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

Temporal Dynamics of Neural Computations for Stimulus Value and Effort Cost

We often make decisions not only based on an item’s value, but also the effort required to obtain it: e.g., using a vending machine versus walking to a café. Whereas good-based value is represented in ventromedial prefrontal cortex (vmPFC), recent data has implicated dorsomedial frontal cortex (dmFC) in integrating stimulus value with effort cost to derive net (combined) value. However, the temporal dynamics of net value computation remain unclear. Here we examined this question using event-related potentials (ERP) while hungry subjects decided whether to work at different levels of physical effort cost (low, medium, or high grip strength) for the opportunity to obtain food. Subjects’ decisions generally incorporated both stimulus value and effort cost, as indicated by significant logistic fits to their choice curves. Parametric ERP responses associated with net value were visible from 100-300 ms after stimulus onset, negatively correlated with effort cost, and from ~450-650 ms, positively correlated with stimulus value. Distributed reconstruction of stimulus-locked responses revealed significant sources in the vmPFC, but not dmFC. In contrast, response-locked signals were chiefly localized to dmFC and superior parietal sources rather than vmPFC, and largely reflected effort cost computations preceding response. Together, these data suggest that localization of net value integration to vmPFC and dmFC sources depends on whether the data is time-locked to the onset of stimulus or response. In line with a transition from good-based to action-based valuation, computations of effort cost may play an increasing role in dmFC activity in the time directly leading up to choice

Design synthesis and shape generation

If we are to capitalise on the potential that a design approach might bring to innovation in business and society, we need to build a better understanding of the evolving skill-sets that designers will need and the contexts within which design might operate. This demands more discourse between those involved in cutting edge practice, the researchers who help to uncover principles, codify knowledge and create theories and the educators who are nurturing future design talent. This book promotes such a discourse by reporting on the work of twenty research teams who explored different facets of future design activity as part of Phase 2 of the UK's research council supported Designing for the 21st Century Research Initiative. Each of these contributions describes the origins of the project, the research team and their project aims, the research methods used and the new knowledge and understanding generated. Editor and Initiative Director, Professor Tom Inns, provides an introductory chapter that suggests ways the reader might navigate these viewpoints. This chapter concludes with an overview of the key lessons that might be learnt from this collection of design research activity

Associations between dietary iron and zinc intakes, and between biochemical iron and zinc status in women

Iron and zinc are found in similar foods and absorption of both may be affected by food compounds, thus biochemical iron and zinc status may be related. This cross-sectional study aimed to: (1) describe dietary intakes and biochemical status of iron and zinc; (2) investigate associations between dietary iron and zinc intakes; and (3) investigate associations between biochemical iron and zinc status in a sample of premenopausal women aged 18–50 years who were recruited in Melbourne and Sydney, Australia. Usual dietary intakes were assessed using a 154-item food frequency questionnaire (n = 379). Iron status was assessed using serum ferritin and hemoglobin, zinc status using serum zinc (standardized to 08:00 collection), and presence of infection/inflammation using C-reactive protein (n = 326). Associations were explored using multiple regression and logistic regression. Mean (SD) iron and zinc intakes were 10.5 (3.5) mg/day and 9.3 (3.8) mg/day, respectively. Median (interquartile range) serum ferritin was 22 (12–38) μg/L and mean serum zinc concentrations (SD) were 12.6 (1.7) μmol/L in fasting samples and 11.8 (2.0) μmol/L in nonfasting samples. For each 1 mg/day increase in dietary iron intake, zinc intake increased by 0.4 mg/day. Each 1 μmol/L increase in serum zinc corresponded to a 6% increase in serum ferritin, however women with low serum zinc concentration (AM fasting < 10.7 μmol/L; AM nonfasting < 10.1 μmol/L) were not at increased risk of depleted iron stores (serum ferritin <15 μg/L; p = 0.340). Positive associations were observed between dietary iron and zinc intakes, and between iron and zinc status, however interpreting serum ferritin concentrations was not a useful proxy for estimating the likelihood of low serum zinc concentrations and women with depleted iron stores were not at increased risk of impaired zinc status in this cohort

Electronic Medical Record Cancer Incidence over Six Years Comparing New Users of Glargine with New Users of NPH Insulin

Background: Recent studies suggested that insulin glargine use could be associated with increased risk of cancer. We compared the incidence of cancer in new users of glargine versus new users of NPH in a longitudinal clinical cohort with diabetes for up to 6 years. Methods and Findings: From all patients who had been regularly followed at Massachusetts General Hospital from 1/01/2005 to 12/31/2010, 3,680 patients who had a medication record for glargine or NPH usage were obtained from the electronic medical record (EMR). From those we selected 539 new glargine users (age: 60.1±13.6 years, BMI: 32.7±7.5 kg/m2) and 343 new NPH users (61.5±14.1 years, 32.7±8.3 kg/m2) who had no prevalent cancer during 19 months prior to glargine or NPH initiation. All incident cancer cases were ascertained from the EMR requiring at least 2 ICD-9 codes within a 2 month period. Insulin exposure time and cumulative dose were validated. The statistical analysis compared the rates of cancer in new glargine vs. new NPH users while on treatment, adjusted for the propensity to receive one or the other insulin. There were 26 and 28 new cancer cases in new glargine and new NPH users for 1559 and 1126 person-years follow-up, respectively. There were no differences in the propensity-adjusted clinical characteristics between groups. The adjusted hazard ratio for the cancer incidence comparing glargine vs. NPH use was 0.65 (95% CI: 0.36–1.19). Conclusions: Insulin glargine is not associated with development of cancers when compared with NPH in this longitudinal and carefully retrieved EMR data

Mobile phone app aimed at improving iron intake and bioavailability in premenopausal women: a qualitative evaluation

BACKGROUND: Low iron intake can lead to iron deficiency, which can result in impaired health and iron-deficiency anemia. A mobile phone app, combining successful dietary strategies to increase bioavailable iron with strategies for behavior change, such as goal setting, monitoring, feedback, and resources for knowledge acquisition, was developed with the aim to increase bioavailable iron intake in premenopausal women. OBJECTIVE: To evaluate the content, usability, and acceptability of a mobile phone app designed to improve intake of bioavailable dietary iron. METHODS: Women aged 18-50 years with an Android mobile phone were invited to participate. Over a 2-week period women were asked to interact with the app. Following this period, semistructured focus groups with participants were conducted. Focus groups were audio recorded and analyzed via an inductive open-coding method using the qualitative analysis software NVivo 10. Themes were identified and frequency of code occurrence was calculated. RESULTS: Four focus groups (n=26) were conducted (age range 19-36 years, mean 24.7, SD 5.2). Two themes about the app\u27s functionality were identified (frequency of occurrence in brackets): interface and design (134) and usability (86). Four themes about the app\u27s components were identified: goal tracker (121), facts (78), photo diary (40), and games (46). A number of suggestions to improve the interface and design of the app were provided and will inform the ongoing development of the app. CONCLUSIONS: This research indicates that participants are interested in iron and their health and are willing to use an app utilizing behavior change strategies to increase intake of bioavailable iron. The inclusion of information about the link between diet and health, monitoring and tracking of the achievement of dietary goals, and weekly reviews of goals were also seen as valuable components of the app and should be considered in mobile health apps aimed at adult women

Mammary molecular portraits reveal lineage-specific features and progenitor cell vulnerabilities.

The mammary epithelium depends on specific lineages and their stem and progenitor function to accommodate hormone-triggered physiological demands in the adult female. Perturbations of these lineages underpin breast cancer risk, yet our understanding of normal mammary cell composition is incomplete. Here, we build a multimodal resource for the adult gland through comprehensive profiling of primary cell epigenomes, transcriptomes, and proteomes. We define systems-level relationships between chromatin-DNA-RNA-protein states, identify lineage-specific DNA methylation of transcription factor binding sites, and pinpoint proteins underlying progesterone responsiveness. Comparative proteomics of estrogen and progesterone receptor-positive and -negative cell populations, extensive target validation, and drug testing lead to discovery of stem and progenitor cell vulnerabilities. Top epigenetic drugs exert cytostatic effects; prevent adult mammary cell expansion, clonogenicity, and mammopoiesis; and deplete stem cell frequency. Select drugs also abrogate human breast progenitor cell activity in normal and high-risk patient samples. This integrative computational and functional study provides fundamental insight into mammary lineage and stem cell biology

Sex recognition by odour and variation in the uropygial gland secretion in starlings

1. Although a growing body of evidence supports that olfaction based on chemical compounds emitted by birds may play a role in individual recognition, the possible role of chemical cues in sexual selection of birds has been only preliminarily studied.2. We investigated for the first time whether a passerine bird, the spotless starling Sturnus unicolor, was able to discriminate the sex of conspecifics by using olfactory cues and whether the size and secretion composition of the uropygial gland convey information on sex, age and reproductive status in this species.3. We performed a blind choice experiment during mating, and we found that starlings were able to discriminate the sex of conspecifics by using chemical cues alone. Both male and female starlings preferred male scents. Furthermore, the analysis of the chemical composition of the uropygial gland secretion by using gas chromatography–mass spectrometry (GC–MS) revealed differences between sexes, ages and reproductive status.4. In conclusion, our study reveals for first time that a passerine species can discriminate the sex of conspecifics by relying on chemical cues and suggests that the uropygial gland secretion may potentially function as a chemical signal used in mate choice and/or intrasexual competition in this species.This research was funded by the Spanish Ministry of Education and Science ⁄ FEDER (CGL2008-00718) and PIE 200930I029 to J. M. Avilés and D. Parejo.The study was conducted under licence of the Junta de Andalucía GC–MS analyses were performed by Dr. Rafael Núñez at the Scientific Instrumentation Service (EEZ, CSIC) (Granada, Spain).Peer reviewe

Cancer Incidence Among Those Initiating Insulin Therapy With Glargine Versus Human NPH Insulin

OBJECTIVE To add to the evidence on comparative long-term effects of insulin analog glargine versus human NPH insulin on the risk for cancer. RESEARCH DESIGN AND METHODS We identified cohorts of initiators of glargine and human NPH without an insulin prescription during the prior 19 months among patients covered by the Inovalon Medical Outcomes Research for Effectiveness and Economics Registry (MORE2 Registry) between January 2003 and December 2010. Patients were required to have a second prescription of the same insulin within 180 days and to be free of cancer. We balanced cohorts on risk factors for cancer outcomes based on comorbidities, comedication, and health care use during the prior 12 months using inverse probability of treatment weighting. Incident cancer was defined as having two claims for cancer (any cancer) or the same cancer (breast, prostate, colon) within 2 months. We estimated adjusted hazard ratios (HRs) and their 95% CI using weighted Cox models censoring for stopping, switching, or augmenting insulin treatment, end of enrollment, and mortality. RESULTS More patients initiated glargine (43,306) than NPH (9,147). Initiators of glargine (NPH) were followed for 1.2 (1.1) years and 50,548 (10,011) person-years; 993 (178) developed cancer. The overall HR was 1.12 (95% CI 0.95–1.32). Results were consistent for breast cancer, prostate cancer, and colon cancer; various durations of treatment; and sensitivity analyses. CONCLUSIONS Patients initiating insulin glargine rather than NPH do not seem to be at an increased risk for cancer. While our study contributes significantly to our evidence base for long-term effects, this evidence is very limited mainly based on actual dynamics in insulin prescribing

SMA CO(J=6-5) and 435 micron interferometric imaging of the nuclear region of Arp 220

We have used the Submillimeter Array (SMA) to make the first interferometric observations (beam size ~1") of the 12CO J=6-5 line and 435 micron (690 GHz) continuum emission toward the central region of the nearby ULIRG Arp 220. These observations resolve the eastern and western nuclei from each other, in both the molecular line and dust continuum emission. At 435 micron, the peak intensity of the western nucleus is stronger than the eastern nucleus, and the difference in peak intensities is less than at longer wavelengths. Fitting a simple model to the dust emission observed between 1.3 mm and 435 micron suggests that dust emissivity power law index in the western nucleus is near unity and steeper in the eastern nucleus, about 2, and that the dust emission is optically thick at the shorter wavelength. Comparison with single dish measurements indicate that the interferometer observations are missing ~60% of the dust emission, most likely from a spatially extended component to which these observations are not sensitive. The 12CO J=6-5 line observations clearly resolve kinematically the two nuclei. The distribution and kinematics of the 12CO J=6-5 line appear to be very similar to lower J CO lies observed at similar resolution. Analysis of multiple 12CO line intensities indicates that the molecular gas in both nuclei have similar excitation conditions, although the western nucleus is warmer and denser. The excitation conditions are similar to those found in other extreme environments, including M82, Mrk 231, and BR 1202-0725. Simultaneous lower resolution observations of the 12CO, 13CO, and C18O J=2-1 lines show that the 13CO and C18O lines have similar intensities, which suggests that both of these lines are optically thick, or possibly that extreme high mass star formation has produced in an overabundance of C18O.Comment: 13 pages (emulateapj), 10 figures, Accepted for publication in Ap