Although activation of the STAT3 pathway has been associated with tumor progression in a wide variety of cancer types (including ovarian cancer), the precise mechanism of invasion and metastasis due ...to STAT3 are not fully delineated in ovarian cancer. We found that pSTAT3 Tyr705 is constitutively activated in patient ascites and ascites-derived ovarian cancer cells (ADOCCs), and the range of STAT3 expression could be very high to low. In vivo transplantation of ADOCCs with high pSTAT3 expression into the ovarian bursa of mice resulted in a large primary tumor and widespread peritoneal metastases. In contrast, ADOCCs with low STAT3 expression or ADOCCs with STAT3 expression knockdown, led to reduced tumor growth and an absence of metastases in vivo. Cytokines derived from the ADOCC culture medium activate the interleukin (IL)-6/STAT pathway in the STAT3 knockout (KO) cells, compensating for the absence of inherent STAT3 in the cells. Treatment with HO-3867 (a novel STAT3 inhibitor at 100 p.p.m. in an orthotopic murine model) significantly suppressed ovarian tumor growth, angiogenesis and metastasis by targeting STAT3 and its downstream proteins. HO-3867 was found to have cytotoxic effects in ex vivo cultures of freshly collected human ovarian cancers, including those resistant to platinum-based chemotherapy. Our results show that STAT3 is necessary for ovarian tumor progression/metastasis and highlight the potential for targeting STAT3 by HO-3867 as a therapeutic strategy for ovarian cancer.
In this paper we present the first large-scale scene attribute database. First, we perform crowd-sourced human studies to find a taxonomy of 102 discriminative attributes. Next, we build the "SUN ...attribute database" on top of the diverse SUN categorical database. Our attribute database spans more than 700 categories and 14,000 images and has potential for use in high-level scene understanding and fine-grained scene recognition. We use our dataset to train attribute classifiers and evaluate how well these relatively simple classifiers can recognize a variety of attributes related to materials, surface properties, lighting, functions and affordances, and spatial envelope properties.
Multipartner fertility (MPF), which occurs when individuals have children with multiple partners, is associated with psychological distress, but it is unclear whether MPF is linked to increase in ...psychological distress or whether those with higher levels of psychological distress disproportionately enter MPF. I adjudicate between these possibilities using prospective panel data from the National Longitudinal Survey of Youth 1997 (NLSY97;
n
= 3321). I find that the association between MPF and psychological distress is driven by selection. Hybrid (or between-within) models indicate that men and women who have multipartner fertility have higher levels of psychological distress (the between-effect), but among those who experience MPF, having a child with a second fertility partner it is not associated with changes in psychological distress (the within-effect). Instead, psychological distress predicts MPF (versus having two or more children with the same partner) net of childhood family context, socioeconomic status, first birth characteristics, and prior union instability. The findings suggest that social selection is crucial to understanding the link between complex family formation and mental health in the current era of stable family complexity.
We sought to assess physician knowledge/beliefs, self-efficacy, and experience/practice patterns surrounding smoking cessation and electronic cigarettes.
An eight-page survey sent via US Postal ...service. The initial invitation included a $10 cash incentive and up to three invitations were sent. Fifteen hundred US physicians were identified with equal representation from primary care physicians (internal medicine and family practice), surgical care physicians (general surgeons and anesthesiologists), and pulmonologists.
Two hundred fourteen were not included in the analysis (183 non-deliverable, one deceased, 30 not practicing). 561/1286 (44%) remaining surveys were returned for analysis. Greater than 90% agreed that advising and assisting with smoking cessation is their responsibility; 86% advise and 65% assist their patients with smoking cessation more than 75% of the time. Approximately two-thirds of respondents report that their patients ask them about electronic cigarettes at least some of the time (≥25%); 58.4% report that they ask their patients about electronic cigarette use at least some of the time. Overall, 37.9% have at some point recommended electronic cigarettes to their patients that smoke, with 11.5% reporting recommending them at least 25% of the time. Surgical care providers appear less confident and less self-efficacious with smoking cessation, as well as with electronic cigarettes and appear less likely to endorse use of electronic cigarettes.
US physicians are frequently discussing electronic cigarettes in a clinical context and a substantial proportion of US physicians have recommended electronic cigarettes to their patients.
This study documents several important previously poorly characterized aspects of the role of electronic cigarettes in clinical care. The majority of US physicians are discussing electronic cigarettes in clinical contexts and a substantial proportion of US physicians have recommended electronic cigarettes to their patients. The extent of physician engagement on the topic of electronic cigarettes should be met with increased efforts to better characterize electronic cigarettes' appropriate role in smoking cessation and reduction.
We present the first performance results obtained with microwave multiplexed Transition Edge Sensors prototypes specifically designed for the HOLMES experiment, a project aimed at directly measuring ...the electron neutrino mass through the calorimetric measurement of the
163
Ho electron capture spectrum. The detectors required for such an experiment feature a high energy resolution at the
Q
–value of the transition, around
∼
2.8 keV, and a fast response time combined with the compatibility to be multiplexed in large arrays in order to collect a large statistics while keeping the pile-up contribution as small as possible. In addition, the design has to be suitable for future ion-implantation of
163
Ho. The results obtained in these tests allowed us to identify the optimal detector design among several prototypes. The chosen detector achieved an energy resolution of (4.5 ± 0.3) eV on the chlorine K
α
line, at
∼
2.6 keV, obtained with an exponential rise time of 14
μ
s. The achievements described in this paper pose a milestone for the HOLMES detectors, setting a baseline for the subsequent developments, aiming to the actual ion-implantation of the
163
Ho nuclei. In the first section the HOLMES experiment is outlined along with its physics goal, while in the second section the HOLMES detectors are described; the experimental set-up and the calibration source used for the measurements described in this paper are reported in Sects.
3
and
4
, respectively; finally, the details of the data analysis and the results obtained are reported in Sect.
6
.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: Quitting smoking is enhanced by the use of pharmacotherapies, but concerns have been raised regarding the cardiovascular safety of such medications. OBJECTIVE: To compare the relative ...cardiovascular safety risk of smoking cessation treatments. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, triple-dummy, placebo- and active-controlled trial (Evaluating Adverse Events in a Global Smoking Cessation Study EAGLES) and its nontreatment extension trial was conducted at 140 multinational centers. Smokers, with or without established psychiatric diagnoses, who received at least 1 dose of study medication (n = 8058), as well as a subset of those who completed 12 weeks of treatment plus 12 weeks of follow up and agreed to be followed up for an additional 28 weeks (n = 4595), were included. INTERVENTIONS: Varenicline, 1 mg twice daily; bupropion hydrochloride, 150 mg twice daily; and nicotine replacement therapy, 21-mg/d patch with tapering. MAIN OUTCOMES AND MEASURES: The primary end point was the time to development of a major adverse cardiovascular event (MACE: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) during treatment; secondary end points were the occurrence of MACE and other pertinent cardiovascular events (MACE+: MACE or new-onset or worsening peripheral vascular disease requiring intervention, coronary revascularization, or hospitalization for unstable angina). RESULTS: Of the 8058 participants, 3553 (44.1%) were male (mean SD age, 46.5 12.3 years). The incidence of cardiovascular events during treatment and follow-up was low (<0.5% for MACE; <0.8% for MACE+) and did not differ significantly by treatment. No significant treatment differences were observed in time to cardiovascular events, blood pressure, or heart rate. There was no significant difference in time to onset of MACE for either varenicline or bupropion treatment vs placebo (varenicline: hazard ratio, 0.29; 95% CI, 0.05-1.68 and bupropion: hazard ratio, 0.50; 95% CI, 0.10-2.50). CONCLUSIONS AND RELEVANCE: No evidence that the use of smoking cessation pharmacotherapies increased the risk of serious cardiovascular adverse events during or after treatment was observed. The findings of EAGLES and its extension trial provide further evidence that smoking cessation medications do not increase the risk of serious cardiovascular events in the general population of smokers. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01574703
Moving towards NetZero requires robust information to enable good decision making at all levels: covering hardware procurement, workload management and operations, as well as higher level aspects ...encompassing grant funding processes and policy framework development. The IRISCAST project is a proofof-concept study funded as part of the UKRI DRI Net-Zero Scoping Project. IRISCAST performed an audit of carbon costs across a multi-site heterogeneous infrastructure by collecting and analysing snapshots of actual usage across different facilities within the IRIS community (https://iris.ac.uk). Combining usage information with an analysis of the embodied carbon costs and careful mapping and consideration of the underlying assumptions resulted in an estimate of the overall carbon cost, an understanding of the key elements that contribute to the carbon cost, and the important metrics needed to measure it. IRISCAST makes reccomendations to allow high level feedback of carbon costs to funding bodies to inform strategic decisions as well as low level feedback of carbon costs to users and user communities to drive changes in user code bases and behaviors to be more carbon efficient. IRISCAST carbon modeling shows that estimates of carbon costs can vary by factors of 10, hence there is significant opportunity for the carbon footprint of Digital Research Infrastructures to be reduced.
Genetic disorders and congenital anomalies are the leading causes of infant mortality. Diagnosis of most genetic diseases in neonatal and paediatric intensive care units (NICU and PICU) is not ...sufficiently timely to guide acute clinical management. We used rapid whole-genome sequencing (STATseq) in a level 4 NICU and PICU to assess the rate and types of molecular diagnoses, and the prevalence, types, and effect of diagnoses that are likely to change medical management in critically ill infants.
We did a retrospective comparison of STATseq and standard genetic testing in a case series from the NICU and PICU of a large children's hospital between Nov 11, 2011, and Oct 1, 2014. The participants were families with an infant younger than 4 months with an acute illness of suspected genetic cause. The intervention was STATseq of trios (both parents and their affected infant). The main measures were the diagnostic rate, time to diagnosis, and rate of change in management after standard genetic testing and STATseq.
20 (57%) of 35 infants were diagnosed with a genetic disease by use of STATseq and three (9%) of 32 by use of standard genetic testing (p=0·0002). Median time to genome analysis was 5 days (range 3-153) and median time to STATseq report was 23 days (5-912). 13 (65%) of 20 STATseq diagnoses were associated with de-novo mutations. Acute clinical usefulness was noted in 13 (65%) of 20 infants with a STATseq diagnosis, four (20%) had diagnoses with strongly favourable effects on management, and six (30%) were started on palliative care. 120-day mortality was 57% (12 of 21) in infants with a genetic diagnosis.
In selected acutely ill infants, STATseq had a high rate of diagnosis of genetic disorders. Most diagnoses altered the management of infants in the NICU or PICU. The very high infant mortality rate indicates a substantial need for rapid genomic diagnoses to be allied with a novel framework for precision medicine for infants in NICU and PICU who are diagnosed with genetic diseases to improve outcomes.
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, and National Center for Advancing Translational Sciences.
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