Jennifer S. Davis

Poor Adherence to US Dietary Guidelines for Children and Adolescents in the National Health and Nutrition Examination Survey Population

BACKGROUND Poor diet quality in childhood and adolescence is associated with adverse health outcomes throughout life, yet the dietary habits of American children and how they change across childhood and adolescence are unknown. OBJECTIVES This study sought to describe diet quality among children and adolescents by assessing adherence to the 2010 Dietary Guidelines for Americans (DGA) and to determine whether any differences in adherence occurred across childhood. DESIGN, SETTING, AND PARTICIPANTS We employed a cross-sectional design using data from the National Health and Nutrition Examination Survey (NHANES). Of 9,280 children aged 4 to 18 years who participated in NHANES from 2005 to 2010, those with insufficient data on dietary recall (n=852) or who were pregnant or lactating during the time of interview (n=38) were excluded from the final study sample (n=8,390). MAIN OUTCOME MEASURES We measured adherence to the DGA using the Healthy Eating Index 2010 (HEI-2010) and stratified participants into three age groups (4 to 8, 9 to 13, and 14 to 18 years of age). We analyzed each of 12 HEI-2010 components and total HEI-2010 score. RESULTS The youngest children had the highest overall diet quality due to significantly greater scores for total fruit, whole fruit, dairy, and whole grains. These children also had the highest scores for sodium, refined grains, and empty calories. Total HEI-2010 scores ranged from 43.59 to 52.11 out of 100, much lower than the minimum score of 80 that is thought to indicate a diet associated with good health. CONCLUSIONS Overall, children and adolescents are failing to meet the DGA and may be at an increased risk of chronic diseases throughout life. By analyzing which food groups show differences between age groups, we provide data that can inform the development of dietary interventions to promote specific food groups targeting specific ages and improve diet quality among children and adolescents.

Immunoglobulin Fc Domain Fusion to TRAIL Significantly Prolongs Its Plasma Half-Life and Enhances Its Antitumor Activity

TRAIL (Apo2L) is a potent inducer of cell death. Interest in TRAIL has increased, following the observation that TRAIL can selectively kill a wide variety of human cancer cells without killing normal cells both in vitro and when grown as xenografts. Therefore, TRAIL has been proposed as a promising anticancer agent and currently is being tested in clinical trials. However, recombinant TRAIL has a very short plasma half-life, which limits its therapeutic potential. To overcome this limitation, we investigated the ability of the human IgG1 fragment crystallizable region (Fc) to enhance TRAIL stability. In this report, we show that Fc-TRAIL chimeric protein displays higher specific activity in vitro and a significantly longer half-life in mice than recombinant human TRAIL (rh-TRAIL). No short-term toxicity, especially liver toxicity, was observed. More importantly, Fc-TRAIL was much more effective in inhibiting tumor growth in a xenograft tumor model compared with rh-TRAIL. Our data suggest that fusion of Fc to TRAIL is able to improve the bioavailability and activity of TRAIL both in vitro and in vivo, and Fc-TRAIL may be explored for future clinical applications in cancer treatment and prevention. Mol Cancer Ther; 13(3); 643–50. ©2014 AACR.

Streptococcus gallolyticus subsp. gallolyticus promotes colorectal tumor development

Streptococcus gallolyticus subsp. gallolyticus (Sg) has long been known to have a strong association with colorectal cancer (CRC). This knowledge has important clinical implications, and yet little is known about the role of Sg in the development of CRC. Here we demonstrate that Sg promotes human colon cancer cell proliferation in a manner that depends on cell context, bacterial growth phase and direct contact between bacteria and colon cancer cells. In addition, we observed increased level of β-catenin, c-Myc and PCNA in colon cancer cells following incubation with Sg. Knockdown or inhibition of β-catenin abolished the effect of Sg. Furthermore, mice administered with Sg had significantly more tumors, higher tumor burden and dysplasia grade, and increased cell proliferation and β-catenin staining in colonic crypts compared to mice receiving control bacteria. Finally, we showed that Sg is present in the majority of CRC patients and is preferentially associated with tumor compared to normal tissues obtained from CRC patients. These results taken together establish for the first time a tumor-promoting role of Sg that involves specific bacterial and host factors and have important clinical implications.

Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention

After more than a century, aspirin remains one of the most commonly used drugs in western medicine. Although mainly used for its anti-thrombotic, anti-pyretic, and analgesic properties, a multitude of clinical studies have provided convincing evidence that regular, low-dose aspirin use dramatically lowers the risk of cancer. These observations coincide with recent studies showing a functional relationship between platelets and tumors, suggesting that aspirin’s chemopreventive properties may result, in part, from direct modulation of platelet biology and biochemistry. Here, we present a review of the biochemistry and pharmacology of aspirin with particular emphasis on its cyclooxygenase-dependent and cyclooxygenase-independent effects in platelets. We also correlate the results of proteomic-based studies of aspirin acetylation in eukaryotic cells with recent developments in platelet proteomics to identify non-cyclooxygenase targets of aspirin-mediated acetylation in platelets that may play a role in its chemopreventive mechanism.

In cross-sectional observations, dietary quality is not associated with CVD risk in women; in men the positive association is accounted for by BMI.

The role that BMI plays in the association between dietary quality and CVD risk is not known. We aimed to better understand this relationship using statistical methods which correct for sex-specific underreporting of dietary intake. Overall, dietary quality was assessed using the Healthy Eating Index (HEI) on data from 9797 non-pregnant adults (aged >20 years) who participated in the National Health and Nutrition Examination Survey from 2005 to 2010. CVD risk factors included blood pressure, fasting glucose and insulin, homeostatic models of insulin resistance (HOMA-IR), HDL- and LDL-cholesterol (HDL-C and LDL-C), TAG and C-reactive protein (CRP). We controlled for demographic and lifestyle covariates, and we used the population ratio approach (which adjusts for the underreporting of intake) to compare mean HEI scores between the top and bottom quartiles of covariate-adjusted CVD risk factors. In women, the total HEI score was not associated with any CVD risk factors (all Q>0·11). In men, the total HEI score was associated with covariate-adjusted residuals for fasting insulin (Q<0.001), HOMA-IR (Q<0.001), HDL-C (Q=0.01) and CRP (Q<0.001). When we additionally adjusted for BMI, the association with total HEI score was not significant (all P>0.10). In the present analyses, dietary quality was associated with five CVD risk factors in a sex-specific manner. Moreover, the association of BMI with CVD risk attenuated the relationship between CVD risk and diet, which suggests that BMI is an important factor in heart disease prevention.

The potential role of platelets in the consensus molecular subtypes of colorectal cancer

The consensus molecular subtypes (CMS) in colorectal cancer (CRC) represent distinct molecular subcategories of disease as reflected by comprehensive molecular profiling. The four CMS subtypes represent unique biology. CMS1 represents high immune infiltration. CMS2 demonstrates upregulation of canonical pathways such as WNT signaling. Widespread metabolic changes are seen in CMS3. CMS4 represents a mesenchymal phenotype with hallmark features including complement activation, matrix remodeling, angiogenesis, epithelial-mesechymal transition (EMT), integrin upregulation and stromal infiltration. In contrast to this new paradigm, a number of observations regarding CRC remain disconnected. Cancers are associated with thrombocytosis. Venous thromboembolic events are more likely in malignancy and may signify worse prognosis. Aspirin, an anti-platelet agent, has been linked in large observational studies to decrease incidence of adenocarcinoma and less advanced presentations of cancer, in particular CRC. Inflammatory bowel disease is a risk factor for CRC. Gross markers to recognize the immunothrombotic link such as the platelet to lymphocyte ratio are associated with poorer outcomes in many cancers. Platelets are increasingly recognized for their dual roles in coordinating the immune response in addition to hemostasis. Here, we explore how these different but related observations coalesce. Platelets, as first responders to pathogens and injury, form the link between hemostasis and immunity. We outline how platelets contribute to tumorigenesis and how some disconnected ideas may be linked through inflammation. CMS4 through its shared mechanisms has predicted platelet activation as a hallmark feature. We demonstrate a platelet gene expression signature that predicts platelet presence within CMS4 tumors.

Use of non-steroidal anti-inflammatory drugs in US adults: changes over time and by demographic

Objective Aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) are preventive against cardiovascular disease (CVD) and several cancer types, but long-term use has been associated with significant health risks, resulting in conflicting recommendations on NSAID use for prevention of CVD and cancer. Previous research indicates that aspirin use increases with age and CVD risk factors and that a large percentage of the US population regularly use analgesics, including NSAIDs, but there has not been a recent, in-depth assessment of NSAID use prevalence, changes in use over time or predictors of NSAID use in the USA. Methods We used the cross-sectional, National Health And Nutrition Examination Survey (NHANES) from 1988 to 1994 and three continuous cycles (1999–2004) to assess regular NSAID use prevalence, changes over time and predictors of regular NSAID use. Results Overall, regular NSAID use increased over time and varied by demographic features. Participants over 60 years of age, women, participants with high body mass index, increased waist circumference or heart disease were significantly more likely to be regular NSAID users. By contrast, non-Hispanic African American and Mexican American participants were significantly less likely to regularly use NSAIDs. Conclusions This study uses a nationally representative data set (NHANES) to provide an exploration of regular NSAID use patterns over time, highlighting several demographic, lifestyle and clinical conditions associated with regular NSAID use. Understanding who is likely to regularly use NSAIDs enables more targeted messaging both for increasing the preventive benefits and for limiting the toxicities associated with regular use of NSAIDs.

Platelets: “First Responders” in Cancer Progression and Metastasis

A long-standing postulate in oncology is that platelets facilitate cancer metastasis (Menter et al. Cancer Metastasis Rev 33:231–269, 2014; Menter et al. Invasion Metastasis 7:109–128, 1987; Gasic et al. Proc Natl Acad Sci USA 61:46–52, 1968; Woods Bulletin der Schweizerischen Akademie der Medizinischen Wissenschaften 20:92–121, 1964). As their most critical biological response, platelets serve as “first responders” during the wounding process and hemostasis. As a part of the metastatic process, platelet receptors recognize complexes of tumor cell receptors and surface-bound matrix proteins or cellular products as they invade blood vessels. This recognition triggers platelet activation and platelet-tumor cell interactions. Once activated by tumor cells, platelets change shape, degranulate, and release proteins, growth factors, bioactive lipids, and other factors that recruit additional platelets and immune cells along with initiating thrombogenesis. Extensive membrane changes occur at bilayer interfaces between platelets and tumor cells. Tumor cells form extensive membrane/cytoskeletal processes that heavily interdigitate with a central platelet aggregate and involves the uptake of platelet fragments and mitochondria. These interactions are thought to result in the suppression of immune recognition/cytotoxicity or the promotion of cell arrest at the endothelium or entrapment in the microvasculature. These responses all support survival and spread of cancer cells and the establishment of secondary lesions. Additional mechanisms of the platelet-metastasis relationship may include the production of platelet exosomes or extravascular migratory behavior of platelets helping to drive cancer progression or preconditioning of secondary metastatic sites. In contrast to the many mechanisms involved in platelet-metastasis relationships, little is known about the role of platelets in precancerous lesion development. This paucity of knowledge exists despite numerous large randomized clinical trials illustrating the cancer preventive effects of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin in reducing the cancer incidence, mortality, and metastasis. Aspirin covalently acetylates and inactivates platelet cyclooxygenase 1 and thereby eliminates all downstream prostaglandin production from arachidonic acid (AA) by platelets. This includes the key bioactive lipid involved in platelet activation, thromboxane A2 (TxA2). Another prostaglandin, prostacyclin (PGI2), counterbalances and inhibits platelet activation (Honn et al. Science 212:1270–1272, 1981). Metabolically, the genesis of TxA2 and other bioactive lipids are also impacted by ω-3 polyunsaturated fatty acid substrate substitution for AA. Although not well studied, this places platelets not only at the center of the metastasis discussion but also the progression of premalignancies. Since neoangiogenesis produces leaky blood vessels during early cancer progression, it stands to reason that platelets are the “first responders” to extravasate, activate, and release their stroma-stimulating, proangiogenic, chemoattractive, and immunomodulatory contents. These normal platelet functions and products undoubtedly promote precancerous lesion progression as a series of cyclic amplification events. Platelets are suspected to have a key role within the full spectrum of the cancer progression continuum, which makes limiting their first response an important target for both prevention and therapy.

Avelumab: A Review of Its Application in Metastatic Merkel Cell Carcinoma:

Objective: To summarize the clinical development of avelumab and its clinical relevance in metastatic Merkel cell carcinoma (MCC). Data Sources: An English-language literature search using PubMed was performed using the terms avelumab, anti-PD-1, anti-PD-L1, and MCC from January of 1950 to March 2018. Data were also obtained from package inserts, meeting abstracts, and clinical registries. Study Selection/Data Extraction: All relevant published articles of avelumab were reviewed. Clinical trial registries and meeting abstracts were used for information about ongoing trials. Data Synthesis: Avelumab is a fully human monoclonal antibody that inhibits programmed death ligand-1, which reverses T-cell exhaustion and induces antitumor responses. Avelumab is safe and effective in previously treated metastatic MCC based on a phase II trial of previously treated patients with objective response rates in 28 of 88 patients, including 10 complete responses and 19 partial responses. Median overall survival (OS) was 12.9 months, and 1-year progression-free survival and OS were 30% and 52%, respectively. Grade 3 treatment-related side effects included lymphopenia (2 patients), serum creatine phosphokinase increase (1 patient), aminotransferase elevation (1 patient), and serum cholesterol increase (1 patient). Relevance to Patient Care and Clinical Practice: This review outlines the pharmacology and clinical trial data for avelumab in metastatic MCC and guides clinicians on avelumab’s place in therapy. Conclusions: Avelumab is the first Food and Drug Administration–approved medication for metastatic MCC and provides an advantage of durable responses and possibly improved tolerability compared with traditional platinum-based chemotherapy. Clinical trials are under way to expand its utility into the adjuvant and frontline settings.

An advanced histologic method for evaluation of intestinal adenomas in mice using digital slides

Background and Methods Mice are used for modelling the biology of many human diseases, including colorectal cancer (CRC). Mouse models recapitulate many aspects of human disease and are invaluable tools for studying the biology, treatment and prevention of CRC. Unlike humans, many mouse models develop lesions primarily in the small intestine, which necessitates removal and examination of this organ in order to evaluate treatment efficacy. Commonly, the small intestine is visually examined for gross lesions and then selectively embedded in paraffin blocks for further microscopic analysis. Unfortunately, this method suffers from inherent bias toward counting large lesions and simultaneously missing smaller lesions. Even more, this method leaves no permanent record of diagnosed and measured lesions. We evaluated inter-observer variability in a mouse model of CRC using visual examination, and directly compared the visual, gross examination with a histologic analytic method using digital slides of hematoxylin and eosin stained tissue sections. Results Using visual examination, there was a high degree of inter-observer variability. As this method does not provide a permanent record of measurements, there is no capability to arbitrate between differing observations. In contrast, histologic analysis allowed for the creation of a permanent record of lesion measurements taken. When compared directly, histologic analysis of annotated digital images has significantly improved accuracy. Using this method we were able to distinguish mutant mice from wild type littermates even at a very young age. With gross visual examination, this distinction was not possible. Conclusion Histologic analysis of digital images of murine intestinal tissue provides a vital improvement over the commonly used visual, gross examination method. Unlike visual gross examination, histologic analysis is not biased by the size of intestinal adenoma, misdiagnosis of another lesion type, or presence of a Peyer’s patch. It also provides accountability in the form of a permanent record of lesions counted. Histologic analysis using digital slides represents a critical improvement over the current, widely used method of visual gross examination and should be considered for future studies using mouse models of CRC.