The role of insulin and IGF2 signalling on metabolic pathways in prostate cancer progression

Prostate cancer (CaP) is the most commonly diagnosed cancer in males in Australia, North America, and Europe. If found early and locally confined, CaP can be treated with radical prostatectomy or radiation therapy; however, 25-40% patients will relapse and go on to advanced disease. The most common therapy in these cases is androgen deprivation therapy (ADT), which suppresses androgen production from the testis. Lack of the testicular androgen supply causes cells of the prostate to undergo apoptosis. However, in some cases the regression initially seen with ADT eventually gives way to a growth of a population of cancerous cells that no longer require testicular androgens. This phenotype is essentially fatal and is termed castrate resistant prostate cancer (CRPC). In addition to eventual regression, there are many undesirable side effects which accompany ADT, including development of a metabolic syndrome, which is defined by the U.S. National Library of Medicine as “a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes.” This project will focus on the effect of ADT induced hyperinsulinemia, as mimicked by treating androgen receptor positive CaP cells with insulin in a serum (hormone) deprived environment. While this side effect is not widely explored, in this thesis it is demonstrated for the first time that insulin upregulates pathways important to CaP progression. Our group has previously shown that during CaP progression, the enzymes necessary for de novo steroidogenesis are upregulated in the LNCaP xenograft model, total steroid levels are increased in tumours compared to pre castrate levels, and de novo steroidogenesis from radio-labelled acetate has been demonstrated. Because of the CaP dependence on AR for survival, we and other groups believe that CaP cells carry out de novo steroidogenesis to survive in androgen deprived conditions. Because (a) men on ADT often develop metabolic syndrome, and (b) men with lifestyle-induced obesity and hyperinsulinemia have worse prognosis and faster disease progression, and because (c) insulin causes steroidogenesis in other cell lines, the hypothesis that insulin may contribute to CaP progression through upregulation of steroidogenesis was explored. Insulin upregulates steroidogenesis enzymes at the mRNA level in three AR positive cell lines, as well as upregulating these enzymes at the protein level in two cell lines. It has also been demonstrated that insulin increases mitochondrial (functional) levels of steroid acute regulatory protein (StAR). Furthermore, insulin causes increased levels of total steroids in and induction of de novo steroid synthesis by insulin has been demonstrated at levels induced sufficient to activate AR. The effect of insulin analogs on CaP steroidogenesis in LNCaP and VCaP cells has also been investigated because epidemiological studies suggest that some of the analogs developed may have more cancer stimulatory effects than normal insulin. In this project, despite the signalling differences between glargine, X10, and insulin, these analogs did not appear to induce steroidogenesis any more potently that normal insulin. The effect of insulin of MCF7breast cancer cells was also investigated with results suggesting that breast cancer cells may be capable of de novo steroidogenesis, and that increase in estradiol production may be exacerbated by insulin. Insulin has also been long known to stimulate lipogenesis in the liver and adipocytes, and has been demonstrated to increase lipogenesis in breast cancer cells; therefore, investigation of the effect of insulin on lipogenesis, which is a hallmark of aggressive cancers, was investigated. In CaP progression sterol regulatory element binding protein (SREBP) is dysregulated and upregulates fatty acid synthase (FASN), acetyl CoA-carboxylase, and other lipogenesis genes. SREBP is important for steroidogenesis and in this project has been shown to be upregulated by insulin in CaP cells. Fatty acid synthesis provides building blocks of membrane growth, provides substrates for acid oxidation, the main energy source for CaP cells, provides building blocks for anti-apoptotic and proinflammatory molecules, and provides molecules that stimulate steroidogenesis. In this project it has been shown that insulin upregulates FASN and ACC, which synthesize fatty acids, as well as upregulating hormone sensitive lipase (HSL), diazepam-binding inhibitor (DBI), and long-chain acyl-CoA synthetase 3 (ACSL3), which contribute to lipid activation of steroidogenesis. Insulin also upregulates total lipid levels and de novo lipogenesis, which can be suppressed by inhibition of the insulin receptor (INSR). The fatty acids synthesized after insulin treatment are those that have been associated with CaP; furthermore, microarray data suggests insulin may upregulate fatty acid biosynthesis, metabolism and arachidonic acid metabolism pathways, which have been implicated in CaP growth and survival. Pharmacological agents used to treat patients with hyperinsulinemia/ hyperlipidemia have gained much interest in regards to CaP risk and treatment; however, the scientific rationale behind these clinical applications has not been examined. This thesis explores whether the use of metformin or simvastatin would decrease either lipogenesis or steroidogenesis or both in CaP cells. Simvastatin is a 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) inhibitor, which blocks synthesis of cholesterol, the building block of steroids/ androgens. It has also been postulated to down regulate SREBP in other metabolic disorders. It has been shown in this thesis, in LNCaP cells, that simvastatin inhibited and decreased insulin induced steroidogenesis and lipogenesis, respectively, but increased these pathways in the absence of insulin. Conversely, metformin, which activates AMP-activated protein kinase (AMPK) to shut down lipogenesis, cholesterol synthesis, and protein synthesis, highly suppresses both steroidogenesis and lipogenesis in the presence and absence of insulin. Lastly, because it has been demonstrated to increase steroidogenesis in other cell lines, and because the elucidation of any factors affecting steroidogenesis is important to understanding CaP, the effect of IGF2 on steroidogenesis in CaP cells was investigated. In patient samples, as men progress to CRPC, IGF2 mRNA and the protein levels of the receptors it may signal through are upregulated. It has also been demonstrated that IGF2 upregulates steroidogenic enzymes at both the mRNA and protein levels in LNCaP cells, increases intracellular and secreted steroid/androgen levels in LNCaPs to levels sufficient to stimulate the AR, and upregulated de novo steroidogenesis in LNCaPs and VCaPs. As well, inhibition of INSR and insulin-like growth factor 1 receptor (IGF1R), which IGF2 signals through, suggests that induction of steroidogenesis may be occurring predominantly through IGF1R. In summary, this project has illuminated for the first time that insulin is likely to play a large role in cancer progression, through upregulation of the steroidogenesis and lipogenesis pathways at the mRNA and protein levels, and production levels, and demonstrates a novel role for IGF-II in CaP progression through stimulation of steroidogenesis. It has also been demonstrated that metformin and simvastatin drugs may be useful in suppressing the insulin induction of these pathways. This project affirms the pathways by which ADT- induced metabolic syndrome may exacerbate CaP progression and strongly suggests that the monitoring and modulation of the metabolic state of CaP patients could have a strong impact on their therapeutic outcomes.

Theraplay : staying in life's performance zone with play - Homo ludens: Man the player - Homo Cogito: Man the thinker

The paper introduces an update on a therapy originally developed by Jernberg (1979) for the American Head Start Programme for use with children and parents. Theraplay was based on John Bowlby's (1969) attachment theory and was started by Jernberg in Chicago. The present use of theraplay is for young adults to deal with negative mood and mood disorders resulting from stress, anxiety or depression. It is for the sad, lonely, sluggish, miserable or melancholic amongst us as well as the worried well.

Community participation in the development of digital radio : the Australian experience

The participation of the community broadcasting sector in the development of digital radio provides a potentially valuable opportunity for non-market, end user-driven experimentation in the development of these new services in Australia. However this development path is constrained by various factors, some of which are specific to the community broadcasting sector and others that are generic to the broader media and communications policy, industrial and technological context. This paper filters recent developments in digital radio policy and implementation through the perspectives of community radio stakeholders, obtained through interviews, to describe and analyse these constraints. The early stage of digital community radio presented here is intended as a baseline for tracking the development of the sector as digital radio broadcasting develops. We also draw upon insights from scholarly debates about citizens media and participatory culture to identify and discuss two sets of opportunities for social benefit that are enabled by the inclusion of community radio in digital radio service development. The first arises from community broadcasting’s involvement in the propagation of the multi-literacies that drive new digital economies, not only through formal and informal multi- and trans-media training, but also in the ‘co-creative’ forms of collaborative and participatory media production that are fostered in the sector. The second arises from the fact that community radio is uniquely placed — indeed charged with the responsibility — to facilitate social participation in the design and operation of media institutions themselves, not just their service outputs.

‘They get fed up with playing.’ Parents’ views on play-based learning in the Preparatory Year

Within early childhood education two ideas are firmly held: play is the best way for children to learn and parents are partners in the child’s learning. While these ideas have been explored, limited research to date has investigated the confluence of the two - how parents of young children view the concept of play. This paper investigates parents’ views on play by analysing the views of small group of parents of Prep Year children in Queensland, Australia. The parents in this study held varying definitions of what constitutes play, and complex and contradictory notions of its value. Positive views of play were linked to learning without knowing it, engaging in hands-on activities, and preparation for Year One through a strong focus on academic progress. Some parents held that Prep was play-based, while others did not. The complexities and diversity of parental opinion in this study echo the ongoing commentary about how play ought to be defined. Moreover, the notion that adults may interpret play in different ways is also reflected here. The authors suggest that for early childhood educators these complexities require an ongoing engagement, debate and reconceptualisation of the place of play in light of broader curricular and socio-political agendas.

Chaos and creativity of play : designing emotional engagement in public spaces

How do we create strong urban narratives? How do we create affection for our cities? Play, an essential part of any species' biological existence and development, can often be perceived as chaotic and derogatory to social and spatial order. Play is also often perceived as a creative force which generates social and spatial value. This paper looks at the design approaches to both chaotic and creative perceptions of publics at play in urban space. Commonly, Urban and Architectural Design constitutes reactive management of perceived chaos, which derogatorily effects our sensory and emotional engagement with space. Alternatively, Urban and Architectural Design can appeal to the creativity of play, by encouraging unsolicited novelty that is vital to strong experiential narratives in the city and iterating environments that encourage the emergence of physical, emotional and cultural invention. These perceptions of chaos and creativity affect the design methodology of professional practice. Tested through the exciting vehicle of Parkour as urban narrative, the constraints and opportunities of both approaches are presented.

Explicit, latent and meta-criteria : types of criteria at play in professional judgement practice

This paper engages with debates about whether comprehensive prior specification of criteria and standards is sufficient for informed professional judgement. A preoccupation has emerged with the specificity and explication of criteria intended to regulate judgement. This has resulted in criteria-compliance in the use of defined standards to validate judgements and improve reliability and consistency. Compliance has become a priority, the consequence being the prominence of explicit criteria, to the lack of acknowledgement of the operation of latent and meta-criteria within judgement practice. This paper examines judgement as a process involving three categories of assessment criteria in the context of standards-referenced systems: explicit, latent and meta-criteria. These are understood to be wholly interrelated and interdependent. A conceptualisation of judgement involving the interplay of the three criteria types is presented with an exploration of how they function to focus or alter assessments of quality in judgements of achievement in English and Mathematics.

Leucocytes, cytokines and satellite cells : what role do they play in muscle damage and regeneration following eccentric exercise?

Exercise-induced muscle damage is an important topic in exercise physiology. However several aspects of our understanding of how muscles respond to highly stressful exercise remain unclear In the first section of this review we address the evidence that exercise can cause muscle damage and inflammation in otherwise healthy human skeletal muscles. We approach this concept by comparing changes in muscle function (i.e., the force-generating capacity) with the degree of leucocyte accumulation in muscle following exercise. In the second section, we explore the cytokine response to 'muscle-damaging exercise', primarily eccentric exercise. We review the evidence for the notion that the degree of muscle damage is related to the magnitude of the cytokine response. In the third and final section, we look at the satellite cell response to a single bout of eccentric exercise, as well as the role of the cyclooxygenase enzymes (COX1 and 2). In summary, we propose that muscle damage as evaluated by changes in muscle function is related to leucocyte accumulation in the exercised muscles. 'Extreme' exercise protocols, encompassing unaccustomed maximal eccentric exercise across a large range of motion, generally inflict severe muscle damage, inflammation and prolonged recovery (> 1 week). By contrast, exercise resembling regular athletic training (resistance exercise and downhill running) typically causes mild muscle damage (myofibrillar disruptions) and full recovery normally occurs within a few days. Large variation in individual responses to a given exercise should, however be expected. The link between cytokine and satellite cell responses and exercise-induced muscle damage is not so clear The systemic cytokine response may be linked more closely to the metabolic demands of exercise rather than muscle damage. With the exception of IL-6, the sources of systemic cytokines following exercise remain unclear The satellite cell response to severe muscle damage is related to regeneration, whereas the biological significance of satellite cell proliferation after mild damage or non-damaging exercise remains uncertain. The COX enzymes regulate satellite cell activity, as demonstrated in animal models; however the roles of the COX enzymes in human skeletal muscle need further investigation. We suggest using the term 'muscle damage' with care. Comparisons between studies and individuals must consider changes in and recovery of muscle force-generating capacity.

Personality, genre and videogame play experience

This study explored relationships between personality, videogame preference and gaming experiences. Four hundred and sixty-six participants completed an online survey in which they recalled a recent gaming experience, and provided measures of personality and their gaming experience via the Game Experience Questionnaire (GEQ). Relationships between game genre, personality and gaming experience were found. Results are interpreted with reference to possible implications for a positive impact on wellbeing of videogame play and possible means of improving the breadth of appeal of specific genres.

Could BFFB mode breath aerosol play a role in H5N1 transmission?

Recent findings concerning exhaled aerosol size distributions and the regions in the respiratory tract in which they are generated could have significant implications for human to human spread of lower respiratory tract-specific infections. Even in healthy people, measurable quantities of aerosol are routinely generated from the Lower Respiratory Tract (LRT) during breathing(1-3). We have found that there at least three modes in the exhaled aerosol size distribution of healthy adults(4) (see Figure 1). These modes each have a characteristic size and arise from different parts of the respiratory tract. The respiratory bronchioles produce aerosol during breathing, the larynx during speech and the oral cavity also during speech. The model of the resulting droplet size distribution is therefore called the Bronchial Laryngeal Oral (B.L.O.) tri-modal model of expired aerosol.

Videogame control device impact on the play experience

New types of control devices for videogames have emerged and expanded the demographics of the game playing public, yet little is known about which populations of gamers prefer which style of interaction and why. This paper presents data from a study that seeks to clarify the influence the control interface has on the play experience. Three commercial control devices were categorised using an existing typology, according to how the interface maps physical control inputs with the virtual gameplay actions. The devices were then used in a within-groups experimental design aimed at measuring differences in play experience across 64 participants. Descriptive analysis is undertaken on the performance, play experience and preference results for each device. Potential explanations for these results are discussed, as well as the direction of future work.

Spectrum sensing, detection and optimisation in cognitive radio for non-stationary primary user signals

Cognitive radio is an emerging technology proposing the concept of dynamic spec- trum access as a solution to the looming problem of spectrum scarcity caused by the growth in wireless communication systems. Under the proposed concept, non- licensed, secondary users (SU) can access spectrum owned by licensed, primary users (PU) so long as interference to PU are kept minimal. Spectrum sensing is a crucial task in cognitive radio whereby the SU senses the spectrum to detect the presence or absence of any PU signal. Conventional spectrum sensing assumes the PU signal as ‘stationary’ and remains in the same activity state during the sensing cycle, while an emerging trend models PU as ‘non-stationary’ and undergoes state changes. Existing studies have focused on non-stationary PU during the transmission period, however very little research considered the impact on spectrum sensing when the PU is non-stationary during the sensing period. The concept of PU duty cycle is developed as a tool to analyse the performance of spectrum sensing detectors when detecting non-stationary PU signals. New detectors are also proposed to optimise detection with respect to duty cycle ex- hibited by the PU. This research consists of two major investigations. The first stage investigates the impact of duty cycle on the performance of existing detec- tors and the extent of the problem in existing studies. The second stage develops new detection models and frameworks to ensure the integrity of spectrum sensing when detecting non-stationary PU signals. The first investigation demonstrates that conventional signal model formulated for stationary PU does not accurately reflect the behaviour of a non-stationary PU. Therefore the performance calculated and assumed to be achievable by the conventional detector does not reflect actual performance achieved. Through analysing the statistical properties of duty cycle, performance degradation is proved to be a problem that cannot be easily neglected in existing sensing studies when PU is modelled as non-stationary. The second investigation presents detectors that are aware of the duty cycle ex- hibited by a non-stationary PU. A two stage detection model is proposed to improve the detection performance and robustness to changes in duty cycle. This detector is most suitable for applications that require long sensing periods. A second detector, the duty cycle based energy detector is formulated by integrat- ing the distribution of duty cycle into the test statistic of the energy detector and suitable for short sensing periods. The decision threshold is optimised with respect to the traffic model of the PU, hence the proposed detector can calculate average detection performance that reflect realistic results. A detection framework for the application of spectrum sensing optimisation is proposed to provide clear guidance on the constraints on sensing and detection model. Following this framework will ensure the signal model accurately reflects practical behaviour while the detection model implemented is also suitable for the desired detection assumption. Based on this framework, a spectrum sensing optimisation algorithm is further developed to maximise the sensing efficiency for non-stationary PU. New optimisation constraints are derived to account for any PU state changes within the sensing cycle while implementing the proposed duty cycle based detector.

'Pretend I was Mummy': Children's Production of Authority and Subordinance in Their Pretend Play Interaction During Disputes

Purpose – This chapter examines an episode of pretend play amongst a group of young girls in an elementary school in Australia, highlighting how they interact within the membership categorization device ‘family’ to manage their social and power relationships. Approach – Using conversation analysis and membership categorization analysis, an episode of video-recorded interaction that occurs amongst a group of four young girls is analyzed. Findings – As disputes arise amongst the girls, the mother category is produced as authoritative through authoritative actions by the girl in the category of mother, and displays of subordination on the part of the other children, in the categories of sister, dog and cat. Value of paper – Examining play as a social practice provides insight into the social worlds of children. The analysis shows how the children draw upon and co-construct family-style relationships in a pretend play context, in ways that enable them to build and organize peer interaction. Authority is highlighted as a joint accomplishment that is part of the social and moral order continuously being negotiated by the children. The authority of the mother category is produced and oriented to as a means of managing the disputes within the pretend frame of play.

Energy-efficient localization : GPS duty cycling with radio ranging

GPS is a commonly used and convenient technology for determining absolute position in outdoor environments, but its high power consumption leads to rapid battery depletion in mobile devices. An obvious solution is to duty cycle the GPS module, which prolongs the device lifetime at the cost of increased position uncertainty while the GPS is off. This article addresses the trade-off between energy consumption and localization performance in a mobile sensor network application. The focus is on augmenting GPS location with more energy-efficient location sensors to bound position estimate uncertainty while GPS is off. Empirical GPS and radio contact data from a large-scale animal tracking deployment is used to model node mobility, radio performance, and GPS. Because GPS takes a considerable, and variable, time after powering up before it delivers a good position measurement, we model the GPS behaviour through empirical measurements of two GPS modules. These models are then used to explore duty cycling strategies for maintaining position uncertainty within specified bounds. We then explore the benefits of using short-range radio contact logging alongside GPS as an energy-inexpensive means of lowering uncertainty while the GPS is off, and we propose strategies that use RSSI ranging and GPS back-offs to further reduce energy consumption. Results show that our combined strategies can cut node energy consumption by one third while still meeting application-specific positioning criteria.