Advances in breast cancer treatment and prevention: preclinical studies on aromatase inhibitors and new selective estrogen receptor modulators (SERMs).

Intensive basic and clinical research over the past 20 years has yielded crucial molecular understanding into how estrogen and the estrogen receptor act to regulate breast cancer and has led to the development of more effective, less toxic, and safer hormonal therapy agents for breast cancer management and prevention. Selective potent aromatase inhibitors are now challenging the hitherto gold standard of hormonal therapy, the selective estrogen-receptor modulator tamoxifen. Furthermore, new selective estrogen-receptor modulators such as arzoxifene, currently under clinical development, offer the possibility of selecting one with a more ideal pharmacological profile for treatment and prevention of breast cancer. Two recent studies in preclinical model systems that evaluate mechanisms of action of these new drugs and suggestions about their optimal clinical use are discussed

Repurposing designed mutants: a valuable strategy for computer-aided laccase engineering – the case of POXA1b

The broad specificity of laccases, a direct consequence of their shallow binding site, makes this class of enzymes a suitable template to build specificity toward putative substrates. In this work, a computational methodology that accumulates beneficial interactions between the enzyme and the substrate in productive conformations is applied to oxidize 2,4-diamino-benzenesulfonic acid with POXA1b laccase. Although the experimental validation of two designed variants yielded negative results, most likely due to the hard oxidizability of the target substrate, molecular simulations suggest that a novel polar binding scaffold was designed to anchor negatively charged groups. Consequently, the oxidation of three such molecules, selected as representative of different classes of substances with different industrial applications, significantly improved. According to molecular simulations, the reason behind such an improvement lies in the more productive enzyme–substrate binding achieved thanks to the designed polar scaffold. In the future, mutant repurposing toward other substrates could be first carried out computationally, as done here, testing molecules that share some similarity with the initial target. In this way, repurposing would not be a mere safety net (as it is in the laboratory and as it was here) but rather a powerful approach to transform laccases into more efficient multitasking enzymes.This work was funded by INDOX (KBBE-2013-7-613549) European project and CTQ2013-48287-R Spanish National Project. V. G. and E. M. acknowledge Università degli Studi di Napoli and Generalitat de Catalunya for their respective predoctoral fellowships.Peer ReviewedPostprint (author's final draft

Leadership conversations: the impact on patient environments

Purpose – The aim of this study is to examine 15 NHS acute trusts in England that achieved high scores at all their hospitals in the first four national Patient Environment audits. No common external explanations were discernible. This paper seeks to examine whether the facilities managers responsible for the Patient Environment displayed a consistent leadership style. Design/methodology/approach – Overall, six of the 15 trusts gave permission for the research to take place and a series of unstructured interviews and observations were arranged with 22 facilities managers in these trusts. Responses were transcribed and categorised through multiple iteration. Findings – The research found common leadership and managerial behaviours, many of which could be identified from other literature. The research also identified managers deliberately devoting energy and time to creating networks of conversations. This creation of networks through managing conversation is behaviour less evident in mainstream leadership literature or in the current Department of Health and NHS leadership models. Practical implications – The findings of this study offer managers (particularly those in FM and managers across NHS) a unique insight into the potential impact of leaders giving an opportunity to re-model thinking on management and leadership and the related managerial development opportunities. It provides the leverage to move facilities management from the role of a commodity or support service, to a position as a true enabler of business. Originality/value – Original research is presented in a previously under-examined area. The paper illuminates how facilities management within trusts achieving high Patient Environment Action Team (PEAT) scores is led.</p

An Updated Visual Orbit of the Directly Imaged Exoplanet 51 Eridani b and Prospects for a Dynamical Mass Measurement with Gaia

We present a revision to the visual orbit of the young, directly imaged exoplanet 51 Eridani b using four years of observations with the Gemini Planet Imager. The relative astrometry is consistent with an eccentric (e = 0.53^(+0.09)_(−0.13)) orbit at an intermediate inclination (i = 136^(+10)_(−11)°), although circular orbits cannot be excluded due to the complex shape of the multidimensional posterior distribution. We find a semimajor axis of 11.1^(+4.2)_(−1.3) au and a period of 28.1^(+17.2)_(−4.9) yr, assuming a mass of 1.75 M⊙ for the host star. We find consistent values with a recent analysis of VLT/SPHERE data covering a similar baseline. We investigate the potential of using the absolute astrometry of the host star to obtain a dynamical mass constraint for the planet. The astrometric acceleration of 51 Eri derived from a comparison of the Hipparcos and Gaia catalogs was found to be inconsistent at the 2σ–3σ level with the predicted reflex motion induced by the orbiting planet. Potential sources of this inconsistency include a combination of random and systematic errors between the two astrometric catalogs and the signature of an additional companion within the system interior to current detection limits. We also explored the potential of using Gaia astrometry alone for a dynamical mass measurement of the planet by simulating Gaia measurements of the motion of the photocenter of the system over the course of the extended 8 yr mission. We find that such a measurement is only possible (>98% probability) given the most optimistic predictions for the Gaia scan astrometric uncertainties for bright stars and a high mass for the planet (≳3.6 M_(Jup))

Synergy between RA and TLR3 promotes type I IFN-dependent apoptosis through upregulation of TRAIL pathway in breast cancer cells

This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License.Due to its ability to regulate the growth, differentiation and apoptosis of cancer cells, retinoic acid (RA) is considered a signaling molecule with promising therapeutic potential in oncology. In this study, we show that RA is able to induce the intrinsic ability of breast cancer cells to recognize double-stranded RNA (dsRNA) through the upregulation of Toll-like receptor 3 (TLR3) expression. RA, co-administered with the dsRNA mimicker polyinosinic–polycytidylic acid (poly(I:C)), synergizes to mount a specific response program able to sense dsRNA through the concurrent upregulation of TLR3, the dsRNA helicases melanoma differentiation-associated antigen-5 (MDA-5) and RA-inducible gene-1 (RIG-1), and the dsRNA-activated protein kinase (PKR) expression, leading breast cancer cells to specifically express downstream transcriptional targets of dsRNA sensors, such as interferon-β (IFNβ), interleukin-8 (IL-8), chemokine (C-C motif) ligand 5 (CCL5), and C-X-C motif Chemokine 10 (CXCL10). A TLR3-dependent apoptotic program is also induced by RA and poly(I:C) co-treatment that correlates with the induction of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and contributes to block breast cancer cell proliferation. The mechanisms of apoptosis induced by RA/poly(I:C) in breast cancer cells involve type I IFN autocrine signaling, caspase-8 and caspase-3 activation, as well as TRAIL signaling. Our results reveal important links among RA, TLR3 and TRAIL and highlight the combined use of RA and poly(I:C) as a potential effective tumor therapy by improving the apoptotic response of cancer cells with low sensitivity to the action of synthetic dsRNA.This work was supported by funds from the MICINN (SAF2007-63634 and SAF2010-21195), CSIC (201120E105), and Fundación Médica Mutua Madrileña (2005 0584). ARBV was supported by funds from the MICINN. AMJ-L is a recipient of a grant from the Spanish MICINN (Ramón y Cajal Program).Peer reviewe

Sweatshop Watch Newsletter

Spring 2007 newsletter of Sweatshop Watch includes coverage of garment workers fighting for justice in the global apparel industry, new anti-sweatshop reforms, the California’s Garment Special Account, and the hiring of an independent monitor to Los Angeles’ sweat-free law

Understanding the lived experiences of Mexican informal caregivers with Ambient Assisted Living Technologies

Ambient Assisted Living (AAL) Technologies, have the potential to support the people with dementia living in their homes for longer. Dementia is a major public health concern. It currently affects approximately 46.8 million people worldwide and by 2050 this figure will increase to 131.5 million. Low-and-middle income countries (LMIC) will be particularly affected by this situation as their poor health infrastructures and governmental support will mean that they have to rely on the informal caregiver (IC) sector. ICs are people who care for a dependent or disabled family member, commonly spouses or daughters. Mexico was the first Spanish speaking country in the world to recognise dementia as a public health priority. In-home technologies, such as AAL Technologies, are used in dementia care in order to improve patients’ and caregivers’ quality of life. This paper explores the way in which Mexican ICs of people with dementia (PWD) make sense of their lived experiences with AAL technologies

Finding optimal stimuli ensemble of a cortical network

We explore the determination of the optimal stimuli ensemble of a cortical network on the basis of numerical simulations of a local recurrent network. The optimal stimulus ensemble is determined with the Blahut-Arimoto algorithm using indices of population activity (multiunit activity and local field potentials). We show that the optimal stimulus ensemble is characterized by a distribution where the stimulus which induces a change in the dynamics of the network is highly represented. These results suggests that bifurcation points in the networks dynamic are highly informative and were in accordance with preliminary observation of electrophysiological recordings

Indian tuna fishery - production trend during yesteryears and scope for the future

Fishery for tuna and tuna like fishes in the country has been in vogue from time immemorial and presently involves fishery by coastal based fleets of varying specifications with different craft-gear combinations and longline fishery by large oceanic fishing vessels. The former undertakes short duration fishing trips and exploit mainly surface tunas in the outer shelf and adjacent oceanic waters. The tuna landings though nominal during 1950-2005, registered a continuous increase over the years from a minimum of 848 t (1951) to 46,334 t (2000). With the introduction of targeted fishing for oceanic tunas during 2005-‘06, the landings improved and reached the maximum of 129,801 t in 2008. The fishery was supported by nine species, five coastal/neritic species and four oceanic species. Coastal tunas formed 57% of the tuna catch during 2006-’10 and was represented by the little tuna (Euthynnus affinis), frigate tuna (Auxis thazard), bullet tuna (Auxis rochei), longtail tuna (Thunnus tonggol) and bonito (Sarda orientalis). The oceanic species, which formed 43% of tuna catch, were yellowfin tuna (Thunnus albacares), skipjack tuna (Katsuwonus pelamis), dogtooth tuna (Gymnosarda unicolor) and bigeye tuna (Thunnus obesus). Information collected from different sources suggested that longliners operating in Indian EEZ and adjacent international waters caught around 87,000 t of tuna annually during 2006-'10. Catch was supported by three species dominated by yellowfin tuna and small proportion of big-eye and dogtooth tuna. Since fishery by coastal based units restricted to small areas and share of the catch by longliners from EEZ are not clearly known, systematic assessment of tuna stock in Indian EEZ is very difficult. However, the evaluation of the fishery scenario indicated only limited scope for improving tuna production from certain areas of coastal waters; whereas enormous scope remain for increasing tuna production from the oceanic waters of EEZ. However, since tunas being straddling resources shared by several nations, exploitation at one area will influence the fishery in other areas