Residential Radon and Brain Tumour Incidence in a Danish Cohort

BACKGROUND: Increased brain tumour incidence over recent decades may reflect improved diagnostic methods and clinical practice, but remain unexplained. Although estimated doses are low a relationship between radon and brain tumours may exist. OBJECTIVE: To investigate the long-term effect of exposure to residential radon on the risk of primary brain tumour in a prospective Danish cohort. METHODS: During 1993-1997 we recruited 57,053 persons. We followed each cohort member for cancer occurrence from enrolment until 31 December 2009, identifying 121 primary brain tumour cases. We traced residential addresses from 1 January 1971 until 31 December 2009 and calculated radon concentrations at each address using information from central databases regarding geology and house construction. Cox proportional hazards models were used to estimate incidence rate-ratios (IRR) and 95% confidence intervals (CI) for the risk of primary brain tumours associated with residential radon exposure with adjustment for age, sex, occupation, fruit and vegetable consumption and traffic-related air pollution. Effect modification by air pollution was assessed. RESULTS: Median estimated radon was 40.5 Bq/m(3). The adjusted IRR for primary brain tumour associated with each 100 Bq/m(3) increment in average residential radon levels was 1.96 (95% CI: 1.07; 3.58) and this was exposure-dependently higher over the four radon exposure quartiles. This association was not modified by air pollution. CONCLUSIONS: We found significant associations and exposure-response patterns between long-term residential radon exposure radon in a general population and risk of primary brain tumours, adding new knowledge to this field. This finding could be chance and needs to be challenged in future studies

Intracranial tumors of the central nervous system and air pollution - A nationwide case-control study from Denmark

Background: Inconclusive evidence has suggested a possible link between air pollution and central nervous system (CNS) tumors. We investigated a range of air pollutants in relation to types of CNS tumors. Methods: We identified all (n = 21,057) intracranial tumors in brain, meninges and cranial nerves diagnosed in Denmark between 1989 and 2014 and matched controls on age, sex and year of birth. We established personal 10- year mean residential outdoor exposure to particulate matter < 2.5 μm (PM2.5), nitrous oxides (NOX), primary emitted black carbon (BC) and ozone. We used conditional logistic regression to calculate odds ratios (OR) linearly (per interquartile range (IQR)) and categorically. We accounted for personal income, employment, marital status, use of medication as well as socio-demographic conditions at area level. Results: Malignant tumors of the intracranial CNS was associated with BC (OR: 1.034, 95%CI: 1.005–1.065 per IQR. For NOx the OR per IQR was 1.026 (95%CI: 0.998–1.056). For malignant non-glioma tumors of the brain we found associations with PM2.5 (OR: 1.267, 95%CI: 1.053–1.524 per IQR), BC (OR: 1.049, 95%CI: 0.996–1.106) and NOx (OR: 1.051, 95% CI: 0.996–1.110). Conclusion: Our results suggest that air pollution is associated with malignant intracranial CNS tumors and malignant non-glioma of the brain. However, additional studies are needed

Determinants of frequent attendance in Danish general practice: a cohort-based cross-sectional study

BACKGROUND: Previous studies addressing determinants of frequent attendance have mainly focused on socio-demographic, psychosocial and medical factors, and few had data on lifestyle and gender-specific factors. This study aims to describe determinants of general practice frequent attendance in Danish adult population, by examining lifestyle, socio-demographic, medical and gender-specific factors. METHOD: For 54,849 participants of the Danish Diet, Cancer and Health cohort (50–65 year old) we obtained data on visits to general practitioner (GP) from the Danish National Health Service Register at cohort baseline (1993–97), when information on medical conditions and lifestyle, socio-demographic and gender-specific factors was collected by questionnaire. Logistic regression was used to identify determinants of frequent attendance, defined as top 10 % GP users at the year of recruitment into the cohort (baseline) in the period between 1993 and 1997. RESULTS: Frequent attenders accounted for 40 % of all face-to-face GP consultations with a mean 12 visits/year. Women were more likely to be frequent attenders, in crude (Odds ratio: 1.95; 95 % Confidence Interval: 1.85–2.06) and fully adjusted (1.26; 1.09–1.47) model. In a fully adjusted model, strongest determinants of frequent attendance were pre-existing medical conditions, with hypertension (2.58; 2.42–2.75), diabetes (2.24; 1.94–2.59), and mental illness (2.29; 2.09–2.52) more than doubling the odds of being FA. High education (0.63; 0.57–0.69, >4 years higher education vs. no vocational training) and employment (0.61; 0.57–0.65) were inversely associated with frequent attendance. Finally, obesity (1.54; 1.14–2.08), smoking (1.21; 1.12–1.30, current vs. never), physical activity (0.84; 0.80–89), alcohol consumption (0.83; 0.78–0.87 above vs. below recommended level), and hormone therapy in women (1.52; 1.42–1.63) were all significant determinants of frequent attendance. CONCLUSIONS: In addition to pre-existing medical conditions, gender, socio-demographic and gender-specific factors, lifestyle (obesity, smoking, exercise and alcohol use) is also an independent determinant of frequent attendance at general practitioner

Integrative analyses of gene expression and DNA methylation profiles in breast cancer cell line models of tamoxifen-resistance indicate a potential role of cells with stem-like properties

INTRODUCTION: Development of resistance to tamoxifen is an important clinical issue in the treatment of breast cancer. Tamoxifen resistance may be the result of acquisition of epigenetic regulation within breast cancer cells, such as DNA methylation, resulting in changed mRNA expression of genes pivotal for estrogen-dependent growth. Alternatively, tamoxifen resistance may be due to selection of pre-existing resistant cells, or a combination of the two mechanisms. METHODS: To evaluate the contribution of these possible tamoxifen resistance mechanisms, we applied modified DNA methylation-specific digital karyotyping (MMSDK) and digital gene expression (DGE) in combination with massive parallel sequencing to analyze a well-established tamoxifen-resistant cell line model (TAM(R)), consisting of 4 resistant and one parental cell line. Another tamoxifen-resistant cell line model system (LCC1/LCC2) was used to validate the DNA methylation and gene expression results. RESULTS: Significant differences were observed in global gene expression and DNA methylation profiles between the parental tamoxifen-sensitive cell line and the 4 tamoxifen-resistant TAM(R) sublines. The 4 TAM(R) cell lines exhibited higher methylation levels as well as an inverse relationship between gene expression and DNA methylation in the promoter regions. A panel of genes, including NRIP1, HECA and FIS1, exhibited lower gene expression in resistant vs. parental cells and concurrent increased promoter CGI methylation in resistant vs. parental cell lines. A major part of the methylation, gene expression, and pathway alterations observed in the TAM(R) model were also present in the LCC1/LCC2 cell line model. More importantly, high expression of SOX2 and alterations of other SOX and E2F gene family members, as well as RB-related pocket protein genes in TAM(R) highlighted stem cell-associated pathways as being central in the resistant cells and imply that cancer-initiating cells/cancer stem-like cells may be involved in tamoxifen resistance in this model. CONCLUSION: Our data highlight the likelihood that resistant cells emerge from cancer-initiating cells/cancer stem-like cells and imply that these cells may gain further advantage in growth via epigenetic mechanisms. Illuminating the expression and DNA methylation features of putative cancer-initiating cells/cancer stem cells may suggest novel strategies to overcome tamoxifen resistance