Aromatase expression is increased in BRCA1 mutation carriers

<p>Abstract</p> <p>Background</p> <p>Until recently, the molecular mechanisms explaining increased incidence of ovarian and breast cancers in carriers of <it>BRCA1 </it>gene mutations had not been clearly understood. Of significance is the finding that BRCA1 negatively regulates aromatase expression <it>in vitro</it>. Our objective was to characterise aromatase gene <it>(CYP19A1) </it>and its promoter expression in breast adipose and ovarian tissue in <it>BRCA1 </it>mutation carriers and unaffected controls.</p> <p>Methods</p> <p>We measured aromatase transcripts, total and promoter-specific (PII, PI.3, PI.4) in prophylactic oophorectomy or mastectomy, therapeutic mastectomy, ovarian and breast tissue from unaffected women.</p> <p>Results</p> <p>We demonstrate that the lack of functional BRCA1 protein correlates to higher aromatase levels in 85% of <it>BRCA1 </it>mutation carriers. This increase is mediated by aberrant transcriptional regulation of aromatase; in breast adipose by increases in promoter II/I.3 and I.4-specific transcripts; and in the ovary with elevation in promoter I.3 and II-specific transcripts.</p> <p>Conclusion</p> <p>Understanding the link between BRCA1 and aromatase is significant in terms of understanding why carcinogenesis is restricted to estrogen-producing tissues in <it>BRCA1 </it>mutation carriers.</p

Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus

BACKGROUND: Diabetic nephropathy is a serious complication of diabetes mellitus and is associated with considerable morbidity and high mortality. There is increasing evidence to suggest that dysregulation of the epigenome is involved in diabetic nephropathy. We assessed whether epigenetic modification of DNA methylation is associated with diabetic nephropathy in a case-control study of 192 Irish patients with type 1 diabetes mellitus (T1D). Cases had T1D and nephropathy whereas controls had T1D but no evidence of renal disease. METHODS: We performed DNA methylation profiling in bisulphite converted DNA from cases and controls using the recently developed Illumina Infinium(R) HumanMethylation27 BeadChip, that enables the direct investigation of 27,578 individual cytosines at CpG loci throughout the genome, which are focused on the promoter regions of 14,495 genes. RESULTS: Singular Value Decomposition (SVD) analysis indicated that significant components of DNA methylation variation correlated with patient age, time to onset of diabetic nephropathy, and sex. Adjusting for confounding factors using multivariate Cox-regression analyses, and with a false discovery rate (FDR) of 0.05, we observed 19 CpG sites that demonstrated correlations with time to development of diabetic nephropathy. Of note, this included one CpG site located 18 bp upstream of the transcription start site of UNC13B, a gene in which the first intronic SNP rs13293564 has recently been reported to be associated with diabetic nephropathy. CONCLUSION: This high throughput platform was able to successfully interrogate the methylation state of individual cytosines and identified 19 prospective CpG sites associated with risk of diabetic nephropathy. These differences in DNA methylation are worthy of further follow-up in replication studies using larger cohorts of diabetic patients with and without nephropathy

Human behaviour in emergency situations: comparisons between aviation and rail domains

This article presents a comparative review of the knowledge base regarding human behaviour in emergencies for both aviation and rail domains. Generic models of human behaviour in emergency situations are introduced and specific attention is then focussed on methods of behaviour prediction, exhibited behaviours in emergencies and methods of aiding evacuation across both modes of transport. Using established knowledge from the aviation domain, it has been possible to make observations and comparisons about the rail domain. Traditionally, the aviation domain has been a major focus of research attention and this is used to inform and interpret the rail domain. By drawing comparisons across these domains for human behaviour in emergency situations, the observations are discussed along with recommendations for future policies/planning for emergencies and future research areas

Time intervals from first symptom to treatment of cancer: a cohort study of 2,212 newly diagnosed cancer patients

<p>Abstract</p> <p>Background</p> <p>Delay in diagnosis of cancer may worsen prognosis. The aim of this study is to explore patient-, general practitioner (GP)- and system-related delay in the interval from first cancer symptom to diagnosis and treatment, and to analyse the extent to which delays differ by cancer type.</p> <p>Methods</p> <p>Population-based cohort study conducted in 2004-05 in the County of Aarhus, Denmark (640,000 inhabitants). Data were collected from administrative registries and questionnaires completed by GPs on 2,212 cancer patients newly diagnosed during a 1-year period. Median delay (in days) with interquartile interval (IQI) was the main outcome measure.</p> <p>Results</p> <p>Median total delay was 98 days (IQI 57-168). Most of the total delay stemmed from patient (median 21 days (7-56)) and system delay (median 55 days (32-93)). Median GP delay was 0 (0-2) days. Total delay was shortest among patients with ovarian (median 60 days (45-112)) and breast cancer (median 65 days (39-106)) and longest among patients with prostate (median 130 days (89-254)) and bladder cancer (median 134 days (93-181)).</p> <p>Conclusion</p> <p>System delay accounted for a substantial part of the total delay experienced by cancer patients. This points to a need for shortening clinical pathways if possible. A long patient delay calls for research into patient awareness of cancer. For all delay components, special focus should be given to the 4^thquartile of patients with the longest time intervals and we need research into the quality of the diagnostic work-up process. We found large variations in delay for different types of cancer. Improvements should therefore target both the population at large and the specific needs associated with individual cancer types and their symptoms.</p

The influence on survival of delay in the presentation and treatment of symptomatic breast cancer

The aim of this study was to examine the possible influence on survival of delays prior to presentation and/or treatment among women with breast cancer. Duration of symptoms prior to hospital referral was recorded for 2964 women who presented with any stage of breast cancer to Guy's Hospital between 1975 and 1990. Median follow-up is 12.5 years. The impact of delay (defined as having symptoms for 12 or more weeks) on survival was measured from the date of diagnosis and from the date when the patient first noticed symptoms to control for lead-time bias. Thirty-two per cent (942/2964) of patients had symptoms for 12 or more weeks before their first hospital visit and 32% (302/942) of patients with delays of 12 or more weeks had locally advanced or metastatic disease, compared with only 10% (210/2022) of those with delays of less than 12 weeks (P< 0.0001). Survival measured both from the date of diagnosis (P< 0.001) and from the onset of the patient's symptoms (P= 0.003) was worse among women with longer delays. Ten years after the onset of symptoms, survival was 52% for women with delays less than 12 weeks and 47% for those with longer delays. At 20 years the survival rates were 34% and 24% respectively. Furthermore, patients with delays of 12–26 weeks had significantly worse survival rates than those with delays of less than 12 weeks. Multivariate analyses indicated that the adverse impact of delay in presentation on survival was attributable to an association between longer delays and more advanced stage. However, within individual stages, longer delay had no adverse impact on survival. Analyses based on ‘total delay’ (i.e. the interval between a patient first noticing symptoms and starting treatment) yielded very similar results in terms of survival to those based on delay to first hospital visit (delay in presentation). © 1999 Cancer Research Campaig

A Workshop on Cognitive Aging and Impairment in the 9/11-Exposed Population

The terrorist attacks on 11 September 2001 potentially exposed more than 400,000 responders, workers, and residents to psychological and physical stressors, and numerous hazardous pollutants. In 2011, the World Trade Center Health Program (WTCHP) was mandated to monitor and treat persons with 9/11-related adverse health conditions and conduct research on physical and mental health conditions related to the attacks. Emerging evidence suggests that persons exposed to 9/11 may be at increased risk of developing mild cognitive impairment. To investigate further, the WTCHP convened a scientific workshop that examined the natural history of cognitive aging and impairment, biomarkers in the pathway of neurodegenerative diseases, the neuropathological changes associated with hazardous exposures, and the evidence of cognitive decline and impairment in the 9/11-exposed population. Invited participants included scientists actively involved in health-effects research of 9/11-exposed persons and other at-risk populations. Attendees shared relevant research results from their respective programs and discussed several options for enhancements to research and surveillance activities, including the development of a multi-institutional collaborative research network. The goal of this report is to outline the meeting’s agenda and provide an overview of the presentation materials and group discussion

Electromagnetic fields in biological studies

For biological or cellular experiments using electromagnetic fields, it is essential that the parameters defining the field be carefully specified if the results are to be meaningful and are to be compared with the same experiment conducted in a different laboratory. The interaction of living systems with electric and magnetic fields can come only through forces exerted on the charges on the system. If the charges are stationary, the only origin of the force is the electric field. This electric field may be established by charge distributions, as in “capacitive plate” experiments, or by time-varying magnetic fields.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43995/1/10439_2006_Article_BF00000002.pd