Crosstalk between developmental and tumour-specific signalling pathways : kallikrein-related serine peptidases and nodal in prostrate cancer

Prostate cancer is an important male health issue. The strategies used to diagnose and treat prostate cancer underscore the cell and molecular interactions that promote disease progression. Prostate cancer is histologically defined by increasingly undifferentiated tumour cells and therapeutically targeted by androgen ablation. Even as the normal glandular architecture of the adult prostate is lost, prostate cancer cells remain dependent on the androgen receptor (AR) for growth and survival. This project focused on androgen-regulated gene expression, altered cellular differentiation, and the nexus between these two concepts. The AR controls prostate development, homeostasis and cancer progression by regulating the expression of downstream genes. Kallikrein-related serine peptidases are prominent transcriptional targets of AR in the adult prostate. Kallikrein 3 (KLK3), which is commonly referred to as prostate-specific antigen, is the current serum biomarker for prostate cancer. Other kallikreins are potential adjunct biomarkers. As secreted proteases, kallikreins act through enzyme cascades that may modulate the prostate cancer microenvironment. Both as a panel of biomarkers and cascade of proteases, the roles of kallikreins are interconnected. Yet the expression and regulation of different kallikreins in prostate cancer has not been compared. In this study, a spectrum of prostate cell lines was used to evaluate the expression profile of all 15 members of the kallikrein family. A cluster of genes was co-ordinately expressed in androgenresponsive cell lines. This group of kallikreins included KLK2, 3, 4 and 15, which are located adjacent to one another at the centromeric end of the kallikrein locus. KLK14 was also of interest, because it was ubiquitously expressed among the prostate cell lines. Immunohistochemistry showed that these 5 kallikreins are co-expressed in benign and malignant prostate tissue. The androgen-regulated expression of KLK2 and KLK3 is well-characterised, but has not been compared with other kallikreins. Therefore, KLK2, 3, 4, 14 and 15 expression were all measured in time course and dose response experiments with androgens, AR-antagonist treatments, hormone deprivation experiments and cells transfected with AR siRNA. Collectively, these experiments demonstrated that prostatic kallikreins are specifically and directly regulated by the AR. The data also revealed that kallikrein genes are differentially regulated by androgens; KLK2 and KLK3 were strongly up-regulated, KLK4 and KLK15 were modestly up-regulated, and KLK14 was repressed. Notably, KLK14 is located at the telomeric end of the kallikrein locus, far away from the centromeric cluster of kallikreins that are stimulated by androgens. These results show that the expression of KLK2, 3, 4, 14 and 15 is maintained in prostate cancer, but that these genes exhibit different responses to androgens. This makes the kallikrein locus an ideal model to investigate AR signalling. The increasingly dedifferentiated phenotype of aggressive prostate cancer cells is accompanied by the re-expression of signalling molecules that are usually expressed during embryogenesis and foetal tissue development. The Wnt pathway is one developmental cascade that is reactivated in prostate cancer. The canonical Wnt cascade regulates the intracellular levels of β-catenin, a potent transcriptional co-activator of T-cell factor (TCF) transcription factors. Notably, β-catenin can also bind to the AR and synergistically stimulate androgen-mediated gene expression. This is at the expense of typical Wnt/TCF target genes, because the AR:β-catenin and TCF:β-catenin interactions are mutually exclusive. The effect of β-catenin on kallikrein expression was examined to further investigate the role of β-catenin in prostate cancer. Stable knockdown of β-catenin in LNCaP prostate cancer cells attenuated the androgen-regulated expression of KLK2, 3, 4 and 15, but not KLK14. To test whether KLK14 is instead a TCF:β-catenin target gene, the endogenous levels of β-catenin were increased by inhibiting its degradation. Although KLK14 expression was up-regulated by these treatments, siRNA knockdown of β-catenin demonstrated that this effect was independent of β-catenin. These results show that β-catenin is required for maximal expression of KLK2, 3, 4 and 15, but not KLK14. Developmental cells and tumour cells express a similar repertoire of signalling molecules, which means that these different cell types are responsive to one another. Previous reports have shown that stem cells and foetal tissues can reprogram aggressive cancer cells to less aggressive phenotypes by restoring the balance to developmental signalling pathways that are highly dysregulated in cancer. To investigate this phenomenon in prostate cancer, DU145 and PC-3 prostate cancer cells were cultured on matrices pre-conditioned with human embryonic stem cells (hESCs). Soft agar assays showed that prostate cancer cells exposed to hESC conditioned matrices had reduced clonogenicity compared with cells harvested from control matrices. A recent study demonstrated that this effect was partially due to hESC-derived Lefty, an antagonist of Nodal. A member of the transforming growth factor β (TGFβ) superfamily, Nodal regulates embryogenesis and is re-expressed in cancer. The role of Nodal in prostate cancer has not previously been reported. Therefore, the expression and function of the Nodal signalling pathway in prostate cancer was investigated. Western blots confirmed that Nodal is expressed in DU145 and PC-3 cells. Immunohistochemistry revealed greater expression of Nodal in malignant versus benign glands. Notably, the Nodal inhibitor, Lefty, was not expressed at the mRNA level in any prostate cell lines tested. The Nodal signalling pathway is functionally active in prostate cancer cells. Recombinant Nodal treatments triggered downstream phosphorylation of Smad2 in DU145 and LNCaP cells, and stably-transfected Nodal increased the clonogencity of LNCaP cells. Nodal was also found to modulate AR signalling. Nodal reduced the activity of an androgen-regulated KLK3 promoter construct in luciferase assays and attenuated the endogenous expression of AR target genes including prostatic kallikreins. These results demonstrate that Nodal is a novel example of a developmental signalling molecule that is reexpressed in prostate cancer and may have a functional role in prostate cancer progression. In summary, this project clarifies the role of androgens and changing cellular differentiation in prostate cancer by characterising the expression and function of the downstream genes encoding kallikrein-related serine proteases and Nodal. Furthermore, this study emphasises the similarities between prostate cancer and early development, and the crosstalk between developmental signalling pathways and the AR axis. The outcomes of this project also affirm the utility of the kallikrein locus as a model system to monitor tumour progression and the phenotype of prostate cancer cells.

Publishing Engineering Education Resources: A Collaborative Web Project.

Web is a powerful hypermedia-based information retrieval mechanism that provides a user-friendly access across all major computer platforms connected over Internet. This paper demonstrates the application of Web technology when used as an educational delivery tool. It also reports on the development of a prototype electronic publishing project where Web technology was used to deliver power engineering educational resources. The resulting hyperbook will contain diverse teaching resources such as hypermedia-based modular educational units and computer simulation programs that are linked in a meaningful and structured way. The use of Web for disseminating information of this nature has many advantages that cannot possibly be achieved otherwise. PREAMBLE The continual increase of low-cost functionality available in desktop computing has opened up a new possibility in learning within a wider educational framework. This technology also is supported by enhanced features offered by new and ...

Shall we dance? The story of The Radiance Dance Project

Community workers are often described as unsung heroes who work for, with, and alongside others in order to make qualitative differences to the communities they serve. This paper reports on the story of a community based arts educator, Morgan Jai-Morincome, winner of the ACT Adult Learners Week Award for an outstanding program in 2007. This program, referred to as The Radiance Dance Project, is an inclusive performance project open to women with and without disabilities that culminates in a yearly performance. Via an interview with Morgan, observations of a workshop she provided for the women in her 2009 program, and a viewing of a DVD of the 2008 dance performance, this case study provides an illustration of the power of arts based educative processes for breaking down barriers between people with and without disabilities. It draws upon constructs from ethical leadership theory and empowerment theory to interpret her ideas and practices.

Benchmarking framework to measure extent of ICT adoption for building project management

This project discusses a component of the research study conducted to provide construction organizations with a generic benchmarking framework to assess their extent of information communication technology (ICT) adoption for building project management processes. It defines benchmarking and discusses objectives of the required benchmarking framework and development of the framework. The study focuses on ICT adoption by small and medium enterprises (SMEs) in the construction industry and with respect to SMEs it is important to understand processes, their indicators, and measures in the local context. Structure of the suggested benchmarking framework has been derived after extensive literature survey and a questionnaire survey conducted in the Indian construction industry. The suggested benchmarking process is an iterative process divided into four stages. It can be implemented at organization and industry levels for rating the construction organizations for ICT adoption and performance measurement. The framework has a generic structure and can be generalized and applied for other countries with due considerations.

An empirical test of causal relationships of factors affecting ICT adoption for building project management : an Indian SME case study

Purpose - Building project management (BPM) requires effective coordination and collaboration between multiple project team organisations which can be achieved by real time information flow between all participants. In the present scenario, this can be achieved by the use of information communication technologies (ICT). The purpose of this paper is to present part of a research project conducted to study the causal relationships between factors affecting ICT adoption for BPM by small and medium enterprises. Design/methodology/approach - This paper discusses structural equation modelling (SEM) analysis conducted to test the causal relationships between quantitative factors. Data for quantitative analysis were gathered through a questionnaire survey conducted in the Indian construction industry. Findings - SEM analysis results help in demonstrating that an increased and matured use of ICT for general administration within the organisation would lead to: an improved ICT infrastructure within the organisation; development of electronic databases; and a staff that is confident of using information technology (IT) tools. In such a scenario, staff would use advanced software and IT technologies for project management (PM) processes and that would lead to an increased adoption of ICT for PM processes. But, for general administration also, ICT adoption would be enhanced if the organisation is interacting more with geographically separated agencies and senior management perceives that significant benefits would accrue by adoption of ICT. All the factors are inter-related and their effect cannot be maximized in isolation. Originality/value - The results provide direction to building project managements for strategically adopting the effective use of ICT within their organisations and for BPM general.

Embedding 'philosophy in the classroom' in pre-service teacher education

The holistic conception of the troika, as described in the first chapter, centres on the relationship between the implicit and explicit teaching of values the nurturing of the specific dimensions of quality teaching and the opportunity to ‘walk the talk’ of the values education program through aspects such as practical citizenship (Lovat, Toomey, Clement, Crotty & Nielsen, 2009). It is proposed in this chapter that the conception can be realized through the embedding of Philosophy in the Classroom within pre-service teaching programs. The troika, a Russian sleigh with three horses, only function well when there is complete synergy and balance between all Classroom is a scaffold for ensuring that all three elements of the troika, namely, quality teaching, values education and service learning in the form of education for citizenship, exist within the classroom to achieve an optimal learning, growth and wellbeing for all students. For this to be more widely accomplished Philosophy in the Classroom and discusses how it constitutes a successful synergy and balance of the troika for effective teaching. It then proposes how it might be embedded into pre-service teacher education.

Response to the apology : Queenslanders reflect : a State Library of Queensland project

On the 13th February 2008 Prime Minister Kevin Rudd made an apology to Australia’s Indigenous Peoples on behalf of the Australian Parliament. The State Library of Queensland (SLQ) with assistance from Queensland University of Technology and Queensland’s Aboriginal and Torres Strait Islander communities, has captured responses to this historic event. ‘Responses to the 2008 Apology’ is a collection of digital stories created as part of this research initiative. Until recently, digital storytelling has not generally been treated as a necessary addition to the research collections of Australian libraries. However, libraries increasingly aim to promote new literacies and active audiences as they seek innovative ways to encourage life-long learning by their users, and digital storytelling is one methodology that can contribute to these goals. The State Library of Queensland is the only Australian State Library to have undertaken a major role in the collection of digital stories. They currently lead the way with their Queensland Stories digital storytelling program. This presentation will report findings and outcomes from this research project.

Sustainable infrastructure project planning : progress in contemporary decision support tools

Most infrastructure project developments are complex in nature, particularly in the planning phase. During this stage, many vague alternatives are tabled - from the strategic to operational level. Human judgement and decision making are characterised by biases, errors and the use of heuristics. These factors are intangible and hard to measure because they are subjective and qualitative in nature. The problem with human judgement becomes more complex when a group of people are involved. The variety of different stakeholders may cause conflict due to differences in personal judgements. Hence, the available alternatives increase the complexities of the decision making process. Therefore, it is desirable to find ways of enhancing the efficiency of decision making to avoid misunderstandings and conflict within organisations. As a result, numerous attempts have been made to solve problems in this area by leveraging technologies such as decision support systems. However, most construction project management decision support systems only concentrate on model development and neglect fundamentals of computing such as requirement engineering, data communication, data management and human centred computing. Thus, decision support systems are complicated and are less efficient in supporting the decision making of project team members. It is desirable for decision support systems to be simpler, to provide a better collaborative platform, to allow for efficient data manipulation, and to adequately reflect user needs. In this chapter, a framework for a more desirable decision support system environment is presented. Some key issues related to decision support system implementation are also described.

Fostering cultural awareness in pre-service teacher education : an experiment in Asia literacy capacity building in an Australian university

This paper presents the findings of a small pilot study conducted with a group of final year pre-service teachers studying a secondary social science curriculum method unit in an Australian university. One of the study’s research objectives aimed at identifying how students responded to efforts to embed intercultural understanding through Studies of Asia in their final curriculum method unit. The unit was designed and taught by the researcher on the assumption that beginning social science teachers need to be empowered with pedagogical skills and new dispositions to deal with value laden emerging regional and global concerns in their Australian secondary school classrooms. This pilot study’s research methodology was located within the qualitative framework of a participatory action research model whereby the lecturer who designed, coordinated and taught the unit was also the researcher. Its scope was limited to one semester with volunteer students. The pilot study sought to investigate responses to several issues, and this paper reports on pre-service teacher reflections on the content, pedagogy and learning they experienced in their weekly sessions with specific reference to cultural understanding, Studies of Asia and the development of Asia literacy. It also reports on pre-service teacher reflections about their own evolving capacity as beginning teachers. The findings indicate that pre-service teachers valued the opportunity to engage with learning experiences which enhanced their conceptual understandings about culture whilst also extending their pedagogical and content knowledge.

Embedding values through global education in social sciences pre-service teacher education : linking the head and heart

This chapter aims to situate values education as a core component of social science pre-service teacher education. In particular, it reflects on an experiment in embedding a values laden Global Education perspective in a fourth year social science curriculum method unit. This unit was designed and taught by the researcher on the assumption that beginning social science teachers need to be empowered with pedagogical skills and new dispositions to deal with value laden emerging global and regional concerns in their secondary school classrooms. Moreover, it was assumed that when pre-service teachers engage in dynamic and interactive learning experiences in their curriculum unit, they commence the process of ‘capacity building’ those skills which prepare them for their own lifelong professional learning. This approach to values education also aimed at providing pre-service teachers with opportunities to ‘create deep understandings of teaching and learning’ (Barnes, 1989, p. 17) by reflecting on the ways in which ‘pedagogy can be transformative’ (Lovat and Toomey, 2011 add page no from Chapter One). It was assumed that this tertiary experience would foster the sine qua non of teaching – a commitment to students and their learning. Central to fostering new ‘dispositions’ through this approach, was the belief in the power of pedagogy to make the difference in enhancing student participation and learning. In this sense, this experiment in values education in secondary social science pre-service teacher education aligns with the Troika metaphor for a paradigm change, articulated by Lovat and Toomey (2009) in Chapter One.

Aligning project stakeholder motivation through incentivisation : a client-driven approach

The use of appropriate financial incentives within construction projects can contribute to strong alignment of project stakeholder motivation with project goals. However, effective incentive system design can be a challenging task and takes skillful planning by client managers in the early stages of a project. In response to a lack of information currently available to construction clients in this area, this paper explores the features of a successful incentive system and identifies key learnings for client managers to consider when designing incentives. Our findings, based on data from a large Australian case study, suggest that key stakeholders place greater emphasis on the project management processes that support incentives than on the incentive itself. Further, contractors need adequate time and information to accurately estimate construction costs prior to their tender price submission to ensure cost-focused incentive goals remain achievable. Thus, client managers should be designing incentives as part of a supportive procurement strategy to maximize project stakeholder motivation and prevent goal misalignment.