ΔNp73 antisense activates PUMA and induces apoptosis in neuroblastoma cells

The p73 gene codes for various different protein isoforms. They include proteins expressed under the control of the P1 promoter that contain a transactivation domain and are similar in function to p53 (TAp73 isoforms), as well as proteins regulated by the P2 promoter that lack this domain and function as dominant negative inhibitors of TAp73 and p53 (ΔNp73 isoforms). Whereas TAp73 functions as a tumor suppressor with pro-apoptotic function, ΔNp73 is likely to prevent the induction of apoptosis in tumor cells and to participate in oncogenesis. Here we used a loss-of-function strategy to assess the role of ΔNp73 in SH-SY5Y neuroblastoma cells. An antisense oligonucleotide designed to target ΔNp73 mRNA, but not TAp73, was used to effectively downregulate this transcript. ΔNp73 downregulation was accompanied by increased levels of the pro-apoptotic BH3 family member PUMA at the mRNA and protein level, and by conformational activation of BAX which translocated to mitochondria. These ΔNp73 antisense-mediated alterations led to the induction of apoptosis as detected by decreased cell viability, augmented DNA fragmentation and increased caspase-3 activity in cell lysates. Our results demonstrate the cytoprotective role of ΔNp73 in neuroblastoma and suggest its use as a target for molecular intervention therap

Developing young people's sense of self and place through sport

Previous research has recognized positive health implications, both physical and mental, as an outcome of participation in leisure pursuits. They provide opportunities for self-expression and stress reduction, as well as an environment in which people can socialize. Leisure activities, specifically sport activities, can play a significant role in young people's identity development. This paper explores the leisure activities in which young people in Adelaide, Australia participate. It examines the role of leisure activities in terms of young people's identity and feelings towards their hometown. This study consisted of semi-structured focus groups conducted with 24 senior high school students, followed by a survey resulting in 226 useable responses. Respondents were aged between 16 and 18 years of age. From the range of activities identified and explored, the results revealed sports activities to have the greatest impact on young people's lives. The results demonstrated that frequency of participation has a significant effect on young people's involvement levels and how they identify with the activity

Corporate financing decisions: UK survey evidence

Despite theoretical developments in recent years, our understanding of corporate capital structure remains incomplete. Prior empirical research has been dominated by archival regression studies which are limited in their ability to fully reflect the diversity found in practice. The present paper reports on a comprehensive survey of corporate financing decision-making in UK listed companies. A key finding is that firms are heterogeneous in their capital structure policies. About half of the firms seek to maintain a target debt level, consistent with trade-off theory, but 60 per cent claim to follow a financing hierarchy, consistent with pecking order theory. These two theories are not viewed by respondents as either mutually exclusive or exhaustive. Many of the theoretical determinants of debt levels are widely accepted by respondents, in particular the importance of interest tax shield, financial distress, agency costs and also, at least implicitly, information asymmetry. Results also indicate that cross-country institutional differences have a significant impact on financial decisions

Fivebranes and 4-manifolds

We describe rules for building 2d theories labeled by 4-manifolds. Using the proposed dictionary between building blocks of 4-manifolds and 2d N=(0,2) theories, we obtain a number of results, which include new 3d N=2 theories T[M_3] associated with rational homology spheres and new results for Vafa-Witten partition functions on 4-manifolds. In particular, we point out that the gluing measure for the latter is precisely the superconformal index of 2d (0,2) vector multiplet and relate the basic building blocks with coset branching functions. We also offer a new look at the fusion of defect lines / walls, and a physical interpretation of the 4d and 3d Kirby calculus as dualities of 2d N=(0,2) theories and 3d N=2 theories, respectivelyComment: 81 pages, 18 figures. v2: misprints corrected, clarifications and references added. v3: additions and corrections about lens space theory, 4-manifold gluing, smooth structure

Resource Allocation in a National Dental Service Using Program Budgeting Marginal Analysis

Introduction: In any health system, choices must be made about the allocation of resources (budget), which are often scarce. Economics has defined frameworks to aid resource allocation, and program budgeting marginal analysis (PBMA) is one such framework. In principle, patient and public values can be incorporated into these frameworks, using techniques such as willingness to pay (WTP). However, this has not been done before, and few formal resource allocation processes have been undertaken in dentistry. This study aimed to undertake a PBMA with embedded WTP values in a national dental setting. Methods: The PBMA process was undertaken by a panel of participant-researchers representing commissioners, dentists, dental public health staff, and academics. The panel reviewed current allocations and generated a set of weighted criteria to evaluate services against. Services to be considered for removal and investment were determined by the panel and wider discussion and then scored against the criteria. Values from a nationally representative WTP survey of the public contributed to the scores for interventions. Final decisions on removal and investment were taken after panel discussion using individual anonymous electronic voting. Results: The PBMA process resulted in recommendations to invest in new program components to improve access to general dentists, care home dentistry, and extra support for dental public health input into local government decisions. Disinvestments were recommended in orthodontics and to remove routine scaling and polishing of teeth. Discussion: The PBMA process was successful in raising awareness of resource allocation issues. Implementation of findings will depend on the ability of decision makers to find ways of operationalizing the decisions. The process illustrates practical aspects of the process that future dental PBMAs could learn from. Knowledge Transfer Statement: This study illustrates a framework for resource allocation in dental health services and will aid decision makers in implementing their own resource allocation systems

Resource Allocation in a National Dental Service Using Program Budgeting Marginal Analysis

Introduction: In any health system, choices must be made about the allocation of resources (budget), which are often scarce. Economics has defined frameworks to aid resource allocation, and program budgeting marginal analysis (PBMA) is one such framework. In principle, patient and public values can be incorporated into these frameworks, using techniques such as willingness to pay (WTP). However, this has not been done before, and few formal resource allocation processes have been undertaken in dentistry. This study aimed to undertake a PBMA with embedded WTP values in a national dental setting. Methods: The PBMA process was undertaken by a panel of participant-researchers representing commissioners, dentists, dental public health staff, and academics. The panel reviewed current allocations and generated a set of weighted criteria to evaluate services against. Services to be considered for removal and investment were determined by the panel and wider discussion and then scored against the criteria. Values from a nationally representative WTP survey of the public contributed to the scores for interventions. Final decisions on removal and investment were taken after panel discussion using individual anonymous electronic voting. Results: The PBMA process resulted in recommendations to invest in new program components to improve access to general dentists, care home dentistry, and extra support for dental public health input into local government decisions. Disinvestments were recommended in orthodontics and to remove routine scaling and polishing of teeth. Discussion: The PBMA process was successful in raising awareness of resource allocation issues. Implementation of findings will depend on the ability of decision makers to find ways of operationalizing the decisions. The process illustrates practical aspects of the process that future dental PBMAs could learn from. Knowledge Transfer Statement: This study illustrates a framework for resource allocation in dental health services and will aid decision makers in implementing their own resource allocation systems

Data visualization in yield component analysis: an expert study

Even though data visualization is a common analytical tool in numerous disciplines, it has rarely been used in agricultural sciences, particularly in agronomy. In this paper, we discuss a study on employing data visualization to analyze a multiplicative model. This model is often used by agronomists, for example in the so-called yield component analysis. The multiplicative model in agronomy is normally analyzed by statistical or related methods. In practice, unfortunately, usefulness of these methods is limited since they help to answer only a few questions, not allowing for a complex view of the phenomena studied. We believe that data visualization could be used for such complex analysis and presentation of the multiplicative model. To that end, we conducted an expert survey. It showed that visualization methods could indeed be useful for analysis and presentation of the multiplicative model

Quantification of the pathological response and fate in the lung and pleura of chrysotile in combination with fine particles compared to amosite-asbestos following short-term inhalation exposure

The marked difference in biopersistence and pathological response between chrysotile and amphibole asbestos has been well documented. This study is unique in that it has examined a commercial chrysotile product that was used as a joint compound. The pathological response was quantified in the lung and translocation of fibers to and pathological response in the pleural cavity determined. This paper presents the final results from the study. Rats were exposed by inhalation 6 h/day for 5 days to a well-defined fiber aerosol. Subgroups were examined through 1 year. The translocation to and pathological response in the pleura was examined by scanning electron microscopy and confocal microscopy (CM) using noninvasive methods.The number and size of fibers was quantified using transmission electron microscopy and CM. This is the first study to use such techniques to characterize fiber translocation to and the response of the pleural cavity. Amosite fibers were found to remain partly or fully imbedded in the interstitial space through 1 year and quickly produced granulomas (0 days) and interstitial fibrosis (28 days). Amosite fibers were observed penetrating the visceral pleural wall and were found on the parietal pleural within 7 days postexposure with a concomitant inflammatory response seen by 14 days. Pleural fibrin deposition, fibrosis, and adhesions were observed, similar to that reported in humans in response to amphibole asbestos. No cellular or inflammatory response was observed in the lung or the pleural cavity in response to the chrysotile and sanded particles (CSP) exposure. These results provide confirmation of the important differences between CSP and amphibole asbestos

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation