In vitro functional characterisation of IGF-I : VN-induced breast cancer progression

Members of the insulin-like growth factor (IGF) family have been shown to play critical roles in normal growth and development, as well as in tumour biology. The IGF system is complex and the biological effects of the IGFs are determined by their diverse interactions between many molecules, including their interactions with extracellular matrix (ECM) proteins. Recent studies have demonstrated that IGFs associate with the ECM protein vitronectin (VN) through IGF-binding proteins (IGFBP) and that this interaction modulates IGF-stimulated biological functions, namely cell migration and cell survival through the cooperative involvement of the type-I IGF receptor (IGF-1R) and VN-binding integrins. Since IGFs play important roles in the transformation and progression of breast cancer and VN has been found to be over-expressed at the leading edge of breast tumours, this project aimed to describe the effects of IGF-I:VN interactions on breast cell function. This was undertaken to dissect the molecular mechanisms underlying IGF-I:VN-induced responses and to design inhibitors to block the effects of such interactions. The studies described herein demonstrate that the increase in migration of MCF-7 breast cancer cells in response to the IGF-I:IGFBP-5:VN complex is accompanied by differential expression of genes known to be involved in migration, invasion and/or survival, including Tissue-factor (TF), Stratifin (SFN), Ephrin-B2, Sharp-2 and PAI-1. This „migration gene signature‟ was confirmed using real-time PCR analysis. Substitution of the native IGF-I within the IGF-I:IGFBP:VN complex with the IGF-I analogue, \[L24]\[A31]-IGF-I, which has a reduced affinity for the IGF-1R, failed to stimulate cell migration and interestingly, also failed to induce the differential gene expression. This supports the involvement of the IGF-1R in mediating these changes in gene expression. Furthermore, lentiviral shRNA-mediated stable knockdown of TF and SFN completely abrogated the increased cell migration induced by IGF-I:IGFBP:VN complexes in MCF-7 cells. Indeed, when these cells were grown in 3D Matrigel™ cultures a decrease in the overall size of the 3D spheroids in response to the IGF-I:IGFBP:VN complexes was observed compared to the parental MCF-7 cells. This suggests that TF and SFN have a role in complex-stimulated cell survival. Moreover, signalling studies performed on cells with the reduced expression of either TF or SFN had a decreased IGF-1R activation, suggesting the involvement of signalling pathways downstream of IGF-1R in TF- and/or SFN-mediated cell migration and cell survival. Taken together, these studies provide evidence for a common mechanism activated downstream of the IGF-1R that induces the expression of the „migration gene signature‟ in response to the IGF-I:IGFBP:VN complex that confers breast cancer cells the propensity to migrate and survive. Given the functional significance of the interdependence of ECM and growth factor (GF) interactions in stimulating processes key to breast cancer progression, this project aimed at developing strategies to prevent such growth factor:ECM interactions in an effort to inhibit the downstream functional effects. This may result in the reduction in the levels of ECM-bound IGF-I present in close proximity to the cells, thereby leading to a reduction in the stimulation of IGF-1R present on the cell surface. Indeed, the inhibition of IGF-I-mediated effects through the disruption of its association with ECM would not alter the physiological levels of IGF-I and potentially only exert effects in situations where abnormal over expression of ECM proteins are found; namely carcinomas and hyperproliferative diseases. In summary, this PhD project has identified novel, innovative and realistic strategies that can be used in vitro to inhibit the functions exerted by the IGF-I:IGFBP:VN multiprotein complexes critical for cancer progression, with a potential to be translated into in vivo investigations. Furthermore, TF and SFN were found to mediate IGF-I:IGFBP:VN-induced effects, thereby revealing their potential to be used as therapeutic targets or as predictive biomarkers for the efficacy of IGF-1R targeting therapies in breast cancer patients. In addition to its therapeutic and clinical scope, this PhD project has significantly contributed to the understanding of the role of the IGF system in breast tumour biology by providing valuable new information on the mechanistic events underpinning IGF-I:VN-mediated effects on breast cell functions. Furthermore, this is the first instance where favourable binding sites for IGF-II, IGFBP-3 and IGFBP-5 on VN have been identified. Taken together, this study has functionally characterised the interactions between IGF-I and VN and through innovative strategies has provided a platform for the development of novel therapies targeting these interactions and their downstream effects.

The role of intensity of interval training on fat oxidation and eating behaviour in overweight/obese men

The increasing prevalence of obesity in society has been associated with a number of atherogenic risk factors such as insulin resistance. Aerobic training is often recommended as a strategy to induce weight loss, with a greater impact of high-intensity levels on cardiovascular function and insulin sensitivity, and a greater impact of moderate-intensity levels on fat oxidation. Anaerobic high-intensity (supramaximal) interval training has been advocated to improve cardiovascular function, insulin sensitivity and fat oxidation. However, obese individuals tend to have a lower tolerance of high-intensity exercise due to discomfort. Furthermore, some obese individuals may compensate for the increased energy expenditure by eating more and/or becoming less active. Recently, both moderate- and high-intensity aerobic interval training have been advocated as alternative approaches. However, it is still uncertain as to which approach is more effective in terms of increasing fat oxidation given the issues with levels of fitness and motivation, and compensatory behaviours. Accordingly, the objectives of this thesis were to compare the influence of moderate- and high-intensity interval training on fat oxidation and eating behaviour in overweight/obese men. Two exercise interventions were undertaken by 10-12 overweight/obese men to compare their responses to study variables, including fat oxidation and eating behaviour during moderate- and high-intensity interval training (MIIT and HIIT). The acute training intervention was a methodological study designed to examine the validity of using exercise intensity from the graded exercise test (GXT) - which measured the intensity that elicits maximal fat oxidation (FATmax) - to prescribe interval training during 30-min MIIT. The 30-min MIIT session involved 5-min repetitions of workloads 20% below and 20% above the FATmax. The acute intervention was extended to involve HIIT in a cross-over design to compare the influence of MIIT and HIIT on eating behaviour using subjective appetite sensation and food preference through the liking and wanting test. The HIIT consisted of 15-sec interval training at 85 %VO2peak interspersed by 15-sec unloaded recovery, with a total mechanical work equal to MIIT. The medium term training intervention was a cross-over 4-week (12 sessions) MIIT and HIIT exercise training with a 6-week detraining washout period. The MIIT sessions consisted of 5-min cycling stages at ±20% of mechanical work at 45 %VO2peak, and the HIIT sessions consisted of repetitive 30-sec work at 90 %VO2peak and 30-sec interval rests, during identical exercise sessions of between 30 and 45 mins. Assessments included a constant-load test (45 %VO2peak for 45 mins) followed by 60-min recovery at baseline and the end of 4-week training, to determine fat oxidation rate. Participants’ responses to exercise were measured using blood lactate (BLa), heart rate (HR) and rating of perceived exertion (RPE) and were measured during the constant-load test and in the first intervention training session of every week during training. Eating behaviour responses were assessed by measuring subjective appetite sensations, liking and wanting and ad libitum energy intake. Results of the acute intervention showed that FATmax is a valid method to estimate VO2 and BLa, but is not valid to estimate HR and RPE in the MIIT session. While the average rate of fat oxidation during 30-min MIIT was comparable with the rate of fat oxidation at FATmax (0.16 ±0.09 and 0.14 ±0.08 g/min, respectively), fat oxidation was significantly higher at minute 25 of MIIT (P≤0.01). In addition, there was no significant difference between MIIT and HIIT in the rate of appetite sensations after exercise, but there was a tendency towards a lower rate of hunger after HIIT. Different intensities of interval exercise also did not affect explicit liking or implicit wanting. Results of the medium-term intervention indicated that current interval training levels did not affect body composition, fasting insulin and fasting glucose. Maximal aerobic capacity significantly increased (P≤0.01) (2.8 and 7.0% after MIIT and HIIT respectively) during GXT, and fat oxidation significantly increased (P≤0.01) (96 and 43% after MIIT and HIIT respectively) during the acute constant-load exercise test. RPE significantly decreased after HIIT greater than MIIT (P≤0.05), and the decrease in BLa was greater during the constant-load test after HIIT than MIIT, but this difference did not reach statistical significance (P=0.09). In addition, following constant-load exercise, exercise-induced hunger and desire to eat decreased after HIIT greater than MIIT but were not significant (p value for desire to eat was 0.07). Exercise-induced liking of high-fat sweet (HFSW) and high-fat non-sweet (HFNS) foods increased after MIIT and decreased after HIIT (p value for HFNS was 0.09). The intervention explained 12.4% of the change in fat intake (p = 0.07). This research is significant in that it confirmed two points in the acute study. While the rate of fat oxidation increased during MIIT, the average rate of fat oxidation during 30-min MIIT was comparable with the rate of fat oxidation at FATmax. In addition, manipulating the intensity of acute interval exercise did not affect appetite sensations and liking and wanting. In the medium-term intervention, constant-load exercise-induced fat oxidation significantly increased after interval training, independent of exercise intensity. In addition, desire to eat, explicit liking for HFNS and fat intake collectively confirmed that MIIT is accompanied by a greater compensation of eating behaviour than HIIT. Findings from this research will assist in developing exercise strategies to provide obese men with various training options. In addition, the finding that overweight/obese men expressed a lower RPE and decreased BLa after HIIT compared with MIIT is contrary to the view that obese individuals may not tolerate high-intensity interval training. Therefore, high-intensity interval training can be advocated among the obese adult male population. Future studies may extend this work by using a longer-term intervention.

Developing research skills for civil engineers: A library contribution

A course-integrated programme of library instruction has been developed for the School of Civil Engineering at the Queensland University of Technology, Australia; library instruction being one of the means selected to improve the research efforts of fourth year project students. The programme has been developed through consultation between the Civil Engineering Research Project Coordinator and the Civil Engineering Reference Librarian. Its aims are derived from those established for the fourth year research projects. Attention is focussed on the nature of the programme and the impact of instruction on fourth year research project students. Students who had received extended library instruction were compared with students from the previous year. Evidence suggests that the instruction has improved the information seeking behaviour of the students and their literature reviews.

The rise of government in Early Childhood Education and Care following the Child Care Act 1972 : the lasting legacy of the 1990s in setting the reform agenda for ECEC in Australia

Less than twenty years on from the proclamation of the Child Care Act 1972, and introduction of funding for not-for-profit child care centres, a series of market-driven public policies paved the way for the emergence of Australia’s current ECEC quasi-market. Seeking to respond to increasing demand for work-related child care in the 1990s, and to manage associated costs, a succession of Australian Governments turned to market theory and New Public Management (NPM) principles to inform ECEC policy. Reflecting on an era of high policy activity within ECEC, this paper examines a series of policy events and texts that set the course for the reform agenda that was to ensue in ECEC.

Consumer engagement with eHealth information through smartphones and tablets : an Australian perspective

This paper is a work in progress that examines current consumer engagement with eHealth information through Smartphones or tablets. We focus on three activity types: seeking, posting and ‘other’ engagement activity and compare two age groups, 25-40s and over 40-55s. Findings show that around 30% of the younger age group is engaging with Government and other Health providers’ websites, receiving eHealth emails, and reading other people’s comments about health related issues in online discussion groups/websites/blog. Approximately 20% engage with Government and other Health providers’ social media and watch or listen to audio or video podcasts. For the older age group, their most active engagement with eHealth information is in the seeking category through Government or other health websites (approximately 15%), and less than 10% for social media sites. Their posting activity is less than 5%. Other activities show that less than 15% of the older age group engages through receiving emails and reading blogs, less than 10% watch or listen to podcasts, and their online consulting activity is less than 7%. We note that scores are low for both groups in terms of engaging with eHealth information through Twitter.

Determinants of drink-driving and association between drink-driving and road traffic fatalities in Ghana

Aim The objective is to establish determinants of drink-driving and its association with traffic crashes in Ghana. Methods A multivariable logistic regression was used to establish significant determinants of drink-driving and a bivariate logistic regression to establish the association between drink–driving and road traffic crashes in Ghana. Results In total, 2,736 motorists were randomly stopped for breath testing of whom 8.7% tested positive for alcohol. Among the total participants, 5.5% exceeded the legal BAC limit of 0.08%. Formal education is associated with a reduced likelihood of drink-driving compared with drivers without formal education. The propensity to drink-drive is 1.8 times higher among illiterate drivers compared with drivers with basic education. Young adult drivers also recorded elevated likelihoods for driving under alcohol impairment compared with adult drivers. The odds of drink-driving among truck drivers is OR=1.81, (95% CI=1.16 to 2.82) and two wheeler riders is OR=1.41, (95% CI=0.47 to 4.28) compared with car drivers. Contrary to general perception, commercial car drivers have a significant reduced likelihood of 41%, OR=0.59, (95% CI=0.38 to 0.92) compared with the private car driver. Bivariate analysis conducted showed a significant association between the proportion of drivers exceeding the legal BAC limit and road traffic fatalities, p<0.001. The model predicts a 1% increase in the proportion of drivers exceeding the legal BAC to be associated with a 4% increase in road traffic fatalities, 95% CI= 3% to 5% and vice versa. Conclusion A positive and significant association between roadside alcohol prevalence and road traffic fatality has been established. Scaling up roadside breath test, determining standard drink and disseminating to the populace and formulating policies targeting the youth such as increasing minimum legal drinking age and reduced legal BAC limit for the youth and novice drivers might improve drink-driving related crashes in Ghana.

Knowledge based urban development lessons from a non-western country : the Malaysia experience

Knowledge based urban development (KBUD) is seen as a new paradigm in urban planning and development which is now being implemented across the globe in order to increase the competitiveness of cities and regions. The KBUD concept has been widely applied in western and more developed countries over the last decade, and many have been proven successful. This paper, however, aims to provide an overview of the KBUD exercise in a context of a non western country scenario—Malaysia. Literature suggests that the urban development process in non western countries is different and very much focusing on physical elements. Whether this is the case or otherwise, this paper scrutinises the project of Multimedia Super Corridor (MSC), Malaysia, which is regarded as one of the first large scale manifestations of KBUD exercise in South East Asia. Based on development policies analysis and results of the interviews with the major stakeholders, this paper investigates the application of KBUD concept within the Malaysian context by examining the development and evolution of the city of Cyberjaya—the leading intelligent city of the MSC project. In the light of the literature and case findings, the paper provides recommendations and lessons learned, on the orchestration of KBUD, for other non western cities and regions that are working hard to develop KBUD strategies, strengthening their sustainable socio-spatial policies and seeking a global recognition.

Trauma and survival in African humanitarian entrants to Australia

Former refugees have been resettled in Australia since the 1940’s through the Humanitarian Migration Stream. This chapter highlights the impact of forced migration and the refugee experience of trauma on survival. The journey from pre-migration crises, to the process of fleeing one’s country, through to the challenges associated with resettlement, can have a significant impact on the mental health of Humanitarian Entrants to Australia. Differences in culture can have an impact on the meaning constructed from these experiences, and on help-seeking behaviour and preferred methods of intervention. To date, Western mental health services have used an understanding of trauma based on pathology and largely individualist intervention techniques. In this chapter, however, we seek to understand the experience of trauma for former refugees from a salutogenic perspective, and acknowledge community based coping methods and the strengths and resilience of former refugees. Using the construct of posttraumatic growth, adaptive factors of strength, religion, compassion, and new possibilities are identified as relevant to African Humanitarian Entrants in Australia.

Creative entrepreneurship education for graduate employability in the creative arts

The higher education sector in Australia is under increasing pressure to prove quality and efficacy of education provision, including graduate outcomes. One of the central tasks of higher education has become to prepare nascent professionals as far as possible for initial employment and future working lives beyond this (Boden & Nedeva, 2010). Tertiary educators in the creative arts face significant and distinctive challenges in demonstrating graduate employability, and creative graduates consistently have the poorest outcomes of any subject grouping. In part, this is because the national graduate destinations survey (Graduate Careers Council of Australia, 2012) does not cater to the distinctive ‘portfolio’ nature of creative careers, or take account of the fact that creative careers can take concerted effort over several years to establish (e.g., McCowan & Wyganowska, 2010). However, it is worth asking whether we as tertiary arts educators are doing enough to prepare creative arts students for the world of work, particularly given that the majority of them will be self-employed to some degree (Bureau of Labour Statistics, 2011, Throsby & Zednik, 2010), and will be challenged to build their own careers without recourse to the support of HR departments or intra-firm promotion schemes. It has been demonstrated empirically that career management and creative enterprise skills are among the most important graduate capabilities in determining early creative career success (Bridgstock, 2011), although these skills do not appear in the Learning and Teaching Academic Standards for the Creative and Performing Arts (2010). This paper explores the nature and development of enterprise capabilities for creative arts students (as distinct from students of the business school), examines best practice in the field internationally, and proposes a theoretically-driven creative arts-specific enterprise curriculum model which commences in first year, for demonstrable impact on student enterprise behaviours (such as grant seeking, professional networking and intention to start an enterprise) and employability.

Retrieval of health advice on the web: AEHRC at ShARe/CLEF eHealth Evaluation Lab Task 3

This paper details the participation of the Australian e- Health Research Centre (AEHRC) in the ShARe/CLEF 2013 eHealth Evaluation Lab { Task 3. This task aims to evaluate the use of information retrieval (IR) systems to aid consumers (e.g. patients and their relatives) in seeking health advice on the Web. Our submissions to the ShARe/CLEF challenge are based on language models generated from the web corpus provided by the organisers. Our baseline system is a standard Dirichlet smoothed language model. We enhance the baseline by identifying and correcting spelling mistakes in queries, as well as expanding acronyms using AEHRC's Medtex medical text analysis platform. We then consider the readability and the authoritativeness of web pages to further enhance the quality of the document ranking. Measures of readability are integrated in the language models used for retrieval via prior probabilities. Prior probabilities are also used to encode authoritativeness information derived from a list of top-100 consumer health websites. Empirical results show that correcting spelling mistakes and expanding acronyms found in queries signi cantly improves the e ectiveness of the language model baseline. Readability priors seem to increase retrieval e ectiveness for graded relevance at early ranks (nDCG@5, but not precision), but no improvements are found at later ranks and when considering binary relevance. The authoritativeness prior does not appear to provide retrieval gains over the baseline: this is likely to be because of the small overlap between websites in the corpus and those in the top-100 consumer-health websites we acquired.

Assessing testamentary and decision-making competence/capacity in the Australian context

Australia lacks a satisfactory, national paradigm for assessing competence and capacity in the context of testamentary, enduring power of attorney and advance care directive documents. Competence/capacity assessments are currently conducted on an ad hoc basis by legal and/or medical professionals. The reliability of the assessment process is subject to the skill set and mutual understanding of the legal and/or medical professional conducting the assessment. There is a growth in the prevalence of diseases such as dementia. Such diseases impact upon cognition which increasingly necessitates collaboration between the legal and medical professions when assessing the effect of mentally disabling conditions upon competency/capacity. Miscommunication and lack of understanding between legal and medical professionals involved could impede the development of a satisfactory paradigm. A qualitative study seeking the views of legal and medical professionals who practise in this area has been conducted. This incorporated surveys and interviews of 10 legal and 20 medical practitioners. Some of the results are discussed here. Practitioners were asked whether there is a standard approach and whether national guidelines were desirable. There was general agreement that uniform guidelines for the assessment of competence/capacity would be desirable. The interviews also canvassed views as to the state of the relationship between the professions. The results of the empirical research support the hypothesis that relations between the professions could be improved. The development of a national paradigm would promote consistency and transparency of process, helping to improve the professional relationship and maximising the principles of autonomy, participation and dignity.

Capturing gazelles : features of high potential firms and new venture growth

This paper investigates the characteristics of ventures which have the potential to reach high growth and compares this with ‘everyday’ new ventures. Findings of interest in this paper include: • HP firms are characterised by higher human capital, are more likely to have a team of founders, are more likely to be product based. • HP firms are more likely to achieve more extreme levels of growth (both positive and negative). • HP ventures that make a loss are more likely to do so early in the venture process. Those that do hold on show that there can higher levels of loss made later on in firm development. HP firms have higher resource needs, in terms of seeking external finance, but are no more likely to receive external finance than regular firms.

A framework for cost-aware process management : cost reporting and cost prediction

Organisations are constantly seeking efficiency gains for their business processes in terms of time and cost. Management accounting enables detailed cost reporting of business operations for decision making purposes, although significant effort is required to gather accurate operational data. Process mining, on the other hand, may provide valuable insight into processes through analysis of events recorded in logs by IT systems, but its primary focus is not on cost implications. In this paper, a framework is proposed which aims to exploit the strengths of both fields in order to better support management decisions on cost control. This is achieved by automatically merging cost data with historical data from event logs for the purposes of monitoring, predicting, and reporting process-related costs. The on-demand generation of accurate, relevant and timely cost reports, in a style akin to reports in the area of management accounting, will also be illustrated. This is achieved through extending the open-source process mining framework ProM.

“Would you; could you; on a boat?” Wait-time and travel-time activities during river ferry journeys and their relationship to overall satisfaction in Brisbane Queensland

This study investigates travel behaviour and wait-time activities as a component of passenger satisfaction with public transport in Brisbane, Australia. Australian transport planners recognise a variety of benefits to encouraging a mode shift away from automobile travel in favour of active and public transport use. Efforts to increase public transport ridership have included introducing state of the art passenger information systems, improving physical station access, and integrating system pricing, routes and scheduling for train, bus and ferry. Previous research regarding satisfaction with public transport emphasizes technical dimensions of service quality, including the timing and reliability of service. Those factors might be especially significant for frequent (commuting) travellers who look to balance the cost and efficiency of their travel options. In contrast, infrequent (leisure) passengers may be more concerned with way finding and the sensory experience of the journey. Perhaps due to the small relative proportion of trips made by river ferry compared to bus and rail, this mode of public transport has not received as much attention in travel-behaviour research. This case study of Brisbane’s river ferry system examines ferry passengers at selected terminals during peak and off-peak travel times to find out how travel behaviours and activities correlate to satisfaction with ferry travel. Data include 416 questionnaires completed by passengers intercepted during wait times at seven CityCat terminals in Brisbane. Descriptive statistical analysis revealed associations between specific wait time activities and satisfaction levels that could inform planners seeking to increase ridership and quality of life through ferry-oriented development.

Soundage : a practice-led approach to Gertrude Stein, sound, and generative language

In this practice-led research project I work to show how a re-reading and a particular form of listening to the sound-riddled nature of Gertrude Stein's work, Two: Gertrude Stein and her Brother, presents us with a contemporary theory of sound in language. This theory, though in its infancy, is a particular enjambment of sounded language that presents itself as an event, engaged with meaning, with its own inherent voice. It displays a propensity through engagement with the 'other' to erupt into love. In this thesis these qualities are reverberated further through the work of Seth Kim-Cohen's notion of the non-cochlear, Simon Jarvis's notion of musical thinking, Jean-Jacques Lecercle's notion of délire or nonsense, Luce Irigaray's notion of jouissant love and the Bracha Ettinger's notion of the generative matrixial border space. This reading then is simultaneously paired with my own work of scoring and creating a digital opera from Stein's work, thereby testing and performing Stein's theory. In this I show how a re-reading and relistening to Stein's work can be significant to feminist ethical language frames, contemporary philosophy, sonic art theory and digital language frames. Further significance of this study is that when the reverberation of Stein's engagements with language through sound can be listened to, a pattern emerges, one that encouragingly problematizes subjectivity and interweaves genres/methods and means, creating a new frame for sound in language, one with its own voice that I call soundage.