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.

Anatomy of a Sub-tropical Positive Energy Home (PEH)

Zero energy buildings (ZEB) and zero energy homes (ZEH) are a current hot topic globally for policy makers (what are the benefits and costs), designers (how do we design them), the construction industry (can we build them), marketing (will consumers buy them) and researchers (do they work and what are the implications). This paper presents initial findings from actual measured data from a 9 star (as built), off-ground detached family home constructed in south-east Queensland in 2008. The integrated systems approach to the design of the house is analysed in each of its three main goals: maximising the thermal performance of the building envelope, minimising energy demand whilst maintaining energy service levels, and implementing a multi-pronged low carbon approach to energy supply. The performance outcomes of each of these stages are evaluated against definitions of Net Zero Carbon / Net Zero Emissions (Site and Source) and Net Zero Energy (onsite generation vs primary energy imports). The paper will conclude with a summary of the multiple benefits of combining very high efficiency building envelopes with diverse energy management strategies: a robustness, resilience, affordability and autonomy not generally seen in housing.

Positive energy homes : impacts on, and implications for, ecologically sustainable design

A zero-energy home (ZEH) is a residential dwelling that generates as much energy annually from onsite renewable sources, as it consumes in its operation. A positive energy home (PEH) generates more energy than it consumes. The key design and construction elements, and costs and benefits of such buildings, are the subject of increasing research globally. Approaching this topic from the perspective of the role of such homes in the planning and development ‘supply chain’, this paper presents the measured outcomes of a PEH and discusses urban design implications. Using twelve months of detailed performance data of an occupied sub-tropical home, the paper analyses the design approach and performance outcomes that enable it to be classified as ‘positive energy’. Second, it analyses both the urban design strategies that assisted the house in achieving its positive energy status, and the impacts of such housing on urban design and infrastructure. Third, the triple bottom line implications are discussed from the viewpoint of both the individual household and the broader community. The paper concludes with recommendations for research areas required to further underpin and quantify the role of ZEHs and PEHs in enabling and supporting the economic, social and ecological sustainability of urban developments.

Investigation to enhance high speed rail accessibility

High Speed Rail (HSR) is rapidly gaining popularity worldwide as a safe and efficient transport option for long-distance travel. Designed to win market shares from air transport, HSR systems optimise their productivity between increasing speeds and station spacing to offer high quality service and gain ridership. Recent studies have investigated the effects that the deployment of HSR infrastructure has on spatial distribution and the economic development of cities and regions. Findings appear mostly positive at higher geographical scales, where HSR links connect major urban centres several hundred kilometres apart and already well positioned within a national or international context. Also, at the urban level, studies have shown regeneration and concentration effects around HSR station areas with positive returns on city’s image and economy. However, doubts persist on the effects of HSR at an intermediate scale, where the accessibility trade off on station spacing limits access to many small and medium agglomerations. Thereby, their ability to participate in the development opportunities facilitated by HSR infrastructure is significantly reduced. The locational advantages deriving from transport improvements appear contrasting especially in regions that tend to have a polycentric structure, where cities may present greater accessibility disparities between those served by HSR and those left behind. This thesis fits in this context where intermediate and regional cities do not directly enjoy the presence of an HSR station while having an existing or planned proximate HSR corridor. With the aim of understanding whether there might be a solution to this apparent incongruity, the research investigates strategies to integrate HSR accessibility at the regional level. While current literature recommends to commit with ancillary investments to the uplift of station areas and the renewal of feeder systems, I hypothesised the interoperability between the HSR and the conventional networks to explore the possibilities offered by mixed traffic and infrastructure sharing. Thus, I developed a methodology to quantify the exchange of benefits deriving from this synergistic interaction. In this way, it was possible to understand which level of service quality offered by alternative transit strategies best facilitates the distribution of accessibility benefits for areas far from actual HSR stations. Therefore, strategies were selected for their type of service capable of regional extensions and urban penetrations, while incorporating a combination of specific advantages (e.g. speed, sub-urbanity, capacity, frequency and automation) in order to emulate HSR quality with increasingly efficient services. The North-eastern Italian macro region was selected as case study to ground the research offering concurrently a peripheral polycentric metropolitan form, the presence of a planned HSR corridor with some portions of HSR infrastructure implementation, and the project to develop a suburban rail service extended regionally. Results show significant distributive potential, in terms of network effects produced in relation with HSR, in increasing proportions for all the strategies considered: a regional metro rail strategy (abbreviated RMR), a regional high speed rail strategy (abbreviated RHSR), a regional light rail transit (abbreviated LRT) strategy, and a non-stopping continuous railway system (abbreviated CRS) strategy. The provision of additional tools to value HSR infrastructure against its accessibility benefits and their regional distribution through alternative strategies beyond the actual HSR stations, would have great implications, both politically and technically, in moving towards new dimensions of HSR evaluation and development.

The internal validity of web-based studies

Honing and Ladinig (2008) make the assertion that while the internal validity of web-based studies may be reduced, this is offset by an increase in external validity possible when experimenters can sample a wider range of participants and experimental settings. In this paper, the issue of internal validity is more closely examined, and it is agued that there is no necessary reason why internal validity of a web-based study should be worse than that of a lab-based one. Errors of measurement or inconsistencies of manipulation will typically balance across conditions of the experiment, and thus need not necessarily threaten the validity of a study’s findings.

Cultural studies and the urgency of interdisciplinarity : sooner, not later, we're going to need a cultural science (Os Estudos Culturais e a urgência por interdisciplinaridade: cedo, e não tarde, vamos precisar de uma Ciência da Cultura)

Most of creativity in the digital world passes unnoticed by the industry practices and policies, and it isn't taken into account in the cultural and economic strategies of the creative industries. We should find ways to catalyze this creative production, showing how the user's contribution may contribute to social learning, cultural and economic advancement. To that effect, we must know what is an open creative system and how it works. Based on this diagnosis, the author that interdisciplinarity is urgent and there is also a need for a science of culture. What is at stake is a strategy of integrated development, as regards the upcoming innovation in its complex, productive and learning aspects.

Communication, Cultural and Media Studies : The Key Concepts (4th Edition)

This fourth edition of Communication, Cultural and Media Studies: The Key Concepts is an indispensible guide to the most important terms in the field. It offers clear explanations of the key concepts, exploring their origins, what they’re used for and why they provoke discussion. The author provides a multi-disciplinary explanation and assessment of the key concepts, from ‘authorship’ to ‘censorship’; ‘creative industries’ to ‘network theory’; ‘complexity’ to ‘visual culture’. The new edition of this classic text includes: * Over 200 entries including 50 new entries * All entries revised, rewritten and updated * Coverage of recent developments in the field * Insight into interactive media and the knowledge-based economy * A fully updated bibliography with 400 items and suggestions for further reading throughout the text

Exploring the contested role of mandatory reporting laws in the identification of severe child abuse and neglect

Significant numbers of children are severely abused and neglected by parents and caregivers. Infants and very young children are the most vulnerable and are unable to seek help. To identify these situations and enable child protection and the provision of appropriate assistance, many jurisdictions have enacted ‘mandatory reporting laws’ requiring designated professionals such as doctors, nurses, police and teachers to report suspected cases of severe child abuse and neglect. Other jurisdictions have not adopted this legislative approach, at least partly motivated by a concern that the laws produce dramatic increases in unwarranted reports, which, it is argued, lead to investigations which infringe on people’s privacy, cause trauma to innocent parents and families, and divert scarce government resources from deserving cases. The primary purpose of this paper is to explore the extent to which opposition to mandatory reporting laws is valid based on the claim that the laws produce ‘overreporting’. The first part of this paper revisits the original mandatory reporting laws, discusses their development into various current forms, explains their relationship with policy and common law reporting obligations, and situates them in the context of their place in modern child protection systems. This part of the paper shows that in general, contemporary reporting laws have expanded far beyond their original conceptualisation, but that there is also now a deeper understanding of the nature, incidence, timing and effects of different types of severe maltreatment, an awareness that the real incidence of maltreatment is far higher than that officially recorded, and that there is strong evidence showing the majority of identified cases of severe maltreatment are the result of reports by mandated reporters. The second part of this paper discusses the apparent effect of mandatory reporting laws on ‘overreporting’ by referring to Australian government data about reporting patterns and outcomes, with a particular focus on New South Wales. It will be seen that raw descriptive data about report numbers and outcomes appear to show that reporting laws produce both desirable consequences (identification of severe cases) and problematic consequences (increased numbers of unsubstantiated reports). Yet, to explore the extent to which the data supports the overreporting claim, and because numbers of unsubstantiated reports alone cannot demonstrate overreporting, this part of the paper asks further questions of the data. Who makes reports, about which maltreatment types, and what are the outcomes of those reports? What is the nature of these reports; for example, to what extent are multiple numbers of reports made about the same child? What meaning can be attached to an ‘unsubstantiated’ report, and can such reports be used to show flaws in reporting effectiveness and problems in reporting laws? It will be suggested that available evidence from Australia is not sufficiently detailed or strong to demonstrate the overreporting claim. However, it is also apparent that, whether adopting an approach based on public health and or other principles, much better evidence about reporting needs to be collected and analyzed. As well, more nuanced research needs to be conducted to identify what can reasonably be said to constitute ‘overreports’, and efforts must be made to minimize unsatisfactory reporting practice, informed by the relevant jurisdiction’s context and aims. It is also concluded that, depending on the jurisdiction, the available data may provide useful indicators of positive, negative and unanticipated effects of specific components of the laws, and of the strengths, weaknesses and needs of the child protection system.

Development of an Innovative Hybrid-Composite Floor System

This paper discusses the research carried out towards the development of a hybrid-composite floor plate systems (HCFPS) using polyurethane (PU), glass-fibre reinforced cement (GRC) and thin perforated steel laminate. HCFPS is configured in such a way where positive inherent properties of individual component materials are combined to offset any weakness and achieve the optimum performance. Finite Element modeling of HCFPS with ABAQUS 6.9-1, comparative studies of HCFPS with the steel deck composite system and experimental investigations which will be carried out are briefly described in the paper.

Creative writing, literary studies, and global thinkers

There has been growing interest in how to make tertiary education more global and international not only in context but, also, in approach and methodology. One area of the education sector that has come under specific focus is the higher education sector curriculum and its design. This paper addresses the process of ‘internationalising’ the curriculum through the specific example of designing a new literary unit for undergraduate students, mainly literary studies and creative writing students. The literary unit entitled: Imagining the Americas: Contemporary American Literature and Culture, has the added complexity of being a unit about national fiction. This paper explores the practical problems and obstacles encountered in setting up this unit while using a framework of internationalisation. The case study examines the practicalities in implementing strategies that reflect the overall objective of creating global thinkers within a tertiary environment.

Reflections around artefacts : using a deliberative approach to teaching reflective practices in fashion studies

While requiring students to think reflectively is a desirable teaching goal, it is often fraught with complexity and is sometimes poorly implemented in higher education. In this paper, we describe an approach to academic reflective practices that fitted a design subject in fashion education and was perceived as effective in enhancing student learning outcomes. In many design-based disciplines, it is essential to evaluate, through a reflective lens, the quality of tangible design outcomes - referred to here as artefacts. Fashion studio based practice (unlike many other theory based disciplines)requires an artefact to be viewed in order to initiate the reflective process. This reflection is not solely limited to reflective writing; the reflection happens through sight, touch and other non-traditional approaches. Fashion students were asked to reflect before, during and after the development of an artefact. Through a variety of media, a review of the first garment prototype - called a Sample Review - occurred. The reflective practices of students during the Sample Review provided a valuable insight into their own learning, as well as a valid assessment indicator for the lecturer. It also mirrored industry practices for design evaluation. We believe that this deliberative approach, characterised by artefact-prompted reflection, has wide applicability across undergraduate courses in a variety of discipline areas.

Limestone and speleothem trace element geochemistry as tools for palaeoclimatic reconstruction, Mount Etna region, central-coastal Queensland

This study investigated potential palaeoclimate proxies provided by rare earth element (REE) geochemistry in speleothems and in clay mineralogy of cave sediments. Speleothem and sediment samples were collected from a series of cave fill deposits that occurred with rich vertebrate fossil assemblages in and around Mount Etna National Park, Rockhampton (central coastal Queensland). The fossil deposits range from Plio- Pleistocene to Holocene in age (based on uranium/thorium dating) and appear to represent depositional environments ranging from enclosed rainforest to semi-arid grasslands. Therefore, the Mount Etna cave deposits offer the perfect opportunity to test new palaeoclimate tools as they include deposits that span a known significant climate shift on the basis of independent faunal data. The first section of this study investigates the REE distribution of the host limestone to provide baseline geochemistry for subsequent speleothem investigations. The Devonian Mount Etna Beds were found to be more complex than previous literature had documented. The studied limestone massif is overturned, highly recrystallised in parts and consists of numerous allochthonous blocks with different spatial orientations. Despite the complex geologic history of the Mount Etna Beds, Devonian seawater-like REE patterns were recovered in some parts of the limestone and baseline geochemistry was determined for the bulk limestone for comparison with speleothem REE patterns. The second part of the study focused on REE distribution in the karst system and the palaeoclimatic implications of such records. It was found that REEs have a high affinity for calcite surfaces and that REE distributions in speleothems vary between growth bands much more than along growth bands, thus providing a temporal record that may relate to environmental changes. The morphology of different speleothems (i.e., stalactites, stalagmites, and flowstones) has little bearing on REE distributions provided they are not contaminated with particulate fines. Thus, baseline knowledge developed in the study suggested that speleothems were basically comparable for assessing palaeoclimatically controlled variations in REE distributions. Speleothems from rainforest and semi-arid phases were compared and it was found that there are definable differences in REE distribution that can be attributed to climate. In particular during semiarid phases, total REE concentration decreased, LREE became more depleted, Y/Ho increased, La anomalies were more positive and Ce anomalies were more negative. This may reflect more soil development during rainforest phases and more organic particles and colloids, which are known to transport REEs, in karst waters. However, on a finer temporal scale (i.e. growth bands) within speleothems from the same climate regime, no difference was seen. It is suggested that this may be due to inadequate time for soil development changes on the time frames represented by differences in growth band density. The third part of the study was a reconnaissance investigation focused on mineralogy of clay cave sediments, illite/kaolinite ratios in particular, and the potential palaeoclimatic implications of such records. Although the sample distribution was not optimal, the preliminary results suggest that the illite/kaolinite ratio increased during cold and dry intervals, consistent with decreased chemical weathering during those times. The study provides a basic framework for future studies at differing latitudes to further constrain the parameters of the proxy. The identification of such a proxy recorded in cave sediment has broad implications as clay ratios could potentially provide a basic local climate proxy in the absence of fossil faunas and speleothem material. This study suggests that REEs distributed in speleothems may provide information about water throughput and soil formation, thus providing a potential palaeoclimate proxy. It highlights the importance of understanding the host limestone geochemistry and broadens the distribution and potential number of cave field sites as palaeoclimate information no longer relies solely on the presence of fossil faunas and or speleothems. However, additional research is required to better understand the temporal scales required for the proxies to be recognised.

Case studies of statutory interventions into the common law concept of charity

This paper considers four examples of statutory interventions into the common law concept of charity, namely, those of Pennsylvania, Barbados, the definition recommended by the Report of the Inquiry into the Definition of Charities in Australia, and the Recreational Charities legislation of the United Kingdom. It comments on some issues affecting each style of intervention. The paper does not argue against statutory intervention but submits that legislative changes are best made by deeming a particular purpose to be charitable, or not charitable, so that, except to that extent, the common law concept remains intact – this is the approach adopted by the Recreational Charities legislation.

Strengthening the Foundations: Mutuality and the Performing Arts

Following the positive response by governments to the report of Helen Nugent's major performing arts inquiry, urgent attention needs to be given to the seedbed companies where so often audiences are introduced to the performing arts and practitioners are launched on their professional careers. Doing so calls for lateral thinking such as will enable the widest possible range of stakeholders to become involved. One solution may be to develop multi-stakeholder arts mutuals from the simpler arts mutuals such as co-operatives which are already widespread in many spheres of arts activity. Relevant models include the multi-stakeholder mutuals of the Mondragon Co-operative Corporation and the employee mutuals which are being trialled currently in Britain. Possible stakeholders in an arts mutual could include employed, unemployed and trainee practitioners, professional, quasi-professional and amateur theatre bodies, community groups, municipal councils and statutory bodies such as the ABC. Mutualist models may also be helpful to major performing arts companies facing erosion of their subscription incomes or incurring higher support services costs.