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

Studies of Diffuse Interstellar Bands. V. Pairwise Correlations of Eight Strong DIBs and Neutral Hydrogen, Molecular Hydrogen, and Color Excess

We establish correlations between equivalent widths of eight diffuse interstellar bands (DIBs), and examine their correlations with atomic hydrogen, molecular hydrogen, and EB-V . The DIBs are centered at \lambda\lambda 5780.5, 6204.5, 6283.8, 6196.0, 6613.6, 5705.1, 5797.1, and 5487.7, in decreasing order of Pearson\^as correlation coefficient with N(H) (here defined as the column density of neutral hydrogen), ranging from 0.96 to 0.82. We find the equivalent width of \lambda 5780.5 is better correlated with column densities of H than with E(B-V) or H2, confirming earlier results based on smaller datasets. We show the same is true for six of the seven other DIBs presented here. Despite this similarity, the eight strong DIBs chosen are not well enough correlated with each other to suggest they come from the same carrier. We further conclude that these eight DIBs are more likely to be associated with H than with H2, and hence are not preferentially located in the densest, most UV shielded parts of interstellar clouds. We suggest they arise from different molecules found in diffuse H regions with very little H (molecular fraction f<0.01). Of the 133 stars with available data in our study, there are three with significantly weaker \lambda 5780.5 than our mean H-5780.5 relationship, all of which are in regions of high radiation fields, as previously noted by Herbig. The correlations will be useful in deriving interstellar parameters when direct methods are not available. For instance, with care, the value of N(H) can be derived from W{\lambda}(5780.5).Comment: Accepted for publication in The Astrophysical Journal; 37 pages, 11 figures, 6 table

Parents' involvement in child care: do parental and work identities matter?

The current study draws on identity theory to explore mothers' and fathers' involvement in childcare. It examined the relationships between the salience and centrality of individuals’ parental and work-related identities and the extent to which they are involved in various forms of childcare. A sample of 148 couples with at least one child aged 6 years or younger completed extensive questionnaires. As hypothesized, the salience and centrality of parental identities were positively related to mothers' and fathers' involvement in childcare. Moreover, maternal identity salience was negatively related to fathers' hours of childcare and share of childcare tasks. Finally, work hours mediated the negative relationships between the centrality of work identities and time invested in childcare, and gender moderated this mediation effect. That is, the more central a mother's work identity, the more hours she worked for pay and the fewer hours she invested in childcare. These findings shed light on the role of parental identities in guiding behavioral choices, and attest to the importance of distinguishing between identity salience and centrality as two components of self-structure

Non-integrable aspects of the multi-frequency Sine-Gordon model

We consider the two-dimensional quantum field theory of a scalar field self-interacting via two periodic terms of frequencies $\alpha$ and $\beta$. Looking at the theory as a perturbed Sine-Gordon model, we use Form Factor Perturbation Theory to analyse the evolution of the spectrum of particle excitations. We show how, within this formalism, the non-locality of the perturbation with respect to the solitons is responsible for their confinement in the perturbed theory. The effects of the frequency ratio $\alpha/\beta$ being a rational or irrational number and the occurrence of massless flows from the gaussian to the Ising fixed point are also discussed. A generalisation of the Ashkin-Teller model and the massive Schwinger model are presented as examples of application of the formalism.Comment: 39 pages, latex, 10 figure

Efficacy and Safety of Daridorexant in Older and Younger Adults with Insomnia Disorder: A Secondary Analysis of a Randomised Placebo-Controlled Trial.

BACKGROUND AND OBJECTIVE The dual orexin receptor antagonist daridorexant, studied in two phase III trials, dose-dependently improved objective and subjective sleep variables and daytime functioning in adults with insomnia. Because treatment of insomnia in older adults is challenging and has limited options, the purpose of the current analysis was to further analyse the phase III trial studying the higher doses of daridorexant, those that showed efficacy (daridorexant 50 mg, daridorexant 25 mg and placebo, nightly for 3 months), and compare the safety and efficacy of daridorexant in patients aged ≥ 65 ('older adults') to those aged < 65 years ('younger adults'). METHODS Analyses by age (≥ 65 years, n = 364; < 65 years, n = 566) were performed on data from the randomised, double-blind, placebo-controlled Trial 1 in adult patients with insomnia (NCT03545191). Efficacy endpoints included a change from baseline at month 1 and month 3 in polysomnography-measured wake after sleep onset (WASO) and latency to persistent sleep (LPS), self-reported total sleep time (sTST) and daytime functioning assessed using the validated Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). Safety endpoints included adverse events and the Visual Analog Scale for morning sleepiness. RESULTS At baseline, mean [standard deviation] WASO was numerically greater (110 [39] vs 92 [38] min) in older than younger adults, while LPS was comparable (~ 65 min). Mean baseline IDSIQ total and all domain scores were numerically lower (i.e. better) in older adults. Daridorexant caused similar reductions in WASO and LPS, and similar increases in sTST, from baseline, in both age groups; improvements were numerically greater with daridorexant 50 mg than 25 mg. At month 3, daridorexant 50 mg, compared with placebo, decreased WASO by a least-squares mean of 19.6 (95% confidence interval 9.7, 29.5) in older patients versus 17.4 min (10.7, 24.0) in younger patients and decreased LPS by a least-squares mean of 14.9 (7.5, 22.3) in older patients versus 9.7 min (3.7, 15.7) in younger patients. Daridorexant 50 mg increased sTST from baseline to month 3 by a least-squares mean of 59.9 (49.6, 70.3) in older patients versus 57.1 min (48.9, 65.3) in younger patients. Daridorexant 50 mg progressively improved IDSIQ total and domain scores from week 1 onwards similarly in both groups; daridorexant 25 mg improved IDSIQ scores, but only in younger adults. In both age groups, in comparison with placebo, the overall incidence of adverse events was comparable, and there were fewer falls on daridorexant. Daridorexant improved Visual Analog Scale morning sleepiness in both groups; daridorexant 50 mg increased the mean (standard deviation) Visual Analog Scale morning sleepiness score by 15.9 (20.7) in older adults and by 14.9 (18.7) in younger adults from baseline to month 3. In older adults, there was one case of sleep paralysis, and no cases of narcolepsy, cataplexy, or complex sleep behaviour. CONCLUSIONS In older patients with insomnia, as in younger patients, the efficacy of daridorexant is maximal on night-time and daytime variables at the higher dose of 50 mg. Older patients particularly require this dose to improve daytime functioning. Older patients are not at an increased risk of adverse events or residual effects the next morning after night-time administration of daridorexant, even at 50 mg. The dose of daridorexant does not need to be decreased for older patients. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov (NCT03545191) [first posted: 4 June, 4 2018], https://clinicaltrials.gov/ct2/show/NCT03545191

Leakage of an invagination pancreaticojejunostomy may have an influence on mortality

Purpose: No consensus exists regarding the most effective form of pancreaticojejunostomy (PJ) following pancreaticoduodenectomy (PD). Methods: Data were gathered through the American College of Surgeons-National Surgical Quality Improvement Program, Pancreatectomy Demonstration Project. A total of 1781 patients underwent a PD at 43 institutions. After appropriate exclusions, 890 patients were analyzed. Patients were divided into duct-to-mucosa (n = 734, 82%) and invagination (n = 156, 18%) groups and were compared by unadjusted analysis. Type of PJ was included in eight separate morbidity and mortality multivariable analyses. Results: Invagination patients had higher serum albumin (p &lt; 0.01) and lower body mass index (p &lt; 0.01), were less likely to have a preoperative biliary stent (p &lt; 0.01), and were more likely to have a soft gland (p &lt; 0.01). PJ anastomosis type was not associated with morbidity but was associated with mortality (duct-to-mucosa vs. invagination, odds ratio = 0.22, p &lt; 0.01). Among patients who developed a clinically relevant pancreatic fistula, none of the 119 duct-to-mucosa, compared with 5 of 21 invagination, patients died (p &lt; 0.01). Conclusion: Patients who undergo a PJ by duct-to-mucosa or invagination differ with respect to preoperative and intraoperative variables. When an invagination PJ leaks, there may be a greater influence on mortality than when a duct-to-mucosa PJ leaks

Gender differences in identities and their socio-structural correlates: how gendered lives shape parental and work identities

This study draws on identity theory to explore parental and work identities. It examined gender differences in identities, as well as the moderating role of gender in the effects of individuals’ socio-structural characteristics. A sample of 148 couples with young children completed extensive questionnaires. As hypothesized, couples’ paid work strategy moderated gender differences in the salience and centrality of parental and work identities. Whereas significant differences in identities were found between stay-at-home mothers and their breadwinning husbands, no differences were found among dual-earner couples. Moreover, men’s work identity centrality increased when they had more and younger children, whereas women’s work identity centrality decreased. Finally, men’s parental identity centrality increased with their income, whereas women’s parental identity centrality decreased the more they earned. These findings attest to the importance of examining differences within as well as between genders, by taking into account the interactive effects of gender with other socio-structural characteristics