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.

Geological control of physiography in Southeast Queensland: A multi-scale analysis using GIS

The study reported here, constitutes a full review of the major geological events that have influenced the morphological development of the southeast Queensland region. Most importantly, it provides evidence that the region’s physiography continues to be geologically ‘active’ and although earthquakes are presently few and of low magnitude, many past events and tectonic regimes continue to be strongly influential over drainage, morphology and topography. Southeast Queensland is typified by highland terrain of metasedimentary and igneous rocks that are parallel and close to younger, lowland coastal terrain. The region is currently situated in a passive margin tectonic setting that is now under compressive stress, although in the past, the region was subject to alternating extensional and compressive regimes. As part of the investigation, the effects of many past geological events upon landscape morphology have been assessed at multiple scales using features such as the location and orientation of drainage channels, topography, faults, fractures, scarps, cleavage, volcanic centres and deposits, and recent earthquake activity. A number of hypotheses for local geological evolution are proposed and discussed. This study has also utilised a geographic information system (GIS) approach that successfully amalgamates the various types and scales of datasets used. A new method of stream ordination has been developed and is used to compare the orientation of channels of similar orders with rock fabric, in a topologically controlled approach that other ordering systems are unable to achieve. Stream pattern analysis has been performed and the results provide evidence that many drainage systems in southeast Queensland are controlled by known geological structures and by past geological events. The results conclude that drainage at a fine scale is controlled by cleavage, joints and faults, and at a broader scale, large river valleys, such as those of the Brisbane River and North Pine River, closely follow the location of faults. These rivers appear to have become entrenched by differential weathering along these planes of weakness. Significantly, stream pattern analysis has also identified some ‘anomalous’ drainage that suggests the orientations of these watercourses are geologically controlled, but by unknown causes. To the north of Brisbane, a ‘coastal drainage divide’ has been recognized and is described here. The divide crosses several lithological units of different age, continues parallel to the coast and prevents drainage from the highlands flowing directly to the coast for its entire length. Diversion of low order streams away from the divide may be evidence that a more recent process may be the driving force. Although there is no conclusive evidence for this at present, it is postulated that the divide may have been generated by uplift or doming associated with mid-Cenozoic volcanism or a blind thrust at depth. Also north of Brisbane, on the D’Aguilar Range, an elevated valley (the ‘Kilcoy Gap’) has been identified that may have once drained towards the coast and now displays reversed drainage that may have resulted from uplift along the coastal drainage divide and of the D’Aguilar blocks. An assessment of the distribution and intensity of recent earthquakes in the region indicates that activity may be associated with ancient faults. However, recent movement on these faults during these events would have been unlikely, given that earthquakes in the region are characteristically of low magnitude. There is, however, evidence that compressive stress is building and being released periodically and ancient faults may be a likely place for this stress to be released. The relationship between ancient fault systems and the Tweed Shield Volcano has also been discussed and it is suggested here that the volcanic activity was associated with renewed faulting on the Great Moreton Fault System during the Cenozoic. The geomorphology and drainage patterns of southeast Queensland have been compared with expected morphological characteristics found at passive and other tectonic settings, both in Australia and globally. Of note are the comparisons with the East Brazilian Highlands, the Gulf of Mexico and the Blue Ridge Escarpment, for example. In conclusion, the results of the study clearly show that, although the region is described as a passive margin, its complex, past geological history and present compressive stress regime provide a more intricate and varied landscape than would be expected along typical passive continental margins. The literature review provides background to the subject and discusses previous work and methods, whilst the findings are presented in three peer-reviewed, published papers. The methods, hypotheses, suggestions and evidence are discussed at length in the final chapter.

Granule-based knowledge representation for intra and inter transaction association mining

Abstract With the phenomenal growth of electronic data and information, there are many demands for the development of efficient and effective systems (tools) to perform the issue of data mining tasks on multidimensional databases. Association rules describe associations between items in the same transactions (intra) or in different transactions (inter). Association mining attempts to find interesting or useful association rules in databases: this is the crucial issue for the application of data mining in the real world. Association mining can be used in many application areas, such as the discovery of associations between customers’ locations and shopping behaviours in market basket analysis. Association mining includes two phases. The first phase, called pattern mining, is the discovery of frequent patterns. The second phase, called rule generation, is the discovery of interesting and useful association rules in the discovered patterns. The first phase, however, often takes a long time to find all frequent patterns; these also include much noise. The second phase is also a time consuming activity that can generate many redundant rules. To improve the quality of association mining in databases, this thesis provides an alternative technique, granule-based association mining, for knowledge discovery in databases, where a granule refers to a predicate that describes common features of a group of transactions. The new technique first transfers transaction databases into basic decision tables, then uses multi-tier structures to integrate pattern mining and rule generation in one phase for both intra and inter transaction association rule mining. To evaluate the proposed new technique, this research defines the concept of meaningless rules by considering the co-relations between data-dimensions for intratransaction-association rule mining. It also uses precision to evaluate the effectiveness of intertransaction association rules. The experimental results show that the proposed technique is promising.

Industrial Relations: Proceedings from the 1999 Australasian Drama Studies Association Conference

These papers were presented at “Industrial Relations”, the Australasian Drama Studies Association conference hosted by Theatre & Teaching Studies in the Academy of the Arts, Queensland University of Technology, from the 5th to the 9th of July, 1999. Conference delegates included scholars and artists from across the tertiary education and professional theatre sectors, including, of course, many individuals who work across and between both those worlds. More than a hundred delegates from Australia, New Zealand, England, Belgium and Canada attended the week’s events, which included: • Over sixty conference papers covering a variety of topics from project reports to academy/industry partnerships, theatre history, audience reception studies, health & safety, cultural policy, performance theory, theatre technology and more; • Performances ranging from drama to dance, music and cabaret; • Workshops, panel discussions, forums and interviews; • Keynote addresses from Wesley Enoch, Josette Feral and Keith Johnstone; and • A special “Links with Industry” day, which included the launch of ADSA’s “Links with Industry” brochure, an interview between Mark Radvan and David Williamson, and a panel session featuring Jules Holledge, Zane Trow, Katharine Brisbane, John Kotzas, Gay McAuley and David Watt.

The 2006 CSRC guidelines for articles of Association of Chinese listed companies : critiquing from an Australian perspective

Compares the Chinese Securities and Regulatory Commission's guidelines for articles of association of listed companies issued in 2006 with 'replaceable' rules in the Australian Corporations Act 2001. Discusses the provisions of the Chinese guidelines and the Australian rules on corporate constitution, interpretation, a company's representative, object clauses, shareholders' powers and meetings and directors. Questions whether the Chinese guidelines facilitate effective corporate governance.

Augmenting RatSLAM using FAB-MAP-based visual data association

This paper investigates the use of the FAB-MAP appearance-only SLAM algorithm as a method for performing visual data association for RatSLAM, a semi-metric full SLAM system. While both systems have shown the ability to map large (60-70km) outdoor locations of approximately the same scale, for either larger areas or across longer time periods both algorithms encounter difficulties with false positive matches. By combining these algorithms using a mapping between appearance and pose space, both false positives and false negatives generated by FAB-MAP are significantly reduced during outdoor mapping using a forward-facing camera. The hybrid FAB-MAP-RatSLAM system developed demonstrates the potential for successful SLAM over large periods of time.

The 2010 Native American and Indigenous Studies Association Conference

The 2010 Native American Indigenous Studies Conference was held at The Westin La Paloma Resort, Tucson, Arizona, USA from 20-22 May. The conference was scholarly and interdisciplinary and intended for Indigenous and non-Indigenous scholars who work in American Indian/ Native American/ First Nations/ Aboriginal/ Indigenous Studies. The 2010 gathering attracted 768 registrations from the USA, Canada, Hawaii, Mexico, New Zealand and Australia and other countries. This paper is a personal reflection and overview of the 2010 Conference.

The politics of literacy in David Almond and Dave McKean’s "The Savage" (2008)

Competency in language and literacy are central to contemporary debates about education in Anglophone nations around the world. This paper suggests that such debates are informing not just educational policy but children’s literature itself as can be seen in Almond and McKean’s The Savage. This hybrid text combines prose and graphic narrative and narration in order to tell the story of Blue, a young British boy negotiating his identity in the aftermath of his father's death. While foregrounding a narrative of ideal masculinity, The Savage enacts and privileges a formal and thematic ideal of literacy as index of individual agency and development. Almond and McKean produce a politicised understanding of language and literacy that simultaneously positions The Savage in a textual tradition of socio-culturally disenfranchised youth, and intervenes in that tradition to (perhaps ironically) affirm the very conditions previously critiqued by that very tradition. Where earlier authors such as Barry Hines sought to challenge normative accounts of language and literacy in order to indict educational policy and praxes, Almond and McKean work to naturalise the very logics of education and agency by which their protagonist has been disenfranchised. In doing so, The Savage exemplifies current approaches to education which claim to value social and cultural diversity while imposing national standardised testing predicated on assumptions about the legitimacy of uniform standards and definitions of literacy.

Pretreatment malnutrition and quality of life - association with prolonged length of hospital stay among patients with gynecological cancer: A cohort study

Background Length of hospital stay (LOS) is a surrogate marker for patients' well-being during hospital treatment and is associated with health care costs. Identifying pretreatment factors associated with LOS in surgical patients may enable early intervention in order to reduce postoperative LOS. Methods This cohort study enrolled 157 patients with suspected or proven gynecological cancer at a tertiary cancer centre (2004-2006). Before commencing treatment, the scored Patient Generated - Subjective Global Assessment (PG-SGA) measuring nutritional status and the Functional Assessment of Cancer Therapy-General (FACT-G) scale measuring quality of life (QOL) were completed. Clinical and demographic patient characteristics were prospectively obtained. Patients were grouped into those with prolonged LOS if their hospital stay was greater than the median LOS and those with average or below average LOS. Results Patients' mean age was 58 years (SD 14 years). Preoperatively, 81 (52%) patients presented with suspected benign disease/pelvic mass, 23 (15%) with suspected advanced ovarian cancer, 36 (23%) patients with suspected endometrial and 17 (11%) with cervical cancer, respectively. In univariate models prolonged LOS was associated with low serum albumin or hemoglobin, malnutrition (PG-SGA score and PG-SGA group B or C), low pretreatment FACT-G score, and suspected diagnosis of cancer. In multivariable models, PG-SGA group B or C, FACT-G score and suspected diagnosis of advanced ovarian cancer independently predicted LOS. Conclusions Malnutrition, low quality of life scores and being diagnosed with advanced ovarian cancer are the major determinants of prolonged LOS amongst gynecological cancer patients. Interventions addressing malnutrition and poor QOL may decrease LOS in gynecological cancer patients.

A systematic review of the association between physical activity and colorectal cancer risk

This review evaluated the strength of the evidence for a causal relationship between physical activity (PA) and colorectal cancer (CRC). A systematic review of databases through February 2008 was conducted to identify studies that assessed the association between total or recreational PA and incidence or mortality of CRC (including CRC, rectal cancer, colon cancer, and proximal or distal colon cancer). Studies were evaluated for significant associations between PA and risk of CRC endpoints and for evidence of dose–response relationships in the highest quality studies. Twenty cohort studies were evaluated; 11 were high-quality. Fifty percent of all studies and 64%of highest quality studies reported at least one significant association between PA and risk of a CRC endpoint (Po0.05).However, only 28%of all analyses (31% of analyses of highest quality studies) were significant (Po0.05). Only 40% of analyses of highest quality studies resulted in a significant P for trend (Po0.05); however, a non-significant inverse linear association between PA and colon cancer riskwas apparent.Heterogeneity in the evidence from all studies and from the highest quality studies was evident. Evidence from cohort studies is not sufficient to claim a convincing relationship exists between PA and CRC risk.

Is the association between temperature and mortality modified by age, gender and socio-economic status?

Background: A number of studies have examined the relationship between high ambient temperature and mortality. Recently, concern has arisen about whether this relationship is modified by socio-demographic factors. However, data for this type of study is relatively scarce in subtropical/tropical regions where people are well accustomed to warm temperatures. Objective: To investigate whether the relationship between daily mean temperature and daily all-cause mortality is modified by age, gender and socio-economic status (SES) in Brisbane, Australia. Methods: We obtained daily mean temperature and all-cause mortality data for Brisbane, Australia during 1996–2004. A generalised additive model was fitted to assess the percentage increase in all deaths with every one degree increment above the threshold temperature. Different age, gender and SES groups were included in the model as categorical variables and their modification effects were estimated separately. Results: A total of 53,316 non-external deaths were included during the study period. There was a clear increasing trend in the harmful effect of high temperature on mortality with age. The effect estimate among women was more than 20 times that among men. We did not find an SES effect on the percent increase associated with temperature. Conclusions: The effects of high temperature on all deaths were modified by age and gender but not by SES in Brisbane, Australia.