 2012 by Drs. Jed Fahey and Thomas Kensler as whole-plant foods and/or extract-based interventions demonstrating cancer prevention activity. Refining concepts and research demonstrating proof-of-principle approaches are highlighted within this review. Early approaches included extensively investigated whole foods, including broccoli sprouts and black raspberries showing dose-responsive effects across a range of activities in both animals and humans with minimal or no apparent toxicity. A recent randomized crossover trial evaluating the detoxification of tobacco carcinogens by a broccoli seed and sprout extract in the high-risk cohort of current smokers highlights the use of a dietary supplement as a potential next-generation green chemoprevention or green cancer prevention approach. Challenges are addressed, including the selection of dose, duration and mode of delivery, choice of control group, and standardization of the plant food or extract. Identification and characterization of molecular targets and careful selection of high-risk cohorts for study are additional important considerations when designing studies. Goals for precision green cancer prevention include acquiring robust evidence from carefully controlled human studies linking plant foods, extracts, and compounds to modulation of targets for cancer risk reduction in individual cancer types.

Discrete Correlation Summation Clustering Reveals Differential Regulation of Liver Metabolism by Thrombospondin-1 in Low-Fat and High-Fat Diet-Fed Mice.

Thrombospondin-1 (TSP1) is a matricellular protein with many important roles in mediating carcinogenesis, fibrosis, leukocyte recruitment, and metabolism. We have previously shown a role of diet in the absence of TSP1 in liver metabolism in the context of a colorectal cancer model. However, the metabolic implications of TSP1 regulation by diet in the liver metabolism are currently understudied. Therefore Discrete correlation summation (DCS) was used to re-interrogate data and determine the metabolic alterations of TSP1 deficiency in the liver, providing new insights into the role of TSP1 in liver injury and the progression of liver pathologies such as nonalcoholic fatty liver disease (NAFLD). DCS analysis provides a straightforward approach to rank covariance and data clustering when analyzing complex data sets. Using this approach, our previous liver metabolite data was re-analyzed by comparing wild-type (WT) and Thrombospondin-1 null (Thbs1-/-) mice, identifying changes driven by genotype and diet. Principal component analysis showed clustering of animals by genotype regardless of diet, indicating that TSP1 deficiency alters metabolite handling in the liver. High-fat diet consumption significantly altered over 150 metabolites in the Thbs1-/- livers versus approximately 90 in the wild-type livers, most involved in amino acid metabolism. The absence of Thbs1 differentially regulated tryptophan and tricarboxylic acid cycle metabolites implicated in the progression of NAFLD. Overall, the lack of Thbs1 caused a significant shift in liver metabolism with potential implications for liver injury and the progression of NAFLD.

Cancer cell survival depends on collagen uptake into tumor-associated stroma.

Collagen I, the most abundant protein in humans, is ubiquitous in solid tumors where it provides a rich source of exploitable metabolic fuel for cancer cells. While tumor cells were unable to exploit collagen directly, here we show they can usurp metabolic byproducts of collagen-consuming tumor-associated stroma. Using genetically engineered mouse models, we discovered that solid tumor growth depends upon collagen binding and uptake mediated by the TEM8/ANTXR1 cell surface protein in tumor-associated stroma. Tumor-associated stromal cells processed collagen into glutamine, which was then released and internalized by cancer cells. Under chronic nutrient starvation, a condition driven by the high metabolic demand of tumors, cancer cells exploited glutamine to survive, an effect that could be reversed by blocking collagen uptake with TEM8 neutralizing antibodies. These studies reveal that cancer cells exploit collagen-consuming stromal cells for survival, exposing an important vulnerability across solid tumors with implications for developing improved anticancer therapy.

A discussion of the gut microbiome's development, determinants, and dysbiosis in cancers of the esophagus and stomach.

The microbiome refers to a population of microbes that colonize the skin, nasopharynx, oral cavity, gastrointestinal tract, and urogenital tract. The human microbiome consists of bacteria, archaea, fungi, viruses, and phages. Recent advances in genomic sequencing have catalyzed a deeper understanding of complex microbe-microbe and host-microbe interactions. Dysregulation of these interactions, or dysbiosis of the gastrointestinal tract, has been implicated in a growing list of pathologies including nonalcoholic fatty liver disease, cardiovascular disease, obesity, diabetes, depression, Parkinson's disease, autism, and various gastrointestinal cancers. Gastric and esophageal cancer, for example, continue to remain as two of the most common causes of cancer-related deaths worldwide, therefore there is an increased emphasis on investigating the role of dysbiosis on these cancers. In this review, we discuss the development and structure of the gut microbiome, its homeostatic and dysbiotic mechanisms, and the key microbes in esophageal and gastric carcinogenesis with a focus on bacterial biology. Further clarification of these pathways and discovery of diagnostic or therapeutic targets could have broad impacts on global subpopulations. It is important to understand the nature of the gastrointestinal tract microbiome and its potentional risk factors for dysbiosis in order to tailor its application to the individual patient and create an era of highly personalized, precision medicine.

Revising the Academy's Research Priorities: Methods of the Research Priorities and Strategies Development Task Force, 2017-2019.

The Academy of Nutrition and Dietetics, as the largest member-based nutrition organization in the world, is dedicated to advancing the world of nutrition and dietetics through research. It is essential for the Academy to identify both current and future research priorities for nutrition and dietetics professionals. To address this, the Academy convened a task force charged with developing research priorities relevant for its members. Specifically, it would define key issues of the nutrition and dietetics profession going into the second century and identify relevant research topics and questions related to the defined issues. The task force leveraged multiple data sources to develop the research priorities. These data sources included existing interviews from a previous Academy event (Nutrition Impact Summit) held in 2016 and answers from an Academy Member Engagement Zone survey. This led to the development of draft research priorities that were included in a more extensive survey e-mailed to all Academy members. Results of this member-wide survey, in addition to multiple stakeholder checks, informed the final Academy research priorities. Thirteen final priorities were established across 4 domains: nutrition-related discovery, clinical nutrition research, implementation science, and public health. These priorities have relevance for all nutrition and dietetics professionals across diverse areas of practice and will be used internally to prioritize research efforts, inform the allocation of resources across Academy units, and guide Academy advocacy for national nutrition research agendas and initiatives. This article will summarize the task force's updated research priorities and detail the 9-step process used to generate them.

Perspective: Dietary Biomarkers of Intake and Exposure-Exploration with Omics Approaches.

While conventional nutrition research has yielded biomarkers such as doubly labeled water for energy metabolism and 24-h urinary nitrogen for protein intake, a critical need exists for additional, equally robust biomarkers that allow for objective assessment of specific food intake and dietary exposure. Recent advances in high-throughput MS combined with improved metabolomics techniques and bioinformatic tools provide new opportunities for dietary biomarker development. In September 2018, the NIH organized a 2-d workshop to engage nutrition and omics researchers and explore the potential of multiomics approaches in nutritional biomarker research. The current Perspective summarizes key gaps and challenges identified, as well as the recommendations from the workshop that could serve as a guide for scientists interested in dietary biomarkers research. Topics addressed included study designs for biomarker development, analytical and bioinformatic considerations, and integration of dietary biomarkers with other omics techniques. Several clear needs were identified, including larger controlled feeding studies, testing a variety of foods and dietary patterns across diverse populations, improved reporting standards to support study replication, more chemical standards covering a broader range of food constituents and human metabolites, standardized approaches for biomarker validation, comprehensive and accessible food composition databases, a common ontology for dietary biomarker literature, and methodologic work on statistical procedures for intake biomarker discovery. Multidisciplinary research teams with appropriate expertise are critical to moving forward the field of dietary biomarkers and producing robust, reproducible biomarkers that can be used in public health and clinical research.

Poverty, obesity, and malnutrition: an international perspective recognizing the paradox.

In the year 2000, multiple global health agencies and stakeholders convened and established eight tenets that, if followed, would make our world a vastly better place. These tenets are called the Millennium Development Goals. Most of these goals are either directly or indirectly related to nutrition. The United Nations has led an evaluation team to monitor and assess the progress toward achieving these goals until 2015. We are midway between when the goals were set and the year 2015. The first goal is to "eradicate extreme poverty and hunger." Our greatest responsibility as nutrition professionals is to understand the ramifications of poverty, chronic hunger, and food insecurity. Food insecurity is complex, and the paradox is that not only can it lead to undernutrition and recurring hunger, but also to overnutrition, which can lead to overweight and obesity. It is estimated that by the year 2015 noncommunicable diseases associated with overnutrition will surpass undernutrition as the leading causes of death in low-income communities. Therefore, we need to take heed of the double burden of malnutrition caused by poverty, hunger, and food insecurity. Informing current practitioners, educators, and policymakers and passing this information on to future generations of nutrition students is of paramount importance.

Cellular proliferation, apoptosis and angiogenesis: molecular targets for nutritional preemption of cancer.

Malignant cells are characterized by abnormal signaling pathways involving proliferation, apoptosis, and angiogenesis. These cancer centric pathways are known to be modified by several bioactive dietary components, although admittedly there are inconsistencies in the response. The response is dependent on the amount and duration of exposure to the dietary component and the cell type. While caution should be exercised when extrapolating in vitro data to in vivo conditions, such studies do provide valuable insights into plausible mechanisms. Significant gene-nutrient and nutrient-nutrient interactions may contribute to the uncertainty of the response to foods and/or their components. One of the challenges is the identification of which process(es), either singly or in combination, is/are most important in leading to a dietary-mediated phenotypic change. The dearth of controlled intervention studies that have investigated molecular targets for nutritional preemption in humans make firm dietary recommendations difficult. Until more definite information surfaces, a balanced but varied diet is most prudent.