The 5-hydroxymethylcytosine landscape of prostate cancer

UNLABELLED: Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease. SIGNIFICANCE: In prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880

Physical activity monitoring in Europe : the European physical activity surveillance system (EUPASS) approach and indicator testing.

Objectives: The main objective of this paper is to describe the approach and specific findings of the European Physical Activity Surveillance System (EUPASS) research project. In particular, the analysis presented aims at testing the reliability, comparability and predictive power of different sets of physical activity (PA) indicators. Design: First, a panel study based on computer-aided telephone interview (CATI) was designed to report PA data of a representative, selected group of about 100 persons per country at three points in time. Second, a CATI time series survey was carried out with the goal of realising about 100 interviews per month over six consecutive months. Setting: The project was carried out in eight European countries to support the development of the European Union's (EU) Health Monitoring Programme. Subjects: Random population samples (subjects aged 18 years and older) were drawn from each participating country. Results: While many PA indicators used in EU countries to date as well as the psychosocial and environmental measures tested in the present study had acceptable to good reliability coefficients, the test–retest reliability scores of the International Physical Activity Questionnaire (IPAQ) version tested (the short (last 7 days) telephone interview IPAQ; IPAQ-S7T) were rather low. The comparability between extant national PA items and the IPAQ-S7T was low for all countries. The strongest predictors of perceived health were the psychosocial and environmental PA indicators. Conclusions: According to the results of the present study, more research is needed to further investigate and improve the quality of the IPAQ. In addition, the specific predictive power of the tested psychosocial and environmental PA indicators on perceived health should be of particular interest for designing health surveillance activities in the future

Carbon isotope values of hazelnut shells: a new proxy for canopy density

Hazel (Corylus avellana) has been abundant in the vegetation of northern and central Europe since the early Holocene and has provided food and materials for humans ever since. Here we use stable carbon isotope (δ13 14 C) values of hazelnut shells to infer woodland openness based on the premise of the “canopy effect”. It is well established that plants growing in dense, shaded forests have lower carbon isotope (δ13C) values than plants growing in open areas. By measuring δ13 C values in hazelnuts collected from trees growing in different levels of light intensity, we show that the canopy effect is preserved in hazelnuts and that their δ13 C values can be used to infer woodland openness in the past. We apply the method to hazelnuts recovered from sites dated to between the Mesolithic and Iron Age (c. 7000 BCE to 1000 CE) in southern Sweden. Our results show that the nuts dated to the Mesolithic were harvested from hazels growing in a range of closed to open settings while nuts from subsequent periods were harvested from progressively more open environments. Given the abundance of hazelnuts recovered from many archaeological contexts, this method has the potential to reconstruct the microhabitats exploited by humans in the past and explore the impact of humans on their environment

Evaluation of satellite based indices for gross primary production estimates in a sparse savanna in the Sudan

One of the more frequently applied methods for integrating controls on primary production through satellite data is the Light Use Efficiency (LUE) approach. Satellite indices such as the Normalized Difference Vegetation Index (NDVI), Enhanced Vegetation Index (EVI) and the Shortwave Infrared Water Stress Index (SIWSI) have previously shown promise as predictors of primary production in several different environments. In this study, we evaluate NDVI, EVI and SIWSI derived from the Moderate Resolution Imaging Spectroradiometer (MODIS) satellite sensor against in-situ measurements from central Sudan in order to asses their applicability in LUE-based primary production modeling within a water limited environment. Results show a strong correlation between vegetation indices and gross primary production (GPP), demonstrating the significance of vegetation indices for deriving information on primary production with relatively high accuracy at similar areas. Evaluation of SIWSI however, reveal that the fraction of vegetation apparently is to low for the index to provide accurate information on canopy water content, indicating that the use of SIWSI as a predictor of water stress in satellite data-driven primary production modeling in similar semi-arid ecosystems is limited

Dissemination of Resistant Escherichia coli Among Wild Birds, Rodents, Flies, and Calves on Dairy Farms

Antimicrobial resistance (AMR) in bacteria in the livestock is a growing problem, partly due to inappropriate use of antimicrobial drugs. Antimicrobial use (AMU) occurs in Swedish dairy farming but is restricted to the treatment of sick animals based on prescription by a veterinary practitioner. Despite these strict rules, calves shedding antimicrobial resistant Enterobacteriaceae have been recorded both in dairy farms and in slaughterhouses. Yet, not much is known how these bacteria disseminate into the local environment around dairy farms. In this study, we collected samples from four animal sources (fecal samples from calves, birds and rodents, and whole flies) and two environmental sources (cow manure drains and manure pits). From the samples, Escherichia coli was isolated and antimicrobial susceptibility testing performed. A subset of isolates was whole genome sequenced to evaluate relatedness between sources and genomic determinants such as antimicrobial resistance genes (ARGs) and the presence of plasmids were assessed. We detected both ARGs, mobile genetic elements and low rates of AMR. In particular, we observed four potential instances of bacterial clonal sharing in two different animal sources. This demonstrates resistant E. coli dissemination potential within the dairy farm, between calves and scavenger animals (rodents and flies). AMR dissemination and the zoonotic AMR risk is generally low in countries with low and restricted AMU. However, we show that interspecies dissemination does occur, and in countries that have little to no AMU restrictions this risk could be under-estimated

Tumour microvessel density as predictor of chemotherapy response in breast cancer patients

The aim of this study was to evaluate the predictive value of intratumoural microvessel density in breast cancer. We studied immunohistochemically primary tumours of 104 patients with metastasised breast cancer who took part in a randomised multicentre trial comparing docetaxel to sequential methotrexate and 5-fluorouracil. Vessels were highlighted with factor VIII staining and counted microscopically. Microvessel density was compared with clinical response to chemotherapy and patient survival. The microvessel density of the primary tumour was not significantly associated with patient's response to chemotherapy, time to progression or overall survival in the whole patient population or in the docetaxel or methotrexate and 5-fluorouracil groups. However, disease-free survival was longer in patients with low microvessel density (P=0.01). These findings suggest that microvessel density of the primary tumour cannot be used as a predictive marker for chemotherapy response in advanced breast cancer