Differential Modulation of Transcriptional Activity of Estrogen Receptors by Direct Protein-Protein Interactions with the T Cell Factor Family of Transcription Factors

Two major signaling pathways, those triggered by estrogen (E(2)) and by the Wnt family, interact in the breast to cause growth and differentiation. The estrogen receptors ER(alpha) and ER(beta) are activated by binding E(2) and act as ligand-dependent transcription factors. The effector for the Wnt family is the Tcf family of transcription factors. Both sets of transcription factors recognize discrete but different nucleotide sequences in the promoters of their target genes. By using transient transfections of reporter constructs for the osteopontin and thymidine kinase promoters in rat mammary cells, we show that Tcf-4 antagonizes and Tcf-1 stimulates the effects of activated ER/E(2). For mutants of the former promoter, the stimulatory effects of ER(alpha)/E(2) can be made to be dependent on Tcf-1, and for the latter promoter the effects of the T cell factors (TCFs) are dependent on ER/E(2). Direct interaction between ERs and Tcfs either at the Tcf/ER(alpha)-binding site on the DNA or in the absence of DNA is established by gel retardation assays or by coimmunoprecipitation/biosensor methods, respectively. These results show that the two sets of transcription factors can interact directly, the interaction between ERs and Tcf-4 being antagonistic and that between ERs and Tcf-1 being synergistic on the activity of the promoters employed. Since Tcf-4 is the major Tcf family member in the breast, it is suggested that the antagonistic interaction is normally dominant in vivo in this tissue.

Development and evaluation of a vaginal ring device for sustained delivery of HIV microbicides to non-human primate

Background There is considerable interest in developing coitally indepen- dent, sustained release formulations for long-term administration of HIV microbicides. Vaginal ring devices are at the forefront of this formulation strategy. Methods Non-medicated silicone elastomer vaginal rings were prepared having a range of appropriate dimensions for testing vaginal ?t in pig- tailed and Chinese rhesus macaques. Cervicovaginal proin?ammatory markers were evaluated. Compression testing was performed to compare the relative ?exibility of various macaque and commercial human rings. Results All rings remained in place during the study period and no tissue irritation or signi?cant induction of cervicovaginal proin?ammatory mark- ers or signs of physical discomfort were observed during the 8-week study period. Conclusions Qualitative evaluation suggests that the 25 · 5-mm ring pro- vided optimal ?t in both macaque species. Based on the results presented here, low-consistency silicone elastomers do not cause irritation in maca-

Estrogen Receptor-beta Affects the Prognosis of Human Malignant Mesothelioma

Malignant pleural mesothelioma is an asbestos-related neoplasm with poor prognosis, refractory to current therapies, the incidence of which is expected to increase in the next decades. Female gender was identified as a positive prognostic factor among other clinical and biological prognostic markers for malignant mesothelioma, yet a role of estrogen receptors (ERs) has not been studied. Our goal was to investigate ERs expression in malignant mesothelioma and to assess whether their expression correlates with prognosis. Immunohistochemical analysis revealed intense nuclear ER beta staining in normal pleura that was reduced in tumor tissues. Conversely, neither tumors nor normal pleura stained positive for ER alpha. Multivariate analysis of 78 malignant mesothelioma patients with pathologic stage, histologic type, therapy, sex, and age at diagnosis indicated that FRO expression is an independent prognostic factor of better survival. Moreover, studies in vitro confirmed that treatment with 17 beta-estradiol led to an ER beta-mediated inhibition of malignant mesothelioma cell proliferation as well as p21(CIP1) and p27(KIP1) up-regulation. Consistently cell growth was suppressed by ER beta overexpression, causing a G(2)-M-phase cell cycle arrest, paralleled by cyclin B1 and survivin down-regulation. Our data support the notion that ER beta acting as a tumor suppressor is of high potential relevance to prediction of disease progression and to therapeutic response of malignant mesothelioma patients. [Cancer Res 2009;69(11):4598-604]

Tobramycin Inhalation Powder™:a novel drug delivery system for treating chronic Pseudomonas aeruginosa infection in cystic fibrosis

Lung disease in cystic fibrosis (CF) is typified by the development of chronic airways infection culminating in bronchiectasis and progression to end-stage respiratory disease. Pseudomonas aeruginosa, a ubiquitous gram-negative bacteria, is the archetypical CF pathogen and is associated with an accelerated clinical decline. The development and widespread use of chronic suppressive aerosolized antibacterial therapies, in particular Tobramycin Inhalation Solution (TIS), in CF has contributed to reduced lung function decline and improved survival. However, the requirement for the aerosolization of these agents through nebulizers has been associated with increased treatment burden, reduced quality of life and remain a barrier to broader uptake. Tobramycin Inhalation Powder (TIP™) has been developed by Novartis with the express purpose of delivering the same benefits as TIS in a time-effective manner. Administered via the T-326™ (Novartis) Inhaler in four individual 28-mg capsules, TIP can be administered in a quarter of the time of traditional nebulizers and is inherently portable. In clinical studies, TIP has been shown to be safe, result in equivalent or superior reductions in P. aeruginosa sputum density and produce similar improvements in pulmonary function. TIP offers significant advantages in time saving, portability and convenience over traditional nebulized TIS with comparable clinical outcomes for individuals with CF.

The impact of personalised therapies on respiratory medicine

Stratified approaches to treating disease are very attractive, as efficacy is maximised by identifying responders using a companion diagnostic or by careful phenotyping. This approach will spare non-responders form potential side-effects. This has been pioneered in oncology where single genes or gene signatures indicate tumours that will respond to specific chemotherapies. Stratified approaches to the treatment of asthma with biological therapies are currently being extensively studied. In cystic fibrosis (CF), therapies have been developed that are targeted at specific functional classes of mutations. Ivacaftor, the first of such therapies, potentiates dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein Class III mutations and is now available in the USA and some European countries. Pivotal studies in patients with a G551D mutation, the most common Class III mutation, have demonstrated significant improvements in clinically important outcomes such as spirometry and exacerbations. Sweat chloride was significantly reduced demonstrating a functional effect on the dysfunctional CFTR protein produced by the G551D mutation. Symptom scores are also greatly improved to a level that indicates that this is a transformational treatment for many patients. This stratified approach to the development of therapies based on the functional class of the mutations in CF is likely to lead to new drugs or combinations that will correct the basic defect in many patients with CF. © ERS 2013.

Assessment Of various sensors for structural health monitoring for bridge weigh-in-motion (B-WIM).

In recent years, Structural Health Monitoring (SHM) systems have been developed to monitor bridge deterioration, assess real load levels and hence extend bridge life and safety. A road bridge is only safe if the stresses caused by the passing vehicles are less than the capacity of the bridge to resist them. Conventional SHM systems can be used to improve knowledge of the bridges capacity to resist stresses but generally give no information on the causes of any increase in stresses (based on measuring strain). The concept of in Bridge Weigh-in-Motion (B-WIM) is to establish axle loads, without interruption to traffic flow, by using strain sensors at a bridge soffit and subsequently converting the data to real time axle loads or stresses. Recent studies have shown it would be most beneficial to develop a portable system which can be easily attached to existing and new bridge structures for a specified monitoring period. The sensors could then be left in place while the data acquisition can be moved for various other sites. Therefore it is necessary to find accurate sensors capable of capturing peak strains under dynamic load and suitable methods for attaching these strain sensors to existing and new bridge structures. Additionally, it is important to ensure accurate strain transfer between concrete and steel, the adhesives layer and the strain sensor. This paper describes research investigating the suitably of using various sensors for the monitoring of concrete structures under dynamic vehicle load. Electrical resistance strain (ERS) gauges, vibrating wire (VW) gauges and fibre optic sensors (FOS) are commonly used for SHM. A comparative study will be carried out to select a suitable sensor for a bridge Weigh in Motion System. This study will look at fixing methods, durability, scanning rate and accuracy range. Finite element modeling is used to predict the strains which are then validated in laboratory trials.

Transiting Exoplanet Studies and Community Targets for JWST's Early Release Science Program

The James Webb Space Telescope (JWST) will likely revolutionize transiting exoplanet atmospheric science, due to a combination of its capability for continuous, long duration observations and its larger collecting area, spectral coverage, and spectral resolution compared to existing space-based facilities. However, it is unclear precisely how well JWST will perform and which of its myriad instruments and observing modes will be best suited for transiting exoplanet studies. In this article, we describe a prefatory JWST Early Release Science (ERS) Cycle 1 program that focuses on testing specific observing modes to quickly give the community the data and experience it needs to plan more efficient and successful transiting exoplanet characterization programs in later cycles. We propose a multi-pronged approach wherein one aspect of the program focuses on observing transits of a single target with all of the recommended observing modes to identify and understand potential systematics, compare transmission spectra at overlapping and neighboring wavelength regions, confirm throughputs, and determine overall performances. In our search for transiting exoplanets that are well suited to achieving these goals, we identify 12 objects (dubbed “community targets”) that meet our defined criteria. Currently, the most favorable target is WASP-62b because of its large predicted signal size, relatively bright host star, and location in JWST's continuous viewing zone. Since most of the community targets do not have well-characterized atmospheres, we recommend initiating preparatory observing programs to determine the presence of obscuring clouds/hazes within their atmospheres. Measurable spectroscopic features are needed to establish the optimal resolution and wavelength regions for exoplanet characterization. Other initiatives from our proposed ERS program include testing the instrument brightness limits and performing phase-curve observations. The latter are a unique challenge compared to transit observations because of their significantly longer durations. Using only a single mode, we propose to observe a full-orbit phase curve of one of the previously characterized, short-orbital-period planets to evaluate the facility-level aspects of long, uninterrupted time-series observations.

Posterior Probability Modeling and Image Classification for Archaeological Site Prospection: Building a Survey Efficacy Model for Identifying Neolithic Felsite Workshops in the Shetland Islands

The application of custom classification techniques and posterior probability modeling (PPM) using Worldview-2 multispectral imagery to archaeological field survey is presented in this paper. Research is focused on the identification of Neolithic felsite stone tool workshops in the North Mavine region of the Shetland Islands in Northern Scotland. Sample data from known workshops surveyed using differential GPS are used alongside known non-sites to train a linear discriminant analysis (LDA) classifier based on a combination of datasets including Worldview-2 bands, band difference ratios (BDR) and topographical derivatives. Principal components analysis is further used to test and reduce dimensionality caused by redundant datasets. Probability models were generated by LDA using principal components and tested with sites identified through geological field survey. Testing shows the prospective ability of this technique and significance between 0.05 and 0.01, and gain statistics between 0.90 and 0.94, higher than those obtained using maximum likelihood and random forest classifiers. Results suggest that this approach is best suited to relatively homogenous site types, and performs better with correlated data sources. Finally, by combining posterior probability models and least-cost analysis, a survey least-cost efficacy model is generated showing the utility of such approaches to archaeological field survey.

Future trends in cystic fibrosis demography in 34 European countries

Median survival has increased in people with cystic fibrosis (CF) during the past six decades, which has led to an increased number of adults with CF. The future impact of changes in CF demographics has not been evaluated. The aim of this study was to estimate the number of children and adults with CF in 34 European countries by 2025. Data were obtained from the European Cystic Fibrosis Society Patient Registry. Population forecasts were performed for countries that have extensive CF population coverage and at least 4 years of longitudinal data by modelling future entering and exiting flows in registry cohorts. For the other countries, population projections were performed based on assumptions from knowledge of current CF epidemiology. Western European countries' forecasts indicate that an increase in the overall number of CF patients by 2025, by approximately 50%, corresponds to an increase by 20% and by 75% in children and adults, respectively. In Eastern European countries the projections suggest a predominant increase in the CF child population, although the CF adult population would also increase.It was concluded that a large increase in the adult CF population is expected in the next decade. A significant increase in adult CF services throughout Europe is urgently required.