Ames, IA, United States
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Horst R.L.,Heartland Assays | Kopp W.,Frederick National Laboratory for Cancer Research | Rager H.,Frederick National Laboratory for Cancer Research
International Journal of Cancer | Year: 2014

The potential role of vitamin D in cancer prevention has generated substantial interest, and laboratory experiments indicate several anti-cancer properties for vitamin D compounds. Prospective studies of circulating 25-hydroxyvitamin D [25(OH)D], the accepted biomarker of vitamin D status, suggest an inverse association with colorectal cancer risk, but with some inconsistencies. Furthermore, the direct or indirect impact of the key transport protein, vitamin D binding protein (DBP), has not been examined. We conducted a prospective study of serum 25(OH)D and DBP concentrations and colorectal cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, based on 476 colorectal cancer cases and 476 controls, matched on age, sex, race and date of serum collection. All subjects underwent sigmoidoscopic screening at baseline and once during follow-up. Conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs). Circulating 25(OH)D was inversely associated with colorectal cancer (OR=0.60, 95% CI 0.38-0.94 for highest versus lowest quintile, p trend 0.01). Adjusting for recognized colorectal cancer risk factors and accounting for seasonal vitamin D variation did not alter the findings. Neither circulating DBP nor the 25(OH)D:DBP molar ratio, a proxy for free circulating 25(OH)D, was associated with risk (OR=0.82, 95% CI 0.54-1.26, and OR=0.79, 95% CI 0.52-1.21, respectively), and DBP did not modify the 25(OH)D association. The current study eliminated confounding by colorectal cancer screening behavior, and supports an association between higher vitamin D status and substantially lower colorectal cancer risk, but does not indicate a direct or modifying role for DBP. © 2014 UICC.


Spoo J.W.,Best Care Pet Hospital | Downey R.L.,Annamaet Petfoods | Griffitts C.,The Traveling Vet | Horst R.J.,Heartland Assays | And 3 more authors.
Journal of Veterinary Internal Medicine | Year: 2015

Background: Dogs are a unique model for examining the effects of exercise on vitamin D status because of their lack of vitamin D synthesis by UV exposure. In addition, the inflammatory response may be associated with hypovitaminosis D. Objectives: To investigate the effects of several days of endurance exercise on plasma vitamin D (25-(OH)D3, 24,25-(OH)D3 and 1,25(OH)D3) and serum C-reactive protein (CRP) concentrations in stage-stop racing sled dogs. Animals: 12 racing sled dogs and 8 control dogs. Methods: Blood was collected before the race and immediately after racing on days 2 and 8. Plasma vitamin D metabolites and serum CRP concentrations were measured. Results: Racing dogs showed a significant increase in 25(OH)D3 on day 2 (P = .027) and day 8 of the race (P < .001), whereas no increases were observed in control dogs. The plasma concentration of 24,25(OH)D3 showed a significant increase by day 8 (P < .001). There were no significant changes in 1,25(OH) D3 concentrations across all time points and groups. Racing dogs had significantly increased CRP concentrations by day 2 (39.3 ± 30.1 μg/mL; P < .001). Conclusions and Clinical Importance: Increases in vitamin D metabolites as well as increases in CRP concentrations were observed in racing sled dogs. This finding was contrary to the hypothesis that decreases in vitamin D status in athletes may be related to the acute phase inflammatory response during exercise. In addition, the increased 24,25(OH)D3 concentrations compared to what is observed in other species suggests metabolic variations in dogs that lead to enhanced disposal of vitamin D. © 2015 The Authors.


Weinstein S.J.,U.S. National Cancer Institute | Horst R.L.,Heartland Assays | Virtamo J.,Finnish National Institute for Health and Welfare | Yu K.,U.S. National Cancer Institute | And 2 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2011

Background: Published studies suggesting a relationship between vitamin D and some common cancers sparked interest in the association of vitamin D with head and neck cancers. Prolonged darker months in Finland are associated with lower levels of ultraviolet B radiation, raising concerns about low vitamin D levels. Methods: We used a nested case-control study in the prospective Alpha-Tocopherol Beta Carotene (ATBC) Study of male smokers in Finland, to examine the relationship between serum 25(OH)D and risk of developing squamous cancers of the head and neck. Using conditional logistic regression, we calculated the multivariate adjusted ORs and CIs comparing those with serum 25(OH)D adequate levels of 50 to <75 nmol/L to those <25.0. Results: We identified incident cancers of the oral cavity (n = 134), pharynx (n = 48), and larynx (n = 158). Median serum vitamin D was 31 nmol/L (interquartile range: 21-48), which is below the 50 nmol/L cutoff point was considered adequate for bone and overall health. Comparing those with serum 25(OH)D below 25 nmol/L to those 50 to <75 nmol/L as the referent, the OR was 1.35 (95% CI: 0.53-3.43, Ptrend = 0.65) for overall head and neck cancers. Stratification by cancer subsites of the oral cavity, pharynx, and larynx (Ptrend = 0.93, 0.78, 0.26, respectively) or by season of blood draw also showed no association. Conclusions: Our study showed no association between serum 25(OH)D and risk of head and neck cancers. Impact: This study does not support the hypothesis that greater vitamin D exposure would reduce the risk of developing head and neck squamous cancers. ©2011 AACR.


Wang Z.,University of Washington | Wong T.,University of Washington | Hashizume T.,Osaka Ohtani University | Dickmann L.Z.,Amgen | And 8 more authors.
Endocrinology | Year: 2014

25-Hydroxyvitamin D3 (25OHD3) is used as a clinical biomarker for assessment of vitamin D status. Blood levels of 25OHD3 represent a balance between its formation rate and clearance by several oxidative and conjugative processes. In the present study, the identity of human uridine 5β-diphosphoglucuronyltransferases (UGTs) capable of catalyzing the 25OHD3 glucuronidation reaction was investigated.Twoisozymes, UGT1A4andUGT1A3, were identified as the principal catalysts of25OHD3 glucuronidation inhumanliver. Three25OHD3 monoglucuronides (25OHD3-25-glucuronide,25OHD3- 3-glucuronide, and 5,6-trans-25OHD3-25-glucuronide) were generated by recombinant UGT1A4/ UGT1A3, human liver microsomes, and human hepatocytes. The kinetics of 25OHD3 glucuronide formation in all systems tested conformed to the Michaelis-Menten model. An association between the UGT1A4*3 (Leu48Val) gene polymorphism with the rates of glucuronide formation was also investigated usinghumanliver microsomes isolated from 80 genotyped livers.Avariant allele dose effect was observed:thehomozygousUGT1A4*3livers(GG) hadthehighestglucuronidationactivity,whereasthe wild type (TT) had the lowest activity. Induction of UGT1A4 and UGT1A3 gene expression was also determined inhumanhepatocytes treated withpregnaneXreceptor/constitutive androstane receptor agonists, such as rifampin, carbamazepine, and phenobarbital. Although UGT mRNA levels were increased significantly by all of the known pregnane X receptor/constitutive androstane receptor agonists tested, rifampin, the most potent of the inducers, significantly induced total25OHD3 glucuronide formation activity in human hepatocytes measured after 2, but not 4 and 24 hours, of incubation. Finally, the presence of 25OHD3-3-glucuronide in both human plasma and bile was confirmed, suggesting that the glucuronidation pathway might be physiologically relevant and contribute to vitamin D homeostasis in humans. Copyright © 2014 by the Endocrine Society.


Asgari M.M.,Kaiser Permanente | Asgari M.M.,University of California at San Francisco | Tang J.,Stanford University | Warton M.E.,Kaiser Permanente | And 9 more authors.
Journal of Investigative Dermatology | Year: 2010

We investigated the association between serum 25-hydroxyvitamin D (25(OH)D) levels and basal cell carcinoma (BCC) risk in a nested case-control study at Kaiser Permanente Northern California (KPNC). A total of 220 case patients with BCC diagnosed after serum collection were matched to 220 control subjects. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression. Fully adjusted models included body mass index (BMI), smoking, education, sun-exposure variables, X-ray exposure, and personal history of cancer. For each measure of serum 25(OH)D (continuous, clinically relevant tertiles, quintiles), we found an increased risk of BCC in unadjusted models (OR=1.03, 95% CI 1.00-1.05, P<0.05; OR=3.98, 95% CI: 1.31-12.31, deficient vs. sufficient, test for trend P-value 0.01; OR=2.32, 95% CI: 1.20-4.50, 1st vs. 5th quintile, test for trend P-value 0.03). In fully adjusted models, the values attenuated slightly (OR=1.02, 95% CI 1.00-1.05, P<0.05; OR=3.61, 95% CI: 1.00-13.10, deficient vs. sufficient, t-trend P<0.03; OR=2.09 1st vs. 5th quintile, 95% CI: 0.95-4.58, t-trend P<0.11). Our findings suggest that higher prediagnostic serum 25(OH)D levels may be associated with increased risk of subsequent BCC. Further studies to evaluate the effect of sun exposure on BCC and serum 25(OH)D levels may be warranted. © 2010 The Society for Investigative Dermatology.


Flohr J.R.,Kansas State University | Tokach M.D.,Kansas State University | Dritz S.S.,Kansas State University | Derouchey J.M.,Kansas State University | And 10 more authors.
Journal of Animal Science | Year: 2014

Four experiments were conducted to investigate the effects of varying concentrations of supplemental vitamin D3 on pig growth, feed preference, serum 25-hydroxycholecalciferol [25(OH)D3], and bone mineralization of nursing and weanling pigs. In Exp. 1, 270 pigs (1.71 ± 0.01 kg BW) were administered 1 of 3 oral vitamin D3 dosages (none, 40,000, or 80,000 IU vitamin D3) on d 1 or 2 of age. Increasing oral vitamin D3 increased serum 25(OH)D3 on d10 and 20 (quadratic, P < 0.01) and d 30 (linear, P < 0.01). No differences were observed in ADG before weaning or for nursery ADG, ADFI, or G:F. Vitamin D3 concentration had no effect on bone ash concentration or bone histological traits evaluated on d 19 or 35. In Exp. 2, 398 barrows (initially 7 d of age) were used in a 2 × 2 split plot design to determine the influence of vitamin D3 before (none or 40,000 IU vitamin D3 in an oral dose) or after weaning (1,378 or 13,780 IU vitamin D3/kg in nursery diets from d 21 to 31 of age) in a 45-d trial. Before weaning (7 to 21 d of age), oral vitamin D3 dose did not influence growth but increased (P < 0.01) serum 25(OH)D3 at weaning (d21) and tended (P = 0.08) to increase 25(OH)D3 on d 31. Increasing dietary vitamin D3 concentration from d 21 to 31 increased (P < 0.01) serum 25(OH)D3 on d31. Neither the oral vitamin D3 dose nor nursery vitamin D3 supplements influenced nursery ADG, ADFI, or G:F. In Exp. 3, 864 pigs (initially 21 d of age) were allotted to 1 of 2 water solubilized vitamin D3 treatments (none or 16,516 IU/L vitamin D3 provided in the drinking water from d 0 to 10) in a 30-d study. Providing vitamin D3 increased serum 25(OH)D3 concentrations on d 10, 20, and 30; however, vitamin D3 supplementation did not affect overall (d 0 to 30) ADG, ADFI, or G:F. In Exp. 4, 72 pigs were used in a feed preference study consisting of 2 feed preference comparisons. Pigs did not differentiate diets containing either 1,378 or 13,780 IU vitamin D3/kg but consumed less (P < 0.01) of a diet containing 44,100 IU vitamin D3/kg compared with the diet containing 1,378 IU vitamin D3/kg. Overall, these studies demonstrate that supplementing vitamin D3 above basal concentrations used in these studies is effective at increasing circulating 25(OH)D3, but the supplement did not influence growth or bone mineralization. Also, concentrations of vitamin D3 of 44,100 IU/kg of the diet may negatively affect feed preference of nursery pigs. © 2014 American Society of Animal Science. All rights reserved.


Mohr S.B.,University of California at San Diego | Mohr S.B.,Naval Health Research Center | Gorham E.D.,University of California at San Diego | Gorham E.D.,Naval Health Research Center | And 8 more authors.
Cancer Causes and Control | Year: 2013

Purpose: The objective of this study was to ascertain whether a relationship exists between pre-diagnostic serum levels of 25-hydroxyvitamin D (25(OH)D) and risk of breast cancer in young women. Methods: About 600 incident cases of breast cancer were matched to 600 controls as part of a nested case-control study that utilized pre-diagnostic sera. Logistic regression was used to assess the relationship between serum 25(OH)D concentration and breast cancer risk, controlling for race and age. Results: According to the conditional logistic regression for all subjects, odds ratios for breast cancer by quintile of serum 25(OH)D from lowest to highest were 1.2, 1.0, 0.9, 1.1, and 1.0 (reference) (p trend = 0.72). After multivariate regression for subjects whose blood had been collected within 90 days preceding diagnosis, odds ratios for breast cancer by quintile of serum 25(OH)D from lowest to highest were 3.3, 1.9, 1.7, 2.6, and 1.0 (reference) (p trend = 0.09). Conclusions: An inverse association between serum 25(OH)D concentration and risk of breast cancer was not present in the principal analysis, although an inverse association was present in a small subgroup analysis of subjects whose blood had been collected within 90 days preceding diagnosis. Further prospective studies of 25(OH)D and breast cancer risk are needed. © 2013 Springer Science+Business Media Dordrecht.


PubMed | Heartland Assays, U.S. National Institutes of Health, Howard University and VA Long Beach Healthcare System
Type: Journal Article | Journal: PloS one | Year: 2016

Higher vitamin D status was not beneficially associated with responses to therapy; if anything, patients with higher vitamin D concentrations were less likely to attain SVR. Our data do not support a role for vitamin D supplementation as an adjuvant therapy for HCV.


Nesterova G.,Human Genome Research Institutes | Malicdan M.C.,Human Genome Research Institutes | Yasuda K.,Toyama Prefectural University | Sakaki T.,Toyama Prefectural University | And 11 more authors.
Clinical Journal of the American Society of Nephrology | Year: 2013

Background and objectives Elevated serum vitamin D with hypercalciuria can result in nephrocalcinosis and nephrolithiasis. This study evaluated the cause of excess 1,25-dihydroxycholecalciferol (1α,25(OH)2D3) in the development of those disorders in two individuals. Design, setting, participants, & measurements Two patients with elevated vitamin D levels and nephrocalcinosis or nephrolithiasis were investigated at the National Institutes of Health (NIH) Clinical Center and the NIH Undiagnosed Diseases Program, by measuring calcium, phosphate, and vitamin D metabolites, and by performing CYP24A1 mutation analysis. Results Both patients exhibited hypercalciuria, hypercalcemia, low parathyroid hormone, elevated vitamin D (1α,25(OH)2D3), normal 25-OHD3, decreased 24,25(OH)2D, and undetectable activity of 1,25(OH)2D-24- hydroxylase (CYP24A1), the enzyme that inactivates 1α,25(OH)2D3. Both patients had bi-allelic mutations in CYP24A1 leading to loss of function of this enzyme. On the basis of dbSNP data, the frequency of predicted deleterious bi-allelic CYP24A1 variants in the general population is estimated to be as high as 4%-20%. Conclusions The results of this study showthat 1,25(OH)2D-24-hydroxylase deficiency due to bi-allelicmutations in CYP24A1 causes elevated serum vitamin D, hypercalciuria, nephrocalcinosis, and renal stones. © 2013 by the American Society of Nephrology.


Olds J.E.,Iowa State University | Burrough E.,Iowa State University | Madson D.,Iowa State University | Ensley S.,Iowa State University | And 8 more authors.
Journal of Zoo and Wildlife Medicine | Year: 2015

The Blank Park Zoo began suffering mortalities in the spring of 2012 within a flock of 229 captive budgerigars (Melopsittacus undulatus) housed in an interactive public-feeding aviary. Clinical signs in affected birds included weakness, posterior paresis, inability to fly, or acute death. Gross and microscopic lesions were not initially apparent in acutely affected deceased birds. Many birds had evidence of trauma, which is now hypothesized to have been related to the birds' weakness. Investigation into the cause(s) of morbidity and mortality were complicated by the opening of a new interactive enclosure. For this reason, environmental conditions and husbandry protocols were heavily scrutinized. Microscopic examination of dead budgies later in the course of the investigation revealed mineralization of soft tissues consistent with hypervitaminosis D. Pooled serum analysis of deceased birds identified elevated vitamin D3 levels. Vitamin D3 analysis was performed on the feed sticks offered by the public and the formulated maintenance diet fed to the flock. This analysis detected elevated levels of vitamin D3 that were 22.5-times the manufacturer's labeled content in the formulated diet. These findings contributed to a manufacturer recall of more than 100 formulated diets fed to a wide variety of domestic and captive wild animal species throughout the United States and internationally. This case report discusses the complexities of determining the etiology of a toxic event in a zoologic institution. Copyright 2015 by American Association of Zoo Veterinarians.

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