A review of models of spatial innovation infrastructures in support of high growth SMEs

This Paper first provides a review and analysis of the recent trends on innovation infrastructures developed in industrialised countries to promote innovation and competitiveness for high growth SMEs. It specifically aims to examine various spatial models developed to support provision of innovation infrastructure for high growth sector.

Passive control of a bi-ventricular assist device : an experimental and numerical investigation

For the last two decades heart disease has been the highest single cause of death for the human population. With an alarming number of patients requiring heart transplant, and donations not able to satisfy the demand, treatment looks to mechanical alternatives. Rotary Ventricular Assist Devices, VADs, are miniature pumps which can be implanted alongside the heart to assist its pumping function. These constant flow devices are smaller, more efficient and promise a longer operational life than more traditional pulsatile VADs. The development of rotary VADs has focused on single pumps assisting the left ventricle only to supply blood for the body. In many patients however, failure of both ventricles demands that an additional pulsatile device be used to support the failing right ventricle. This condition renders them hospital bound while they wait for an unlikely heart donation. Reported attempts to use two rotary pumps to support both ventricles concurrently have warned of inherent haemodynamic instability. Poor balancing of the pumps’ flow rates quickly leads to vascular congestion increasing the risk of oedema and ventricular ‘suckdown’ occluding the inlet to the pump. This thesis introduces a novel Bi-Ventricular Assist Device (BiVAD) configuration where the pump outputs are passively balanced by vascular pressure. The BiVAD consists of two rotary pumps straddling the mechanical passive controller. Fluctuations in vascular pressure induce small deflections within both pumps adjusting their outputs allowing them to maintain arterial pressure. To optimise the passive controller’s interaction with the circulation, the controller’s dynamic response is optimised with a spring, mass, damper arrangement. This two part study presents a comprehensive assessment of the prototype’s ‘viability’ as a support device. Its ‘viability’ was considered based on its sensitivity to pathogenic haemodynamics and the ability of the passive response to maintain healthy circulation. The first part of the study is an experimental investigation where a prototype device was designed and built, and then tested in a pulsatile mock circulation loop. The BiVAD was subjected to a range of haemodynamic imbalances as well as a dynamic analysis to assess the functionality of the mechanical damper. The second part introduces the development of a numerical program to simulate human circulation supported by the passively controlled BiVAD. Both investigations showed that the prototype was able to mimic the native baroreceptor response. Simulating hypertension, poor flow balancing and subsequent ventricular failure during BiVAD support allowed the passive controller’s response to be assessed. Triggered by the resulting pressure imbalance, the controller responded by passively adjusting the VAD outputs in order to maintain healthy arterial pressures. This baroreceptor-like response demonstrated the inherent stability of the auto regulating BiVAD prototype. Simulating pulmonary hypertension in the more observable numerical model, however, revealed a serious issue with the passive response. The subsequent decrease in venous return into the left heart went unnoticed by the passive controller. Meanwhile the coupled nature of the passive response not only decreased RVAD output to reduce pulmonary arterial pressure, but it also increased LVAD output. Consequently, the LVAD increased fluid evacuation from the left ventricle, LV, and so actually accelerated the onset of LV collapse. It was concluded that despite the inherently stable baroreceptor-like response of the passive controller, its lack of sensitivity to venous return made it unviable in its present configuration. The study revealed a number of other important findings. Perhaps the most significant was that the reduced pulse experienced during constant flow support unbalanced the ratio of effective resistances of both vascular circuits. Even during steady rotary support therefore, the resulting ventricle volume imbalance increased the likelihood of suckdown. Additionally, mechanical damping of the passive controller’s response successfully filtered out pressure fluctuations from residual ventricular function. Finally, the importance of recognising inertial contributions to blood flow in the atria and ventricles in a numerical simulation were highlighted. This thesis documents the first attempt to create a fully auto regulated rotary cardiac assist device. Initial results encourage development of an inlet configuration sensitive to low flow such as collapsible inlet cannulae. Combining this with the existing baroreceptor-like response of the passive controller will render a highly stable passively controlled BiVAD configuration. The prototype controller’s passive interaction with the vasculature is a significant step towards a highly stable new generation of artificial heart.

Is the sum more than the corporate entrepreneurship parts? the different effects of social capital on innovation, venturing, and renewal processes

Principal Topic Although corporate entrepreneurship is of vital importance for long-term firm survival and growth (Zahra and Covin, 1995), researchers still struggle with understanding how to manage corporate entrepreneurship activities. Corporate entrepreneurship consists of three parts: innovation, venturing, and renewal processes (Guth and Ginsberg, 1990). Innovation refers to the development of new products, venturing to the creation of new businesses, and renewal to redefining existing businesses (Sharma, and Chrisman, 1999; Verbeke et al., 2007). Although there are many studies focusing on one of these aspects (cf. Burgelman, 1985; Huff et al., 1992), it is very difficult to compare the outcomes of these studies due to differences in contexts, measures, and methodologies. This is a significant lack in our understanding of CE, as firms engage in all three aspects of CE, making it important to compare managerial and organizational antecedents of innovation, venturing and renewal processes. Because factors that may enhance venturing activities may simultaneously inhibit renewal activities. The limited studies that did empirically compare the individual dimensions (cf. Zahra, 1996; Zahra et al., 2000; Yiu and Lau, 2008; Yiu et al., 2007) generally failed to provide a systematic explanation for potential different effects of organizational antecedents on innovation, venturing, and renewal. With this study we aim to investigate the different effects of structural separation and social capital on corporate entrepreneurship activities. The access to existing and the development of new knowledge has been deemed of critical importance in CE-activities (Floyd and Wooldridge, 1999; Covin and Miles, 2007; Katila and Ahuja, 2002). Developing new knowledge can be facilitated by structurally separating corporate entrepreneurial units from mainstream units (cf. Burgelman, 1983; Hill and Rothaermel, 2003; O'Reilly and Tushman, 2004). Existing knowledge and resources are available through networks of social relationships, defined as social capital (Nahapiet and Ghoshal, 1998; Yiu and Lau, 2008). Although social capital has primarily been studied at the organizational level, it might be equally important at top management level (Belliveau et al., 1996). However, little is known about the joint effects of structural separation and integrative mechanisms to provide access to social capital on corporate entrepreneurship. Could these integrative mechanisms for example connect the separated units to facilitate both knowledge creation and sharing? Do these effects differ for innovation, venturing, and renewal processes? Are the effects different for organizational versus top management team integration mechanisms? Corporate entrepreneurship activities have for example been suggested to take place at different levels. Whereas innovation is suggested to be a more bottom-up process, strategic renewal is a more top-down process (Floyd and Lane, 2000; Volberda et al., 2001). Corporate venturing is also a more bottom-up process, but due to the greater required resource commitments relative to innovation, it ventures need to be approved by top management (Burgelman, 1983). As such we will explore the following key research question in this paper: How do social capital and structural separation on organizational and TMT level differentially influence innovation, venturing, and renewal processes? Methodology/Key Propositions We investigated our hypotheses on a final sample of 240 companies in a variety of industries in the Netherlands. All our measures were validated in previous studies. We targeted a second respondent in each firm to reduce problems with single-rater data (James et al., 1984). We separated the measurement of the independent and the dependent variables in two surveys to create a one-year time lag and reduce potential common method bias (Podsakoff et al., 2003). Results and Implications Consistent with our hypotheses, our results show that configurations of structural separation and integrative mechanisms have different effects on the three aspects of corporate entrepreneurship. Innovation was affected by organizational level mechanisms, renewal by integrative mechanisms on top management team level and venturing by mechanisms on both levels. Surprisingly, our results indicated that integrative mechanisms on top management team level had negative effects on corporate entrepreneurship activities. We believe this paper makes two significant contributions. First, we provide more insight in what the effects of ambidextrous organizational forms (i.e. combinations of differentiation and integration mechanisms) are on venturing, innovation and renewal processes. Our findings show that more valuable insights can be gained by comparing the individual parts of corporate entrepreneurship instead of focusing on the whole. Second, we deliver insights in how management can create a facilitative organizational context for these corporate entrepreneurship activities.

Development of a biaxial compression device for biological samples : preliminary experimental results for a closed cell foam

Biological tissues are subjected to complex loading states in vivo and in order to define constitutive equations that effectively simulate their mechanical behaviour under these loads, it is necessary to obtain data on the tissue's response to multiaxial loading. Single axis and shear testing of biological tissues is often carried out, but biaxial testing is less common. We sought to design and commission a biaxial compression testing device, capable of obtaining repeatable data for biological samples. The apparatus comprised a sealed stainless steel pressure vessel specifically designed such that a state of hydrostatic compression could be created on the test specimen while simultaneously unloading the sample along one axis with an equilibrating tensile pressure. Thus a state of equibiaxial compression was created perpendicular to the long axis of a rectangular sample. For the purpose of calibration and commissioning of the vessel, rectangular samples of closed cell ethylene vinyl acetate (EVA) foam were tested. Each sample was subjected to repeated loading, and nine separate biaxial experiments were carried out to a maximum pressure of 204 kPa (30 psi), with a relaxation time of two hours between them. Calibration testing demonstrated the force applied to the samples had a maximum error of 0.026 N (0.423% of maximum applied force). Under repeated loading, the foam sample demonstrated lower stiffness during the first load cycle. Following this cycle, an increased stiffness, repeatable response was observed with successive loading. While the experimental protocol was developed for EVA foam, preliminary results on this material suggest that this device may be capable of providing test data for biological tissue samples. The load response of the foam was characteristic of closed cell foams, with consolidation during the early loading cycles, then a repeatable load-displacement response upon repeated loading. The repeatability of the test results demonstrated the ability of the test device to provide reproducible test data and the low experimental error in the force demonstrated the reliability of the test data.

What is that place? Observations of the impact of environment colour through photographic analysis

Isolating the impact of a colour, or a combination of colours, is extremely difficult to achieve because it is difficult to remove other environmental elements such as sound, odours, light, and occasion from the experience of being in a place. In order to ascertain the impact of colour on how we interpret the world in day to day situations, the current study records participant responses to achromatic scenes of the built environment prior to viewing the same scene in colour. A number of environments were photographed in colour or copied from design books; and copies of the images saved as both colour and black/grey/white. An overview of the study will be introduced by firstly providing examples of studies which have linked colour to meaning and emotions. For example, yellow is said to be connected to happiness1 ; or red evokes feelings of anger2 or passion. A link between colour and the way we understand and/or feel is established however, there is a further need for knowledge of colour in context. In response to this need, the current achromatic/chromatic environmental study will be described and discussed in light of the findings. Finally, suggestions for future research are posed. Based on previous research the authors hypothesised that a shift in environmental perception by participants would occur. It was found that the impact of colour includes a shift in perception of aspects such as its atmosphere and youthfulness. Through studio-class discussions it was also noted that the predicted age of the place, the function, and in association, the potential users when colour was added (or deleted) were often challenged. It is posited that the ability of a designer (for example, interior designer, architect, or landscape architect) to design for a particular target group—user and/or clients will be enhanced through more targeted studies relating colour in situ. The importance of noting the perceptual shift for the participants in our study, who were young designers, is the realisation that colour potentially holds the power to impact on the identity of an architectural form, an interior space, and/or particular elements such as doorways, furniture settings, and the like.

Evaluation of the in vitro bioactivity of bioceramics

Two common methods have been used to evaluate the in vitro bioactivity of bioceramics for the application of bone repair. One is to evaluate the ability of apatite formation by soaking ceramics in simulated body fluids (SBF); the other method is to evaluate the effect of ceramics on osteogenic differentiation using cell experiments. Both methods have their own drawbacks in evaluating the in vitro bioactivity of bioceramics. In this commentary paper we review the application of both methods in bioactivity of bioceramics and conclude that (i) SBF method is an efficient method to investigate the in vitro bioactivity of silicate-based bioceramics, (ii) cellular bioactivity of bioceramics should be investigated by evaluating their stimulatory ability using standard bioceramics as controls; and (iii) the combination of these two methods to evaluate the in vitro bioactivity of bioceramics can improve the screening efficiency for the selection of bioactive ceramics for bone regeneration.

Building information modelling : an issue of adoption and change management

Building Information Modelling (BIM) is an IT enabled technology that allows storage, management, sharing, access, update and use of all the data relevant to a project through out the project life-cycle in the form of a data repository. BIM enables improved inter-disciplinary collaboration across distributed teams, intelligent documentation and information retrieval, greater consistency in building data, better conflict detection and enhanced facilities management. While the technology itself may not be new, and similar approaches have been in use in some other sectors like Aircraft and Automobile industry for well over a decade now, the AEC/FM (Architecture, Engineering and Construction/ Facilities Management) industry is still to catch up with them in its ability to exploit the benefits of the IT revolution. Though the potential benefits of the technology in terms of knowledge sharing, project management, project co-ordination and collaboration are near to obvious, the adoption rate has been rather lethargic, inspite of some well directed efforts and availability of supporting commercial tools. Since the technology itself has been well tested over the years in some other domains the plausible causes must be rooted well beyond the explanation of the ‘Bell Curve of innovation adoption’. This paper discusses the preliminary findings of an ongoing research project funded by the Cooperative Research Centre for Construction Innovation (CRC-CI) which aims to identify these gaps and come up with specifications and guidelines to enable greater adoption of the BIM approach in practice. A detailed literature review is conducted that looks at some of the similar research reported in the recent years. A desktop audit of some of the existing commercial tools that support BIM application has been conducted to identify the technological issues and concerns, and a workshop was organized with industry partners and various players in the AEC industry for needs analysis, expectations and feedback on the possible deterrents and inhibitions surrounding the BIM adoption.

Cryoreservation of alginate-fibrin beads involving bone marrow derived mesenchymal stromal cells by vitrification

Application of cell-–biomaterial systems in regenerative medicine can be facilitated by their successful low temperature preservation. Vitrification, which avoids ice crystal formation by amorphous solidification, is an emerging approach to cryopreservation. Developing vitrification strategy, effective cryopreservation of alginate–fibrin beads with porcine mesenchymal stromal cells has been achieved in this study. The cell–biomaterial constructs were pre-cultured for 20 days before cryopreservation, allowing for cell proliferation and construct stabilization. Ethylene glycol (EG) was employed as the basic cryoprotectant for two equilibration solutions. Successful cryopreservation of the constructs was achieved using vitrification solution composed of penetrating (EG MW 62 Da) and non-penetrating (sucrose MW 342 Da) cryoprotectants. Stepwise procedure of introduction to and removal of cryoprotectants was brief; direct plunging into liquid nitrogen was applied. Cell viability, evaluated by combining live/death staining and confocal laser microscopy, was similar for both control and vitrified cells in the beads. No detectable damage of microstructure of cryopreserved beads was found as shown by scanning electron microscopy. Both osteogenically induced control and vitrified cells in the constructs were equally capable of mineral production and deposition. There was no statistically significant difference in metabolic activity and proliferation between both groups during the entire culture period. Our study leads to the conclusion that the developed cryopreservation protocol allowed to maintain the integrity of the beads while preserving the ability of the pig bone marrow derived mesenchymal stromal cells to proliferate and subsequently differentiate; demonstrating that vitrification is a promising approach for cryopreser-vation of “ready-to-use” cell–biomaterial constructs.

Innovation implementation effectiveness : a multiorganizational test of Klein Conn and Sorra’s model.

In an empirical test and extension of Klein Conn and Sorra’s model of innovation implementation effectiveness, we apply structural equation modelling to identify the generalizability of their data-modified model in comparison with their theorised model. We examined the implementation of various types of innovations in a sample of 135 organizations. We found that the data supported the original model rather than the data-modified model, such that implementation climate mediated polices and practices and implementation effectiveness, while implementation effectiveness partially mediated the relationship between implementation climate and innovation effectiveness. Furthermore, we extend their model to suggest that non-financial resources availability plays a critical role in implementation policies and practices.

An empirical study : a role of financial and non-financial performance measurement and perceived innovation effectiveness

Practitioners and academics often assume that investments in innovation will lead to organizational improvements. However, previous research has often shown that implemented innovations fail to realise these potential improvements. On the other hand, organisation, perhaps, has been growing and productive because of the innovation, but traditional measurements have failed to capture that growth. In order to help organizations capture their innovation performance effectively, this study examined the organizations which employ different types of performance measurement and their perception of innovation effectiveness.

Modulation of the SHBG signalling axis

Sex hormone-binding globulin (SHBG) is a homodimeric plasma glycoprotein that is the major sex steroid carrier-protein in the bloodstream and functions also as a key regulator of steroid bioavailability within target tissues, such as the prostate. Additionally, SHBG binds to prostatic cell membranes via the putative and unidentified SHBG receptor (RSHBG), activating a signal transduction pathway implicated in stimulating both proliferation and expression of prostate specific antigen (PSA) in prostate cell lines in vitro. A yeast-two hybrid assay suggested an interaction between SHBG and kallikrein-related protease (KLK) 4, which is a serine protease implicated in the progression of prostate cancer. The potential interaction between these two proteins was investigated in this PhD thesis to determine whether SHBG is a proteolytic substrate of KLK4 and other members of the KLK family including KLK3/PSA, KLK7 and KLK14. Furthermore, the effects from SHBG proteolytic degradation on SHBG-regulated steroid bioavailability and the activation of the putative RSHBG signal transduction pathway were examined in the LNCaP prostate cancer cell line. SHBG was found to be a proteolytic substrate of the trypsin-like KLK4 and KLK14 in vitro, yielding several proteolysis fragments. Both chymotrypsin-like PSA and KLK7 displayed insignificant proteolytic activity against SHBG. The kinetic parameters of SHBG proteolysis by KLK4 and KLK14 demonstrate a strong enzyme-substrate binding capacity, possessing a Km of 1.2 ± 0.7 µM and 2.1 ± 0.6 µM respectively. The catalytic efficiencies (kcat/Km) of KLK4 and KLK14 proteolysis of SHBG were 1.6 x 104 M-1s-1 and 3.8 x 104 M-1s-1 respectively, which were comparable to parameters previously reported for peptide substrates. N-terminal sequencing of the fragments revealed cleavage near the junction of the N- and C-terminal laminin globulin-like (G-like) domains of SHBG, resulting in the division of the two globulins and ultimately the full degradation of these fragments by KLK4 and KLK14 over time. Proteolytic fragments that may retain steroid binding were rapidly degraded by both proteases, while fragments containing residues beyond the steroid binding pocket were less degraded over the same period of time. Degradation of SHBG was inhibited by the divalent metal cations calcium and zinc for KLK4, and calcium, zinc and magnesium for KLK14. The human secreted serine protease inhibitors (serpins), α1-antitrypsin and α2-antiplasmin, inhibited KLK4 and KLK14 proteolysis of SHBG; α1-antichymotrypsin inhibited KLK4 but not KLK14 activity. The inhibition by these serpins was comparable and in some cases more effective than general trypsin protease inhibitors such as aprotinin and phenylmethanesulfonyl fluoride (PMSF). The binding of 5α-dihydrotestosterone (DHT) to SHBG modulated interactions with KLK4 and KLK14. Steroid-free SHBG was more readily digested by both enzymes than DHT-bound SHBG. Moreover, a binding interaction exists between SHBG and pro-KLK4 and pro-KLK14, with DHT strengthening the binding to pro-KLK4 only. The inhibition of androgen uptake by cultured prostate cancer cells, mediated by SHBG steroid-binding, was examined to assess whether SHBG proteolysis by KLK4 and KLK14 modulated this process. Proteolytic digestion eliminated the ability of SHBG to inhibit the uptake of DHT from conditioned media into LNCaP cells. Therefore, the proteolysis of SHBG by KLK4 and KLK14 increased steroid bioavailability in vitro, leading to an increased uptake of androgens by prostate cancer cells. Interestingly, different transcriptional responses of PSA and KLK2, which are androgen-regulated genes, to DHT-bounsd SHBG treatment were observed between low and high passage number LNCaP cells (lpLNCaP and hpLNCaP respectively). HpLNCaP cells treated with DHT-bound SHBG demonstrated a significant synergistic upregulation of PSA and KLK2 above DHT or SHBG treatment alone, which is similar to previously reported downstream responses from RSHBG-mediated signaling activation. As this result was not seen in lpLNCaP cells, only hpLNCaP cells were further investigated to examine the modulation of potential RSHBG activity by KLK4 and KLK14 proteolysis of SHBG. Contrary to reported results, no increase in intracellular cAMP was observed in hpLNCaP cells when treated with SHBG in the presence and absence of either DHT or estradiol. As a result, the modulation of RSHBG-mediated signaling activation could not be determined. Finally, the identification of the RSHBG from both breast (MCF-7) and prostate cancer (LNCaP) cell lines was attempted. Fluorescently labeled peptides corresponding to the putative receptor binding domain (RBD) of SHBG were shown to be internalized by MCF-7 cells. Crosslinking of the RBD peptide to the cell surfaces of both MCF-7 and LNCaP cells, demonstrated the interaction of the peptide with several targets. These targets were then captured using RBD peptides synthesized onto a hydrophilic scaffold and analysed by mass spectrometry. The samples captured by the RBD peptide returned statistically significantly matches for cytokeratin 8, 18 and 19 as well as microtubule-actin crosslinking factor 1, which may indicate a novel interaction between SHBG and these proteins, but ultimately failed to detect a membrane receptor potentially responsible for the putative RSHBG-mediated signaling. This PhD project has reported the proteolytic processing of SHBG by two members of the kallikrein family, KLK4 and KLK14. The effect of SHBG proteolysis by KLK4 and KLK14 on RSHBG-mediated signaling activation was unable to be determined as the reported signal transduction pathway was not activated after treatment with SHBG, in combination with either DHT or estradiol. However, the digestion of SHBG by these two proteases positively regulated androgen bioavailability to prostate cancer cells in vitro. The increased uptake of androgens is deleterious in prostate cancer due to the promotion of proliferation, metastasis, invasion and the inhibition of apoptosis. The increased bioavailability of androgens, from SHBG proteolysis by KLK4 and KLK14, may therefore promote both carcinogenesis and progression of prostate cancer. Finally, this information may contribute to the development of therapeutic treatment strategies for prostate cancer by inhibiting the proteolysis of SHBG, by KLK4 and KLK14, to prevent the increased uptake of androgens by hormone-dependent cancerous tissues.

Explaining International new venture internationalisation: an innovation adoption model

The increasing prevalence of International New Ventures (INVs) during the past twenty years has been highlighted by numerous studies (Knight and Cavusgil, 1996, Moen, 2002). International New Ventures are firms, typically small to medium enterprises, that internationalise within six years of inception (Oviatt and McDougall, 1997). To date there has been no general consensus within the literature on a theoretical framework of internationalisation to explain the internationalisation process of INVs (Madsen and Servais, 1997). However, some researchers have suggested that the innovation diffusion model may provide a suitable theoretical framework (Chetty & Hamilton, 1996, Fan & Phan, 2007).The proposed model was based on the existing and well-established innovation diffusion theories drawn from consumer behaviour and internationalisation literature to explain the internationalisation process of INVs (Lim, Sharkey, and Kim, 1991, Reid, 1981, Robertson, 1971, Rogers, 1962, Wickramasekera and Oczkowski, 2006). The results of this analysis indicated that the synthesied model of export adoption was effective in explaining the internationalisation process of INVs within the Queensland Food and Beverage Industry. Significantly the results of the analysis also indicated that features of the original I-models developed in the consumer behaviour literature, that had limited examination within the internationalisation literature were confirmed. This includes the ability of firms, or specifically decision-makers, to skip stages based om previous experience.

From education to work in Australia’s creative digital industries : comparing the opinions and practices of employers and aspiring creatives

This report represents the second of two reports that aim to explore views about the employability of aspiring creatives. The first report, released in June 2009, presented findings from a survey of 507 aspiring creatives, defined as recent graduates and/or people with less than two years industry experience. It presents findings from a project that administered an survey to employers in Australia’s Creative Digital Industries. The survey included questions on employer characteristics, recruitment and training practices, employers’ views of the capabilities of aspiring creatives, and participation in communities of interest/networks, mentoring and internships. The main purpose of the project was to identify capability gaps of aspiring creatives as well as those factors that enhance or inhibit employers’ views of the capabilities of aspiring creatives – both of which impact on the ability of aspiring creatives to find work in their preferred occupations in Australia’s Creative Digital Industries.

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.

Explaining international new venture internationalisation : an innovation adoption mode

The increasing prevalence of International New Ventures (INVs) during the past twenty years has been highlighted by numerous studies (Knight and Cavusgil, 1996, Moen, 2002). International New Ventures are firms, typically small to medium enterprises, that internationalise within six years of inception (Oviatt and McDougall, 1997). To date there has been no general consensus within the literature on a theoretical framework of internationalisation to explain the internationalisation process of INVs (Madsen and Servais, 1997). However, some researchers have suggested that the innovation diffusion model may provide a suitable theoretical framework (Chetty & Hamilton, 1996, Fan & Phan, 2007).The proposed model was based on the existing and well-established innovation diffusion theories drawn from consumer behaviour and internationalisation literature to explain the internationalisation process of INVs (Lim, Sharkey, and Kim, 1991, Reid, 1981, Robertson, 1971, Rogers, 1962, Wickramasekera and Oczkowski, 2006). The results of this analysis indicated that the synthesied model of export adoption was effective in explaining the internationalisation process of INVs within the Queensland Food and Beverage Industry. Significantly the results of the analysis also indicated that features of the original I-models developed in the consumer behaviour literature, that had limited examination within the internationalisation literature were confirmed. This includes the ability of firms, or specifically decision-makers, to skip stages based om previous experience.