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 ...

An architecture for user configurable mobile collaborative geographic applications

Geographic information is increasingly being touted for use in research and industrial projects. While the technology is now available and affordable, there is a lack of easy to use software that takes advantage of geographic information. This is an important problem because users are often researchers or scientists who have insufficient software skills, and by providing applications that are easier to use, time and financial resources can be taken from training and be better applied to the actual research and development work. A solution for this problem must cater for the user and research needs. In particular it must allow for mobile operation for fieldwork, flexibility or customisability of data input, sharing of data with other tools and collaborative capabilities for the usual teamwork environment. This thesis has developed a new architecture and data model to achieve the solution. The result is the Mobile Collaborative Annotation framework providing an implementation of the new architecture and data model. Mobile Collaborative Mapping implements the framework as a Web 2.0 mashup rich internet application and has proven to be an effective solution through its positive application to a case study with fieldwork scientists. This thesis has contributed to research into mobile computing, collaborative computing and geospatial systems by creating a simpler entry point to mobile geospatial applications, enabling simplified collaboration and providing tangible time savings.

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.

Osteogenic induction of human bone marrow-derived mesenchymal progenitor cells in novel synthetic polymer-hydrogel matrices

The aim of this project was to investigate the in vitro osteogenic potential of human mesenchymal progenitor cells in novel matrix architectures built by means of a three-dimensional bioresorbable synthetic framework in combination with a hydrogel. Human mesenchymal progenitor cells (hMPCs) were isolated from a human bone marrow aspirate by gradient centrifugation. Before in vitro engineering of scaffold-hMPC constructs, the adipogenic and osteogenic differentiation potential was demonstrated by staining of neutral lipids and induction of bone-specific proteins, respectively. After expansion in monolayer cultures, the cells were enzymatically detached and then seeded in combination with a hydrogel into polycaprolactone (PCL) and polycaprolactone-hydroxyapatite (PCL-HA) frameworks. This scaffold design concept is characterized by novel matrix architecture, good mechanical properties, and slow degradation kinetics of the framework and a biomimetic milieu for cell delivery and proliferation. To induce osteogenic differentiation, the specimens were cultured in an osteogenic cell culture medium and were maintained in vitro for 6 weeks. Cellular distribution and viability within three-dimensional hMPC bone grafts were documented by scanning electron microscopy, cell metabolism assays, and confocal laser microscopy. Secretion of the osteogenic marker molecules type I procollagen and osteocalcin was analyzed by semiquantitative immunocytochemistry assays. Alkaline phosphatase activity was visualized by p-nitrophenyl phosphate substrate reaction. During osteogenic stimulation, hMPCs proliferated toward and onto the PCL and PCL-HA scaffold surfaces and metabolic activity increased, reaching a plateau by day 15. The temporal pattern of bone-related marker molecules produced by in vitro tissue-engineered scaffold-cell constructs revealed that hMPCs differentiated better within the biomimetic matrix architecture along the osteogenic lineage.

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.

Elements of public asset management framework for local governments in developing countries

There is a widespread recognition to the need of better manage municipal property in most cities in the world. Structural problems across regional, state, and territorial governments that have legal powers to own and maintain real property are similar, regardless of the level of development of each country. Start from a very basic level of property inventory records. The need for better manage to the local government owned property is the result of widespread decentralisation initiatives that often have devolved huge property portfolios from central to local governments almost “overnight”. At the same time municipal or regional governments were and continue to be unprepared to deal with multiple issues related to the role of property owners and managers. The lack of discussion of public asset management especially the elements that should be incorporated in the framework creates an important challenge to study the discipline of public asset management further. The aim of this paper is to study the practices of public asset management in developed countries, especially the elements of public asset management framework, and its transferability to developing countries. A case study was selected and conducted to achieve this aim. They involved interviews and a focus group. The study found that in public asset management framework, proper asset identification, public asset needs analysis, asset life cycle and performance measurements are an important element that should be incorporated in the framework. Those elements are transferable and applicable to developing countries’ local governments. Finally, findings from this study provide useful input for the local government policy makers, scholars and asset management practitioners to establish a public asset management framework toward more efficient and effective local governments in managing their assets as well as increasing public services quality.

Architecture for a free subjectivity : Deleuze and Guattari at the Horizon of the Real

Architecture for a Free Subjectivity reformulates the French philosopher Gilles Deleuze's model of subjectivity for architecture, by surveying the prolific effects of architectural encounter, and the spaces that figure in them. For Deleuze and his Lacanian collaborator Félix Guattari, subjectivity does not refer to a person, but to the potential for and event of matter becoming subject, and the myriad ways for this to take place. By extension, this book theorizes architecture as a self-actuating or creative agency for the liberation of purely "impersonal effects." Imagine a chemical reaction, a riot in the banlieues, indeed a walk through a city. Simone Brott declares that the architectural object does not merely take part in the production of subjectivity, but that it constitutes its own.

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.

Research and application of Building Information Modelling (BIM) in the Architecture, Engineering and Construction (AEC) industry : a review and direction for future research

With an increasing level of collaboration amongst researchers, software developers and industry practitioners in the past three decades, building information modelling (BIM) is now recognized as an emerging technological and procedural shift within the architect, engineering and construction (AEC) industry. BIM is not only considered as a way to make a profound impact on the professions of AEC, but is also regarded as an approach to assist the industry to develop new ways of thinking and practice. Despite the widespread development and recognition of BIM, a succinct and systematic review of the existing BIM research and achievement is scarce. It is also necessary to take stock on existing applications and have a fresh look at where BIM should be heading and how it can benefit from the advances being made. This paper first presents a review of BIM research and achievement in AEC industry. A number of suggestions are then made for future research in BIM. This paper maintains that the value of BIM during design and construction phases is well documented over the last decade, and new research needs to expand the level of development and analysis from design/build stage to postconstruction and facility asset management. New research in BIM could also move beyond the traditional building type to managing the broader range of facilities and built assets and providing preventative maintenance schedules for sustainable and intelligent buildings

Agree or disagree? Level of alignment between project manager and stakeholders on performance indicators

Studies indicate project success should be viewed from the different perspectives of the individual stakeholders. Project managers are owner’s agents. In order to allow early corrective actions to take place in case a project is diverted from plan, to accurately report perceived success of the stakeholders by project managers is essential, though there has been little systematic research in this area. The aim of this paper is to report the findings of an empirical study that compares the level of alignment between project managers and key stakeholders on a list of project performance indicators. A telephone survey involving 18 complex project managers and various key project stakeholder groups was conducted in this study. Krippendorff’s Kappa alpha reliability test was used to assess the alignment levels between project managers and stakeholders. Despite the overall agreement level between project manager and stakeholders is only medium; results have also identified 12 performance indicators that have significant level of agreement between project managers and stakeholders.

Cultural determinants of stress in the construction industry

The need to better understand and deal with workplace stress has major implications for the construction industry, especially on a project level, because of its potential to directly impact on site productivity and safety, and ultimately, the achievement of project objectives. While there has been some understanding of the effect of workplace stress within the construction industry, the majority of these studies have explored individual determinants of workplace stress among construction professionals such as architects, engineers, quantity surveyors etc. To date, very little research has focused on workplace stress as encountered by construction site operatives. This is an important research deficiency as construction site operatives typically make up a significant percentage of on-site workforce and contribute most directly to project success. To address this imbalance in research, this paper proposes a theoretical framework to better understand site operatives’ experience of stress from a cultural perspective on three levels: individual, project and organizational which has been largely neglected in previous studies.

Talking the talk and walking the walk : how managers can influence the quality of work-life balance in a construction project

Purpose – The construction industry in Australia is characterised by a long work-hours culture, with conditions that make it difficult for staff to balance their work and non-work lives. The objective of this paper is to measure the success of a work-place intervention designed to improve work-life balance (WLB) in an alliance project in the construction industry, and the role the project manager plays in this success. Design/methodology/approach – The paper focuses on an alliance case study. Interviews were conducted at two points in time, several months apart, after the interventions were implemented. Findings – Results showed that staff on the whole were more satisfied with their work experience after the interventions, and indicated the important role that managers' attitudes and behaviours played. Originality/value – Managerial support for work-life initiatives is a critical element in achieving WLB and satisfaction with working arrangements. The fact that the manager “talked the talk and walked the walk” was a major contributing success factor, which has not previously been demonstrated.