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.

Towards a unified service description language for the internet of services : requirements and first developments

Service-oriented Architectures (SOA) and Web services leverage the technical value of solutions in the areas of distributed systems and cross-enterprise integration. The emergence of Internet marketplaces for business services is driving the need to describe services, not only from a technical level, but also from a business and operational perspective. While, SOA and Web services reside in an IT layer, organizations owing Internet marketplaces are requiring advertising and trading business services which reside in a business layer. As a result, the gap between business and IT needs to be closed. This paper presents USDL (Unified Service Description Language), a specification language to describe services from a business, operational and technical perspective. USDL plays a major role in the Internet of Services to describe tradable services which are advertised in electronic marketplaces. The language has been tested using two service marketplaces as use cases.

Professional capabilities for twenty-first century creative careers : lessons from outstandingly successful Australian artists and designers

Artists and designers are positioned at the centre of the 21st century creative economy. In order to recognise and make the most of the opportunities afforded by this new era, artists and designers still require the creativity, disciplinary depth of knowledge, and technical skills traditionally possessed by professionals in these fields – skills which are a core strength of higher and further art and design education. However, they may also require a range of other, ‘21st century’ creative capabilities which are harder to define, teach for and assess, and are not the focus of traditional art and design pedagogies. This article draws upon the findings of nine in-depth interviews with award-winning Australian artists and designers about their careers and working practices, along with recent international research about the characteristics of the 21st century creative career, in order to highlight the importance of certain professional capabilities for art and design. It discusses the implications of these findings for art and design educators in universities, and curricular and pedagogic considerations associated with embedding these capabilities into undergraduate courses.

Diffusion determinants for passive building technologies

This summary is based on an international review of leading peer reviewed journals, in both technical and management fields. It draws on highly cited articles published between 2000 and 2009 to investigate the research question, "What are the diffusion determinants for passive building technologies in Australia?". Using a conceptual framework drawn from the innovation systems literature, this paper synthesises and interprets the literature to map the current state of passive building technologies in Australia and to analyse the drivers for, and obstacles to, their optimal diffusion. The paper concludes that the government has a key role to play through its influence over the specification of building codes.

Sensitivity of building cooling loads to future weather predictions

The interaction and relationship between the global warming and the thermal performance buildings are dynamic in nature. In order to model and understand this behavior, different approaches, including keeping weather variable unchanged, morphing approach and diurnal modelling method, have been used to project and generate future weather data. Among these approaches, various assumptions on the change of solar radiation, air humidity and/or wind characteristics may be adopted. In this paper, an example to illustrate the generation of future weather data for the different global warming scenarios in Australia is presented. The sensitivity of building cooling loads to the possible changes of assumed values used in the future weather data generation is investigated. It is shown that with ± 10% change of the proposed future values for solar radiation, air humidity or wind characteristics, the corresponding change in the cooling load of the modeled sample office building at different Australian capital cities would not exceed 6%, 4% and 1.5% respectively. It is also found that with ±10% changes on the proposed weather variables for both the 2070-high future scenario and the current weather scenario, the corresponding change in the cooling loads at different locations may be weaker (up to 2% difference in Hobart for ±10% change in global solar radiation), similar (less than 0.6%) difference in Hobart for ±10% change in wind speed), or stronger (up to 1.6% difference in Hobart for ±10% change in relative humidity) in the 2070-high future scenario than in the current weather scenario.

Investigation of cooling energy performance of commercial building in sub-tropical climate through the application of green roof and living wall

This paper investigates cooling energy performance of commercial building before and after green roof and living wall application based on integrated building heat gain model developed from Overall Thermal Transfer Value (OTTV) of building wall and steady state heat transfer process of roof in sub-tropical climate. Using the modelled equation and eQUEST energy simulation tool, commercial building envelope parameters and relevant heat gain parameters have been accumulated to analyse the heat gain and cooling energy consumption of commercial building. Real life commercial building envelope and air-conditioned load data for the sub-tropical climate zone have been collected and compared with the modelled analysis. Relevant temperature data required for living wall and green roof analysis have been collected from experimental setup comprised of both green roof and west facing living wall. Then, Commercial building heat flux and cooling energy performance before and after green roof and living wall application have been scrutinized.

Air Conditioning Systems : Design and Energy efficiency

Air conditioning systems have become an integral part of many modern buildings. Proper design and operation of air conditioning systems have significant impact not only on the energy use and greenhouse gas emissions from the buildings, but also on the thermal comfort and productivity of the occupants. In this paper, the purpose and need of installing air conditioning systems is first introduced. The methods used for the classification of air conditioning systems are then presented. This is followed by a discussion on the pros and cons of each type of the air conditioning systems, including both common and new air conditioning technologies. The procedures used to design air conditioning systems are also outlined, and the implications of air conditioning systems, including design, selection, operation and maintenance, on building energy efficiency is also discussed.

Their children's first educators : parents' views about child sexual abuse prevention education

In this descriptive focus group study, we investigated parents’ views about child sexual abuse prevention education at home and in schools. Focus groups were conducted with a sample of 30 Australian adults who identified as the parent or caregiver of a child/children aged 0–5 years. The study explored (1) parents’ knowledge about child sexual abuse prevention, (2) the child sexual abuse prevention messages they provided to their children and the topics they discussed, (3) their attitudes towards child sexual abuse prevention education in schools, and (4) their preferences for content. Data analysis provided seven key themes in these four areas: knowledge (the inadequacy of their own prevention education; and how important is stranger danger now?); messages (bodies, touching, and relationships; the role of protective adults; and parent–child communication); attitudes (voice and choice); and preferences (not the nitty gritty, just the basics). The findings may be useful in assisting school authorities and providers of child sexual abuse prevention programs to better understand parents’ contributions to child sexual abuse prevention education, and their perspectives in relation to provision of school-based prevention programs.

Trust, reputation and the small firm : building online brand reputation for SMEs

Social media provides numerous opportunities for small businesses to promote their products and services, build brand communities and reach diverse market niches. An important factor in seizing these opportunities is developing trust and creating reputation among consumers. This qualitative study examines how a group of Australian small business managers utilize social media websites to connect to, communicate with and maintain their customer base. For the purpose of this paper we are using case studies of four companies physically based in Victoria, Australia. These businesses have a high presence in online consumer groups, being both active members of communities and representatives of their businesses. The duality of their role as participant and company representative imposes difficulties in creating reputation among community members. We have used in-depth interviews as a primary research method, additionally monitoring their activities on social media sites such as forums, social networking services, blogs and micro-blogs. We have identified practices helpful for developing trust, building reputation and create a brand image in online communities.

Profiling and characterisation of key weather variables and their implication on building design

Local climate is a critical element in the design of buildings. In this paper, ten years of historical weather data in Australia's all eight capital cities are analyzed to characterize the variation profiles of climatic variables. The method of descriptive statistics is employed. Either the pattern of cumulative distribution and/or the profile of percentage distribution are used to graphically illustrate the similarity and difference between different study locations. It is found that although the weather variables vary with different locations, except for the extreme parts, there is often a good, nearly linear relation between weather variable and its cumulative percentage for the majority of middle part. The implication of these extreme parts and the slopes of the middle parts on building design is also discussed.

An investigation of building physical properties selection to combat global warming

Global warming can have a significant impact on building energy performance and indoor thermal environment, as well as the health and productivity of people living and working inside them. Through the building simulation technique, this paper investigates the adaptation potential of different selections of building physical properties to increased outdoor temperature in Australia. It is found that overall, an office building with lower insulation level, smaller window to wall ratio and/or a glass type with lower shading coefficient, and lower internal load density will have the effect of lowering building cooling load and total energy use, and therefore have a better potential to adapt to the warming external climate. Compared with clear glass, it is shown that the use of reflective glass for the sample building with WWR being 0.5 reduces the building cooling load by more than 12%. A lower internal load can also have a significant impact on the reduction of building cooling load, as well as the building energy use. Through the comparison of results between current and future weather scenarios, it is found that the patterns found in the current weather scenario also exist in the future weather scenarios, but to a smaller extent.

Sensitivity of office building zones to global warming

As global warming entails new conditions for the built environment, the thermal behavior of existing buildings, which were designed based on current weather data, may become unclear and remain a great concern. Through building computer simulation, this paper investigates the sensitivity of different office building zoning to the potential global warming. From the sample office building examined, it is found that compared with the middle and top floors, the ground floor for most cities appears to be most sensitive to the effect of global warming and has the highest tendency to having the overheating problem. From the analysis of the responses of different zone orientations to the outdoor air temperature increase, it is also found that there are widely different responses between different zone orientations, with South or Core zone being most sensitive. With an increased external air temperature, the difference between different floors or different zone orientations will become more significant.

The relationship between organizational and professional commitment in the case of project workers : implications for project management

The purpose of this article is to investigate the relationship between organizational and professional commitment of project workers. We first present (1) role-conflict theory and exchange theory to establish the multiple dimensions of commitment (affective, continuance, and normative) and (2) social identity theory to support our argument for different foci of commitment—organization and profession. Building on these theoretical lenses, we present the literature review that compares organizational and professional commitment of project workers with respect to the three dimensions of commitment. Adopting a positivist approach and a sample of 141 project workers, we use Pearson’s correlation to identify the relationship between affective organizational and affective professional, continuance organizational and continuance professional, and normative organizational and normative professional commitment. We report significant correlation between affective organizational commitment and affective professional commitment of project workers. The correlations between continuance organizational commitment and continuance professional commitment and normative organizational commitment and normative professional commitment are moderate. We then discuss the implications of these findings for the project management profession.

The relation between organizational and professional commitment in case of project workers : implications for the project management

The purpose of this paper is to investigate the relationship between organizational and professional commitment of project workers. We first present (i) role–conflict theory, and exchange theory to establish the multiple dimensions of commitment—affective, continuance, and normative; and (ii). social–identity theory to support our argument for different foci of commitment—organization and profession. Building on these theoretical lenses, we present the literature review that compares organizational and professional commitment of project workers with respect to the 3 dimensions of commitment. Adopting a positivist approach and a sample of 141 project workers, we use Pearson’s correlation to identify the relationship between affective organizational and affective professional, continuance organizational and continuance professional, and normative organizational and normative professional commitment. We report significant correlation between affective organizational commitment and affective professional commitment of project workers. The correlations between continuance organizational commitment, and continuance professional commitment; and normative organizational commitment, and normative professional commitment are moderate. We then discuss the implications of these findings for the project management profession.

The resourceful adolescent project : building psychological resilience in adolescents and their parents

"The model of adolescent depression underlying the Resourceful Adolescent Project (RAP) suggests that adolescent depression and suicide result from a combination of some or all of three interrelating factors: (a) deficits in adolescent psychological wellbeing and coping resources; (b) escalating or chronic family conflict; and (c) depressive adolescent thoughts, feelings and behaviour. This overview of the activities of RAP outlines the need for the project, the benefits of early intervention in preventing adolescent depression, and the empirical and theoretical bases of the programs used in the project. The programs for adolescents and for their parents, their efficacy and the future directions of RAP are also discussed." -- from Libraries Australia