Citations

AbstractThe biological role of vitamin D receptors (VDR), which are abundantly expressed in developing zebrafish (Danio rerio) as early as 48 h after fertilization, and before the development of a mineralized skeleton and mature intestine and kidney, is unknown. We probed the role of VDR in developing zebrafish biology by examining changes in expression of RNA by whole transcriptome shotgun sequencing (RNA-seq) in fish treated with picomolar concentrations of the VDR ligand and hormonal form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3)].We observed significant changes in RNAs of transcription factors, leptin, peptide hormones, and RNAs encoding proteins of fatty acid, amino acid, xenobiotic metabolism, receptor-activator of NFκB ligand (RANKL), and calcitonin-like ligand receptor pathways. Early highly restricted, and subsequent massive changes in more than 10% of expressed cellular RNA were observed. At days post fertilization (dpf) 2 [24 h 1α,25(OH)2D3-treatment], only four RNAs were differentially expressed (hormone vs. vehicle). On dpf 4 (72 h treatment), 77 RNAs; on dpf 6 (120 h treatment) 1039 RNAs; and on dpf 7 (144 h treatment), 2407 RNAs were differentially expressed in response to 1α,25(OH)2D3. Fewer RNAs (n = 481) were altered in dpf 7 larvae treated for 24 h with 1α,25(OH)2D3vs. those treated with hormone for 144 h. At dpf 7, in 1α,25(OH)2D3-treated larvae, pharyngeal cartilage was larger and mineralization was greater. Changes in expression of RNAs for transcription factors, peptide hormones, and RNAs encoding proteins integral to fatty acid, amino acid, leptin, calcitonin-like ligand receptor, RANKL, and xenobiotic metabolism pathways, demonstrate heretofore unrecognized mechanisms by which 1α,25(OH)2D3 functions in vivo in developing eukaryotes.

Abstract Background and Aims: In patients with Barrett's esophagus (BE), reflux-induced injury promotes esophageal adenocarcinoma, presumably through cyclooxygenase 2 (COX-2) related pathways. Proton pump inhibitors (PPIs) and nonsteroidal anti-inflammatory drugs (NSAIDs) may interrupt reflux-associated carcinogenesis by reducing acid exposure and subsequent inflammation. However, clinical trial data regarding the chemopreventive efficacy of a PPI + NSAID combination are limited. The aim of this multi-center, randomized, phase II trial was to assess the effects of a 28-day intervention with esomeprazole 40 mg bid and aspirin 81 mg qd, 325 mg qd, or placebo qd on tissue prostaglandin E2 (PGE2) concentrations in BE patients. Methods: Using the infrastructure of the Cancer Prevention Network, participants (> 18 years) with histologically confirmed non dysplastic BE were randomly assigned to receive one of three interventions for 28 days: (arm A) esomeprazole 40 mg bid+ aspirin 81 mg placebo qd + aspirin 325 mg placebo qd (n=42); (arm B) esomeprazole 40 mg bid+ aspirin 81 mg qd + aspirin placebo 325 qd (n=63); (arm C) esomeprazole 40 mg bid + aspirin 81 mg qd placebo + aspirin 325 mg qd (n=63). Esophageal biopsies were obtained pre- and post-intervention to assess change in PGE2 concentration as the primary endpoint. Results: In total, 122 participants were randomized, 121 (99%) completed the trial per protocol, and 115 (94%) were evaluated for the primary endpoint. Baseline characteristics were similar across intervention arms. The absolute change (mean + SD) in tissue PGE2 concentration was −67.6 (229.68) in Arm A, −120.9 (281.28) in Arm B (p = 0.10 vs Arm A) and −174.9 (263.62) in Arm C (p = 0.02 vs Arm A). Conclusions: In combination with esomeprazole 40 mg twice per day, aspirin 325 mg per day significantly reduced tissue PGE2 concentration in BE patients after a 28-day intervention, as compared to aspirin placebo. Given the relevance of PGE2 pathways in BE-associated carcinogenesis, further evaluation of this chemoprevention strategy in larger, more definitive phase III trials is warranted. Citation Information: Cancer Prev Res 2011;4(10 Suppl):CN06-03.

BackgroundNumerous studies have demonstrated the ability of angiotensin II (Ang II) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors to inhibit intimal hyperplasia after balloon dilatation of noncoronary arteries in small-animal models, suggesting an important role for Ang II in the response to injury. Although ACE inhibitors have not been similarly effective in nonhuman coronary models or in human restenosis trials, questions remain regarding the efficacy of ACE inhibitors against tissue ACE and the contributions of ACE-independent pathways of Ang II generation. Unlike ACE inhibitors, Ang II receptor antagonists have the potential to inhibit responses to Ang II independent of its biosynthetic origin.Methods and ResultsIn separate studies, three Ang II receptor antagonists, including AT1-selective (L-158,809), balanced AT1/AT2(L-163,082), and AT2-selective (L-164,282) agents, were evaluated for their ability to inhibit vascular intimal thickening in a porcine coronary artery model of vascular injury. Preliminary studies in a rat carotid artery model revealed that constant infusion of L-158,809 (0.3 or 1.0 mg·kg−1·d−1) reduced the neointimal cross-sectional area by up to 37% measured 14 days after balloon dilatation. In the porcine studies, animals were treated with vehicle or test compound beginning 2 days before and extending 28 days after experimental angioplasty. Left anterior descending, left circumflex, and/or right coronary arteries were injured by inflation of commercially available angioplasty balloons with placement of coiled metallic stents. Infusion of L-158,809 (1 mg·kg−1·d−1), L-163,082 (1 mg·kg−1·d−1), or L-164,282 (1.5 mg·kg−1·d−1) in the study animals yielded plasma drug levels sufficient either to chronically block or, for L-164,282, to spare pressor responses to exogenous Ang II. Neither L-158,809, L-163,082, nor L-164,282 had statistically significant effects (P=.12,P=.75, andP=.48, respectively, compared with vehicle-treated controls) on neointimal thickness (normalized for degree of injury) measured by morphometric analysis at day 28 after angioplasty.ConclusionsThese findings indicate that chronic blockade of Ang II receptors by either site-selective or balanced AT1/AT2antagonists is insufficient to inhibit intimal hyperplasia after experimental coronary vascular injury in the pig. The results further suggest that, unlike in the rat carotid artery, Ang II is not a major mediator of intimal thickening in the pig coronary artery.

Studies have examined how individual risk factors affect unmet health needs, but few have assessed how factors combine to create compounded risk. Using administrative and survey data from 1,897 publicly insured individuals in Minnesota, this study examines how diagnosed depression—a condition with established functional morbidity—moderates the association between seven common access barriers (e.g., transportation problems, lack of child care, clinic hours) and self-reported unmet health needs. Depression and access barriers were independently, positively associated with unmet need. Depression moderated barriers’ effects: Number of barriers reported had a stronger association with unmet need for individuals with depression. Depressed individuals reporting all barriers had a 70 percent chance of unmet need. Subgroup differences for individual barriers suggest that depressed individuals’ utilization patterns and functional limitations may shape their reactions to access barriers. Findings may inform improvements in public benefit designs and target the unique vulnerabilities associated with depression.

Current genome‐wide association studies still heavily rely on a single‐marker strategy, in which each single nucleotide polymorphism (SNP) is tested individually for association with a phenotype. Although methods and software packages that consider multimarker models have become available, they have been slow to become widely adopted and their efficacy in real data analysis is often questioned. Based on conducting extensive simulations, here we endeavor to provide more insights into the performance of simple multimarker association tests as compared to single‐marker tests. The results reveal the power advantage as well as disadvantage of the two‐ vs. the single‐marker test. Power differentials depend on the correlation structure among tag SNPs, as well as that between tag SNPs and causal variants. A two‐marker test has relatively better performance than single‐marker tests when the correlation of the two adjacent markers is high. However, using HapMap data, two‐marker tests tended to have a greater chance of being less powerful than single‐marker tests, due to constraints on the number of actual possible haplotypes in the HapMap data. Yet, the average power difference was small whenever the one‐marker test is more powerful, while there were many situations where the two‐marker test can be much more powerful. These findings can be useful to guide analyses of future studies. Genet. Epidemiol. 36:480‐487, 2012. © 2012 Wiley Periodicals, Inc.

Abstract Skeletal muscle and bone form highly-integrated systems that undergo significant age-related changes, but the relationships between muscle mass and trabecular versus cortical bone or trabecular microarchitecture have not been systematically investigated. Thus, we examined the association between appendicular skeletal muscle mass (ASM) relative to height squared (relative ASM) and bone parameters at several sites assessed by conventional as well as high-resolution peripheral QCT in a cohort of 272 women and 317 men aged 20 to 97 years. In women, relative ASM was associated with cortical thickness (CtTh) at the femoral neck, lumbar spine, radius, and tibia (age-and physical activity adjusted r = 0.19–0.32; all p < 0.01). Relative ASM was also associated with trabecular volumetric bone mineral density (vBMD) at the femoral neck and spine (all p < 0.05), and trabecular bone volume to tissue volume (BV/TV), number (TbN), thickness (TbTh), and separation (TbSp) at the radius (all p ≤ 0.05). In all men, relative ASM was associated with CtTh at all sites (age- and physical activity–adjusted r = 0.17–0.28; all p < 0.01). Associations between relative ASM and trabecular vBMD at the spine in men were lost after adjusting for age; however, relative ASM was associated with trabecular vBMD at the femoral neck and TbN and TbSp at the radius (all p < 0.01). We also investigated circulating factors associated with bone health that may be indicative of relative ASM and found that serum insulin-like growth factor (IGF) binding protein-2 (IGFBP-2) levels were the most robust negative predictors of relative ASM in both sexes. Collectively, these data add to the growing body of evidence supporting the highly-integrated nature of skeletal muscle and bone, and provide new insights into potential biomarkers that reflect the health of the musculoskeletal system. © 2012 American Society for Bone and Mineral Research.

Abstract Purpose: Obesity is associated with an increased risk of colon cancer. However, the influence of body mass index (BMI) upon the outcome of colon cancer survivors and its relationship to gender remains unknown. Experimental Design: BMI (kg/m2) was calculated and categorized in patients with TNM stage II and III colon carcinomas (n= 4,381) enrolled in 7 randomized trials of 5-fluorouracil-based adjuvant chemotherapy. Cox proportional hazards modeling was used to determine the association of BMI with disease-free and overall survival. Results: Among colon cancer patients, 868 (20%) were obese (BMI ≥30 kg/m2) of which 606 were class 1 (BMI 30–34 kg/m2) and 262 were class 2,3 (BMI ≥35 kg/m2). Obese versus normal-weight patients were more likely to be younger, have distal tumors, show intact DNA mismatch repair (MMR), and have increased lymph node metastases (p <0.017). The association of BMI and MMR status was dependent upon patient age (p= 0.031). In a multivariate analysis, BMI was significantly associated with both disease-free (p=0.030) and overall survival (p=0.0017). Men with class 2,3 obesity showed reduced overall survival compared to normal weight men [HR 1.35 (1.02, 1.79); p=0.039]. Women with class I obesity had reduced overall survival [HR 1.24 (1.01, 1.53), p=0.045] compared to normal weight women. BMI was not predictive of therapeutic benefit. Conclusions: Obesity is associated with intact DNA mismatch repair status and was an adverse, independent prognostic variable in colon cancer survivors. Interventions to reduce obesity have the potential to improve patient outcomes in colon cancer survivors. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B111.