A tissue-engineered humanised xenograft model of human breast cancer-induced bone metastasis and bone colonisation

This thesis focuses on the development of a humanised mouse model to investigate human breast cancer metastasis to bone, an incurable disease presenting a major medical challenge in our society. The method is based on tissue-engineered constructs with human cells that generate a human bone-like organ within mice. This novel platform is further applied to mimic human-specific mechanisms of breast cancer metastasis and growth in human bone, and in particular the role of specific cell adhesion molecules in this process is closely investigated.

Flupirtine enhances the anti-hyperalgesic effects of morphine in a rat model of prostate bone metastasis

Objective Current treatments for cancer pain are often inadequate, particularly when metastasis to bone is involved. The addition to the treatment regimen of another drug that has a complementary analgesic effect may increase the overall analgesia without the necessity to increase doses, thus avoiding dose-related side effects. This project investigated the synergistic effect of the addition of the potassium channel (KCNQ2–3) modulator flupirtine to morphine treatment in a rat model of prostate cancer-induced bone pain. Design Syngeneic prostate cancer cells were injected into the right tibia of male Wistar rats under anesthesia. This led to expanding tumor within the bone in 2 weeks, together with the concurrent development of hyperalgesia to noxious heat. Paw withdrawal thresholds from noxious heat were measured before and after the maximum non-sedating doses of morphine and flupirtine given alone and in combinations. Dose-response curves for morphine (0.13–5.0 mg/kg ip) and flupirtine (1.25–10.0 mg/kg ip) given alone and in fixed-dose combinations were plotted and subjected to an isobolographic analysis. Results Both morphine (ED50 = 0.74 mg/kg) and flupirtine (ED50 = 3.32 mg/kg) caused dose-related anti-hyperalgesia at doses that did not cause sedation. Isobolographic analysis revealed that there was a synergistic interaction between flupirtine and morphine. Addition of flupirtine to morphine treatment improved morphine anti-hyperalgesia, and resulted in the reversal of cancer-induced heat hyperalgesia. Conclusions These results suggest that flupirtine in combination with morphine may be useful clinically to provide better analgesia at lower morphine doses in the management of pain caused by tumors growing in bone.

Whole-of-Curriculum Design in Law

In this book teaching professionalism is characterised by the scholarly underpinning of each contribution; and every contribution provides a rich resource for enhancing teaching practice. The critical concerns for legal education have been identified and discussed: curriculum design that includes graduate attributes; embedding specific attributes across the curriculum; empowering students to learn; academic teamwork to manage large student cohorts; first year and final year transition strategies; tracking students' personal development through the use of ePortfolio; assessment strategies; improving student well-being and promoting resilience; teaching practice to achieve deep learning; flexibility in delivery; the use of Web 2.0 technology; and understanding the 21st century student.

Student knowledge of curriculum literacies as they enter high school

This study explores students' perceptions of their learning, particularly their knowledge of writing, in their first year of high school. Conducted in a large regional high school, the researcher worked with two Year 8 teachers in the subjects of English, Science and History to apply Systemic Functional Linguistics in the development of lessons with a specific focus on writing. This Design Based Research project revealed how external and internal factors are impacting on teachers' abilities to improve students' knowledge and understandings of how specific subjects organise and represent information, particularly through writing.

From certificate chasing to genuine engagement : the contribution of curriculum design to students' career intent in a subfield

Many students enter business degrees without a defined career goal beyond working in the business world and adopt a scattergun approach to employability by accumulating certifications accessed through individual subjects. Yet, space and time limitations commonly prevent extended exposure to rewarding and interesting career subfields within main specialisations. This case study draws on student feedback collected over three years exploring students’ career interest following an elective human resource development subject in the final stage of a human resources major. Project-based curriculum provided students with scaffolded learning while undertaking key multiphase human resource development tasks. Subsequently, students reported human resource development career interest and intent, attributed to more realistic appreciation of human resource development’s activities, scope, and values. The paper makes an important contribution illustrating how curriculum design can transform instrumentalism into logically, emotionally, and intuitively based career engagement. Further, human resource development is a study and career area little mentioned in higher education or careers literature.

A smooth transition logit model of the effects of deregulation in the electricity market

This paper introduces the smooth transition logit (STL) model that is designed to detect and model situations in which there is structural change in the behaviour underlying the latent index from which the binary dependent variable is constructed. The maximum likelihood estimators of the parameters of the model are derived along with their asymptotic properties, together with a Lagrange multiplier test of the null hypothesis of linearity in the underlying latent index. The development of the STL model is motivated by the desire to assess the impact of deregulation in the Queensland electricity market and ascertain whether increased competition has resulted in significant changes in the behaviour of the spot price of electricity, specifically with respect to the occurrence of periodic abnormally high prices. The model allows the timing of any change to be endogenously determined and also market participants' behaviour to change gradually over time. The main results provide clear evidence in support of a structural change in the nature of price events, and the endogenously determined timing of the change is consistent with the process of deregulation in Queensland.

A hierarchical model of social marketing

Purpose This paper aims to set out a new hierarchical and differentiated model of social marketing principles, concepts and techniques that builds on, but supersedes, the existing lists of non-equivalent and undifferentiated benchmark criteria. Design/methodology/approach This is a conceptual paper that proposes a hierarchical model of social marketing principles, concepts and techniques. Findings This new delineation of the social marketing principle, its four core concepts and five techniques, represents a new way to conceptualize and recognize the different elements that constitute social marketing. This new model will help add to and further the development of the theoretical basis of social marketing, building on the definitional work led by the International Social Marketing Association (iSMA), Australian Association of Social Marketing (AASM) and European Social Marketing Association (ESMA). Research limitations/implications This proposed model offers a foundation for future research to expand upon. Further research is recommended to empirically test the proposed model. Originality/value This paper seeks to advance the theoretical base of social marketing by making a reasoned case for the need to differentiate between principles, concepts and techniques when seeking to describe social marketing.

Collaborative learning model of infrastructure construction: A capability perspective

Purpose Performance heterogeneity between collaborative infrastructure projects is typically examined by considering procurement systems and their governance mechanisms at static points in time. The literature neglects to consider the impact of dynamic learning capability, which is thought to reconfigure governance mechanisms over time in response to evolving market conditions. This conceptual paper proposes a new model to show how continuous joint learning of participant organisations improves project performance. Design/methodology/approach There are two stages of conceptual development. In the first stage, the management literature is analysed to explain the Standard Model of dynamic learning capability that emphasises three learning phases for organisations. This Standard Model is extended to derive a novel Circular Model of dynamic learning capability that shows a new feedback loop between performance and learning. In the second stage, the construction management literature is consulted, adding project lifecycle, stakeholder diversity and three organisational levels to the analysis, to arrive at the Collaborative Model of dynamic learning capability. Findings The Collaborative Model should enable construction organisations to successfully adapt and perform under changing market conditions. The complexity of learning cycles results in capabilities that are imperfectly imitable between organisations, explaining performance heterogeneity on projects. Originality/value The Collaborative Model provides a theoretically substantiated description of project performance, driven by the evolution of procurement systems and governance mechanisms. The Model’s empirical value will be tested in future research.

Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors

Introduction: Ankylosing spondylitis (AS) is unique in its pathology where inflammation commences at the entheses before progressing to an osteoproliferative phenotype generating excessive bone formation that can result in joint fusion. The underlying mechanisms of this progression are poorly understood. Recent work has suggested that changes in Wnt signalling, a key bone regulatory pathway, may contribute to joint ankylosis in AS. Using the proteoglycan-induced spondylitis (PGISp) mouse model which displays spondylitis and eventual joint fusion following an initial inflammatory stimulus, we have characterised the structural and molecular changes that underlie disease progression. Methods: PGISp mice were characterised 12 weeks after initiation of inflammation using histology, immunohistochemistry (IHC) and expression profiling. Results: Inflammation initiated at the periphery of the intervertebral discs progressing to disc destruction followed by massively excessive cartilage and bone matrix formation, as demonstrated by toluidine blue staining and IHC for collagen type I and osteocalcin, leading to syndesmophyte formation. Expression levels of DKK1 and SOST, Wnt signalling inhibitors highly expressed in joints, were reduced by 49% and 63% respectively in the spine PGISp compared with control mice (P < 0.05) with SOST inhibition confirmed by IHC. Microarray profiling showed genes involved in inflammation and immune-regulation were altered. Further, a number of genes specifically involved in bone regulation including other members of the Wnt pathway were also dysregulated. Conclusions: This study implicates the Wnt pathway as a likely mediator of the mechanism by which inflammation induces bony ankylosis in spondyloarthritis, raising the potential that therapies targeting this pathway may be effective in preventing this process.

Use of the FAR guide to present a pedagogical analogical model of gel electrophoresis in year 10 Science

This paper is a qualitative, practice based study describing the use of the Focus-Action-Reflection (FAR) Guide (Harrison and Treagust, 2000) to address the shortcomings of a pedagogical analogical model in Year 10 Science. The aim of this paper is to present my experience of the FAR Guide in relation to an analogical model that gave rise to perceived shortcomings by both teachers and students. This study found the FAR Guide to be a highly valuable tool, transforming the presentation of the analogical model, and enabling students to develop a deeper understanding of the nature of scientific knowledge.

Advancing practice in critical care: A model of knowledge integration

It could be argued that advancing practice in critical care has been superseded by the advanced practice agenda. Some would suggest that advancing practice is focused on the core attributes of an individuals practice progressing onto advanced practice status. However, advancing practice is more of a process than identifiable skills and as such is often negated when viewing the development of practitioners to the advanced practice level. For example practice development initiatives can be seen as advancing practice for the masses which ensures that practitioners are following the same level of practice. The question here is; are they developing individually.

Advancing practice in critical care : A model of knowledge integration: A Singaporean context

It could be argued that advancing practice in critical care has been superseded by the advanced practice agenda. Some would suggest that advancing practice is focused on the core attributes of an individuals practice progressing onto advanced practice status. However, advancing practice is more of a process than identifiable skills and as such is often negated when viewing the development of practitioners to the advanced practice level. For example practice development initiatives can be seen as advancing practice for the masses which ensures that practitioners are following the same level of practice. The question here is; are they developing individually. To discuss the potential development of a conceptual model of knowledge integration pertinent to critical care nursing practice. In an attempt to explore the development of leading edge critical care thinking and practice, a new model for advancing practice in critical care is proposed. This paper suggests that reflection may not be the best model for advancing practice unless the individual practitioner has a sound knowledge base both theoretically and experientially. Drawing on the contemporary literature and recent doctoral research, the knowledge integration model presented here uses multiple learning strategies that are focused in practise to develop practice, for example the use of work-based learning and clinical supervision. Ongoing knowledge acquisition and its relationship with previously held theory and experience will enable individual practitioners to advance their own practice as well as being a resource for others.

Advancing practice in critical care: A model of knowledge integration

Explore and describe a conceptual model of knowledge integration pertinent to the development of individual practitioners in critical care. Discussion of how multiple learning strategies that are embedded in practice can be beneficial in developing knowledge.

Mathematical model of arterial stenosis

A mathematical model for pulsatile flow in a partially occluded tube is presented. The problem has applications in studying the effects of blood flow characteristics on atherosclerotic development. The model brings out the importance of the pulsatility of blood flow on separation and the stress distribution. The results obtained show fairly good agreement with the available experimental results.

Zebrafish as a model of Parkinson's disease

Parkinson’s disease (PD) is the second most common neurodegenerative disease among the elderly. Its etiology is unknown and no disease-modifying drugs are available. Thus, more information concerning its pathogenesis is needed. Among other genes, mutated PTEN-induced kinase 1 (PINK1) has been linked to early-onset and sporadic PD, but its mode of action is poorly understood. Most animal models of PD are based on the use of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP is metabolized to MPP+ by monoamine oxidase B (MAO B) and causes cell death of dopaminergic neurons in the substantia nigra in mammals. Zebrafish has been a widely used model organism in developmental biology, but is now emerging as a model for human diseases due to its ideal combination of properties. Zebrafish are inexpensive and easy to maintain, develop rapidly, breed in large quantities producing transparent embryos, and are readily manipulated by various methods, particularly genetic ones. In addition, zebrafish are vertebrate animals and results derived from zebrafish may be more applicable to mammals than results from invertebrate genetic models such as Drosophila melanogaster and Caenorhabditis elegans. However, the similarity cannot be taken for granted. The aim of this study was to establish and test a PD model using larval zebrafish. The developing monoaminergic neuronal systems of larval zebrafish were investigated. We identified and classified 17 catecholaminergic and 9 serotonergic neuron populations in the zebrafish brain. A 3-dimensional atlas was created to facilitate future research. Only one gene encoding MAO was found in the zebrafish genome. Zebrafish MAO showed MAO A-type substrate specificity, but non-A-non-B inhibitor specificity. Distribution of MAO in larval and adult zebrafish brains was both diffuse and distinctly cellular. Inhibition of MAO during larval development led to markedly elevated 5-hydroxytryptamine (serotonin, 5-HT) levels, which decreased the locomotion of the fish. MPTP exposure caused a transient loss of cells in specific aminergic cell populations and decreased locomotion. MPTP-induced changes could be rescued by the MAO B inhibitor deprenyl, suggesting a role for MAO in MPTP toxicity. MPP+ affected only one catecholaminergic cell population; thus, the action of MPP+ was more selective than that of MPTP. The zebrafish PINK1 gene was cloned in zebrafish, and morpholino oligonucleotides were used to suppress its expression in larval zebrafish. The functional domains and expression pattern of zebrafish PINK1 resembled those of other vertebrates, suggesting that zebrafish is a feasible model for studying PINK1. Translation inhibition resulted in cell loss of the same catecholaminergic cell populations as MPTP and MPP+. Inactivation of PINK1 sensitized larval zebrafish to subefficacious doses of MPTP, causing a decrease in locomotion and cell loss in one dopaminergic cell population. Zebrafish appears to be a feasible model for studying PD, since its aminergic systems, mode of action of MPTP, and functions of PINK1 resemble those of mammalians. However, the functions of zebrafish MAO differ from the two forms of MAO found in mammals. Future studies using zebrafish PD models should utilize the advantages specific to zebrafish, such as the ability to execute large-scale genetic or drug screens.