Exploring the genome-wide impact of estrogen receptor alpha and estrogen receptor beta in breast and colon cancer cells

Estrogen signaling is involved in the development and progression of breast cancer and is implicated to be protective in colon cancer. Estrogenic actions are conveyed through transcriptional regulation by ligand stimulated estrogen receptors (ERα and ERβ). ERα is upregulated in most breast cancers and is responsible for the proliferative effect of estrogen. ERβ on the other hand is usually downregulated, and studies indicate an antiproliferative function. Therapies targeting ERα are available and commonly used in the treatment of breast cancer. In the normal colonic epithelia, however, ERβ is the most abundant estrogen receptor and the suggested mediator of the protective effects of estrogen in colon cancer. The role of ERβ in breast cancer and colon cancer is not well understood. Thus, exploring the genome-wide impact and contribution of both receptors in estrogen responsive cancers would substantially help to identify novel therapeutic and preventive strategies for these cancers. In Paper 1, we examined differences in transcriptional regulation between ERα and ERβ in the breast cancer cell line T47D. We could show that ERβ often exhibited an opposing effect on ERα-regulated genes within proliferation and regulation of cell cycle. We also demonstrated a set of genes only regulated by ERβ, indicating that, despite the high homology between the two receptors, there are differences in their transcriptional targets. The fact that ERβ opposed ERα indicates that ERβ activation may be of value in the treatment of breast cancer. To further explore the transcriptional role of ERα in breast cancer, we performed large-scale analyses of microRNA in 24 hours estrogen treated ERα-expressing T47D cells, Paper II. However, we found no evidence of direct and rapid regulation of mature miRNAs by ERα. In Paper III, we studied ERβ gene regulation in colon cancer cells. We could show that ERβ-expressing xenografts grew significantly slower than those lacking ERβ. Further we demonstrated that ERβ induced a transcriptional response independently of ERα and induced inhibition of the proto-oncogene MYC and other G1-phase cell cycle genes. In Paper IV, we dissected the regulatory networks of ERβ-induced transcriptional changes in human colon cancer cells. The set of genes changed by ERβ varied in different colon cancer cell lines, however, corresponded to the same biological processes such as cell cycle regulation and kinase activity. In addition, we identified the ERβ-driven downregulation of the transcription factor PROX1 as a key mechanism behind a large proportion of the transcriptional changes. In Paper V, we studied the effect of long term expression of ERβ on the miRNA pool in SW480 colon cancer cells. While we could not show a direct and rapid effect of ERα on the miRNome, we showed that long term expression of ERβ did induce large changes in the miRNA pool in colon cancer cells. In particular, we found the oncogenic miR-17-92 cluster to be downregulated and proposed this to be a consequence of the ERβ-induced downregulation of MYC. In conclusion, we have shown that ERβ is antiproliferative in breast and colon cancer cells, both when co-expressed with ERα and alone, as well as identified key signaling pathways. We suggest that activation of ERβ will have a beneficial effect for treatment or prevention of estrogen dependent cancers

Initial study on phytoextraction for recovery of metals from sorted and aged waste‐to‐energy bottom ash

Sorted and aged bottom ash from Waste‐to‐Energy plants, i.e., MIBA (the Mineral fraction of Incinerator Bottom Ash) are potential source of metals that could be utilized to meet the increased demand from society. In this work, sunflowers (Helianthus annuus) and rapeseed (Brassica napus) were cultivated in conventional MIBA to evaluate the possibility for phytoextraction, mainly of Zn, during the period of one cultivation season in the Nordic climate. The results show that metal extraction from MIBA using rapeseed and sunflowers is workable but that neither of the used plants is optimal, mainly due to the inhibited root development and low water‐ and nutrient‐holding capacities of MIBA. The addition of fertilizer is also important for growth. There was a simultaneous accumulation of numerous metals in both plant types, and the highest metal content was generally found in the roots. Calculations indicated that the ash from rapeseed root incineration contained about 2% Zn, and the contents of Co, Cu, and Pb were comparable to those in workable ores. This initial study shows that cultivation in and phytoextraction on MIBA is possible, and that the potential for increased metal extraction is high

Technology neutrality in European regulation of GMOs

Objections to the current EU regulatory system on genetically modified organisms (GMOs) in terms of high cost and lack of consistency, speed and scientific underpinning have prompted proposals for a more technology-neutral system. We sketch the conceptual background of the notion of ‘technology neutrality’ and propose a refined definition of the term. The proposed definition implies that technology neutrality of a regulatory system is a gradual and multidimensional feature. We use the definition to analyze two regulatory reform proposals: One proposal from the Netherlands for improving the exemption mechanism for GMOs under Directive 2001/18/EC, and one from the Norwegian Biotechnology Advisory Board, outlining a new stratified risk assessment procedure. While both proposals offer some degree of improved technology neutrality in some dimensions compared to current EU regulation, in some extents and dimensions, they do not. We conclude that proposals for more technology-neutral regulation of GMOs need, first, to make explicit to what extent and in what dimensions the proposal improves neutrality and, second, to present arguments supporting that these specific improvements constitute desirable policy change against the background of objections to current policy

Scenarios and Sustainability A Swedish Case Study of Adaptation Tools for Local Decision-Makers

Adaptation to climate change often involves long time frames and uncer-tainties over consequences of chosen adaptation measures. In this study, two tools developed for assisting local decision-makers in adaptation planning were tested: socio-economic scenarios and sustainability analy-sis. The objective was to study whether these tools could be of practical relevance to Swedish municipalities and foster local level climate change adaptation. We find that the municipal civil servants who participated in the testing generally considered the tools to be useful and of high rele-vance, but that more time was needed for using the tools than provided during the test process.climate change; adaptation; socio-economic scenarios; goal conflict; cost-benefit analysis

Chemical abundances in 43 metal-poor stars

We have derived abundances of O, Na, Mg, Al, Si, Ca, Sc, Ti, V, Cr, Fe, Ni and Ba for 43 metal-poor field stars in the solar neighbourhood with iron abundances [Fe/H] ranging from -0.4 to -3.0. Total abundance errors are estimated to about 0.1-0.2 dex for most elements, while relative abundances are most probably more accurate. We have made an extensive comparison with other similar studies and traced the reasons for the, in most cases, relatively small differences. Among the results we note the following: We find [O/Fe] from the O I IR- triplet lines to possibly increase beyond [Fe/H]=-1.0, though considerably less than obtained by others from abundances based on OH lines. We find correlations among the deviations for individual stars from the trends of individual alpha elements relative to Fe. This may support the idea that the formation of the Halo stars occurred in smaller systems with different star formation rates. We verify the finding by Gratton et al. (2003b) that stars that do not participate in the rotation of the galactic disk show a lower mean and larger spread in [alpha/Fe] than stars participating in the general rotation. The latter stars also seem to show some correlation between [alpha/Fe] and rotation speed. We finally advocate that a spectroscopic study of a larger sample of halo stars with well-defined selection criteria is very important, in addition to the very considerable efforts that various groups have already made. (Abridged)Comment: A&A LaTeX, 24 pages, 18 b/w figures. Astronomy & Astrophysics, accepte

Options to Reform the European Union Legislation on GMOs: Scope and Definitions

We discuss options to reform the EU genetically modified organisms (GMO) regulatory framework, make risk assessment and decision-making more consistent with scientific principles, and lay the groundwork for international coherence. The first in a three-part series, this article focuses on reform options related to the scope of the legislation and the GMO definition.</p

Options to Reform the European Union Legislation on GMOs: Scope and Definitions

We discuss options to reform the EU genetically modified organisms (GMO) regulatory framework, make risk assessment and decision-making more consistent with scientific principles, and lay the groundwork for international coherence. The first in a three-part series, this article focuses on reform options related to the scope of the legislation and the GMO definition

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens