Post-treatment levels of plasma 25- and 1,25-dihydroxy vitamin D and mortality in men with aggressive prostate cancer.

Vitamin D may reduce mortality from prostate cancer (PC). We examined the associations of post-treatment plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations with PC mortality. Participants were PC cases from the New South Wales Prostate Cancer Care. All contactable and consenting participants, at 4.9 to 8.6 years after diagnosis, were interviewed and had plasma 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) measured in blood specimens. Cox regression allowing for left-truncation was used to calculate adjusted mortality hazards ratios (HR) and 95% confidence intervals (95% CI) for all-cause and PC-specific mortality in relation to vitamin D levels and other potentially-predictive variables. Of the participants (n = 111; 75·9% response rate), there were 198 deaths from any cause and 41 from PC in the study period. Plasma 25(OH)D was not associated with all-cause or PC-specific mortality (p-values > 0·10). Plasma 1,25(OH)2D was inversely associated with all-cause mortality (HR for highest relative to lowest quartile = 0·45; 95% CI: 0·29-0·69), and PC-specific mortality (HR = 0·40; 95% CI: 0·14-1·19). These associations were apparent only in men with aggressive PC: all-cause mortality HR = 0·28 (95% CI·0·15-0·52; p-interaction = 0·07) and PC-specific mortality HR = 0·26 (95% CI: 0·07-1.00). Time spent outdoors was also associated with lower all-cause (HR for 4th relative to 1st exposure quartile = 0·42; 95% CI: 0·24-0·75) and PC-specific (HR = 0·48; 95% CI: 0·14-1·64) mortality, although the 95% CI for the latter was wide. The inverse association between post-treatment plasma 1,25(OH)2D levels and all-cause and PC-specific mortality in men with aggressive PC, suggest a possible beneficial effect of vitamin D supplementation in these men

Actin Nemaline Myopathy Mouse Reproduces Disease, Suggests Other Actin Disease Phenotypes and Provides Cautionary Note on Muscle Transgene Expression

Mutations in the skeletal muscle α-actin gene (ACTA1) cause congenital myopathies including nemaline myopathy, actin aggregate myopathy and rod-core disease. The majority of patients with ACTA1 mutations have severe hypotonia and do not survive beyond the age of one. A transgenic mouse model was generated expressing an autosomal dominant mutant (D286G) of ACTA1 (identified in a severe nemaline myopathy patient) fused with EGFP. Nemaline bodies were observed in multiple skeletal muscles, with serial sections showing these correlated to aggregates of the mutant skeletal muscle α-actin-EGFP. Isolated extensor digitorum longus and soleus muscles were significantly weaker than wild-type (WT) muscle at 4 weeks of age, coinciding with the peak in structural lesions. These 4 week-old mice were ∼30% less active on voluntary running wheels than WT mice. The α-actin-EGFP protein clearly demonstrated that the transgene was expressed equally in all myosin heavy chain (MHC) fibre types during the early postnatal period, but subsequently became largely confined to MHCIIB fibres. Ringbinden fibres, internal nuclei and myofibrillar myopathy pathologies, not typical features in nemaline myopathy or patients with ACTA1 mutations, were frequently observed. Ringbinden were found in fast fibre predominant muscles of adult mice and were exclusively MHCIIB-positive fibres. Thus, this mouse model presents a reliable model for the investigation of the pathobiology of nemaline body formation and muscle weakness and for evaluation of potential therapeutic interventions. The occurrence of core-like regions, internal nuclei and ringbinden will allow analysis of the mechanisms underlying these lesions. The occurrence of ringbinden and features of myofibrillar myopathy in this mouse model of ACTA1 disease suggests that patients with these pathologies and no genetic explanation should be screened for ACTA1 mutations

The Future of Liquid Chromatographic Separations Should Include Post Column Derivatisations: The perspective from the analysis of vitamin D

The coupling of high performance liquid chromatography (HPLC) with post column derivatisation (HPLC-PCD) will increase the sensitivity of an instrument to the target molecule, improve specificity by selective derivatisation to remove potential interferences from the matrix, and be cost-effective; all these factors may well prove that PCD is an alternative to existing techniques for routine analysis. Calcidiol (25(OH)D) concentrations are used in the determination of vitamin D deficiency in humans, and there is growing interest and demand in its analysis with some controversy surrounding the sensitivity and specificity of its detection. 25(OH)D analysis is currently performed using either competitive binding assays or HPLC analysis, coupled with detection by a variety of means, such as, UV–Vis absorption, electrochemical or mass spectroscopy (MS) detection. HPLC coupled with MS (HPLC-MS) detection is the gold standard for 25(OH)D analysis due to its sensitivity and selectivity compared to all other techniques, however, its utility is limited by its high cost. This article reviews the current status of HPLC based techniques in the detection of 25(OH)D (and its metabolites), and further explores the use of HPLC-PCD

Does vitamin D protect against DNA damage?

Vitamin D is a secosteroid best known for its role in maintaining bone and muscle health. Adequate levels of vitamin D may also be beneficial in maintaining DNA integrity. This role of vitamin D can be divided into a primary function that prevents damage from DNA and a secondary function that regulates the growth rate of cells. The potential for vitamin D to reduce oxidative damage to DNA in a human has been suggested by clinical trial where vitamin D supplementation reduced 8-hydroxy-2'-deoxyguanosine, a marker of oxidative damage, in colorectal epithelial crypt cells. Studies in animal models and in different cell types have also shown marked reduction in oxidative stress damage and chromosomal aberrations, prevention of telomere shortening and inhibition of telomerase activity following treatment with vitamin D. The secondary function of vitamin D in preventing DNA damage includes regulation of the poly-ADP-ribose polymerase activity in the DNA damage response pathway involved in the detection of DNA lesions. It is also able to regulate the cell cycle to prevent the propagation of damaged DNA, and to regulate apoptosis to promote cell death. Vitamin D may contribute to prevention of human colorectal cancer, though there is little evidence to suggest that prevention of DNA damage mediates this effect, if real. Very limited human data mean that the intake of vitamin D required to minimise DNA damage remains uncertai

Personal Sun Exposure and Serum 25-hydroxy Vitamin D Concentrations

Solar ultraviolet-B radiation (UVB) is essential for epidermal vitamin D production. We aimed to quantitate the relationship between personal solar UV exposure and serum 25hydroxy vitamin D (25[OH]D) concentration. Blood was collected for 25(OH)D analysis in 207 South Australian adults aged 27-61 years. At the time of blood collection, each participant completed a questionnaire, which included a calendar for recall of sun exposure in the preceding 16 weeks. We examined the association between solar UV exposure and serum 25(OH)D graphically from smoothed scatter plots, and modeled it using multiple linear regression, with age, sex and body mass index as covariates. Estimated erythemal solar UV exposure in the 6 weeks before blood collection best predicted serum 25(OH)D concentrations. Serum 25(OH)D rose with increasing personal solar UV exposure to a maximum of about 89 nmol L(-1) at an estimated mean weekly solar erythemal UV exposure of about 1230 mJ cm(-2) . The maximum was the same after accounting for clothing coverage and was reached at an estimated whole body equivalent exposure to ambient UV of ca 700 mJ cm(-2) . These results suggest that an average maximum serum 25(OH)D of ca 89 nmol L(-1) is achieved from sun exposure in a healthy Australian adult populatio

The association between personal sun exposure, serum vitamin D and global methylation in human lymphocytes in a population of healthy adults in South Australia

BACKGROUND: There is a positive association between solar UV exposure and micronucleus frequency in peripheral blood lymphocytes (PBL) and this association may be stronger when serum vitamin D (25(OH)D) levels are insufficient (<50 nmol/L). Micronucleus formation can result from global hypomethylation of DNA repeat sequences. The aim of this analysis was to evaluate the relationship between solar UV exposure and methylation pattern in LINE-1 repetitive elements in PBL DNA and to see if serum 25(OH)D levels modify it. METHOD: Personal solar UV exposure was estimated from hours of outdoor exposure over 6 weeks recalled at the time of blood collection in 208 male and female participants living in South Australia. Methylation in LINE-1 repetitive elements was assessed in PBL using pyrosequencing. RESULTS: Methylation in LINE-1 decreased with increasing solar UV exposure (% decrease = 0.5% per doubling of sUV; 95%CI: -0.7 to -0.2 p(value) = 0.00003). Although there was no correlation between LINE-1 methylation and micronucleus frequency, there was a 4.3% increase (95%CI: 0.6-8.1 p-value = 0.02) in nucleoplasmic bridges and a 4.3% increase in necrosis (CI: 1.9-6.8 p-value = 0.0005) for every 1% increase in LINE-1 methylation. Serum 25(OH)D was not associated with DNA methylation; or did it modify the association of solar UV with DNA methylation. CONCLUSION: Exposure to solar UV radiation may reduce DNA methylation in circulating lymphocytes. This association does not appear to be influenced or mediated by vitamin D status

The association between personal sun exposure, serum vitamin D and global methylation in human lymphocytes in a population of healthy adults in South Australia

Abstract not availableVisalini Nair-Shalliker, Varinderpal Dhillon, Mark Clements, Bruce K. Armstrong, Michael Fenec

Obesity, physical activity and cancer risks: Results from the Cancer, Lifestyle and Evaluation of Risk Study (CLEAR)

Introduction Physical activity (PA) has been associated with lower risk of cardiovascular diseases, but the evidence linking PA with lower cancer risk is inconclusive. We examined the independent and interactive effects of PA and obesity using body mass index (BMI) as a proxy for obesity, on the risk of developing prostate (PC), postmenopausal breast (BC), colorectal (CRC), ovarian (OC) and uterine (UC) cancers. Methods We estimated odds ratios (OR) and 95% confidence intervals (CI), adjusting for cancer specific confounders, in 6831 self-reported cancer cases and 1992 self-reported cancer-free controls from the Cancer Lifestyle and Evaluation of Risk Study, using unconditional logistic regression. Results For women, BMI was positively associated with UC risk; specifically, obese women (BMI ≥30 kg/m2) had nearly twice the risk of developing UC compared to women with healthy-BMI-range (<25 kg/m2) (OR = 1.99;CI:1.31–3.03). For men, BMI was also positively associated with the risk of developing any cancer type, CRC and PC. In particular, obese men had 37% (OR = 1.37;CI:1.11–1.70), 113% (OR = 2.13;CI:1.55–2.91) and 51% (OR = 1.51;CI:1.17-1.94) higher risks of developing any cancer, CRC and PC respectively, when compared to men with healthy-BMI-range (BMI<25 kg/m2). Among women, PA was inversely associated with the risks of CRC, UC and BC. In particular, the highest level of PA (versus nil activity) was associated with reduced risks of CRC (OR = 0.60;CI:0.44–0.84) and UC (OR = 0.47;CI:0.27–0.80). Reduced risks of BC were associated with low (OR = 0.66;CI:0.51–0.86) and moderate (OR = 0.72;CI:0.57–0.91) levels of PA. There was no association between PA levels and cancer risks for men. We found no evidence of an interaction between BMI and PA in the CLEAR study. Conclusion These findings suggest that PA and obesity are independent cancer risk factors

Sunlight and vitamin D affect DNA damage, cell division and cell death in human lymphocytes: a cross-sectional study in South Australia

The ultraviolet (UV)-B spectrum in solar UV radiation is essential for stimulating the epidermal production of vitamin D but also damages DNA and causes cancer in exposed cells. We examined the role of solar UV in inducing DNA damage in blood lymphocytes and the possible modulation of this damage by serum 25-hydroxy vitamin D (25(OH)D) in 207 male and female participants from South Australia. Personal solar UV exposure was estimated from hours of outdoor exposure recalled at the time of blood collection for analysis of DNA damage in lymphocytes, using the cytokinesis-block micronucleus cytome (CBMN-cyt) assay and of serum 25(OH)D. We examined the association between solar UV exposure, serum 25(OH)D and DNA damage using multiple linear regression, with age, sex, body mass index and alcohol consumption as covariates. The frequency of cells with micronuclei (a biomarker of chromosome breakage or loss) increased with increasing sun exposure [% increase = 5.24; 95% confidence interval (CI): 0.35 to 10.37 P-value = 0.04] but cells with nucleoplasmic bridges (a biomarker of misrepair of DNA strand breaks or telomere end fusions) decreased (% increase = -8.38; 95% CI: -14.32 to -2.03 P-value = 0.01). There was also a fall in the nuclear division index (NDI) (% increase = -1.01; 95% CI: -2.00 to 0.00 P-value = 0.05), suggesting diminished mitogenic response and, possibly, immune suppression. There was no overall relationship between 25(OH)D and DNA damage. There were, however, weak modulating effects of 25(OH)D on the associations of solar UV exposure with micronucleus formation and with NDI (P-interaction = 0.03 and 0.05, respectively), where the increase in micronuclei and fall in NDI with increasing solar UV were greater at serum 25(OH)D levels <50 nmol/l. Thus, the influence of solar UV exposure in causing DNA damage or immune suppression in internal tissues may be stronger when vitamin D levels are low.Visalini Nair-Shalliker, Michael Fenech, Peta M. Forder, Mark S. Clements and Bruce K. Armstron