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.

Road safety messages tailored for young adults : Using the Internet and encouraging protective passenger behaviour

Young drivers are at higher risk of crashes than other drivers when carrying passengers. Graduated Driver Licensing has demonstrated effectiveness in reducing fatalities however there is considerable potential for additional strategies to complement the approach. A survey with 276 young adults (aged 17-25 years, 64% females) was conducted to examine the potential and importance of strategies that are delivered via the Internet and potential strategies for passengers. Strategies delivered via the Internet represent opportunity for widespread dissemination and greater reach to young people at times convenient to them. The current study found some significant differences between males and females with regard to ways the Internet is used to obtain road safety information and the components valued in trusted road safety sites. There were also significant differences between males and females on the kinds of strategies used as passengers to promote driver safety and the context in which it occurred, with females tending to take more proactive strategies than males. In sum, young people see value in Internet delivery for passenger safety information (80% agreed/ strongly agreed) and more than 90% thought it was important to intervene while a passenger of a risky driver. Thus tailoring Internet road safety strategies to young people may differ for males and females however there is considerable potential for a passenger focus in strategies aimed at reducing young driver crashes.

Towards research-based innovation and reform: Singapore education in transition

The challenges facing the Singapore education system in the new millennium are unique and unprecedented in Asia. Demands for new skills, knowledges, and flexible competencies for globalised economies and cosmopolitan cultures will require system-wide innovation and reform. But there is a dearth of international benchmarks and prototypes for such reforms. This paper describes the current Core Research Program underway at the National Institute of Education in Singapore, a multilevel analysis of Singaporean schooling, pedagogy, youth and educational outcomes. It describes student background, performance, classroom practices, student artefacts and outcomes, and student longitudinal life pathways. The case is made that a systematic focus on teachers' and students' work in everyday classroom contexts is the necessary starting point for pedagogical innovation and change. This, it is argued, can constitute a rich multidisciplinary evidence base for educational policy. (Contains 1 figure, 1 table and 3 notes.)

Foundations of technology development, innovation and competitiveness in the globalised knowledge economy

With the growth of high-technology industries and knowledge intensive services, the pursuit of industrial competitiveness has progressed from a broad concern with the processes of industrialisation to a more focused analysis of the factors explaining cross-national variation in the level of participation in knowledge industries. From an examination of cross-national data, the paper develops the proposition that particular elements of the domestic science, technology and industry infrastructure—such as the stock of knowledge and competence in the economy, the capacity for learning and generation of new ideas and the capacity to commercialise new ideas—vary cross-nationally and are related to the level of participation of a nation in knowledge intensive activities. Existing understandings of the role of the state in promoting industrial competitiveness might be expanded to incorporate an analysis of the contribution of the state through the building of competencies in science, technology and industry. Keywords: Knowledge; economy; comparative public policy; innovation; science and technology policy

Work-related driving safety in light vehicle fleets : a review of past research and the development of an intervention framework

This paper presents a critical review of past research in the work-related driving field in light vehicle fleets (e.g., vehicles < 4.5 tonnes) and an intervention framework that provides future direction for practitioners and researchers. Although work-related driving crashes have become the most common cause of death, injury, and absence from work in Australia and overseas, very limited research has progressed in establishing effective strategies to improve safety outcomes. In particular, the majority of past research has been data-driven, and therefore, limited attention has been given to theoretical development in establishing the behavioural mechanism underlying driving behaviour. As such, this paper argues that to move forward in the field of work-related driving safety, practitioners and researchers need to gain a better understanding of the individual and organisational factors influencing safety through adopting relevant theoretical frameworks, which in turn will inform the development of specifically targeted theory-driven interventions. This paper presents an intervention framework that is based on relevant theoretical frameworks and sound methodological design, incorporating interventions that can be directed at the appropriate level, individual and driving target group.

Key competitiveness indicators for new real estate developers

Purpose – The paper aims to explore the key competitiveness indicators (KCIs) that provide the guidelines for helping new real estate developers (REDs) achieve competitiveness during their inception stage in which the organisations start their business. Design/methodology/approach – The research was conducted using a combination of various methods. A literature review was undertaken to provide a proper theoretical understanding of organisational competitiveness within RED's activities and developed a framework of competitiveness indicators (CIs) for REDs. The Delphi forecasting method is employed to investigate a group of 20 experts' perception on the relative importance between CIs. Findings – The results show that the KCIs of new REDs are capital operation capability, entrepreneurship, land reserve capability, high sales revenue from the first real estate development project, and innovation capability. Originality/value – The five KCIs of new REDs are new. In practical terms, the examination of these KCIs would help the business managers of new REDs to effectively plan their business by focusing their efforts on these key indicators. The KCIs can also help REDs provide theoretical constructs of the knowledge base on organisational competitiveness from a dynamic perspective, and assist in providing valuable experiences and in formulating feasible strategies for survival and growth.

Multi-linear strategies for (re)presenting the complexity of young people in research

Within the current climate of unpredictability and constant change, young people at school are faced with a multitude of choices and contradictory influences. In this article, I argue that (re)presentations of young people in youth research need to reflect the complexity and multiplicity of their lives and changing priorities, and I attempt to (re)present a small group of young people in this particular milieu. I illustrate some of the competing influences in their lives, and I outline some specific strategies that are useful for (re)presenting these contextual worlds. The strategies I advocate disrupt the homogenous representations of ‘youth’ as a developmental phase and instead reflect the diverse spheres of influence which shape their subjectivities and practices.

Assessing the vulnerability of eco-environmental health to climate change

There is an urgent need to assess the vulnerability of eco-environmental health to climate change. This paper aims to provide an overview of current research, to identify knowledge gaps, and to propose future research needs in this challenging area. Evidence shows that climate change is affecting and will, in the future, have more (mostly adverse) impacts on ecosystems. Ecosystem degradation, particularly the decline of the life support systems, will undoubtedly affect human health and wellbeing. Therefore, it is important to develop a framework to assess the vulnerability of eco-environmental health to climate change, and to identify appropriate adaptation strategies to minimize the impact of climate change.

Quality of child abuse information for measurement and surveillance : linking hospital and child welfare data

National estimates of the prevalence of child abuse-related injuries are obtained from a variety of sectors including welfare, justice, and health resulting in inconsistent estimates across sectors. The International Classification of Diseases (ICD) is used as the international standard for categorising health data and aggregating data for statistical purposes, though there has been limited validation of the quality, completeness or concordance of these data with other sectors. This research study examined the quality of documentation and coding of child abuse recorded in hospital records in Queensland and the concordance of these data with child welfare records. A retrospective medical record review was used to examine the clinical documentation of over 1000 hospitalised injured children from 20 hospitals in Queensland. A data linkage methodology was used to link these records with records in the child welfare database. Cases were sampled from three sub-groups according to the presence of target ICD codes: Definite abuse, Possible abuse, unintentional injury. Less than 2% of cases coded as being unintentional were recoded after review as being possible abuse, and only 5% of cases coded as possible abuse cases were reclassified as unintentional, though there was greater variation in the classification of cases as definite abuse compared to possible abuse. Concordance of health data with child welfare data varied across patient subgroups. This study will inform the development of strategies to improve the quality, consistency and concordance of information between health and welfare agencies to ensure adequate system responses to children at risk of abuse.

Factors associated with physical activity in Australians with hip or knee osteoarthritis

Background: Physical activity (PA) is recommended for managing osteoarthritis (OA). However, few people with OA are physically active. Understanding the factors associated with PA is necessary to increase PA in this population. This cross-sectional study examined factors associated with leisure-time PA, stretching exercises, and strengthening exercises in people with OA. Methods: For a mail survey, 485 individuals, aged 68.0 y (SD=10.6) with hip or knee OA, were asked about factors that may influence PA participation, including use of non-PA OA management strategies and both psychological and physical health-related factors. Associations between factors and each PA outcome were examined in multivariable logistic regression models. Results: Non-PA management strategies were the main factors associated with the outcomes. Information/education courses, heat/cold treatments, and paracetamol were associated with stretching and strengthening exercises (P<0.05). Hydrotherapy and magnet therapy were associated with leisure-time PA; using orthotics and massage therapy, with stretching exercises; and occupational therapy, with strengthening exercises (P<0.05). Few psychological or health15 related factors were associated with the outcomes. Conclusions: Some management strategies may make it easier for people with OA to be physically active, and could be promoted to encourage PA. Providers of strategies are potential avenues for recruiting people with OA into PA programs.