Estrogen receptor modulators and down regulators: optimal use in postmenopausal women with breast cancer

Endocrine treatments have been used in breast cancer since 1896, when Beatson reported on the results of oophorectomy for advanced breast cancer. In the second half of the last century, different endocrine-based compounds were developed and, in this review, the role of the selective estrogen receptor modulators (SERMs) and selective estrogen receptor down regulators (SERDs) in the postmenopausal setting are discussed. Tamoxifen is the most investigated and most widely used representative of these agents, and has been introduced in the advanced disease, in the neoadjuvant and adjuvant setting, and for the prevention of the disease. Its role has been challenged in recent years by the introduction of third-generation aromatase inhibitors that have proven higher activities than tamoxifen with different toxicity patterns. Several other SERMs have been investigated, but none have been clearly superior to tamoxifen. SERDs act as pure estrogen antagonists and should compare favourably to tamoxifen. For the time being, they have been used in the treatment of advanced breast cancers and their role in other settings still needs investigation. The increased use of aromatase inhibitors as first-line endocrine therapy has resulted in new discussions regarding the role that tamoxifen and other SERMs or SERDs may play in breast cancer. The sequencing of endocrine therapies in hormone-sensitive breast cancer remains a very important research issue.

Analysis of spring break-up and its effects on a biomass feedstock supply chain in northern Michigan

Demand for bio-fuels is expected to increase, due to rising prices of fossil fuels and concerns over greenhouse gas emissions and energy security. The overall cost of biomass energy generation is primarily related to biomass harvesting activity, transportation, and storage. With a commercial-scale cellulosic ethanol processing facility in Kinross Township of Chippewa County, Michigan about to be built, models including a simulation model and an optimization model have been developed to provide decision support for the facility. Both models track cost, emissions and energy consumption. While the optimization model provides guidance for a long-term strategic plan, the simulation model aims to present detailed output for specified operational scenarios over an annual period. Most importantly, the simulation model considers the uncertainty of spring break-up timing, i.e., seasonal road restrictions. Spring break-up timing is important because it will impact the feasibility of harvesting activity and the time duration of transportation restrictions, which significantly changes the availability of feedstock for the processing facility. This thesis focuses on the statistical model of spring break-up used in the simulation model. Spring break-up timing depends on various factors, including temperature, road conditions and soil type, as well as individual decision making processes at the county level. The spring break-up model, based on the historical spring break-up data from 27 counties over the period of 2002-2010, starts by specifying the probability distribution of a particular county’s spring break-up start day and end day, and then relates the spring break-up timing of the other counties in the harvesting zone to the first county. In order to estimate the dependence relationship between counties, regression analyses, including standard linear regression and reduced major axis regression, are conducted. Using realizations (scenarios) of spring break-up generated by the statistical spring breakup model, the simulation model is able to probabilistically evaluate different harvesting and transportation plans to help the bio-fuel facility select the most effective strategy. For early spring break-up, which usually indicates a longer than average break-up period, more log storage is required, total cost increases, and the probability of plant closure increases. The risk of plant closure may be partially offset through increased use of rail transportation, which is not subject to spring break-up restrictions. However, rail availability and rail yard storage may then become limiting factors in the supply chain. Rail use will impact total cost, energy consumption, system-wide CO2 emissions, and the reliability of providing feedstock to the bio-fuel processing facility.

Regulation of woody plant development by auxin and polar auxin transport

Auxin is a key regulator in plant growth and development. This dissertation examines the role of auxin and polar auxin transport in woody growth and development. Strategies of promoter reporter system, microarray expression analysis, transgenic modification, physiological assays, anatomical analysis, and histochemical/biochemical assays were employed to improve our understanding of auxin study in Populus. The results demonstrate various aspects of auxin regulation on shoot growth, root development, wood formation, and gravitropism in woody tissues. We describe the behavior of the DR5 reporter system for measuring auxin concentrations and response in stably transformed Populus trees. Our study shows that DR5 reporter system can be efficiently used in Populus to study auxin biology at a cellular resolution. We investigated the global gene expression in responding to auxin in Populus root. The results revealed groups of IBA up- and down- regulated genes involved in various biological processes including cell wall modification, root growth and lateral root formation, transporter activity and hormone crosstalk. We also verify two of the identified genes' function by transgenic modification in Populus, which encode auxin efflux carrier PtPIN9 and transcription factor PtERF72. We investigated the role of PtPIN9 in woody growth and development, especially in wood formation and gravitropic response in woody stem. We found that overexpressing PtPIN9 enhanced several growth parameters while suppression of PtPIN9 has inhibited tension wood formation. Our results show that PIN9 and other members from PIN family could be possible useful tools for increasing biomass productivity, wood quality, or in modifying plant form.

Tax-Optimal Step-Up and Imperfect Loss Offset

In the field of mergers and acquisitions, German and international tax law allow for several opportunities to step up a firm's assets, i.e., to revaluate the assets at fair market values. When a step-up is performed the taxpayer recognizes a taxable gain, but also obtains tax benefits in the form of higher future depreciation allowances associated with stepping up the tax base of the assets. This tax-planning problem is well known in taxation literature and can also be applied to firm valuation in the presence of taxation. However, the known models usually assume a perfect loss offset. If this assumption is abandoned, the depreciation allowances may lose value as they become tax effective at a later point in time, or even never if there are not enough cash flows to be offset against. This aspect is especiallyrelevant if future cash flows are assumed to be uncertain. This paper shows that a step-up may be disadvantageous or a firm overvalued if these aspects are not integrated into the basic calculus. Compared to the standard approach, assets should be stepped up only in a few cases and - under specific conditions - at a later point in time. Firm values may be considerably lower under imperfect loss offset.

Tracing of patients lost to follow-up and HIV transmission: Mathematical modelling study based on two large ART programmes in Malawi

OBJECTIVES: Treatment as prevention depends on retaining HIV-infected patients in care. We investigated the effect on HIV transmission of bringing patients lost to follow up (LTFU) back into care. DESIGN: Mathematical model. METHODS: Stochastic mathematical model of cohorts of 1000 HIV-infected patients on antiretroviral therapy (ART), based on data from two clinics in Lilongwe, Malawi. We calculated cohort viral load (CVL; sum of individual mean viral loads each year) and used a mathematical relationship between viral load and transmission probability to estimate the number of new HIV infections. We simulated four scenarios: 'no LTFU' (all patients stay in care); 'no tracing' (patients LTFU are not traced); 'immediate tracing' (after missed clinic appointment); and, 'delayed tracing' (after six months). RESULTS: About 440 of 1000 patients were LTFU over five years. CVL (million copies/ml per 1000 patients) were 3.7 (95% prediction interval [PrI] 2.9-4.9) for no LTFU, 8.6 (95% PrI 7.3-10.0) for no tracing, 7.7 (95% PrI 6.2-9.1) for immediate, and 8.0 (95% PrI 6.7-9.5) for delayed tracing. Comparing no LTFU with no tracing the number of new infections increased from 33 (95% PrI 29-38) to 54 (95% PrI 47-60) per 1000 patients. Immediate tracing prevented 3.6 (95% PrI -3.3-12.8) and delayed tracing 2.5 (95% PrI -5.8-11.1) new infections per 1000. Immediate tracing was more efficient than delayed tracing: 116 and to 142 tracing efforts, respectively, were needed to prevent one new infection. CONCLUSION: Tracing of patients LTFU enhances the preventive effect of ART, but the number of transmissions prevented is small.

Combining follow-up and change data is valid in meta-analyses of continuous outcomes: a meta-epidemiological study

OBJECTIVE To investigate whether it is valid to combine follow-up and change data when conducting meta-analyses of continuous outcomes. STUDY DESIGN AND SETTING Meta-epidemiological study of randomized controlled trials in patients with osteoarthritis of the knee/hip, which assessed patient-reported pain. We calculated standardized mean differences (SMDs) based on follow-up and change data, and pooled within-trial differences in SMDs. We also derived pooled SMDs indicating the largest treatment effect within a trial (optimistic selection of SMDs) and derived pooled SMDs from the estimate indicating the smallest treatment effect within a trial (pessimistic selection of SMDs). RESULTS A total of 21 meta-analyses with 189 trials with 292 randomized comparisons in 41,256 patients were included. On average, SMDs were 0.04 standard deviation units more beneficial when follow-up values were used (difference in SMDs: -0.04; 95% confidence interval: -0.13, 0.06; P=0.44). In 13 meta-analyses (62%), there was a relevant difference in clinical and/or significance level between optimistic and pessimistic pooled SMDs. CONCLUSION On average, there is no relevant difference between follow-up and change data SMDs, and combining these estimates in meta-analysis is generally valid. Decision on which type of data to use when both follow-up and change data are available should be prespecified in the meta-analysis protocol.

Translating Research into Practice: HEADS UP and K-12 Science Inspiring Health and Careers in Youth

Introduction: HEADS UP {Health Education And Discovering Science while Unlocking Potential} aims to improve health literacy and increase student interest in health science careers by providing cutting-edge content from world-renowned researchers in the Texas Medical Center and beyond to the K-12 school community. [See PDF for complete abstract]

Virtual Infrastructures as a Service enabling Converged Optical Networks and Data Centres

Abstract Cloud computing service emerged as an essential component of the Enterprise {IT} infrastructure. Migration towards a full range and large-scale convergence of Cloud and network services has become the current trend for addressing requirements of the Cloud environment. Our approach takes the infrastructure as a service paradigm to build converged virtual infrastructures, which allow offering tailored performance and enable multi-tenancy over a common physical infrastructure. Thanks to virtualization, new exploitation activities of the physical infrastructures may arise for both transport network and Data Centres services. This approach makes network and Data Centres’ resources dedicated to Cloud Computing to converge on the same flexible and scalable level. The work presented here is based on the automation of the virtual infrastructure provisioning service. On top of the virtual infrastructures, a coordinated operation and control of the different resources is performed with the objective of automatically tailoring connectivity services to the Cloud service dynamics. Furthermore, in order to support elasticity of the Cloud services through the optical network, dynamic re-planning features have been provided to the virtual infrastructure service, which allows scaling up or down existing virtual infrastructures to optimize resource utilisation and dynamically adapt to users’ demands. Thus, the dynamic re-planning of the service becomes key component for the coordination of Cloud and optical network resource in an optimal way in terms of resource utilisation. The presented work is complemented with a use case of the virtual infrastructure service being adopted in a distributed Enterprise Information System, that scales up and down as a function of the application requests.

Tissue metabolomics of hepatocellular carcinoma: Tumor energy metabolism and the role of transcriptomic classification

Hepatocellular carcinoma (HCC) is one of the commonest causes of death from cancer. A plethora of metabolomic investigations of HCC have yielded molecules in biofluids that are both up- and down-regulated but no real consensus has emerged regarding exploitable biomarkers for early detection of HCC. We report here a different approach, a combined transcriptomics and metabolomics study of energy metabolism in HCC. A panel of 31 pairs of HCC tumors and corresponding nontumor liver tissues from the same patients was investigated by gas chromatography-mass spectrometry (GCMS)-based metabolomics. HCC was characterized by ∼2-fold depletion of glucose, glycerol 3- and 2-phosphate, malate, alanine, myo-inositol, and linoleic acid. Data are consistent with a metabolic remodeling involving a 4-fold increase in glycolysis over mitochondrial oxidative phosphorylation. A second panel of 59 HCC that had been typed by transcriptomics and classified in G1 to G6 subgroups was also subjected to GCMS tissue metabolomics. No differences in glucose, lactate, alanine, glycerol 3-phosphate, malate, myo-inositol, or stearic acid tissue concentrations were found, suggesting that the Wnt/β-catenin pathway activated by CTNNB1 mutation in subgroups G5 and G6 did not exhibit specific metabolic remodeling. However, subgroup G1 had markedly reduced tissue concentrations of 1-stearoylglycerol, 1-palmitoylglycerol, and palmitic acid, suggesting that the high serum α-fetoprotein phenotype of G1, associated with the known overexpression of lipid catabolic enzymes, could be detected through metabolomics as increased lipid catabolism. Conclusion: Tissue metabolomics yielded precise biochemical information regarding HCC tumor metabolic remodeling from mitochondrial oxidation to aerobic glycolysis and the impact of molecular subtypes on this process.

Marital split-up and widowhood in old age: Differential impact on psychological and social well-being

Marital split-up and spousal loss are among the most stressful critical life events. Numerous studies have documented their detrimental effects on well-being, yet the large individual differences in psychological adaptation are still not well understood. Whereas in old age bereavement is normative and can be anticipated, divorce is an “off-time” transition for this age group. In contrast to bereavement which has been amply studied, research on later life divorce is still missing despite the increasing relevance of the topic due to the significant increase of divorces in older age. Based on a modified and extended view of Amato’s divorce-stress-adjustment model (2000), the aim of this contribution is to explore the differential impact of marital split-up and widowhood in older age on psychological (life satisfaction) and social well-being (social loneliness), and the adaptation to these critical life events. Our analyses are based on data gathered in a questionnaire study, which is part of the Swiss National Centre of Competence in Research LIVES. In a first step we compared three groups of individuals aged 60 to 75 years: a sample of 251 persons with a marital split-up (127 women; 123 men), a sample of 270 widowed persons (170 women; 100 men), and a group of 221 continuously married people (110 women; 111 men), which served as control group. In a second step, we investigated the role of socio-demographic variables, intrapersonal and interpersonal resources and variables of the context of loss as predictors for the psychological adaptation to a marital break-up and loss in old age. First results by ANCOVA indicate significant differences with regard to life satisfaction among the three groups, with divorced persons with the lowest scores, followed by the bereaved ones, and the married controls with the highest. Regarding social loneliness, divorced individuals report higher social loneliness than the bereaved group and the married controls (no significant difference between widowed and the married). In both loss groups, financial and intrapersonal resources, as well as the emotional valence of the loss are the most important predictors for the psychological and social adaptation. However, happiness in the past relationship is an important resource regarding the indicators for adaptation for the widowers, but not for individuals with a marital dissolution.

Building up and sharing knowledge for better decision making on soil and water conservation in a changing mountain environment - the WOCAT experience

For successful implementation of any soil and water conservation (SWC) or sustainable land management practice, it is essential to have a proper understanding of the natural and human environment in which these practices are applied. This understanding should be based on comprehensive information concerning the application of the technologies and not solely on the technological details. The World Overview of Conservation Approaches and Technologies (WOCAT) is documenting and evaluating SWC practices worldwide, following a standardised methodology that facilitates exchange and comparison of experiences. Notwithstanding this standardisation, WOCAT allows flexible use of its outputs, adapted to different users and different environments. WOCAT offers a valuable tool for evaluating the strengths and weaknesses of SWC practices and their potential for application in other areas. Besides collecting a wealth of information, gaps in available information are also exposed, showing the need for more research in those fields. Several key issues for development- oriented research have been identified and are being addressed in collaboration with a research programme for mitigating syndromes of global change.

DATED-1: compilation of dates and time-slice reconstruction of the build-up and retreat of the last Eurasian (British-Irish, Scandinavian, Svalbard-Barents-Kara Seas) Ice Sheets 40-10 ka

DATED-1 comprises a compilation of dates related to the build-up and retreat of the Eurasian (British-Irish, Scandinavian, Svalbard-Barents-Kara Seas) Ice Sheets, and time-slice maps of the Eurasian Ice sheet margins. Dates are sourced from the published literature. Ice margins are based on published geological and chronological data and include uncertainty bounds (maximum, minimum) as well as what we consider to be the most-credible (mc) based on the available evidence. DATED-1 has a census date of 1 January 2013. Full description and caveats for use are given in: Hughes, A.L.C., Gyllencreutz, R., Lohne, Ø.S., Mangerud, J., Svendsen, J.I. (2015) The last Eurasian Ice Sheets - a chronological database and time-slice reconstruction, DATED-1.