Phosphorylation of androgen receptors at serine 515 is a potential prognostic marker for triple negative breast cancer

1.7 million cases of breast cancer are diagnosed every year with 522,000 deaths. Molecular classifications of breast cancer have resulted in improved treatments. However, treatments for triple negative breast cancer (TNBC) are lacking. Analysis of molecular targets for TNBC is a priority. One potential candidate is androgen receptor (AR) phosphorylation. This study assessed the role of AR phosphorylation at ser81/ser515 and their two upstream effectors, cyclin-dependent kinase 1 (pCDK1) and extracellular-regulated kinase 1/2 (pERK1/2) in 332 ductal breast cancer patients by immunohistochemistry. pERK1/2 combined with AR-515 associated with improved cancer-specific survival (CSS, p = 0.038), decreased size (p = 0.001), invasive grade (p < 0.001), necrosis (p = 0.003), b-lymphocytes (p = 0.020), molecular subtype (p < 0.001) and estrogen receptor (ER)/progesterone receptor (PR)-status (p < 0.001). The cohort was therefore stratified into ER+ve and ER-ve patients. In ER+ve tumours, pERK1/2 combined with AR-515 associated with improved CSS (p = 0.038), smaller size (p = 0.004), invasive grade (p = 0.001), decreased b-lymphocytes (p = 0.013) and increased plasma cells (p = 0.048). In contrast, in TNBC patients, phosphorylation of AR-515 associated with poorer CSS (p = 0.007). pERK1/2 combined with AR-515 associated with decreased inflammation (p = 0.003), increased tumour stroma (p = 0.003) and tumour budding (p = 0.011), with trends towards decrease CSS (p = 0.065) and macrophage levels (p = 0.093). In Conclusions, AR-515 may be an important regulator of inflammation in breast cancer potential via ERK1/2 phosphorylation. AR-515 is a potential prognostic marker and therapeutic target for TNBC

Nutritional status, growth and disease management in children with single and dual diagnosis of type 1 diabetes mellitus and coeliac disease

Background: The consequences of subclinical coeliac disease (CD) in Type 1 diabetes mellitus (T1DM) remain unclear. We looked at growth, anthropometry and disease management in children with dual diagnosis (T1DM + CD) before and after CD diagnosis.<p></p> Methods: Anthropometry, glycated haemoglobin (HbA1c) and IgA tissue transglutaminase (tTg) were collected prior to, and following CD diagnosis in 23 children with T1DM + CD. This group was matched for demographics, T1DM duration, age at CD diagnosis and at T1DM onset with 23 CD and 44 T1DM controls.<p></p> Results: No differences in growth or anthropometry were found between children with T1DM + CD and controls at any time point. Children with T1DM + CD, had higher BMI z-score two years prior to, than at CD diagnosis (p <0.001). BMI z-score change one year prior to CD diagnosis was lower in the T1DM + CD than the T1DM group (p = 0.009). At two years, height velocity and change in BMI z-scores were similar in all groups. No differences were observed in HbA1c between the T1DM + CD and T1DM groups before or after CD diagnosis. More children with T1DM + CD had raised tTg levels one year after CD diagnosis than CD controls (CDx to CDx + 1 yr; T1DM + CD: 100% to 71%, p = 0.180 and CD: 100% to 45%, p < 0.001); by two years there was no difference.<p></p> Conclusions: No major nutrition or growth deficits were observed in children with T1DM + CD. CD diagnosis does not impact on T1DM glycaemic control. CD specific serology was comparable to children with single CD, but those with dual diagnosis may need more time to adjust to gluten free diet

Gauging the threat: the first population estimate for white sharks in South Africa using photo identification and automated software

South Africa is reputed to host the world’s largest remaining population of white sharks, yet no studies have accurately determined a population estimate based on mark-recapture of live individuals. We used dorsal fin photographs (fin IDs) to identify white sharks in Gansbaai, South Africa, from January 2007 - December 2011. We used the computer programme DARWIN to catalogue and match fin IDs of individuals; this is the first study to successfully use the software for white shark identification. The programme performed well despite a number of individual fins showing drastic changes in dorsal fin shape over time. Of 1682 fin IDs used, 532 unique individuals were identified. We estimated population size using the open-population POPAN parameterisation in Program MARK, which estimated the superpopulation size at 908 (95% confidence interval 808-1008). This estimated population size is considerably larger than those described at other aggregation areas of the species and is comparable to a previous South African population estimate conducted 16 years prior. Our assessment suggests the species has not made a marked recovery since being nationally protected in 1991. As such, additional international protection may prove vital for the long-term conservation of this threatened species

(3R,4R,5R)-5-(Acetamido­meth­yl)-N-benzyl-3,4-dihy­droxy­tetra­hydro­furan-3-carboxamide

X-ray crystallographic analysis with Cu Kα radiation established the relative configurations of the stereogenic centers in the title compound, C15H20N2O5, and clarified mechanistic ambiguities in the synthesis. The conformation of the five-membered ring approximates twisted, about a C—O bond. The absolute configuration of this carbon-branched dipeptide isostere was known based on the use of d-ribose as the starting material. Refinement of the Flack parameter gave an ambiguous result but the refined Hooft parameter is in agreement with the assumed (d-ribose) absolute structure. The crystal structure consists of N—H⋯O and O—H⋯O hydrogen-bonded bi-layers, with the terminal methyl and phenyl groups forming a hydro­phobic inter-layer inter­face. Some weak C—H⋯O inter­actions are also present

Challenges of recruiting emergency department patients to a qualitative study: a thematic analysis of researchers’ experiences

Background: At times of increasing pressure on emergency departments, and the need for research into different models of service delivery, little is known about how to recruit patients for qualitative research in emergency departments. We report from one study which aimed to collect evidence on patients’ experiences of attending emergency departments with different models of using general practitioners, but faced challenges in recruiting patients. This paper aims to identify and reflect on the challenges faced at all stages of patient recruitment, from identifying and inviting eligible patients, consenting them for participation and finally to engaging them in interviews, and make recommendations based on our learning.Methods: A thematic analysis was carried out on field-notes taken during research visits and meeting minutes of discussions to review and improve patient recruitment throughout the study.Results: The following factors influenced the success of patient recruitment in the emergency department setting:complicated or time-consuming electronic health record systems for identifying patients; narrow participant eligibility criteria; limited research nurse support; and lack of face-to-face communication between researchers and eligible patients.Conclusions: This paper adds to the methodological evidence for improving patient recruitment in different settings, with a focus on qualitative research in emergency departments. Our findings have implications for future studies attempting to recruit patients in similar settings

New insights into Dehalococcoides mccartyi metabolism from a reconstructed metabolic network-based systems-level analysis of D. mccartyi transcriptomes

Organohalide respiration, mediated by Dehalococcoides mccartyi, is a useful bioremediation process that transforms ground water pollutants and known human carcinogens such as trichloroethene and vinyl chloride into benign ethenes. Successful application of this process depends on the fundamental understanding of the respiration and metabolism of D. mccartyi. Reductive dehalogenases, encoded by rdhA genes of these anaerobic bacteria, exclusively catalyze organohalide respiration and drive metabolism. To better elucidate D. mccartyi metabolism and physiology, we analyzed available transcriptomic data for a pure isolate (Dehalococcoides mccartyi strain 195) and a mixed microbial consortium (KB-1) using the previously developed pan-genome-scale reconstructed metabolic network of D. mccartyi. The transcriptomic data, together with available proteomic data helped confirm transcription and expression of the majority genes in D. mccartyi genomes. A composite genome of two highly similar D. mccartyi strains (KB-1 Dhc) from the KB-1 metagenome sequence was constructed, and operon prediction was conducted for this composite genome and other single genomes. This operon analysis, together with the quality threshold clustering analysis of transcriptomic data helped generate experimentally testable hypotheses regarding the function of a number of hypothetical proteins and the poorly understood mechanism of energy conservation in D. mccartyi. We also identified functionally enriched important clusters (13 for strain 195 and 11 for KB-1 Dhc) of co-expressed metabolic genes using information from the reconstructed metabolic network. This analysis highlighted some metabolic genes and processes, including lipid metabolism, energy metabolism, and transport that potentially play important roles in organohalide respiration. Overall, this study shows the importance of an organism’s metabolic reconstruction in analyzing various ‘‘omics’’ data to obtain improved understanding of the metabolism and physiology of the organism

Quality of relationships as predictors of outcomes in people with dementia: a systematic review protocol

INTRODUCTION: Serious adverse outcomes for people with dementia include institutionalisation, hospitalisation, death, development of behavioural and psychiatric symptoms, and reduced quality of life. The quality of the relationship between the person with dementia and their informal/family carer is thought to affect the risk of these outcomes. However, little is known about which aspects of relationship quality are important, or how they affect outcomes for people with dementia. METHODS AND ANALYSIS: This will be a systematic review of the literature. Electronic databases MEDLINE, EMBASE, Web of Science, PsycInfo, the Cochrane Database, ALOIS and OpenGrey will be searched from inception. 2 independent reviewers will screen results for eligibility with standardised criteria. Data will be extracted for relevant studies, and information on the associations between relationship quality and dementia outcomes will be synthesised. Meta-analysis will be performed if possible to calculate pooled effect sizes. Narrative synthesis will be performed if study heterogeneity rules out meta-analysis. ETHICS AND DISSEMINATION: Ethical review is not necessary as this review summarises data from previous studies. Results will be disseminated via peer-reviewed publication. Results will also be disseminated to a patient and public involvement group and an expert panel for their views on the findings and implications for future work. TRIAL REGISTRATION NUMBER: CRD42015020518

Penta­fluoro­phenyl (3R,4R,5S)-5-{[(3R,4R,5S)-5-azido­methyl-3,4-dimeth­oxy-2,3,4,5-tetra­hydro­furan-3-carboxamido]­meth­yl}-3,4-dimeth­oxy-2,3,4,5-tetra­hydro­furan-3-carboxyl­ate

The title compound, C22H25F5N4O9, is a stable penta­fluoro­phenyl ester inter­mediate in the synthesis of novel homo-oligomeric structures containing branched carbon chains. The structure is epimeric to the previously characterized dimeric penta­fluoro­phenyl ester with stereochemistry (3R,4R,5R), which was synthesized using d-ribose as starting material. The crystal structure of the title mol­ecule removes any ambiguities arising from the relative stereochemistries of the six chiral centres. Two hydrogen bonds, bifurcating from the NH group, stabilize the crystal: one intra­molecular and one inter­molecular, both involving O atoms of the meth­oxy groups. The asymmetric unit contains two independent mol­ecules not related by any pseudo-symmetry operators. The major conformational differences are localized, leading to one mol­ecule being extended compared to the other. The collected crystal was twinned (twin ratio is 0.939:0.061), and the azide group is positionally disordered over two positions in one mol­ecule [occupancy ratio 0.511 (18):0.489 (18)]

e-Social Science and Evidence-Based Policy Assessment : Challenges and Solutions

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What innovations help with the recruitment and retention of ambulance staff: a rapid evidence summary

Abstract: Ambulance waiting times across the UK have increased in recent years. The numbers of ambulance staff leaving services across the UK is increasing every year. Strategies to help recruit and retain all ambulance staff, including paramedics are important. This rapid evidence summary aimed to investigate what innovations can help with their recruitment and retention. Eight primary studies were identified: Recruitment: Evidence from a UK survey suggests that factors negatively influencing paramedic recruitment include competitive job market, lack of locally trained professionals, and newly qualified professionals starting with higher debt. Evidence from the US suggests that factors supporting recruitment concern future paramedics wanting to enter a caring profession or an exciting job. Additionally, strategies to recruit emergency medical technicians need to include the motivational aspects of growth, advancement, recognition, and responsibility. Evidence indicates that factors hindering recruitment of emergency medical technicians and/ or paramedics include rural working, and ambulance services not seen as a primary career path. Retention: Evidence from a UK survey suggests that pay, reward, stress and workload are factors that hinder paramedic retention. Evidence recommends retention strategies for paramedics, such as reviewing banding, improving work conditions and career progression, changing the way ambulances are dispatched to calls, and providing retention premiums. Evidence from the US suggests that pay, benefits, opportunities for advancement, continuous professional development, burnout, stress, workload, nearing retirement and career change are factors that influence retention of emergency medical technicians and/ or paramedics. Evidence from Thailand suggests that remuneration and professionalism are factors supporting paramedic retention. More up-to-date information is needed on the recruitment and retention of ambulance staff in UK settings. Further research providing a more detailed investigation of factors influencing recruitment and retention may be useful. The development or implementation of future strategies to help the recruitment and retention of paramedics and emergency medical technicians should be accompanied by a planned impact evaluation