Estrogen receptor beta and estrogen response in breast cancer cell lines

Ced Stewart: Estrogen receptor beta and estrogen response in breast cancer cell lines Breast cancer affects 1 in 9 women in Britain and its development and treatment are greatly influenced by hormonal status, such as exposure to endogenous estrogen and expression of estrogen receptors (ERs). ERa is an established prognostic marker in breast cancer, but the role of ERp is less certain. The ERs act to regulate gene transcription via a highly complex variety of mechanisms in response to stimuli such as estrogen, tamoxifen or fulvestrant. In order to further define the role of ERp isoforms in breast cancer, their role in the estrogen response must be characterised. This thesis has used a set of four breast cancer cell lines, as well as an MCF7 cell line engineered to over-express ERpl mRNA (MCF7PIx), to investigate the role of ERp in estrogen response. Cells were - treated with a variety of stimuli (estrogen, tamoxifen, fulvestrant, epidermal growth factor and fibroblast growth factor-2) and expression of a panel of ER isoforms, estrogen responsive genes and housekeeping genes was measured using real-time, quantitative PCR. Estrogen response is cell line specific, both in terms of the genes affected and the level of response. These responses can be partly, but not fully, related to the levels of ERa expressed by the cell lines. Expression of individual ER isoforms varies in response to treatment in a time, stimulus and cell line specific manner. Different cell lines vary expression of different subsets of ER isoforms and MCF7pIx, which constitutively over-expresses ERpl mRNA, shows down-regulation of ERpl mRNA expression in response to estrogen. Together these data suggest that regulation may occur at the level of splicing and mRNA stability, as well as at the transcription level. MCF7 and MCF7P Ix showed.remarkably similar responses to treatments. In both cell lines, similar sets of genes were both up- and down-regulated by estrogenic and growth factor treatments. Most -genes showed a similar pattern of transcriptional activation at 0 to 8 h as at 24 h, except for ERpl and ERp2, indicating the importance of control of ERp expression. It was not possible to measure the levels of ERpl protein in the cells, therefore the similarity in responses in MCF7 and MCF7pIx may indicate that, despite the higher levels of ERpl rnRNA, MCF7pIx cells do not overexpress ERPI protein. Measurement of endogenous expression of a set of estrogen responsive genes in a panel of breast cancer cell lines in response to various stimuli has afforded new insights into the levelS and variation in the response achieved in this system. Expression of ERp mRNA was shown to be controlled in a cell line and treatment specific manner, as has previously been shown for ERa. Additionally, it was shown that this regulation was isofonn specific and was maintained when the ERp was overexpressed under the control of an exogenous promoter. This is particularly interesting, as it suggests various levels of regulation, indicating the important role of ERp in downstream estrogen responses. - Supplied by The British Library - 'The world's knowledge

An early giant planet instability recorded in asteroidal meteorites

Giant planet migration appears widespread among planetary systems in our Galaxy. However, the timescales of this process, which reflect the underlying dynamical mechanisms, are not well constrained, even within the solar system. Since planetary migration scatters smaller bodies onto intersecting orbits, it would have resulted in an epoch of enhanced bombardment in the solar system's asteroid belt. To accurately and precisely quantify the timescales of migration, we interrogate thermochronologic data from asteroidal meteorites, which record the thermal imprint of energetic collisions. We present a database of 40K-40Ar system ages from chondrite meteorites and evaluate it with an asteroid-scale thermal code coupled to a Markov chain Monte Carlo inversion. Simulations require bombardment in order to reproduce the observed age distribution and identify a bombardment event beginning ~11 million years after the Sun formed. Our results associate a giant planet instability in our solar system with the dissipation of the gaseous protoplanetary disk.Comment: 24 pages, 4 figures, 2 tables, 10 extended data items (8 figures, 2 tables). Under review at Nature Astronom

Inorganic–organic nanocomposites of CdSe nanocrystals surface-modified with oligo- and poly(fluorene) moieties

We report a facile grafting-from strategy towards the synthesis of inorganic–organic composites of semiconductor nanocrystals and wide-bandgap polymers. Amino-functional fluorenes have been used as co-ligands for CdSe nanocrystals, thus enabling us to design their surface directly during the synthesis. Highly monodisperse, strongly emitting CdSe nanocrystals have been obtained. Subsequently, a straightforward Yamamoto C–C coupling protocol was used to carry out surface polymerisation, hence modifying CdSe nanocrystals with oligo- and poly(fluorene) moieties. Both amino-fluorene capped CdSe nanocrystals and the resulting nanocrystal–polymer composites were characterized in detail by optical and FT-IR spectroscopy, TEM, AFM, and gel permeation chromatography, showing their potential as novel functional inorganic–organic hybrid materials

Evaluating landscape metrics for characterising hydrological response to storm events in urbanised catchments

Hydrological response of an urban catchment to storm events is determined by a number of factors including the degree of urbanisation and distribution and connectivity of urbanised surfaces. Therefore, the ability of spatially averaged catchment descriptors to characterise storm response is limited. Landscape metrics, widely used in ecology to quantify landscape structure, are employed to quantify urban land-cover patterns across a rural-urban gradient of catchments and attribute hydrological response. Attribution of all response metrics, except peak flow, is improved by combining lumped catchment descriptors with spatially explicit landscape metrics. Those representing connectedness and shape of suburban and natural greenspace improve characterisation of percentage runoff and storm runoff. Connectivity and location of urban surfaces are more important than impervious area alone for attribution of timing, validating findings from distributed hydrological modelling studies. Findings suggest potential improvements in attribution of storm runoff in ungauged urban catchments using landscape metrics

Laminin α5 is necessary for submandibular gland epithelial morphogenesis and influences FGFR expression through β1 integrin signaling

AbstractLaminin α chains have unique spatiotemporal expression patterns during development and defining their function is necessary to understand the regulation of epithelial morphogenesis. We investigated the function of laminin α5 in mouse submandibular glands (SMGs). Lama5−/− SMGs have a striking phenotype: epithelial clefting is delayed, although proliferation occurs; there is decreased FGFR1b and FGFR2b, but no difference in Lama1 expression; later in development, epithelial cell organization and lumen formation are disrupted. In wild-type SMGs α5 and α1 are present in epithelial clefts but as branching begins α5 expression increases while α1 decreases. Lama5 siRNA decreased branching, p42 MAPK phosphorylation, and FGFR expression, and branching was rescued by FGF10. FGFR siRNA decreased Lama5 suggesting that FGFR signaling provides positive feedback for Lama5 expression. Anti-β1 integrin antibodies decreased FGFR and Lama5 expression, suggesting that β1 integrin signaling provides positive feedback for Lama5 and FGFR expression. Interestingly, the Itga3−/−:Itga6−/− SMGs have a similar phenotype to Lama5−/−. Our findings suggest that laminin α5 controls SMG epithelial morphogenesis through β1 integrin signaling by regulating FGFR expression, which also reciprocally regulates the expression of Lama5. These data link changes in basement membrane composition during branching morphogenesis with FGFR expression and signaling

Francisella tularensis subsp. novicida isolated from a human in Arizona

<p>Abstract</p> <p>Background</p> <p><it>Francisella tularensis </it>is the etiologic agent of tularemia and is classified as a select agent by the Centers for Disease Control and Prevention. Currently four known subspecies of <it>F. tularensis </it>that differ in virulence and geographical distribution are recognized:<it>tularensis </it>(type A), <it>holarctica </it>(type B), <it>mediasiatica</it>, and <it>novicida</it>. Because of the Select Agent status and differences in virulence and geographical location, the molecular analysis of any clinical case of tularemia is of particular interest. We analyzed an unusual <it>Francisella </it>clinical isolate from a human infection in Arizona using multiple DNA-based approaches.</p> <p>Findings</p> <p>We report that the isolate is <it>F. tularensis </it>subsp. <it>novicida</it>, a subspecies that is rarely isolated.</p> <p>Conclusion</p> <p>The rarity of this <it>novicida </it>subspecies in clinical settings makes each case study important for our understanding of its role in disease and its genetic relationship with other <it>F. tularensis </it>subspecies.</p

Regional splanchnic oxygen saturation for preterm infants in the first week after birth:reference values

BACKGROUND: Near-infrared spectroscopy is used in the assessment of regional splanchnic oxygen saturation (rsSO2), but solid reference values are scarce. We aimed to establish reference values of rsSO2 for preterm infants during the first week after birth, both crude and modeled based on predictors. METHODS: We included infants with gestational age (GA) <32 weeks and/or birth weight <1200 g. We excluded infants who developed necrotizing enterocolitis or sepsis or who died. In the first week after birth, we determined a daily 2-h mean of rsSO2 to assess its associations with sex, GA, postnatal age (PNA), small-for-gestational age (SGA) status, patent ductus arteriosus, hemoglobin, nutrition, and head circumference at birth and translated those into a prediction model. RESULTS: We included 220 infants. On day 1, the mean ± SD rsSO2 value was 48.2% ± 16.6. The nadir of rsSO2 was on day 4 (38.7% ± 16.6 smoothed line) to 5 (37.4%±17.3, actual data), after which rsSO2 increased to 44.2% ± 16.6 on day 7. The final model of the reference values of rsSO2 included the following coefficients: rsSO2 = 3.2 - 7.0 × PNA + 0.8 × PNA2 - 4.0 × SGA + 1.8 × GA. CONCLUSIONS: We established reference values of rsSO2 for preterm infants during the first week after birth. GA, PNA, and SGA affect these values and need to be taken into account. IMPACT: Regional splanchnic oxygen saturation is lower in infants with a lower gestational age and in small-for-gestational age infants. Regional splanchnic oxygen saturation decreases with a higher postnatal age until day 4 after birth and then increases until day 7 after birth. Gestational age, postnatal age, and small-for-gestational age status affect regional splanchnic oxygen saturation and need to be taken into account when interpreting regional splanchnic oxygen saturations using NIRS. Reference values for infant regional splanchnic oxygen saturation can be computed with a formula based on these variables, as provided by this study

Behavioral features in Prader-Willi syndrome (PWS): consensus paper from the International PWS Clinical Trial Consortium.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder associated with a characteristic behavioral phenotype that includes severe hyperphagia and a variety of other behavioral challenges such as temper outbursts and anxiety. These behaviors have a significant and dramatic impact on the daily functioning and quality of life for the person with PWS and their families. To date, effective therapies addressing these behavioral challenges have proven elusive, but several potential treatments are on the horizon. However, a limiting factor for treatment studies in PWS is the lack of consensus in the field regarding how to best define and measure the complex and interrelated behavioral features of this syndrome. The International PWS Clinical Trials Consortium (PWS-CTC, www.pwsctc.org ) includes expert PWS scientists, clinicians, and patient advocacy organization representatives focused on facilitating clinical trials in this rare disease. To address the above gap in the field, members of the PWS-CTC "Behavior Outcomes Working Group" sought to develop a unified understanding of the key behavioral features in PWS and build a consensus regarding their definition and description. The primary focus of this paper is to present consensus definitions and descriptions of key phenotypic PWS behaviors including hyperphagia, temper outbursts, anxiety, obsessive-compulsive behaviors, rigidity, and social cognition deficits. Patient vignettes are provided to illustrate the interrelatedness and impact of these behaviors. We also review some available assessment tools as well as new instruments in development which may be useful in measuring these behavioral features in PWS

Russell bodies in a skin biopsy: a case report

<p>Abstract</p> <p>Introduction</p> <p>The presence of eosinophilic bodies in a skin biopsy can be found in a variety of situations and this may present a challenge to the pathologist. The differential diagnosis of these eosinophilic structures include microorganisms such as histoplasmosis or cryptococcosis, fungi, Michaelis-Gutmann bodies, deposits of amyloid or immunoglobulins, colloid bodies or elastic bodies.</p> <p>Case presentation</p> <p>During a routine examination of a skin biopsy with actinic keratosis taken from the cheek of a 61-year-old man, clusters of eosinophilic bodies were seen within an inflammatory infiltrate in the dermis, both intracytoplasmic and extracellular. Using additional immunohistochemical staining, these structures were identified as polyclonal Russell bodies.</p> <p>Conclusion</p> <p>The differential diagnosis of intracytoplasmic eosinophilic structures in a skin biopsy includes Russell bodies, an uncommon finding that may be associated with chronic inflammatory conditions.</p

Behavioral features in Prader-Willi syndrome (PWS) : consensus paper from the International PWS Clinical Trial Consortium

UDBELLATERRAPrader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder associated with a characteristic behavioral phenotype that includes severe hyperphagia and a variety of other behavioral challenges such as temper outbursts and anxiety. These behaviors have a significant and dramatic impact on the daily functioning and quality of life for the person with PWS and their families. To date, effective therapies addressing these behavioral challenges have proven elusive, but several potential treatments are on the horizon. However, a limiting factor for treatment studies in PWS is the lack of consensus in the field regarding how to best define and measure the complex and interrelated behavioral features of this syndrome. The International PWS Clinical Trials Consortium (PWS-CTC, ) includes expert PWS scientists, clinicians, and patient advocacy organization representatives focused on facilitating clinical trials in this rare disease. To address the above gap in the field, members of the PWS-CTC "Behavior Outcomes Working Group" sought to develop a unified understanding of the key behavioral features in PWS and build a consensus regarding their definition and description. The primary focus of this paper is to present consensus definitions and descriptions of key phenotypic PWS behaviors including hyperphagia, temper outbursts, anxiety, obsessive-compulsive behaviors, rigidity, and social cognition deficits. Patient vignettes are provided to illustrate the interrelatedness and impact of these behaviors. We also review some available assessment tools as well as new instruments in development which may be useful in measuring these behavioral features in PWS