Kallikrein-related peptidase 4 activation of protease-activated receptor family members and association with prostate cancer

Two areas of particular importance in prostate cancer progression are primary tumour development and metastasis. These processes involve a number of physiological events, the mediators of which are still being discovered and characterised. Serine proteases have been shown to play a major role in cancer invasion and metastasis. The recently discovered phenomenon of their activation of a receptor family known as the protease activated receptors (PARs) has extended their physiological role to that of signaling molecule. Several serine proteases are expressed by malignant prostate cancer cells, including members of the kallikreinrelated peptidase (KLK) serine protease family, and increasingly these are being shown to be associated with prostate cancer progression. KLK4 is highly expressed in the prostate and expression levels increase during prostate cancer progression. Critically, recent studies have implicated KLK4 in processes associated with cancer. For example, the ectopic over-expression of KLK4 in prostate cancer cell lines results in an increased ability of these cells to form colonies, proliferate and migrate. In addition, it has been demonstrated that KLK4 is a potential mediator of cellular interactions between prostate cancer cells and osteoblasts (bone forming cells). The ability of KLK4 to influence cellular behaviour is believed to be through the selective cleavage of specific substrates. Identification of relevant in vivo substrates of KLK4 is critical to understanding the pathophysiological roles of this enzyme. Significantly, recent reports have demonstrated that several members of the KLK family are able to activate PARs. The PARs are relatively new members of the seven transmembrane domain containing G protein coupled receptor (GPCR) family. PARs are activated through proteolytic cleavage of their N-terminus by serine proteases, the resulting nascent N-terminal binds intramolecularly to initiate receptor activation. PARs are involved in a number of patho-physiological processes, including vascular repair and inflammation, and a growing body of evidence suggests roles in cancer. While expression of PAR family members has been documented in several types of cancers, including prostate, the role of these GPCRs in prostate cancer development and progression is yet to be examined. Interestingly, several studies have suggested potential roles in cellular invasion through the induction of cytoskeletal reorganisation and expression of basement membrane-degrading enzymes. Accordingly, this program of research focussed on the activation of the PARs by the prostate cancer associated enzyme KLK4, cellular processing of activated PARs and the expression pattern of receptor and agonist in prostate cancer. For these studies KLK4 was purified from the conditioned media of stably transfected Sf9 insect cells expressing a construct containing the complete human KLK4 coding sequence in frame with a V5 epitope and poly-histidine encoding sequences. The first aspect of this study was the further characterisation of this recombinant zymogen form of KLK4. The recombinant KLK4 zymogen was demonstrated to be activatable by the metalloendopeptidase thermolysin and amino terminal sequencing indicated that thermolysin activated KLK4 had the predicted N-terminus of mature active KLK4 (31IINED). Critically, removal of the pro-region successfully generated a catalytically active enzyme, with comparable activity to a previously published recombinant KLK4 produced from S2 insect cells. The second aspect of this study was the activation of the PARs by KLK4 and the initiation of signal transduction. This study demonstrated that KLK4 can activate PAR-1 and PAR-2 to mobilise intracellular Ca2+, but failed to activate PAR-4. Further, KLK4 activated PAR-1 and PAR-2 over distinct concentration ranges, with KLK4 activation and mobilisation of Ca2+ demonstrating higher efficacy through PAR-2. Thus, the remainder of this study focussed on PAR-2. KLK4 was demonstrated to directly cleave a synthetic peptide that mimicked the PAR-2 Nterminal activation sequence. Further, KLK4 mediated Ca2+ mobilisation through PAR-2 was accompanied by the initiation of the extra-cellular regulated kinase (ERK) cascade. The specificity of intracellular signaling mediated through PAR-2 by KLK4 activation was demonstrated by siRNA mediated protein depletion, with a reduction in PAR-2 protein levels correlating to a reduction in KLK4 mediated Ca2+mobilisation and ERK phosphorylation. The third aspect of this study examined cellular processing of KLK4 activated PAR- 2 in a prostate cancer cell line. PAR-2 was demonstrated to be expressed by five prostate derived cell lines including the prostate cancer cell line PC-3. It was also demonstrated by flow cytometry and confocal microscopy analyses that activation of PC-3 cell surface PAR-2 by KLK4 leads to internalisation of this receptor in a time dependent manner. Critically, in vivo relevance of the interaction between KLK4 and PAR-2 was established by the observation of the co-expression of receptor and agonist in primary prostate cancer and prostate cancer bone lesion samples by immunohistochemical analysis. Based on the results of this study a number of exciting future studies have been proposed, including, delineating differences in KLK4 cellular signaling via PAR-1 and PAR-2 and the role of PAR-1 and PAR-2 activation by KLK4 in prostate cancer cells and bone cells in prostate cancer progression.

Employee engagement : the development of a three dimensional model of engagement; and an exploration of its relationship with affective leader behaviours

This study was designed to examine affective leader behaviours, and their impact on cognitive, affective and behavioural engagement. Researchers (e.g., Cropanzano & Mitchell, 2005; Moorman et al., 1998) have called for more research to be directed toward modelling and testing sets of relationships which better approximate the complexity associated with contemporary organisational experience. This research has attempted to do this by clarifying and defining the construct of engagement, and then by examining how each of the engagement dimensions are impacted by affective leader behaviours. Specifically, a model was tested that identifies leader behaviour antecedents of cognitive, affective and behavioural engagement. Data was collected from five public-sector organisations. Structural equation modelling was used to identify the relationships between the engagement dimensions and leader behaviours. The results suggested that affective leader behaviours had a substantial direct impact on cognitive engagement, which in turn influenced affective engagement, which then influenced intent to stay and extra-role performance. The results indicated a directional process for engagement, but particularly highlighted the significant impact of affective leader behaviours as an antecedent to engagement. In general terms, the findings will provide a platform from which to develop a robust measure of engagement, and will be helpful to human resource practitioners interested in understanding the directional process of engagement and the importance of affective leadership as an antecedent to engagement.

On the (partially) inalienable rights of participants in virtual communities

As virtual communities become more central to the everyday activities of connected individuals, we face increasingly pressing questions about the proper allocation of power, rights and responsibilities. This paper argues that our current legal discourse is ill-equipped to provide answers that will safeguard the legitimate interests of participants and simultaneously refrain from limiting the future innovative development of these spaces. From social networking sites like Facebook to virtual worlds like World of Warcraft and Second Life, participants who are banned from these communities stand to lose their virtual property, their connections to their friends and family, and their personal expression. Because our legal system views the proprietor’s interests as absolute private property rights, however, participants who are arbitrarily, capriciously or maliciously ejected have little recourse under law. This paper argues that, rather than assuming that a private property and freedom of contract model will provide the most desirable outcomes, a more critical approach is warranted. By rejecting the false dichotomy between ‘public’ and ‘private’ spaces, and recognising some of the absolutist and necessitarian trends in the current property debate, we may be able to craft legal rules that respect the social bonds between participants while simultaneously protecting the interests of developers.

Airports in their urban settings : towards a conceptual model of interfaces in the Australian context

In Australia, airports have emerged as important sub-regional activity centres and now pose challenges for both airport operation and planning in the surrounding urban and regional environment. The changing nature of airports in their metropolitan context and the emergence of new pressures and problems require the introduction of a fresh conceptual framework to assist the better understanding of these complex roles and spatial interactions. The approach draws upon the meta-concept of interfaces of an ‘airport metropolis’ as an organising device consisting of four main domains: economic development, land use,infrastructure, and governance. The paper uses the framework to further discuss airport and regional interactions and highlights the use of sustainability criteria to operationalise the model. The approach aims to move research and practice beyond the traditionally compartmentalised analysis of airport issues and policy-making by highlighting interdependencies between airports and regions.

Measuring CRM and SCM benefits : a preliminary measurement model

Organizations invest heavily in Customer Relationship Management (CRM) and Supply Chain Management (SCM) systems, and their related infrastructure, presumably expecting positive benefits to the organization. Assessing the benefits of such applications is an important aspect of managing such systems. Considering the salient differences between CRM and SCM applications with other intra-organizational applications, existing Information Systems benefits measurement models and frameworks are ill-suited to gauge benefits of inter-organizational systems. This paper reports the preliminary findings of a measurement model developed to assess benefits of CRM and SCM applications. The preliminary model, which reflects the characteristics of the Analytic Theory, is derived using a review of 55 academic studies and 44 papers from the practice. Six hundred and six identified benefits were then synthesized in to 74 non-overlapping benefits, arranged under six dimensions.

Thai word segmentation with hidden Markov Model and decision tree

The Thai written language is one of the languages that does not have word boundaries. In order to discover the meaning of the document, all texts must be separated into syllables, words, sentences, and paragraphs. This paper develops a novel method to segment the Thai text by combining a non-dictionary based technique with a dictionary-based technique. This method first applies the Thai language grammar rules to the text for identifying syllables. The hidden Markov model is then used for merging possible syllables into words. The identified words are verified with a lexical dictionary and a decision tree is employed to discover the words unidentified by the lexical dictionary. Documents used in the litigation process of Thai court proceedings have been used in experiments. The results which are segmented words, obtained by the proposed method outperform the results obtained by other existing methods.

Building partnerships as a key strategy in developing an event management model for an international dance event : a case study of the 2008 WDA (World Dance Alliance) Global Summit, Brisbane, Australia

With the increasing growth of cultural events both in Australia and internationally, there has also been an increase in event management studies; in theory and in practice. Although a series of related knowledge and skills required specifically by event managers has already been identified by many researchers (Perry et al., 1996; Getz, 2002 & Silvers et al., 2006) and generic event management models proposed, including ‘project management’ strategies in an event context (Getz, 2007), knowledge gaps still exist in relation to identifying specific types of events, especially for not-for-profit arts events. For events of a largely voluntary nature, insufficient resources are recognised as the most challenging; including finance, human resources and infrastructure. Therefore, the concepts and principles which are adopted by large scale commercial events may not be suitable for not-for-profit arts events aiming at providing professional network opportunities for artists. Building partnerships are identified as a key strategy in developing an effective event management model for this type of event. Using the 2008 World Dance Alliance Global Summit (WDAGS) in Brisbane 13-18 July, as a case study, the level, nature and relationship of key partners are investigated. Data is triangulated from interviews with organisers of the 2008 WDAGS, on-line and email surveys of delegates, participant observation and analysis of formal and informal documents, to produce a management model suited to this kind of event.

A model of teacher professional development based on the principles of lesson study

The researcher’s professional role as an Education Officer was the impetus for this study. Designing and implementing professional development activities is a significant component of the researcher’s position description and as a result of reflection and feedback from participants and colleagues, the creation of a more effective model of professional development became the focus for this study. Few studies have examined all three links between the purposes of professional development that is, increasing teacher knowledge, improving teacher practice, and improving student outcomes. This study is significant in that it investigates the nature of the growth of teachers who participated in a model of professional development which was based upon the principles of Lesson Study. The research provides qualitative and empirical data to establish some links between teacher knowledge, teacher practice, and student learning outcomes. Teacher knowledge in this study refers to mathematics content knowledge as well as pedagogical-content knowledge. The outcomes for students include achievement outcomes, attitudinal outcomes, and behavioural outcomes. As the study was conducted at one school-site, existence proof research was the focus of the methodology and data collection. Developing over the 2007 school year, with five teacher-participants and approximately 160 students from Year Levels 6 to 9, the Lesson Study-principled model of professional development provided the teacher-participants with on-site, on-going, and reflective learning based on their classroom environment. The focus area for the professional development was strategising the engagement with and solution of worded mathematics problems. A design experiment was used to develop the professional development as an intervention of prevailing teacher practice for which data were collected prior to and after the period of intervention. A model of teacher change was developed as an underpinning framework for the development of the study, and was useful in making decisions about data collection and analyses. Data sources consisted of questionnaires, pre-tests and post-tests, interviews, and researcher observations and field notes. The data clearly showed that: content knowledge and pedagogical-content knowledge were increased among the teacher-participants; teacher practice changed in a positive manner; and that a majority of students demonstrated improved learning outcomes. The positive changes to teacher practice are described in this study as the demonstrated use of mixed pedagogical practices rather than a polarisation to either traditional pedagogical practices or contemporary pedagogical practices. The improvement in student learning outcomes was most significant as improved achievement outcomes as indicated by the comparison of pre-test and post-test scores. The effectiveness of the Lesson Study-principled model of professional development used in this study was evaluated using Guskey’s (2005) Five Levels of Professional Development Evaluation.

Developing an integrated decision model for the enhancement of sustainability deliverables for Australian road infrastructure projects

Road and highway infrastructure provides the backbone for a nation's economic growth. The versatile dispersion of population in Australia, from sparsely settled communities in remote areas to regenerated inner city suburbs with high density living in metropolitans, calls for continuing development and improvement on roads infrastructure under the current federal government policies and state governments' strategic plans. As road infrastructure projects involve large resources and mechanism, achieving sustainability not only in economic scales but also through environmental and social responsibility becomes a crucial issue. Current efforts are often impeded by different interpretation on sustainability agenda by stakeholders involved in these types of projects. As a result, sustainability deliverables at the project level is not often as transparent and measurable, compared to promises in project briefs and designs. This paper reviews the past studies on sustainable infrastructure construction, focusing on roads and highway projects. Through literature study and consultation with the industry, key sustainability indicators specific to road infrastructure projects have been identified. Based on these findings, this paper introduces an on-going research project aimed at identifying and integrating the different perceptions and priority needs of the stakeholders, and issues that impact on the gap between sustainability foci and its actual realization at project end level. The exploration helps generate an integrated decision-making model for sustainable road infrastructure projects. The research will promote to the industry more systematic and integrated approaches to decision-making on the implementation of sustainability strategies to achieve deliverable goals throughout the development and delivery process of road infrastructure projects in Australia.