Vorinostat/SAHA-induced apoptosis in malignant mesothelioma is FLIP/caspase 8-dependent and HR23B-independent

Introduction: Malignant pleural mesothelioma (MPM) is a rapidly fatal malignancy that is increasing in incidence. The caspase 8 inhibitor FLIP is an anti-apoptotic protein over-expressed in several cancer types including MPM. The histone deacetylase (HDAC) inhibitor Vorinostat (SAHA) is currently being evaluated in relapsed mesothelioma. We examined the roles of FLIP and caspase 8 in regulating SAHA-induced apoptosis in MPM. Methods: The mechanism of SAHA-induced apoptosis was assessed in 7 MPM cell lines and in a multicellular spheroid model. SiRNA and overexpression approaches were used, and cell death was assessed by flow cytometry, Western blotting and clonogenic assays. Results: RNAi-mediated FLIP silencing resulted in caspase 8-dependent apoptosis in MPM cell line models. SAHA potently down-regulated FLIP protein expression in all 7 MPM cell lines and in a multicellular spheroid model of MPM. In 6/7 MPM cell lines, SAHA treatment resulted in significant levels of apoptosis induction. Moreover, this apoptosis was caspase 8-dependent in all six sensitive cell lines. SAHA-induced apoptosis was also inhibited by stable FLIP overexpression. In contrast, down-regulation of HR23B, a candidate predictive biomarker for HDAC inhibitors, significantly inhibited SAHA-induced apoptosis in only 1/6 SAHA-sensitive MPM cell lines. Analysis of MPM patient samples demonstrated significant inter-patient variations in FLIP and caspase 8 expressions. In addition, SAHA enhanced cisplatin-induced apoptosis in a FLIP-dependent manner. Conclusions: These results indicate that FLIP is a major target for SAHA in MPM and identifies FLIP, caspase 8 and associated signalling molecules as candidate biomarkers for SAHA in this disease. © 2011 Elsevier Ltd. All rights reserved.

Mirror, mirror : claiming digital places of the mundane mapping culture

This paper offers a discussion on the “mundane” or quotidian aspects of that software which might at first glance seem to be a fine example of the extraordinary. It looks at game worlds in terms of an ancient human desire to articulate place in the world and pursues a design concept which resonates with this practice in order to enable a more mundane exploitation of such spatial representations: the claiming of place.

Galectin-1 : a link between tumor hypoxia and tumor immune privilege

Purpose: To identify a 15-KDa novel hypoxia-induced secreted protein in head and neck squamous cell carcinomas (HNSCC) and to determine its role in malignant progression. Methods: We used surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF-MS) and tandem MS to identify a novel hypoxia-induced secreted protein in FaDu cells. We used immunoblots, real-time polymerase chain reaction (PCR), and enzyme-linked immunoabsorbent assay to confirm the hypoxic induction of this secreted protein as galectin-1 in cell lines and xenografts. We stained tumor tissues from 101 HNSCC patients for galectin-1, CA IX (carbonic anhydrase IX, a hypoxia marker) and CDS (a T-cell marker). Expression of these markers was correlated to each other and to treatment outcomes. Results: SELDI-TOF studies yielded a hypoxia-induced peak at 15 kDa that proved to be galectin-1 by MS analysis. Immunoblots and PCR studies confirmed increased galectin-1 expression by hypoxia in several cancer cell lines. Plasma levels of galectin-1 were higher in tumor-bearing severe combined immunodeficiency (SCID) mice breathing 10% O 2 compared with mice breathing room air. In HNSCC patients, there was a significant correlation between galectin-1 and CA IX staining (P = .01) and a strong inverse correlation between galectin-1 and CDS staining (P = .01). Expression of galectin-1 and CDS were significant predictors for overall survival on multivariate analysis. Conclusion: Galectin-1 is a novel hypoxia-regulated protein and a prognostic marker in HNSCC. This study presents a new mechanism on how hypoxia can affect the malignant progression and therapeutic response of solid tumors by regulating the secretion of proteins that modulate immune privilege. © 2005 by American Society of Clinical Oncology.

Block models for improved earthwork allocation planning in linear infrastructure construction

Earthwork planning has been considered in this article and a generic block partitioning and modelling approach has been devised to provide strategic plans of various levels of detail. Conceptually this approach is more accurate and comprehensive than others, for instance those that are section based. In response to environmental concerns the metric for decision making was fuel consumption and emissions. Haulage distance and gradient are also included as they are important components of these metrics. Advantageously the fuel consumption metric is generic and captures the physical difficulties of travelling over inclines of different gradients, that is consistent across all hauling vehicles. For validation, the proposed models and techniques have been applied to a real world road project. The numerical investigations have demonstrated that the models can be solved with relatively little CPU time. The proposed block models also result in solutions of superior quality, i.e. they have reduced fuel consumption and cost. Furthermore the plans differ considerably from those based solely upon a distance based metric thus demonstrating a need for industry to reflect upon their current practices.

Emergency Health Services (EHS) : demand and service delivery models. monograph 3 : patients’ reasons and perceptions

Executive Summary Emergency health is a critical component of Australia’s health system and emergency departments (EDs) are increasingly congested from growing demand and blocked access to inpatient beds. The Emergency Health Services Queensland (EHSQ) study aims to identify the factors driving increased demand for emergency health and to evaluate strategies which may safely reduce the future demand growth. This monograph addresses the perspectives of users of both ambulance services and EDs. The research reported here aimed to identify the perspectives of users of emergency health services, both ambulance services and public hospital Emergency Departments and to identify the factors that they took into consideration when exercising their choice of location for acute health care. A cross-sectional survey design was used involving a survey of patients or their carers presenting to the EDs of a stratified sample of eight hospitals. A specific purpose questionnaire was developed based on a novel theoretical model which had been derived from analysis of the literature (Monograph 1). Two survey versions were developed: one for adult patients (self-complete); and one for children (to be completed by parents/guardians). The questionnaires measured perceptions of social support, health status, illness severity, self-efficacy; beliefs and attitudes towards ED and ambulance services; reasons for using these services, and actions taken prior to the service request. The survey was conducted at a stratified sample of eight hospitals representing major cities (four), inner regional (two) and outer regional and remote (two). Due to practical limitations, data were collected for ambulance and ED users within hospital EDs, while patients were waiting for or under treatment. A sample size quota was determined for each ED based on their 2009/10 presentation volumes. The data collection was conducted by four members of the research team and a group of eight interviewers between March and May 2011 (corresponding to autumn season). Of the total of 1608 patients in all eight emergency departments the interviewers were able to approach 1361 (85%) patients and seek their consent to participate in the study. In total, 911 valid surveys were available for analysis (response rate= 67%). These studies demonstrate that patients elected to attend hospital EDs in a considered fashion after weighing up alternatives and there is no evidence of deliberate or ill-informed misuse. • Patients attending ED have high levels of social support and self-efficacy that speak to the considered and purposeful nature of the exercise of choice. • About one third of patients have new conditions while two thirds have chronic illnesses • More than half the attendees (53.1%) had consulted a healthcare professional prior to making the decision. • The decision to seek urgent care at an ED was mostly constructed around the patient’s perception of the urgency and severity of their illness, reinforced by a strong perception that the hospital ED was the correct location for them (better specialised staff, better care for my condition, other options not as suitable). • 33% of the respondent held private hospital insurance but nevertheless attended a public hospital ED. Similarly patients exercised considered and rational judgements in their choice to seek help from the ambulance service. • The decision to call for ambulance assistance was based on a strong perception about the severity of the illness (too severe to use other means of transport) and that other options were not considered appropriate. • The decision also appeared influenced by a perception that the ambulance provided appropriate access to the ED which was considered most appropriate for their particular condition (too severe to go elsewhere, all facilities in one spot, better specialised and better care). • In 43.8% of cases a health care professional advised use of the ambulance. • Only a small number of people perceived that ambulance should be freely available regardless of severity or appropriateness. These findings confirm a growing understanding that the choice of professional emergency health care services is not made lightly but rather made by reasonable people exercising a judgement which is influenced by public awareness of the risks of acute health and which is most often informed by health professionals. It is also made on the basis of a rational weighing up of alternatives and a deliberate and considered choice to seek assistance from a service which the patient perceived was most appropriate to their needs at that time. These findings add weight to dispensing with public perceptions that ED and ambulance congestion is a result of inappropriate choice by patients. The challenge for health services is to better understand the patient’s needs and to design and validate services that meet those needs. The failure of our health system to do so should not be grounds for blaming the patient, claiming inappropriate patient choices.

Indexing and efficient instance-based retrieval of process models using untanglings

Process-Aware Information Systems (PAISs) support executions of operational processes that involve people, resources, and software applications on the basis of process models. Process models describe vast, often infinite, amounts of process instances, i.e., workflows supported by the systems. With the increasing adoption of PAISs, large process model repositories emerged in companies and public organizations. These repositories constitute significant information resources. Accurate and efficient retrieval of process models and/or process instances from such repositories is interesting for multiple reasons, e.g., searching for similar models/instances, filtering, reuse, standardization, process compliance checking, verification of formal properties, etc. This paper proposes a technique for indexing process models that relies on their alternative representations, called untanglings. We show the use of untanglings for retrieval of process models based on process instances that they specify via a solution to the total executability problem. Experiments with industrial process models testify that the proposed retrieval approach is up to three orders of magnitude faster than the state of the art.

Resistance is feral : digital culture, community arts, and the new cultural gatekeepers

The Community Arts sector in Australia has a history of resistance. It has challenged hegemonic culture through facilitating grassroots creative production, contesting notions of artistic processes, and the role of the artist in society. This paper examines this penchant for resistance through the lens of contemporary digital culture, to establish that the sector is continuing to challenge dominant forms of cultural control. It then proposes that this enthusiasm and activity lacks ethical direction, describing it as feral to encompass the potential of current practices, while highlighting how a level of taming is needed in order to develop ethical approaches.

Examining workload models in online and blended teaching

Over the past decade, most Australian universities have moved increasingly towards online course delivery for both undergraduate and graduate programs. In almost all cases, elements of online teaching are part of routine teaching loads. Yet detailed and accurate workload data are not readily available. As a result, institutional policies on academic staff workload are often guided more by untested assumptions about reduction of costs per student unit, rather than being evidence-based, with the result that implementation of new technologies for online teaching has resulted in poorly defined workload expectations. While the academics in this study often revealed a limited understanding of their institutional workload formulas, which in Australia are negotiated between management and the national union through their local branches, the costs of various types of teaching delivery have become a critical issue in a time of increasing student numbers, declining funding, pressures to increase quality and introduce minimum standards of teaching and curriculum, and substantial expenditure on technologies to support e-learning. There have been relatively few studies on the costs associated with workload for online teaching, and even fewer on the more ubiquitous ‘blended’, ‘hybrid’ or ‘flexible’ modes, in which face-to-face teaching is supplemented by online resources and activities. With this in mind the research reported here has attempted to answer the following question: What insights currently inform Australian universities about staff workload when teaching online?

Data requirements of hedonic models in determining the impact of infrastructure charges on new housing costs

The use of hedonic models to estimate the effects of various factors on house prices is well established. This paper examines a number of international hedonic house price models that seek to quantify the effect of infrastructure charges on new house prices. This work is an important factor in the housing affordability debate, with many governments in high growth areas having user-pays infrastructure charging policies operating in tandem with housing affordability objectives, with no empirical evidence on the impact of one on the other. This research finds there is little consistency between existing models and the data sets utilised. Specification appears dependent upon data availability rather than sound theoretical grounding. This may lead to a lack of external validity with model specification dependent upon data availability rather than sound theoretical grounding.

Characterisation of a human skin equivalent model to study the effects of ultraviolet B radiation on keratinocytes

The incidences of skin cancers resulting from chronic ultraviolet radiation (UVR) exposure are on the incline both in Australia and globally. Hence, the cellular and molecular pathways associated with UVR-induced photocarcinogenesis urgently need to be elucidated, in order to develop more robust preventative and treatment strategies against skin cancers. In vitro investigations into the effects of UVR (in particular the highly-mutagenic UVB wavelength) have, to date, mainly involved the use of cell culture and animal models. However, these models possess biological disparities to native skin, which to some extent have limited their relevance to the in vivo situation. To address this, we characterised a 3-dimensional, tissue-engineered human skin equivalent (HSE) model (consisting of primary human keratinocytes cultured on a dermal-derived scaffold) as a representation of a more physiologically-relevant platform to study keratinocyte responses to UVB. Significantly, we demonstrate that this model retains several important epidermal properties of native skin. Moreover, UVB-irradiation of the HSE constructs was shown to induce key markers of photodamage in the HSE keratinocytes, including the formation of cyclobutane pyrimidine dimers, the activation of apoptotic pathways, the accumulation of p53 and the secretion of inflammatory cytokines. Importantly, we also demonstrate that the UVB-exposed HSE constructs retain the capacity for epidermal repair and regeneration following photodamage. Together, our results demonstrate the potential of this skin equivalent model as a tool to study various aspects of the acute responses of human keratinocytes to UVB radiation damage.

An evaluation of different features and learning models for anomalous event detection

The huge amount of CCTV footage available makes it very burdensome to process these videos manually through human operators. This has made automated processing of video footage through computer vision technologies necessary. During the past several years, there has been a large effort to detect abnormal activities through computer vision techniques. Typically, the problem is formulated as a novelty detection task where the system is trained on normal data and is required to detect events which do not fit the learned ‘normal’ model. There is no precise and exact definition for an abnormal activity; it is dependent on the context of the scene. Hence there is a requirement for different feature sets to detect different kinds of abnormal activities. In this work we evaluate the performance of different state of the art features to detect the presence of the abnormal objects in the scene. These include optical flow vectors to detect motion related anomalies, textures of optical flow and image textures to detect the presence of abnormal objects. These extracted features in different combinations are modeled using different state of the art models such as Gaussian mixture model(GMM) and Semi- 2D Hidden Markov model(HMM) to analyse the performances. Further we apply perspective normalization to the extracted features to compensate for perspective distortion due to the distance between the camera and objects of consideration. The proposed approach is evaluated using the publicly available UCSD datasets and we demonstrate improved performance compared to other state of the art methods.

Acceptability-based QoE models for mobile video

Quality of experience (QoE) measures the overall perceived quality of mobile video delivery from subjective user experience and objective system performance. Current QoE computing models have two main limitations: 1) insufficient consideration of the factors influencing QoE, and; 2) limited studies on QoE models for acceptability prediction. In this paper, a set of novel acceptability-based QoE models, denoted as A-QoE, is proposed based on the results of comprehensive user studies on subjective quality acceptance assessments. The models are able to predict users’ acceptability and pleasantness in various mobile video usage scenarios. Statistical regression analysis has been used to build the models with a group of influencing factors as independent predictors, including encoding parameters and bitrate, video content characteristics, and mobile device display resolution. The performance of the proposed A-QoE models has been compared with three well-known objective Video Quality Assessment metrics: PSNR, SSIM and VQM. The proposed A-QoE models have high prediction accuracy and usage flexibility. Future user-centred mobile video delivery systems can benefit from applying the proposed QoE-based management to optimize video coding and quality delivery decisions.