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.

Temperature dependent electrical resistivity in expoxy : multiwall carbon nanotube nanocomposites

Thin films of expoxy nanocomposites modified by multiwall carbon nanotubes (MWCNTs) were prepared by shear mixing and spin casting. The electrical behaviour and its dependence with temperature between 243 and 353 degrees Kelvin were characterized by measuring the direct current (DC) conductivity. Depending on the fabrication process, both linear and non-linear relationships between conductivity and temperature were observed. In addition, the thermal history also played a role in dictating the conductivity. The implications of these observations for potential application of these files as strain sensors are discussed.

Profiling work motivation of project workers

The purpose of this study is to understand the constructs of work motivation in project-based organizations. We first juxtapose work motivation in traditional and project-based organizations to put forward an operational definition of work motivation for our study. We then present the research methodology where we profile work motivation as perceived by project workers using principal component analysis. We obtain a five factor structure of work motivation. Finally, we discuss these results by putting them within the project management perspective and suggest managerial implications.

Project management deployment : the role of cultural factors

This paper investigates the role of cultural factors as possible partial explanation of the disparity in terms of project management deployment observed between various studied countries. The topic of culture has received increasing attention in the management literature in general during the last decades and in the project management literature in particular during the last few years. The globalization of businesses and worldwide Governmental/International organizations collaborations drives this interest in the national culture to increase more and more. Based on Hofstede national culture framework, the study hypothesizes and tests the impact of the culture and development of the country on the PM deployment. Seventy-four countries are selected to conduct a correlation and regression analysis between Hofstede’s national culture dimensions and the used PM deployment indicator. The results show the relations between various national culture dimensions and development indicator (GDP/Capita) on the project management deployment levels of the considered countries.

Project management deployment : the role of cultural factors

This paper investigates the role of cultural factors as possible partial explanation of the disparity in terms of Project Management Deployment observed between various studied countries. The topic of culture has received increasing attention in the management literature in general during the last decades and in the Project Management literature in particular during the last few years. The globalization of businesses and worldwide Governmental / International organizations collaborations drives this interest in the national culture to increase more and more. Based on Hofstede national culture framework, the study hypothesizes and tests the impact of the culture and development of the country on the PM Deployment. 74 countries are selected to conduct a correlation and regression analysis between Hofstede’s national culture dimensions and the used PM Deployment indicator. The results show the relations between various national culture dimensions and development indicator (GDP/Capita) on the Project Management Deployment levels of the considered countries.

The relation between work motivation and project management success : an empirical investigation

The content and context of work significantly influences an employees’ satisfaction. While managers see work motivation as a tool to engage the employees so that they perform better, academicians value work motivation for its contribution to human behaviour. Though the relationship between employee motivation and project success has been extensively covered in the literature, more research focusing on the nature of job design on project success may have been wanting. We address this gap through this study. The present study contributes to the extant literature by suggesting an operational framework of work motivation for project—based organizations. We are also advancing the conceptual understanding of this variable by understanding how the different facets of work motivation have a differing impact of the various parameters of project performance. A survey instrument using standardized scales of work motivation and project success was used. 199 project workers from various industries completed the survey. We first ‘operationalized’ the definition of work motivation for the purpose of our study through a principal component analysis of work motivation items. We obtained a five factor structure that had items pertaining to employee development, work climate, goal clarity, and job security. We then performed a Pearson’s correlation analysis which revealed moderate to significant relationship between project outcomes ad work climate; project outcomes & employee development. In order to establish a causality between work motivation and project management success, we employed linear regression analysis. The results show that work climate is a significant predictor of client satisfaction, while it moderately influences the project quality. Further, bringing in objectivity to project work is important for a successful implementation.

"Introduction"

Does heat have a cooling effect on culture? Sweat argues the reverse: culture thrives in the subtropical zones. While acknowledging that the subtropical generates ambivalence—being cast as alternately idyllic or hellish—Sweat nonetheless seeks to develop the specific voices of subtropical cultures. The uneasy place of this sweaty discourse is explored across art, literature, architecture, and the built environment. In particular, Sweat focuses on the most commonly experienced situation, the everyday house. While it addresses subjects from Japan, Brazil, and France, Sweat centres on Brisbane, Queensland—long in the shadow of Sydney and Melbourne in the Australian cultural psyche—due to its enduring and self-conscious attention to subtropical living.

Studying the mobile : locating the field

Book Description: The iPhone represents an important moment in both the short history of mobile media and the long history of cultural technologies. Like the Walkman of the 1980s, it marks a juncture in which notions about identity, individualism, lifestyle and sociality require rearticulation. this book explores not only the iPhone’s particular characteristics, uses and "affects," but also how the "iPhone moment" functions as a barometer for broader patterns of change. In the iPhone moment, this study considers the convergent trajectories in the evolution of digital and mobile culture, and their implications for future scholarship. Through the lens of the iPhone—as a symbol, culture and a set of material practices around contemporary convergent mobile media—the essays collected here explore the most productive theoretical and methodological approaches for grasping media practice, consumer culture and networked communication in the twenty-first century.

A Fair Go Beyond the School Gate? Systemic factors affecting participation and attainment in tertiary education by Queensland students from LSES backgrounds

The purpose of this project was to conduct an empirical study that would result in findings that inform systemic policy development aimed at improving tertiary participation and attainment by students from low socioeconomic status (LSES) backgrounds in Queensland. The project focuses on systemic policy, initiatives and programs that encourage tertiary education participation and attainment by individuals from LSES backgrounds, rather than on institution-specific initiatives or programs. While the broad remit was to consider tertiary education participation, the study particularly highlights issues pertaining to LSES student participation and attainment in the higher education sector, given the notable under representation of this demographic subgroup in Australian universities. This study supports the strategic priority of addressing professional skills shortages and innovations aiming to improve human and social capital in the state of Queensland. The ultimate goal is to contribute to the enhancement of Queensland’s education and training system by maximising participation and attainment by people from LSES backgrounds in higher education, thereby improving their quality of life and future life choices and opportunities. The study addressed the following five research questions: 1. What are the major factors that promote or inhibit participation and attainment in tertiary education by LSES students in Queensland? 2. To what extent do systemic policies or practices(systemic factors) of Queensland’s tertiary education system promote or inhibit participation and attainment by LSES students? That is, what features of Queensland’s tertiary education system have a significant effect on participation and attainment by LSES students? 3. What system policies or practices are found to boost participation and attainment by LSES students in other jurisdictions? 4. What evidence is there to suggest that policies or practices that have boosted participation and attainment by LSES students in other jurisdictions would be successful if implemented in Queensland? 5. What are the implications of the research findings for Queensland’s tertiary education system to improve participation and attainment by LSES students? The project adopted a mixed methods approach to data collection. A comprehensive review of the literature was conducted to identify relevant state, national and international literature. Both qualitative and quantitative methodologies were used to collect data from a range of key stakeholders.

A framework for the education of the information professions in Australia.

In recent years there has been considerable discussion afforded to the challenges facing the future of library and information science (LIS) education in Australia. This paper outlines a twelve-month project funded by the Australian Learning and Teaching Council that was undertaken by eleven institutions representing university and vocational LIS education in Australia. The project established a Framework for the Education of the Information Professions in Australia that provides a set of strategic recommendations that will inform future directions of Australian LIS education. This national project represented a bold move within Australian LIS education, and provided a unique opportunity for LIS educators across Australia to collectively unite in order to ‘future-proof’ education for future generations of LIS professionals.

Evaluation of green public road procurement in Australia : current practices and gaps to fill

Public road authorities have a key responsibility in driving initiatives for reducing greenhouse gas (GHG) emissions in the road construction project lifecycle. A coherent and efficient chain of procurement processes and methods is needed to convert green policies into tangible actions that capture the potential for GHG reduction. Yet, many infrastructure clients lack developed methodologies regarding green procurement practices. Designing more efficient solutions for green procurement requires an evaluation of the current initiatives and stages of development. A mapping of the current GHG reduction initiatives in Australian public road procurement is presented in this paper. The study includes the five largest Australian state road authorities, which cover 94% of the total 817,089 km of Australian main roads (not local) and account for 96% of the total A$13 billion annual major road construction and maintenance expenditure. The state road authorities’ green procurement processes and tools are evaluated based on interviews and a review of documents. Altogether 12 people, comprising 1-3 people of each organisation, participated in the interviews and provided documents. An evaluation matrix was developed for mapping the findings across the lifecycle of road construction project delivery. The results show how Australian state road authorities drive decisions with an impact on GHG emissions on the strategic planning phase, project development phase, and project implementation phase. The road authorities demonstrate varying levels of advancement in their green procurement methodologies. Six major gaps in the current green procurement processes are identified and, respectively, six recommendations for future research and development are suggested. The greatest gaps remain in the project development phase, which has a critical role in fixing the project (GHG reduction) goals, identifying risks and opportunities, and selecting the contractor to deliver the project. Specifically, the role of mass-haul optimisation as a part of GHG minimisation was reviewed, and mass-haul management was found to be an underutilised element with GHG reduction potential.

Dealing with unfinished business : preparing pre-service social education teachers for curriculum change

Pre-service teacher education is unfinished business. New social education teachers face the challenge of fluid policy environments in which curriculum content and pedagogy are continually changing. The evolving Australian curriculum is the most recent example of such fluidity with its emphasis on shifting the educational agenda to a focus on discipline-based approaches. This paper addresses the concerns of final year pre-service and early career social education teachers, in terms of their professional development needs, by drawing on the findings of a pilot study with students and recent graduates from a university in south-east Queensland. It concludes that social education curriculum units which embed links to professional practice and professional development in teaching, learning and assessment may provide the way forward for enhancing the transition to practice for beginning teachers and assist them in navigating constant change.

Teacher decision making in early childhood education

The study investigated early childhood teacher decision making at the preschool level in the state of Victoria, Australia. Victorian teachers at the preschool level were in an interesting position in 2004. Unlike most other Australian states Victoria did not have a curriculum framework guiding educational content and pedagogy. Consequently, this study was able to take advantage of this situation and examine teacher decision making at a time when early childhood teachers were relatively autonomous in deciding curriculum content. The opportunity to study teacher decision making in this way has since passed, as Victorian preschool teachers are now regulated by newly introduced state and national curricula frameworks. To identify influences affecting teacher decision making three preschool teachers were interviewed and curricula related policies were analysed. The data were analysed using Fairclough’s critical discourse analysis (CDA) technique. Critical discourse analysis enabled a close analysis of influences on teacher decision making illustrating how discourse is legitimated, marginalised, and silenced in certain curricula practices. Critical theory was the underpinning framework used for the study and enabled taken-for-granted understandings to be uncovered within early childhood policies and teacher interviews. Key findings were that despite there not being a government-mandated curricula framework for Victorian preschool education in 2004, teachers were held accountable for their curricula practice. Yet as professionals, early childhood teachers were denied public acknowledgment of their expertise as they were almost invisible in policy. Subsequently, teachers’ authority as professionals with curricula knowledge was diminished. The study found that developmentally appropriate practice (DAP) was a dominant discourse influencing teacher decision making (TDM). It operated as legitimated discourse in the 2004 Victorian preschool context. Additionally, the study found that teacher directed practice was legitimated, marginalised, and silenced by teachers. The findings have implications for early childhood teacher decision making at the practice, research, and policy levels. Findings show that the dominance of the DAP discourse informing teacher decision making limits other ways of thinking and practising.

The development of teacher assessment identity through participation in online moderation

Teachers’ professional conversations regarding the qualities evidenced in student work provide opportunities to develop a shared understanding of achievement standards. This research investigates social moderation conducted in a synchronous online mode as a specific form of professional conversation. The discussion considers the different factors that influenced these conversations which included the technologic medium of the meeting. The focus of the discussion is how participation in online moderation can support teachers to develop an assessment identity as one who works within a standards-based assessment system. Qualitative data were gathered from middle school teachers from different year levels, in different curriculum areas, in diverse geographic locations, and in a range of sociocultural contexts within Queensland, Australia. Analysis of the data through a sociocultural lens of becoming suggests that participation in online moderation, while challenging for teachers, can also provide opportunities to construct and to negotiate an identity as an assessor of student work.

Jabberwocky : the complexities of mathematical English

Mathematical English is a unique language based on ordinary English, with the addition of highly stylised formal symbol systems. Some words have a redefined status. Mathematical English has its own lexicon, syntax, semantics and literature. It is more difficult to understand than ordinary English. Ability in basic interpersonal communication does not necessarily result in proficiency in the use of mathematical English. The complex nature of mathematical English may impact upon the ability of students to succeed in mathematical and numeracy assessment. This article presents a review of the literature about the complexities of mathematical English. It includes examples of more than fifty language features that have been shown to add to the challenge of interpreting mathematical texts. Awareness of the complexities of mathematical English is an essential skill needed by mathematics teachers when teaching and when designing assessment tasks.