Gonadotropin-induced ovarian cancer cell migration and proliferation require extracellular signal-regulated kinase 1/2 activation regulated by calcium and protein kinase Cδ

The gonadotropin hypothesis proposes that elevated serum gonadotropin levels may increase the risk of epithelial ovarian cancer (EOC). We have studied the effect of treating EOC cell lines (OV207 and OVCAR-3) with FSH or LH. Both gonadotropins activated the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and increased cell migration that was inhibited by the MAPK 1 inhibitor PD98059. Both extra- and intracellular calcium ion signalling were implicated in gonadotropin-induced ERK1/2 activation as treatment with either the calcium chelator EGTA or an inhibitor of intracellular calcium release, dantrolene, inhibited gonadotropin-induced ERK1/2 activation. Verapamil was also inhibitory, indicating that gonadotropins activate calcium influx via L-type voltage-dependent calcium channels. The cAMP/protein kinase A (PKA) pathway was not involved in the mediation of gonadotropin action in these cells as gonadotropins did not increase intracellular cAMP formation and inhibition of PKA did not affect gonadotropin-induced phosphorylation of ERK1/2. Activation of ERK1/2 was inhibited by the protein kinase C (PKC) inhibitor GF 109203X as well as by the PKCδ inhibitor rottlerin, and downregulation of PKCδ was inhibited by small interfering RNA (siRNA), highlighting the importance of PKCδ in the gonadotropin signalling cascade. Furthermore, in addition to inhibition by PD98059, gonadotropin-induced ovarian cancer cell migration was also inhibited by verapamil, GF 109203X and rottlerin. Similarly, gonadotropin-induced proliferation was inhibited by PD98059, verapamil, GF 109203X and PKCδ siRNA. Taken together, these results demonstrate that gonadotropins induce both ovarian cancer cell migration and proliferation by activation of ERK1/2 signalling in a calcium- and PKCδ-dependent manner.

Dopamine responsiveness is regulated by targeted sorting of D2 receptors

Abstract Aberrant dopaminergic signaling is a critical determinant in multiple psychiatric disorders, and in many disease states, dopamine receptor number is altered. Here we identify a molecular mechanism that selectively targets D2 receptors for degradation after their activation by dopamine. The degradative fate of D2 receptors is determined by an interaction with G protein coupled receptor-associated sorting protein (GASP). As a consequence of this GASP interaction, D2 responses in rat brain fail to resensitize after agonist treatment. Disruption of the D2-GASP interaction facilitates recovery of D2 responses, suggesting that modulation of the D2-GASP interaction is important for the functional down-regulation of D2 receptors.

Mission unreachable : how Jaman is shaping the future of on-line distribution

Perhaps the most innovative of all independent OLD ventures specialising in ROW content is Jaman. Founded in 2007 by IT entrepreneur Gaurav Dhillon, and based in San Mateo, California, Jaman is a quality specialist distributor of non-Hollywood films. As of late 2010, Jaman had 1.8 million registered users and attracts viewers from most countries in the world. 75% of all use is generated from outside the U.S. Jaman does very well in English speaking parts of the world, particularly current and former Commonwealth countries. The United Kingdom accounts for 29% of users, North America (U.S. and Canada) 26%, and India represents 23%. Jaman is sometimes referred to as ‘social cinema’: a website which brings together the critique and review of a cinephile website (the forums of Rue-morgue.com for cinefantastique movie fans for example) with the social interaction, community and functionality of a social media site (for example Facebook.com). Jaman could be considered a pioneer in this space; a first mover in wrapping commercial movie downloading in an interactive social experience.

Application of operations research techniques to improve efficiency in the emergency department

The main aim of this thesis is to analyse and optimise a public hospital Emergency Department. The Emergency Department (ED) is a complex system with limited resources and a high demand for these resources. Adding to the complexity is the stochastic nature of almost every element and characteristic in the ED. The interaction with other functional areas also complicates the system as these areas have a huge impact on the ED and the ED is powerless to change them. Therefore it is imperative that OR be applied to the ED to improve the performance within the constraints of the system. The main characteristics of the system to optimise included tardiness, adherence to waiting time targets, access block and length of stay. A validated and verified simulation model was built to model the real life system. This enabled detailed analysis of resources and flow without disruption to the actual ED. A wide range of different policies for the ED and a variety of resources were able to be investigated. Of particular interest was the number and type of beds in the ED and also the shift times of physicians. One point worth noting was that neither of these resources work in isolation and for optimisation of the system both resources need to be investigated in tandem. The ED was likened to a flow shop scheduling problem with the patients and beds being synonymous with the jobs and machines typically found in manufacturing problems. This enabled an analytic scheduling approach. Constructive heuristics were developed to reactively schedule the system in real time and these were able to improve the performance of the system. Metaheuristics that optimised the system were also developed and analysed. An innovative hybrid Simulated Annealing and Tabu Search algorithm was developed that out-performed both simulated annealing and tabu search algorithms by combining some of their features. The new algorithm achieves a more optimal solution and does so in a shorter time.

Sacred cows and crashing boars : ethno-religious minorities and the politics of online representation in Malaysia

Starting with the incident now known as the Cow’s Head Protest, this article traces and unpacks the events, techniques, and conditions surrounding the representation of ethno-religious minorities in Malaysia. The author suggests that the Malaysian Indians’ struggle to correct the dominant reading of their community as an impoverished and humbled underclass is a disruption of the dominant cultural order in Malaysia. It is also among the key events to have has set in motion a set of dynamics—the visual turn—introduced by new media into the politics of ethno-communal representation in Malaysia. Believing that this situation requires urgent examination the author attempts to outline the problematics of the task.

United we stand, divided we fall: the failure of an accounting information system in a major radiology provider

This article explores the way in which a major Australian radiology organization implemented a complex accounting information system and how workers in the 72 radiology practises that had to use it resisted the change. The study reports on the issues that led to the circumvention of the system by individuals and, after only three years, complete withdrawal of the accounting information system by the parent organization. This article has implications for firms in the health care and other sectors considering implementing new accounting information systems. Organizations need to incorporate change management techniques and provide open communication to all stakeholders to minimize disruption and potential problems.

Effects of surgical joint destabilization on load sharing between ligamentous structures in the thoracic spine : a finite element investigation

Background: In vitro investigations have demonstrated the importance of the ribcage in stabilising the thoracic spine. Surgical alterations of the ribcage may change load-sharing patterns in the thoracic spine. Computer models are used in this study to explore the effect of surgical disruption of the rib-vertebrae connections on ligament load-sharing in the thoracic spine. Methods: A finite element model of a T7-8 motion segment, including the T8 rib, was developed using CT-derived spinal anatomy for the Visible Woman. Both the intact motion segment and the motion segment with four successive stages of destabilization (discectomy and removal of right costovertebral joint, right costotransverse joint and left costovertebral joint) were analysed for a 2000Nmm moment in flexion/extension, lateral bending and axial rotation. Joint rotational moments were compared with existing in vitro data and a detailed investigation of the load sharing between the posterior ligaments carried out. Findings: The simulated motion segment demonstrated acceptable agreement with in vitro data at all stages of destabilization. Under lateral bending and axial rotation, the costovertebral joints were of critical importance in resisting applied moments. In comparison to the intact joint, anterior destabilization increases the total moment contributed by the posterior ligaments. Interpretation: Surgical removal of the costovertebral joints may lead to excessive rotational motion in a spinal joint, increasing the risk of overload and damage to the remaining ligaments. The findings of this study are particularly relevant for surgical procedures involving rib head resection, such as some techniques for scoliosis deformity correction.

Like two ships

In this video, the words animated on screen are sometimes the same and sometimes different from those spoken by a male voice. Both narratives, written and spoken, are constructed entirely from clichés and mixed metaphors. This work examines processes of signification. It emphasizes disruption and disconnection as fundamental and generative operations in making meaning. Extending on post-structural and deconstructionist ideas, this work questions the relationship between written and spoken words. It upsets the assumed efficacy of metaphors and clichés to question the sites and mechanisms of signification.

If things were different

In this video, a couple sits on a couch slowly breaking up. A typical shot/reverse-shot filmic structure is offset as the sound and image goes out of synch. At different times, it becomes so out of synch that they mouth each other’s words. This work engages with the signifying processes of romantic narratives. It emphasizes disruption and discontinuity as fundamental and generative operations in making meaning. Extending on post-structural and deconstructionist ideas, this work emphasizes the constructed nature of representations of heterosexual relationships. It draws attention to the gaps, slippages and fragments that pervade signifying acts.

Using operations research methodologies to improve operating theatre scheduling

A hospital consists of a number of wards, units and departments that provide a variety of medical services and interact on a day-to-day basis. Nearly every department within a hospital schedules patients for the operating theatre (OT) and most wards receive patients from the OT following post-operative recovery. Because of the interrelationships between units, disruptions and cancellations within the OT can have a flow-on effect to the rest of the hospital. This often results in dissatisfied patients, nurses and doctors, escalating waiting lists, inefficient resource usage and undesirable waiting times. The objective of this study is to use Operational Research methodologies to enhance the performance of the operating theatre by improving elective patient planning using robust scheduling and improving the overall responsiveness to emergency patients by solving the disruption management and rescheduling problem. OT scheduling considers two types of patients: elective and emergency. Elective patients are selected from a waiting list and scheduled in advance based on resource availability and a set of objectives. This type of scheduling is referred to as ‘offline scheduling’. Disruptions to this schedule can occur for various reasons including variations in length of treatment, equipment restrictions or breakdown, unforeseen delays and the arrival of emergency patients, which may compete for resources. Emergency patients consist of acute patients requiring surgical intervention or in-patients whose conditions have deteriorated. These may or may not be urgent and are triaged accordingly. Most hospitals reserve theatres for emergency cases, but when these or other resources are unavailable, disruptions to the elective schedule result, such as delays in surgery start time, elective surgery cancellations or transfers to another institution. Scheduling of emergency patients and the handling of schedule disruptions is an ‘online’ process typically handled by OT staff. This means that decisions are made ‘on the spot’ in a ‘real-time’ environment. There are three key stages to this study: (1) Analyse the performance of the operating theatre department using simulation. Simulation is used as a decision support tool and involves changing system parameters and elective scheduling policies and observing the effect on the system’s performance measures; (2) Improve viability of elective schedules making offline schedules more robust to differences between expected treatment times and actual treatment times, using robust scheduling techniques. This will improve the access to care and the responsiveness to emergency patients; (3) Address the disruption management and rescheduling problem (which incorporates emergency arrivals) using innovative robust reactive scheduling techniques. The robust schedule will form the baseline schedule for the online robust reactive scheduling model.

A longitudinal assessment of chronic wound fluid to detect biochemical indicators of healing

Chronic venous leg ulcers are a detrimental health issue plaguing our society, resulting in long term pain, immobility and decreased quality of life for a large proportion of sufferers. The frequency of these chronic wounds has led current research to focus on the wound environment to provide important information regarding the prolonged, fluctuated or static healing patterns of these wounds. Disruption to the normal wound healing process results in release of multiple factors in the wound environment that could correlate to wound chronicity. These biochemical factors can often be detected through non-invasively sampling chronic wound fluid (CWF) from the site of injury. Of note, whilst there are numerous studies comparing acute and chronic wound fluids, there have not been any reports in the literature employing a longitudinal study in order to track biochemical changes in wound fluid as patients transition from a non-healing to healed state. Initially the objective of this study was to identify biochemical changes in CWF associated with wound healing using a proteomic approach. The proteomic approach incorporated a multi-dimensional liquid chromatography fractionation technique coupled with mass spectrometry (MS) to enable identification of proteins present in lower concentrations in CWF. Not surprisingly, many of the proteins identified in wound fluid were acute phase proteins normally expressed during the inflammatory phase of healing. However, the number of proteins positively identified by MS was quite low. This was attributed to the diverse range in concentration of protein species in CWF making it challenging to detect the diagnostically relevant low molecular weight proteins. In view of this, SELDI-TOF MS was also explored as a means to target low molecular weight proteins in sequential patient CWF samples during the course of healing. Unfortunately, the results generated did not yield any peaks of interest that were altered as wounds transitioned to a healed state. During the course of proteomic assessment of CWF, it became evident that a fraction of non-proteinaceous compounds strongly absorbed at 280 nm. Subsequent analyses confirmed that most of these compounds were in fact part of the purine catabolic pathway, possessing distinctive aromatic rings and which results in high absorbance at 254 nm. The accumulation of these purinogenic compounds in CWF suggests that the wound bed is poorly oxygenated resulting in a switch to anaerobic metabolism and consequently ATP breakdown. In addition, the presence of the terminal purine catabolite, uric acid (UA), indicates that the enzyme xanthine oxidoreductase (XOR) catalyses the reaction of hypoxanthine to xanthine and finally to UA. More importantly, the studies provide evidence for the first time of the exogenous presence of XOR in CWF. XOR is the only enzyme in humans capable of catalysing the production of UA in conjunction with a burst of the highly reactive superoxide radical and other oxidants like H2O2. Excessive release of these free radicals in the wound environment can cause cellular damage disrupting the normal wound healing process. In view of this, a sensitive and specific assay was established for monitoring low concentrations of these catabolites in CWF. This procedure involved combining high performance liquid chromatography (HPLC) with tandem mass spectrometry and multiple reaction monitoring (MRM). This application was selective, using specific MRM transitions and HPLC separations for each analyte, making it ideal for the detection and quantitation of purine catabolites in CWF. The results demonstrated that elevated levels of UA were detected in wound fluid obtained from patients with clinically worse ulcers. This suggests that XOR is active in the wound site generating significant amounts of reactive oxygen species (ROS). In addition, analysis of the amount of purine precursors in wound fluid revealed elevated levels of purine precursors in wound fluid from patients with less severe ulcers. Taken together, the results generated in this thesis suggest that monitoring changes of purine catabolites in CWF is likely to provide valuable information regarding the healing patterns of chronic venous leg ulcers. XOR catalysis of purine precursors not only provides a method for monitoring the onset, prognosis and progress of chronic venous leg ulcers, but also provides a potential therapeutic target by inhibiting XOR, thus blocking UA and ROS production. Targeting a combination of these purinogenic compounds and XOR could lead to the development of novel point of care diagnostic tests. Therefore, further investigation of these processes during wound healing will be worthwhile and may assist in elucidating the pathogenesis of this disease state, which in turn may lead to the development of new diagnostics and therapies that target these processes.

Class contestations and Australia’s resource boom : the emergence of the ‘cashed-up bogan’

This article examines the figure of the ‘Cashed-up Bogan’ or ‘Cub’ in Australian media from 2006 to 2009. It explains that ‘Bogan’, like that of ‘Chav’ in Britain, is a widely engaged negative descriptor for the white working-class poor. In contrast, ‘Cubs’ have economic capital. This capital, and the Cub’s emergence, is linked to Australia’s resource boom of recent decades when the need for skilled labour allowed for a highly demarcated segment of the working class to earn relatively high incomes in the mining sector and to participate in consumption. We argue that access to economic capital has provided the Cub with mobility to enter the everyday spaces of the middle class, but this has caused disruption and anxiety to middle-class hegemony. As a result, the middle class has redrawn and reinforced class-infused symbolic and cultural boundaries, whereby, despite their wealth, pernicious media representations mark Cubs as ‘other’ to the middle-class deservingness, taste and morality.

On-line film distribution : Its history and global complexion

‘Nobody knows anything’, said William Goldman of studio filmmaking. The rule is ever more apt as we survey the radical changes that digital distribution, along with the digitisation of production and exhibition, is wreaking on global film circulation. Digital Disruption: Cinema Moves On-line helps to make sense of what has happened in the short but turbulent history of on-line distribution. It provides a realistic assessment of the genuine and not-so-promising methods that have been tried to address the disruptions that moving from ‘analogue dollars’ to ‘digital cents’ has provoked in the film industry. Paying close attention to how the Majors have dealt with the challenges – often unsuccessfully – it focuses as much attention on innovations and practices outside the mainstream. Throughout, it is alive to, and showcases, important entrepreneurial innovations such as Mubi, Jaman, Withoutabox and IMDb. Written by leading academic commentators that have followed the fortunes of world cinema closely and passionately, as well as experienced hands close to the fluctuating fortunes of the industry, Digital Disruption: Cinema Moves On-line is an indispensable guide to great changes in film and its audiences.

Why the long face?

In this video, a male voice recites a script comprised entirely of jokes. Words flash on screen in time with the spoken words. Sometimes the two sets of words match, and sometimes they differ. This work examines processes of signification. It emphasizes disruption and disconnection as fundamental and generative operations in making meaning. Extending on post-structural and deconstructionist ideas, this work questions the relationship between written and spoken words. By deliberately confusing the signifying structures of jokes and narratives, it questions the sites and mechanisms of comprehension, humour and signification.