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.

Innovative and entrepreneurial activity in the public sector : the changing face of public sector institutions

This paper investigates the elements which support innovative and entrepreneurial activity in New Zealand’s state owned enterprises (SOEs). An inductive case study design, involving interview data, textual analysis, and observation, was applied to three SOEs. Findings reveal that those aspects typically associated with entrepreneurship, such as innovation, risk acceptance, pro-activeness and growth, are often supported by a number of unexpected elements within the public sector. These elements include culture, branding, operational excellence, cost efficiency, and knowledge transfer. The implications are twofold. First, that innovative and entrepreneurial activity in the public sector can go beyond policy-making, with SOEs representing an important policy decision and sector of the New Zealand Government. And second, that the impact of several SOEs on international markets suggests competition on the global stage will increasingly come from both public and private sector organizations.

Changing pedagogic codes in a class of landscape architects learning 'ecologically sustainable development'

Professional discourse in education has been the focus of research conducted mostly with teachers and professional practitioners but the work of students in the built environment has largely been ignored. This article presents an analysis of students’ visual discourse in the final professional year of a landscape architecture course in Brisbane, Australia. The study has a multi-method design and includes drawings, interviews and documentary materials, but focuses on the drawings in this paper. Using the theory of Bernstein, the analysis considers student representations as interrelations between professional identity and discretionary space for legitimate knowledge formation in landscape planning. It shows a shift in how students persuade the teacher of their expanding views of this field. The discussion of this shift centres on the professional knowledge that students choose rather than need to learn. It points to the differences within a class that a teacher must address in curriculum design in a contemporary professional course.

The use of phase in complex spectrum subtraction for robust speech recognition

In this paper we propose a new method for utilising phase information by complementing it with traditional magnitude-only spectral subtraction speech enhancement through Complex Spectrum Subtraction (CSS). The proposed approach has the following advantages over traditional magnitude-only spectral subtraction: (a) it introduces complementary information to the enhancement algorithm; (b) it reduces the total number of algorithmic parameters, and; (c) is designed for improving clean speech magnitude spectra and is therefore suitable for both automatic speech recognition (ASR) and speech perception applications. Oracle-based ASR experiments verify this approach, showing an average of 20% relative word accuracy improvements when accurate estimates of the phase spectrum are available. Based on sinusoidal analysis and assuming stationarity between observations (which is shown to be better approximated as the frame rate is increased), this paper also proposes a novel method for acquiring the phase information called Phase Estimation via Delay Projection (PEDEP). Further oracle ASR experiments validate the potential for the proposed PEDEP technique in ideal conditions. Realistic implementation of CSS with PEDEP shows performance comparable to state of the art spectral subtraction techniques in a range of 15-20 dB signal-to-noise ratio environments. These results clearly demonstrate the potential for using phase spectra in spectral subtractive enhancement applications, and at the same time highlight the need for deriving more accurate phase estimates in a wider range of noise conditions.

Changing to learner-centred education : challenges experienced by nurse educators in Taiwan

This paper reports the challenges experienced by nurse educators in changing a teacher-centred, content-driven approach to teaching and learning to a learner-centred, process-driven approach within a School of Nursing in Taiwan. While a general movement towards a learner-centred approach was achieved, the curriculum transformation process was complex and inevitably slow with many challenges. First the study is outlined, with the key challenges experienced by the participating nurse educators explicated and illuminated with excerpts drawn from the research data. This is followed by a discussion of possible reasons for the challenges and how they were overcome and the transition process from teacher-centred to learner-centred education facilitated.

Changing perceptions of preservice teachers : innovations in middle schooling teacher education

For the past twenty years, the disengagement of early adolescents has been the focus of much of the literature related to middle schooling. In response, some universities in Australia have introduced teacher education programs that focus upon graduating specialised middle schooling teachers. The aim of this study was to explore and describe the 38 first-year preservice teachers’ perceptions of their first middle schooling elective unit and ascertain whether the combination of university classes and school-based experiences assisted their development of middle schooling concepts and approaches. Data were gathered using pre-test and post-test questionnaires combined with guided written reflections to record their views before, after and during the unit delivery. Results indicated that initially the preservice teachers had little understanding of middle schooling concepts and pedagogical practices, however, 11 participants recognised that bullying and peer pressure were issues experienced by early adolescents. The reflections, which were presented after their field experiences, focused on teaching, learning, behaviour management, and resources and infrastructure. More school-based experiences linked to theoretical underpinnings can help to facilitate understandings about students in the middle phase.

Changing perceptions of preservice teachers : innovations in middle schooling teacher education

For the past twenty years, the disengagement of early adolescents has been the focus of much of the literature related to middle schooling. In response, some universities in Australia have introduced teacher education programs that focus upon graduating specialised middle schooling teachers. Constructing such programs is at the centre of much debate and discussion, however, it is advocated that positive futures for early adolescents can be enhanced through quality middle schooling teacher education programs (Education Queensland, 2004). At a Queensland university campus, middle schooling elective units were introduced as part of the Bachelor of Education (primary) degree. The design of the units was to support preservice teachers to gain the theoretical and pedagogical knowledge to engage and promote early adolescent learning. An innovative approach to the delivery of the units was promoted by a partnership agreement between local schools and the campus. The partnership allowed preservice teachers to combine university classes with opportunities to visit exemplary classrooms to observe, participate and reflect upon middle school teaching practices. The aim of this study was to explore and describe the 38 first-year preservice teachers’ perceptions of their first middle schooling elective unit and to ascertain whether the combination of university classes and school-based experiences assisted their development of middle schooling concepts and approaches. Data were gathered using pre-test and post-test questionnaires combined with guided written reflections to record their views before, after and during the unit delivery. Results indicated that initially 34 preservice teachers had little understanding of middle schooling concepts and pedagogical practices, however, 11 participants recognised that bullying and peer pressure were issues experienced by early adolescents. The collation of the written reflections supported the combined delivery of the middle years unit further supporting the inclusion of school experiences with university delivered units.

Powered two wheelers in a changing world : challenges and opportunities

Powered two wheelers (PTWs) come in diverse forms and are used for a range of purposes in very different parts of the world. In many parts of the world, the forms and uses of PTWs are changing, influenced by social, economic and demographic changes. Most of the challenges associated with PTWs relate to safety, while the majority of the opportunities relate to mobility. The challenges for improving safety relate to the PTW user, other road users, the road environment, the vehicle, data and research, and socio-political dimensions. The relative importance of particular challenges varies between developed and developing countries, and among developing countries according to whether PTWs are largely used for recreation or for transport. PTWs present a range of psychological, transport, economic and environmental opportunities to individuals and societies. The fun and excitement of riding PTWs is a major motivator for their purchase and use for recreational purposes, both off-road and on-road. The transport and economic advantages to the individual also need to be considered. At a societal level, research has examined the potential for increasing PTW volumes to reduce fossil fuel use and traffic congestion in busy cities. The future of PTWs may differ greatly between countries and environmental and technological changes are leading to an evolution in the form of PTWs to encompass new modes of personal transportation.

"Re-imagining animation : the changing face of the moving image by Paul Wells and Johnny Hardstaff" (Book Review)

Advances in digital technology have caused a radical shift in moving image culture. This has occurred in both modes of production and sites of exhibition, resulting in a blurring of boundaries that previously defined a range of creative disciplines. Re-Imagining Animation: The Changing Face of the Moving Image, by Paul Wells and Johnny Hardstaff, argues that as a result of these blurred disciplinary boundaries, the term “animation” has become a “catch all” for describing any form of manipulated moving image practice. Understanding animation predicates the need to (re)define the medium within contemporary moving image culture. Via a series of case studies, the book engages with a range of moving image works, interrogating “how the many and varied approaches to making film, graphics, visual artefacts, multimedia and other intimations of motion pictures can now be delineated and understood” (p. 7). The structure and clarity of content make this book ideally suited to any serious study of contemporary animation which accepts animation as a truly interdisciplinary medium.

Catch me if you can : the effective service of bankruptcy documents in a changing world

This article discusses some recent judicial decisions to assist legal practitioners to overcome some of the problems encountered when serving Bankruptcy Notices and Creditor’s Petitions. Some of the issues covered in the discussion are: What the valid last-known address of the debtor can be, whether a Bankruptcy Notice can be validly served by email on a debtor who is located outside Australia, whether service of a Bankruptcy Notice is valid when the debtor is outside Australia when service on the debtor occurs in Australia, whether the creditor’s failure to obtain leave for service of a Bankruptcy Notice can be excused, what can be done regarding personal service of a Creditor’s Petition when a debtor is outside Australia and whether the Court can set aside a sequestration order. The article goes on to place the issues in the context of broader bankruptcy policies noting that effective service of bankruptcy documents is challenging in a world where mobility of debtors is global and new modes of communication ever changing.