Lack of correlation of stem cell markers in breast cancer stem cells

BACKGROUND: Various markers are used to identify the unique sub-population of breast cancer cells with stem cell properties. Whether these markers are expressed in all breast cancers, identify the same population of cells, or equate to therapeutic response is controversial. METHODS: We investigated the expression of multiple cancer stem cell markers in human breast cancer samples and cell lines in vitro and in vivo, comparing across and within samples and relating expression with growth and therapeutic response to doxorubicin, docetaxol and radiotherapy. RESULTS: CD24, CD44, ALDH and SOX2 expression, the ability to form mammospheres and side-population cells are variably present in human cancers and cell lines. Each marker identifies a unique rather than common population of cancer cells. In vivo, cells expressing these markers are not specifically localized to the presumptive stem cell niche at the tumour/stroma interface. Repeated therapy does not consistently enrich cells expressing these markers, although ER-negative cells accumulate. CONCLUSIONS: Commonly employed methods identify different cancer cell sub-populations with no consistent therapeutic implications, rather than a single population of cells. The relationships of breast cancer stem cells to clinical parameters will require identification of specific markers or panels for the individual cancer

Binary and Millisecond Pulsars at the New Millennium

We review the properties and applications of binary and millisecond pulsars. Our knowledge of these exciting objects has greatly increased in recent years, mainly due to successful surveys which have brought the known pulsar population to over 1300. There are now 56 binary and millisecond pulsars in the Galactic disk and a further 47 in globular clusters. This review is concerned primarily with the results and spin-offs from these surveys which are of particular interest to the relativity community.Comment: 59 pages, 26 figures, 5 tables. Accepted for publication in Living Reviews in Relativity (http://www.livingreviews.org

Is it feasible to deliver a complex intervention to improve the outcome of falls in people with dementia? A protocol for the DIFRID feasibility study

Background: People with dementia (PWD) experience ten times as many incident falls as people without dementia. Little is known about how best to deliver services to people with dementia following a fall. We used an integrated, mixed-methods approach to develop a new intervention which combines theory generated via a realist synthesis and data on current provision and pathways, gathered through a prospective observational study as well as qualitative interviews, focus groups, and ethnographic observation. This intervention is to be tested in a feasibility study in the UK National Health Service. Methods: People living with dementia in one of three geographical areas will be eligible for the study if they experience a fall requiring healthcare attention and have an informal carer. Potential participants will be identified by community services (primary care, paramedics, telecare), secondary care (ED; facilitated discharge services; rehabilitation outreach teams) and research case registers. Participants will receive a complex multidisciplinary intervention focused on their goals and interests for up to 12 weeks. The intervention will be delivered by occupational therapists, physiotherapists and rehabilitation support workers. Feasibility outcomes will include recruitment and retention, suitability and acceptability of outcome measures and acceptability, feasibility and fidelity of intervention components. PWD outcome measures will include number of falls, Montreal Cognitive Assessment (MOCA), European Quality of Life Instrument (EQ-5D-5L), Quality of Life–Alzheimer’s Disease Scale (QOL-AD), Modified Falls Efficacy Scale (MFES) and Goal Attainment Scaling (GAS). PWD outcome measures completed by an informal carer will include Disability Assessment for Dementia (DAD), EQ-5D-5L Proxy, QoL-AD Proxy and a Health Utilisation Questionnaire (HUQ), The carer outcome measure will be the Zarit Burden Interview (ZBI). An embedded process evaluation will explore barriers and facilitators to recruitment and intervention delivery. Discussion: The study results will inform whether and how a larger multicentre RCT should be undertaken. A full RCT would have the potential to show how outcomes can be improved for people with dementia who have fallen. Ethics and dissemination: The National Research Ethics Service Committee Newcastle and North Tyneside 2 approved the feasibility study. Trial registration: International Standard Randomised Controlled Trial Registry Registration number: ISRCTN41760734 Date of registration: 16/11/201

Rational manipulation of mRNA folding free energy allows rheostat control of pneumolysin production by Streptococcus pneumoniae

Rational manipulation of mRNA folding free energy allows rheostat control of pneumolysin production by Streptococcus pneumoniaeThe contribution of specific factors to bacterial virulence is generally investigated through creation of genetic "knockouts" that are then compared to wild-type strains or complemented mutants. This paradigm is useful to understand the effect of presence vs. absence of a specific gene product but cannot account for concentration-dependent effects, such as may occur with some bacterial toxins. In order to assess threshold and dose-response effects of virulence factors, robust systems for tunable expression are required. Recent evidence suggests that the folding free energy (?G) of the 5' end of mRNA transcripts can have a significant effect on translation efficiency and overall protein abundance. Here we demonstrate that rational alteration of 5' mRNA folding free energy by introduction of synonymous mutations allows for predictable changes in pneumolysin (PLY) expression by Streptococcus pneumoniae without the need for chemical inducers or heterologous promoters. We created a panel of isogenic S. pneumoniae strains, differing only in synonymous (silent) mutations at the 5' end of the PLY mRNA that are predicted to alter ?G. Such manipulation allows rheostat-like control of PLY production and alters the cytotoxicity of whole S. pneumoniae on primary and immortalized human cells. These studies provide proof-of-principle for further investigation of mRNA ?G manipulation as a tool in studies of bacterial pathogenesis.National Institutes of Health (www.nih.gov) (R01 AI092743 and R21 AI111020 to A.J.R.). F.E.A. was supported by the Portuguese Foundation for Science and Technology (www.fct.pt) SFRH/BD/33901/2009 and the Luso-American Development Foundation (www.flad.pt). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Nutrition and dementia care: developing an evidence-based model for nutritional care in nursing homes.

BACKGROUND: There is a growing volume of research to offer improvements in nutritional care for people with dementia living in nursing homes. Whilst a number of interventions have been identified to support food and drink intake, there has been no systematic research to understand the factors for improving nutritional care from the perspectives of all those delivering care in nursing homes. The aim of this study was to develop a research informed model for understanding the complex nutritional problems associated with eating and drinking for people with dementia. METHODS: We conducted nine focus groups and five semi-structured interviews with those involved or who have a level of responsibility for providing food and drink and nutritional care in nursing homes (nurses, care workers, catering assistants, dietitians, speech and language therapists) and family carers. The resulting conceptual model was developed by eliciting care-related processes, thus supporting credibility from the perspective of the end-users. RESULTS: The seven identified domain areas were person-centred nutritional care (the overarching theme); availability of food and drink; tools, resources and environment; relationship to others when eating and drinking; participation in activities; consistency of care and provision of information. CONCLUSIONS: This collaboratively developed, person-centred model can support the design of new education and training tools and be readily translated into existing programmes. Further research is needed to evaluate whether these evidence-informed approaches have been implemented successfully and adopted into practice and policy contexts and can demonstrate effectiveness for people living with dementia

Effectiveness of interventions aimed at improving physical and psychological outcomes of fall-related injuries in people with dementia: a narrative systematic review

Background: The annual prevalence of falls in people with dementia ranges from 47 to 90%. Falls are a common reason for hospital admission in people with dementia, and there is limited research evidence regarding the care pathways experienced by this population. In addition to immediate management of an injury, prevention of further falls is likely to be an important part of any successful intervention. This review aims to assess the effectiveness of interventions for improving the physical and psychological wellbeing of people with dementia who have sustained a fall-related injury. Methods: Systematic review methodologies were employed utilising searches across multiple databases (MEDLINE, CENTRAL, Health Management Information Consortium, EMBASE, CINAHL, Web of Science, Allied and Complementary Medicine Database, and Physiotherapy Evidence Database (PEDro)) and citation chaining. Studies including people with a known diagnosis of dementia living in the community and who present at health services with a fall, with or without injury, were included. Outcomes of interest included mobility, recurrent falls, activities of daily living, length of hospital stay, and post-discharge residence. Results were independently reviewed and quality assessed by two researchers, and data extracted using a customised form. A narrative synthesis was performed due to heterogeneity of the included studies. Results: Seven studies were included. Interventions clustered into three broad categories: multidisciplinary in-hospital post-surgical geriatric assessment; pharmaceuticals; and multifactorial assessment. Multidisciplinary care and early mobilisation showed short-term improvements for some outcomes. Only an annual administration of zoledronic acid showed long-term reduction in recurrent falls. Conclusions: Due to high heterogeneity across the studies, definitive conclusions could not be reached. Most post-fall interventions were not aimed at patients with dementia and have shown little efficacy regardless of cognitive status. Minor improvements to some quality of life indicators were shown, but these were generally not statistically significant. Conclusions were also limited due to most studies addressing hip fracture; the interventions provided for this type of injury may not be suitable for other types of fractures or soft tissue injuries, or for use in primary care

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Cerebrospinal fluid biomarker candidates associated with human WNV neuroinvasive disease

During the last decade, the epidemiology of WNV in humans has changed in the southern regions of Europe, with high incidence of West Nile fever (WNF) cases, but also of West Nile neuroinvasive disease (WNND). The lack of human vaccine or specific treatment against WNV infection imparts a pressing need to characterize indicators associated with neurological involvement. By its intimacy with central nervous system (CNS) structures, modifications in the cerebrospinal fluid (CSF) composition could accurately reflect CNS pathological process. Until now, few studies investigated the association between imbalance of CSF elements and severity of WNV infection. The aim of the present study was to apply the iTRAQ technology in order to identify the CSF proteins whose abundances are modified in patients with WNND. Forty-seven proteins were found modified in the CSF of WNND patients as compared to control groups, and most of them are reported for the first time in the context of WNND. On the basis of their known biological functions, several of these proteins were associated with inflammatory response. Among them, Defensin-1 alpha (DEFA1), a protein reported with anti-viral effects, presente

Measurements of integrated and differential cross sections for isolated photon pair production in pp collisions at √s=8 TeV with the ATLAS detector

A measurement of the production cross section for two isolated photons in proton-proton collisions at a center-of-mass energy of √s=8 TeV is presented. The results are based on an integrated luminosity of 20.2 fb−1 recorded by the ATLAS detector at the Large Hadron Collider. The measurement considers photons with pseudorapidities satisfying |ηγ|40GeV and EγT,2>30 GeV for the two leading photons ordered in transverse energy produced in the interaction. The background due to hadronic jets and electrons is subtracted using data-driven techniques. The fiducial cross sections are corrected for detector effects and measured differentially as a function of six kinematic observables. The measured cross section integrated within the fiducial volume is 16.8 ± 0.8  pb . The data are compared to fixed-order QCD calculations at next-to-leading-order and next-to-next-to-leading-order accuracy as well as next-to-leading-order computations including resummation of initial-state gluon radiation at next-to-next-to-leading logarithm or matched to a parton shower, with relative uncertainties varying from 5% to 20%