Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma.

Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease

The Role of Female Sexual-Self Schema in Reactions to Non-Explicit Sexual Advertising Imagery

We explore females’ reactions to a non-explicit, but still sexually themed, advertisement. Specifically, we consider the role of female sexual self-schema (SSS) in the identification of the level of sex present in such an advertisement, and then resultant effects on attitudes and purchase intent. We find that while SSS has no effect on the perceived level of sex present, it does influence resultant dependent variables, particularly for low-SSS females. Informed by our study and extant literature, we also offer areas for further SSS-based advertising research, particularly regarding issues of females’ perceptions of advertisement and brand fit with sexual themes

Routine Dental Extractions Routinely Produce Cavitations

ABSTRACT: Cavitations (CVs) are persistent holes found at the extraction sites of permanent teeth after apparent healing has taken place. Current den-talliterature considers this common phenomenon to be rare. In the scientific literature, CVs have a plethora of synonyms. They have been variably labeled as Ratner, Roberts, or trigger point bone cavities, interference fields, neuralgia-inducing cavitational osteonecrosis (NICO), and alveolar cavitational osteopathosis. Evidence suggests that the incidence of CVs is presently grossly underestimated. Therefore, we reviewed the charts of 112 randomly chosen patients treated at the Huggins Diagnostic Center (HDC) from 1991 through 1995 to determine the incidence of CVs in old extraction sites. We believe this problem to be important to the general health of patients who are being treated for a wide range of diseases where such a dental condition may be the ultimate cause or a significant contributing factor. This manuscript is clearly one written for dental surgeons. It describes, however, a little known phenomenon that is extremely important in the general ill health of many patients with a number of different diseases that are not usually associated with dental problems. Since there is more and mor

A model to assess the technological level of small businesses

none2In this paper we present a three-dimensional framework (named Cu- be of Corporate Technological Level – CCTL) to evaluate the technological po- sition of small enterprises from different points of view. This framework has been developed from existing tools with similar goals, already proposed by oth- er authors. Compared to existing ones, this framework differs primarily for the inclusion of a collaborative perspective. It reflects the distinctive features of the latest interactive and web 2.0 tools (chat, blogs, forums, ...), that allow compa- nies to manage their relationships with the external stakeholders of the supply chain. The proposed framework has been applied to a sample of small business- es to test its validity. Some business cases with different positions in the Cube are described.This paper is the joint effort of the authors. Francesca Maria Cesaroni developed sections 1, 2 and 5 and Domenico Consoli sections 3 and 4.openF.M.Cesaroni; D.ConsoliCesaroni, FRANCESCA MARIA; D., Consol

Verbal Reports and "Real' Reasons" : Confabulation and Conflation

This document is the Accepted Manuscript version of a published work that appeared in final form in Ethical Theory and Moral Practice after peer review and technical editing by the publisher. Constantine Sandis, ‘Verbal Reports and “Real” Reasons: Confabulation and Conflation’, Ethical Theory and Moral Practice, Vol. 18(2): 267-280, first published online 18 March 2015. The final publication is available at Springer via http://dx.doi.org/10.1007/s10677-015-9576-6 © Springer Science+Business Media Dordrecht 2015This paper examines the relation between the various forces which underlie human action and verbal reports about our reasons for acting as we did. I maintain that much of the psychological literature on confabulations rests on a dangerous conflation of the reasons for which people act with a variety of distinct motivational factors. In particular, I argue that subjects frequently give correct answers to questions about the considerations they acted upon while remaining largely unaware of why they take themselves to have such reasons to act. Pari passu, experimental psychologists are wrong to maintain that they have shown our everyday reason talk to be systematically confused. This is significant because our everyday reason-ascriptions affect characterizations of action (in terms of intention, knowledge, foresight, etc.) that are morally and legally relevant. I conclude, more positively, that far from rendering empirical research on confabulations invalid, my account helps to reveal its true insights into human nature.Peer reviewe

Numerical simulation of blood flow and pressure drop in the pulmonary arterial and venous circulation

A novel multiscale mathematical and computational model of the pulmonary circulation is presented and used to analyse both arterial and venous pressure and flow. This work is a major advance over previous studies by Olufsen et al. (Ann Biomed Eng 28:1281–1299, 2012) which only considered the arterial circulation. For the first three generations of vessels within the pulmonary circulation, geometry is specified from patient-specific measurements obtained using magnetic resonance imaging (MRI). Blood flow and pressure in the larger arteries and veins are predicted using a nonlinear, cross-sectional-area-averaged system of equations for a Newtonian fluid in an elastic tube. Inflow into the main pulmonary artery is obtained from MRI measurements, while pressure entering the left atrium from the main pulmonary vein is kept constant at the normal mean value of 2 mmHg. Each terminal vessel in the network of ‘large’ arteries is connected to its corresponding terminal vein via a network of vessels representing the vascular bed of smaller arteries and veins. We develop and implement an algorithm to calculate the admittance of each vascular bed, using bifurcating structured trees and recursion. The structured-tree models take into account the geometry and material properties of the ‘smaller’ arteries and veins of radii ≥ 50 μ m. We study the effects on flow and pressure associated with three classes of pulmonary hypertension expressed via stiffening of larger and smaller vessels, and vascular rarefaction. The results of simulating these pathological conditions are in agreement with clinical observations, showing that the model has potential for assisting with diagnosis and treatment for circulatory diseases within the lung

High use of private providers for first healthcare seeking by drug-resistant tuberculosis patients: a cross-sectional study in Yangon, Myanmar.

BACKGROUND: Drug resistance is a growing challenge to tuberculosis (TB) control worldwide, but particularly salient to countries such as Myanmar, where the health system is fragmented across the public and private sector. A recent systematic review has identified a critical lack of evidence for local policymaking, particularly in relation to drivers of drug-resistance that could be the target of preventative efforts. To address this gap from a health systems perspective, our study investigates the healthcare-seeking behavior and preferences of recently diagnosed patients with drug-resistant tuberculosis (DR-TB), focusing on the use of private versus public healthcare providers. METHODS: The study was conducted in ten townships across Yangon with high DR-TB burden. Patients newly-diagnosed with DR-TB by GeneXpert were enrolled, and data on healthcare-seeking behavior and socio-economic characteristics were collected from patient records and interviews. A descriptive analysis of healthcare-seeking behavior was followed by the investigation of relationships between socio-economic factors and type of provider visited upon first feeling unwell, through univariate logistic regressions. RESULTS: Of 202 participants, only 8% reported first seeking care at public facilities, while 88% reported seeking care at private facilities upon first feeling unwell. Participants aged 25-34 (Odds Ratio = 0.33 [0.12-0.95]) and males (Odds Ratio = 0.39 [0.20-0.75]) were less likely to visit a private clinic or hospital than those aged 18-24 and females, respectively. In contrast, participants with higher income were more likely to utilize private providers. Prior to DR-TB diagnosis, 86% of participants took medications from private providers. After DR-TB diagnosis, only 7% of participants continued to take medications from private providers. CONCLUSION: In urban Myanmar, most patients shifted to being managed exclusively in the public sector after being formally diagnosed with DR-TB. However, since the vast majority of DR-TB patients first visited private providers in the period leading to diagnosis, related issues such as unregulated quality of care, potential delays to diagnosis, and lack of care continuity may greatly influence the emergence of drug-resistance. A greater understanding of the health system and these healthcare-seeking behaviors may simultaneously strengthen TB control programmes and reduce government and out-of-pocket expenditures on the management of DR-TB

Corticosteroid suppression of lipoxin A4 and leukotriene B4from alveolar macrophages in severe asthma

<p>Abstract</p> <p>Background</p> <p>An imbalance in the generation of pro-inflammatory leukotrienes, and counter-regulatory lipoxins is present in severe asthma. We measured leukotriene B₄(LTB₄), and lipoxin A₄(LXA₄) production by alveolar macrophages (AMs) and studied the impact of corticosteroids.</p> <p>Methods</p> <p>AMs obtained by fiberoptic bronchoscopy from 14 non-asthmatics, 12 non-severe and 11 severe asthmatics were stimulated with lipopolysaccharide (LPS,10 μg/ml) with or without dexamethasone (10^-6M). LTB₄and LXA₄were measured by enzyme immunoassay.</p> <p>Results</p> <p>LXA₄biosynthesis was decreased from severe asthma AMs compared to non-severe (p < 0.05) and normal subjects (p < 0.001). LXA₄induced by LPS was highest in normal subjects and lowest in severe asthmatics (p < 0.01). Basal levels of LTB₄were decreased in severe asthmatics compared to normal subjects (p < 0.05), but not to non-severe asthma. LPS-induced LTB₄was increased in severe asthma compared to non-severe asthma (p < 0.05). Dexamethasone inhibited LPS-induced LTB₄and LXA₄, with lesser suppression of LTB₄in severe asthma patients (p < 0.05). There was a significant correlation between LPS-induced LXA₄and FEV₁(% predicted) (r_s= 0.60; p < 0.01).</p> <p>Conclusions</p> <p>Decreased LXA₄and increased LTB₄generation plus impaired corticosteroid sensitivity of LPS-induced LTB₄but not of LXA₄support a role for AMs in establishing a pro-inflammatory balance in severe asthma.</p

Neoliberalisation and 'lad cultures' in higher education

This paper links HE neoliberalisation and ‘lad cultures’, drawing on interviews and focus groups with women students. We argue that retro-sexist ‘laddish’ forms of masculine competitiveness and misogyny have been reshaped by neoliberal rationalities to become modes of consumerist sexualised audit. We also suggest that neoliberal frameworks scaffold an individualistic and adversarial culture among young people that interacts with perceived threats to men’s privilege and intensifies attempts to put women in their place through misogyny and sexual harassment. Furthermore, ‘lad cultures’, sexism and sexual harassment in higher education may be invisibilised by institutions to preserve marketability in a neoliberal context. In response, we ask if we might foster dialogue and partnership between feminist and anti-marketisation politics

Impact of adverse events, treatment modifications, and dose intensity on survival among patients with advanced renal cell carcinoma treated with first‐line sunitinib: a medical chart review across ten centers in five European countries

Angiogenesis inhibitors have become standard of care for advanced and/or metastatic renal cell carcinoma (RCC), but data on the impact of adverse events (AEs) and treatment modifications associated with these agents are limited. Medical records were abstracted at 10 tertiary oncology centers in Europe for 291 patients ≥18 years old treated with sunitinib as first-line treatment for advanced RCC (no prior systemic treatment for advanced disease). Logistic regression models were estimated to compare dose intensity among patients who did and did not experience AEs during the landmark periods (18, 24, and 30 weeks). Cox proportional hazard models were used to explore the possible relationship of low-dose intensity (defined using thresholds of 0.7, 0.8, and 0.9) and treatment modifications during the landmark periods to survival. 64.4% to 67.9% of patients treated with sunitinib reported at least one AE of any grade, and approximately 10% of patients experienced at least one severe (grade 3 or 4) AE. Patients reporting severe AEs were statistically significantly more likely to have dose intensities below either 0.8 or 0.9. Dose intensity below 0.7 and dose discontinuation during all landmark periods were statistically significantly associated with shorter survival time. This study of advanced RCC patients treated with sunitinib in Europe found a significant relationship between AEs and dose intensity. It also found correlations between dose intensity and shorter survival, and between dose discontinuation and shorter survival. These results confirm the importance of tolerable treatment and maintaining dose intensity