Humanised xenograft models of bone metastasis revisited : novel insights into species-specific mechanisms of cancer cell osteotropism

The determinants and key mechanisms of cancer cell osteotropism have not been identified, mainly due to the lack of reproducible animal models representing the biological, genetic and clinical features seen in humans. An ideal model should be capable of recapitulating as many steps of the metastatic cascade as possible, thus facilitating the development of prognostic markers and novel therapeutic strategies. Most animal models of bone metastasis still have to be derived experimentally as most syngeneic and transgeneic approaches do not provide a robust skeletal phenotype and do not recapitulate the biological processes seen in humans. The xenotransplantation of human cancer cells or tumour tissue into immunocompromised murine hosts provides the possibility to simulate early and late stages of the human disease. Human bone or tissue-engineered human bone constructs can be implanted into the animal to recapitulate more subtle, species-specific aspects of the mutual interaction between human cancer cells and the human bone microenvironment. Moreover, the replication of the entire "organ" bone makes it possible to analyse the interaction between cancer cells and the haematopoietic niche and to confer at least a partial human immunity to the murine host. This process of humanisation is facilitated by novel immunocompromised mouse strains that allow a high engraftment rate of human cells or tissue. These humanised xenograft models provide an important research tool to study human biological processes of bone metastasis.

Point of no return : exploring katabatic narrative and deterritorialisation in the Australian outback novel

This thesis consists of the novel Brolga and an exegesis examining in what ways the ideas of katabasis and deterritorialisation inform an understanding of descent narratives in contemporary Australian outback fiction. When writing the creative piece, it was observed that Joseph Campbell’s Hero’s Journey was an imprecise model for my manuscript and indeed for many of the contemporary novels I had read written in similar outback settings. On analysis a better fit lies in the idea of a heroic journey from which there is no clear return from the underworld. This narrative form is defined in this thesis as a katabatic narrative. To unpack this narrative trope, the inverse of territoriality, deterritorialisation, is used as a lens to examine the complex thematic and symbolic resonances of the outback in both Brolga and analogous works of contemporary outback fiction.

A distance too far away : a novel and exegesis

This practice-led research examines the generative function of loss in fiction that explores themes of grief and longing. This research considers how loss may be understood as a structuring mechanism through which characters evaluate time, resolve loss and affect future change. The creative work is a work of literary fiction titled A Distance Too Far Away. Aubrey, the story’s protagonist, is a woman in her twenties living in Brisbane in the early 1980s, carving out an independent life for herself away from her family. Through a flashback narrative sequence, told from the perspective of the twelve year narrator, Aubrey retraces a significant point of rupture in her life following a series of family tragedies. A Distance Too Far Away explores the tension between belonging and freedom, and considers how the past provides a malleable space for illuminating desire in order to traverse the gap between the world as it is and the world as we want it to be. The exegetical component of this research considers an alternative critical frame for interpreting the work of American author Anne Tyler, a writer who has had a significant influence on my own practice. Frequently criticised for creating sentimental and inert characters, many critics observe that nothing happens in Tyler’s circular plots. This research challenges these assertions, and through a contextual analysis of Tyler’s Ladder of Years (1995) investigates how Tyler engages with memory and nostalgia in order to move across time and resolve loss.

Atomic hydrogen diffusion in novel magnesium nanostructures : the impact of incorporated subsurface carbon atoms

Ab initio Density Functional Theory (DFT) calculations are performed to study the diffusion of atomic hydrogen on a Mg(0001) surface and their migration into the subsurface layers. A carbon atom located initially on a Mg(0001) surface can migrate into the sub-surface layer and occupy a fcc site, with charge transfer to the C atom from neighboring Mg atoms. The cluster of postively charged Mg atoms surrounding a sub-surface C is then shown to facilitate the dissociative chemisorption of molecular hydrogen on the Mg(0001) surface, and the surface migration and subsequent diffusion into the subsurface of atomic hydrogen. This helps rationalize the experimentally-observed improvement in absorption kinetics of H2 when graphite or single walled carbon nanotubes (SWCNT) are introduced into the Mg powder during ball milling.

Enhanced skin self-examination : a novel approach to skin cancer monitoring and follow-up

Advances in mobile telephone technology and available dermoscopic attachments for mobile telephones have created a unique opportunity for consumer-initiated mobile teledermoscopy. At least 2 companies market a dermoscope attachment for an iPhone (Apple), forming a mobile teledermoscope. These devices and the corresponding software applications (apps) enable (1) lesion magnification (at least ×20) and visualization with polarized light; (2) photographic documentation using the telephone camera; (3) lesion measurement (ruler); (4) adding of image and lesion details; and (5) e-mail data to a teledermatologist for review. For lesion assessment, the asymmetry-color (AC) rule has 94% sensitivity and 62 specificity for melanoma identification by consumers [1]. Thus, consumers can be educated to recognize asymmetry and color patterns in suspect lesions. However, we know little about consumers' use of mobile teledermoscopy for lesion assessment.

Business model experimentation : what is the role of deign-led prototyping in developing novel business models?

This book presents readers with the opportunity to fundamentally re-evaluate the processes of innovation and entrepreneurship, and to rethink how they might best be stimulated and fostered within our organizations and communities. The fundamental thesis of the book is that the entrepreneurial process is not a linear progression from novel idea to successful innovation, but is an iterative series of experiments, where progress depends on the persistence and resilience of the individuals involved, and their ability and to learn from failure as well as success. From this premise, the authors argue that the ideal environment for new venture creation is a form of “experimental laboratory,” a community of innovators where ideas are generated, shared, and refined; experiments are encouraged; and which in itself serves as a test environment for those ideas and experiments. This environment is quite different from the traditional “incubator,” which may impose the disciplines of the established firm too early in the development of the new venture.

Novel channel tracking and equalization methods in MU-MIMO-OFDM systems

The methodology undertaken, the channel model and the system model created for developing a novel adaptive equalization method and a novel channel tracking method for uplink of MU-MIMO-OFDM systems is presented in this paper. The results show that the channel tracking method works with 97% accuracy, while the training-based initial channel estimation method shows poor performance in estimating the actual channel comparatively.

A novel device using the Nordic hamstring exercise to assess eccentric knee flexors strength : a reliability and retrospective injury study

STUDY DESIGN: Reliability and case-control injury study. OBJECTIVES: 1) To determine if a novel device, designed to measure eccentric knee flexors strength via the Nordic hamstring exercise (NHE), displays acceptable test-retest reliability; 2) to determine normative values for eccentric knee flexors strength derived from the device in individuals without a history of hamstring strain injury (HSI) and; 3) to determine if the device could detect weakness in elite athletes with a previous history of unilateral HSI. BACKGROUND: HSIs and reinjuries are the most common cause of lost playing time in a number of sports. Eccentric knee flexors weakness is a major modifiable risk factor for future HSIs, however there is a lack of easily accessible equipment to assess this strength quality. METHODS: Thirty recreationally active males without a history of HSI completed NHEs on the device on 2 separate occasions. Intraclass correlation coefficients (ICCs), typical error (TE), typical error as a co-efficient of variation (%TE), and minimum detectable change at a 95% confidence interval (MDC95) were calculated. Normative strength data were determined using the most reliable measurement. An additional 20 elite athletes with a unilateral history of HSI within the previous 12 months performed NHEs on the device to determine if residual eccentric muscle weakness existed in the previously injured limb. RESULTS: The device displayed high to moderate reliability (ICC = 0.83 to 0.90; TE = 21.7 N to 27.5 N; %TE = 5.8 to 8.5; MDC95 = 76.2 to 60.1 N). Mean±SD normative eccentric flexors strength, based on the uninjured group, was 344.7 ± 61.1 N for the left and 361.2 ± 65.1 N for the right side. The previously injured limbs were 15% weaker than the contralateral uninjured limbs (mean difference = 50.3 N; 95% CI = 25.7 to 74.9N; P < .01), 15% weaker than the normative left limb data (mean difference = 50.0 N; 95% CI = 1.4 to 98.5 N; P = .04) and 18% weaker than the normative right limb data (mean difference = 66.5 N; 95% CI = 18.0 to 115.1 N; P < .01). CONCLUSIONS: The experimental device offers a reliable method to determine eccentric knee flexors strength and strength asymmetry and revealed residual weakness in previously injured elite athletes.

A micro-level indexing model for the assessment of sustainable urban ecosystems

During the last several decades, the quality of natural resources and their services have been exposed to significant degradation from increased urban populations combined with the sprawl of settlements, development of transportation networks and industrial activities (Dorsey, 2003; Pauleit et al., 2005). As a result of this environmental degradation, a sustainable framework for urban development is required to provide the resilience of natural resources and ecosystems. Sustainable urban development refers to the management of cities with adequate infrastructure to support the needs of its population for the present and future generations as well as maintain the sustainability of its ecosystems (UNEP/IETC, 2002; Yigitcanlar, 2010). One of the important strategic approaches for planning sustainable cities is „ecological planning‟. Ecological planning is a multi-dimensional concept that aims to preserve biodiversity richness and ecosystem productivity through the sustainable management of natural resources (Barnes et al., 2005). As stated by Baldwin (1985, p.4), ecological planning is the initiation and operation of activities to direct and control the acquisition, transformation, disruption and disposal of resources in a manner capable of sustaining human activities with a minimum disruption of ecosystem processes. Therefore, ecological planning is a powerful method for creating sustainable urban ecosystems. In order to explore the city as an ecosystem and investigate the interaction between the urban ecosystem and human activities, a holistic urban ecosystem sustainability assessment approach is required. Urban ecosystem sustainability assessment serves as a tool that helps policy and decision-makers in improving their actions towards sustainable urban development. There are several methods used in urban ecosystem sustainability assessment among which sustainability indicators and composite indices are the most commonly used tools for assessing the progress towards sustainable land use and urban management. Currently, a variety of composite indices are available to measure the sustainability at the local, national and international levels. However, the main conclusion drawn from the literature review is that they are too broad to be applied to assess local and micro level sustainability and no benchmark value for most of the indicators exists due to limited data availability and non-comparable data across countries. Mayer (2008, p. 280) advocates that by stating "as different as the indices may seem, many of them incorporate the same underlying data because of the small number of available sustainability datasets". Mori and Christodoulou (2011) also argue that this relative evaluation and comparison brings along biased assessments, as data only exists for some entities, which also means excluding many nations from evaluation and comparison. Thus, there is a need for developing an accurate and comprehensive micro-level urban ecosystem sustainability assessment method. In order to develop such a model, it is practical to adopt an approach that uses a method to utilise indicators for collecting data, designate certain threshold values or ranges, perform a comparative sustainability assessment via indices at the micro-level, and aggregate these assessment findings to the local level. Hereby, through this approach and model, it is possible to produce sufficient and reliable data to enable comparison at the local level, and provide useful results to inform the local planning, conservation and development decision-making process to secure sustainable ecosystems and urban futures. To advance research in this area, this study investigated the environmental impacts of an existing urban context by using a composite index with an aim to identify the interaction between urban ecosystems and human activities in the context of environmental sustainability. In this respect, this study developed a new comprehensive urban ecosystem sustainability assessment tool entitled the „Micro-level Urban-ecosystem Sustainability IndeX‟ (MUSIX). The MUSIX model is an indicator-based indexing model that investigates the factors affecting urban sustainability in a local context. The model outputs provide local and micro-level sustainability reporting guidance to help policy-making concerning environmental issues. A multi-method research approach, which is based on both quantitative analysis and qualitative analysis, was employed in the construction of the MUSIX model. First, a qualitative research was conducted through an interpretive and critical literature review in developing a theoretical framework and indicator selection. Afterwards, a quantitative research was conducted through statistical and spatial analyses in data collection, processing and model application. The MUSIX model was tested in four pilot study sites selected from the Gold Coast City, Queensland, Australia. The model results detected the sustainability performance of current urban settings referring to six main issues of urban development: (1) hydrology, (2) ecology, (3) pollution, (4) location, (5) design, and; (6) efficiency. For each category, a set of core indicators was assigned which are intended to: (1) benchmark the current situation, strengths and weaknesses, (2) evaluate the efficiency of implemented plans, and; (3) measure the progress towards sustainable development. While the indicator set of the model provided specific information about the environmental impacts in the area at the parcel scale, the composite index score provided general information about the sustainability of the area at the neighbourhood scale. Finally, in light of the model findings, integrated ecological planning strategies were developed to guide the preparation and assessment of development and local area plans in conjunction with the Gold Coast Planning Scheme, which establishes regulatory provisions to achieve ecological sustainability through the formulation of place codes, development codes, constraint codes and other assessment criteria that provide guidance for best practice development solutions. These relevant strategies can be summarised as follows: • Establishing hydrological conservation through sustainable stormwater management in order to preserve the Earth’s water cycle and aquatic ecosystems; • Providing ecological conservation through sustainable ecosystem management in order to protect biological diversity and maintain the integrity of natural ecosystems; • Improving environmental quality through developing pollution prevention regulations and policies in order to promote high quality water resources, clean air and enhanced ecosystem health; • Creating sustainable mobility and accessibility through designing better local services and walkable neighbourhoods in order to promote safe environments and healthy communities; • Sustainable design of urban environment through climate responsive design in order to increase the efficient use of solar energy to provide thermal comfort, and; • Use of renewable resources through creating efficient communities in order to provide long-term management of natural resources for the sustainability of future generations.

Contemporary Australian masculinities and De Certeau’s concept of la perruqe in Christos Tsiolkas’ novel The Slap (2008)

This paper will focus on how Christos Tsiolkas the author of The Slap (2008) invites us to view the complex range of private lives of his male characters living in suburban Melbourne through their daily routines, conversations and innermost thoughts. On the surface most appear to be participating in and achieving a certain level of success in their lives. However, this novel reveals when we agitate and dig below the “practices of everyday life” there is often a disquiet simmering away under the facade of family harmony, male bravado and contentment. This paper will argue that as a result of dissatisfaction with the established order of their lives, each man has managed to create another level of meaning for himself, his own form of la perruque (De Certeau 2011: 29),the concept of living proposed by Michel De Certeau. A treatment of the characters in this article draws on, and is used to illustrate the paradigm.

A genome-wide analysis of 'Bounty' descendants implicates several novel variants in migraine susceptibility

Migraine is a common neurological disease with a complex genetic aetiology. The disease affects ~12% of the Caucasian population and females are three times more likely than males to be diagnosed. In an effort to identify loci involved in migraine susceptibility, we performed a pedigree-based genome-wide association study of the isolated population of Norfolk Island, which has a high prevalence of migraine. This unique population originates from a small number of British and Polynesian founders who are descendents of the Bounty mutiny and forms a very large multigenerational pedigree (Bellis et al.; Human Genetics, 124(5):543-5542, 2008). These population genetic features may facilitate disease gene mapping strategies (Peltonen et al.; Nat Rev Genet, 1(3):182-90, 2000. In this study, we identified a high heritability of migraine in the Norfolk Island population (h (2) = 0.53, P = 0.016). We performed a pedigree-based GWAS and utilised a statistical and pathological prioritisation approach to implicate a number of variants in migraine. An SNP located in the zinc finger protein 555 (ZNF555) gene (rs4807347) showed evidence of statistical association in our Norfolk Island pedigree (P = 9.6 × 10(-6)) as well as replication in a large independent and unrelated cohort with >500 migraineurs. In addition, we utilised a biological prioritisation to implicate four SNPs, in within the ADARB2 gene, two SNPs within the GRM7 gene and a single SNP in close proximity to a HTR7 gene. Association of SNPs within these neurotransmitter-related genes suggests a disrupted serotoninergic system that is perhaps specific to the Norfolk Island pedigree, but that might provide clues to understanding migraine more generally.

A novel multiplex PCR-RFLP method for simultaneous detection of the MTHFR 677 C > T, eNOS +894 G > T and - eNOS -786 T > C variants among Malaysian Malays

Background Hyperhomocysteinemia as a consequence of the MTHFR 677 C > T variant is associated with cardiovascular disease and stroke. Another factor that can potentially contribute to these disorders is a depleted nitric oxide level, which can be due to the presence of eNOS +894 G > T and eNOS −786 T > C variants that make an individual more susceptible to endothelial dysfunction. A number of genotyping methods have been developed to investigate these variants. However, simultaneous detection methods using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis are still lacking. In this study, a novel multiplex PCR-RFLP method for the simultaneous detection of MTHFR 677 C > T and eNOS +894 G > T and eNOS −786 T > C variants was developed. A total of 114 healthy Malay subjects were recruited. The MTHFR 677 C > T and eNOS +894 G > T and eNOS −786 T > C variants were genotyped using the novel multiplex PCR-RFLP and confirmed by DNA sequencing as well as snpBLAST. Allele frequencies of MTHFR 677 C > T and eNOS +894 G > T and eNOS −786 T > C were calculated using the Hardy Weinberg equation. Methods The 114 healthy volunteers were recruited for this study, and their DNA was extracted. Primer pair was designed using Primer 3 Software version 0.4.0 and validated against the BLAST database. The primer specificity, functionality and annealing temperature were tested using uniplex PCR methods that were later combined into a single multiplex PCR. Restriction Fragment Length Polymorphism (RFLP) was performed in three separate tubes followed by agarose gel electrophoresis. PCR product residual was purified and sent for DNA sequencing. Results The allele frequencies for MTHFR 677 C > T were 0.89 (C allele) and 0.11 (T allele); for eNOS +894 G > T, the allele frequencies were 0.58 (G allele) and 0.43 (T allele); and for eNOS −786 T > C, the allele frequencies were 0.87 (T allele) and 0.13 (C allele). Conclusions Our PCR-RFLP method is a simple, cost-effective and time-saving method. It can be used to successfully genotype subjects for the MTHFR 677 C > T and eNOS +894 G > T and eNOS −786 T > C variants simultaneously with 100% concordance from DNA sequencing data. This method can be routinely used for rapid investigation of the MTHFR 677 C > T and eNOS +894 G > T and eNOS −786 T > C variants.

An X chromosome association scan of the Norfolk Island genetic isolate provides evidence for a novel migraine susceptibility locus at Xq12

Migraine is a common and debilitating neurovascular disorder with a complex envirogenomic aetiology. Numerous studies have demonstrated a preponderance of women affected with migraine and previous pedigree linkage studies in our laboratory have identified susceptibility loci on chromosome Xq24-Xq28. In this study we have used the genetic isolate of Norfolk Island to further analyse the X chromosome for migraine susceptibility loci. An association approach was employed to analyse 14,124 SNPs spanning the entire X chromosome. Genotype data from 288 individuals comprising a large core-pedigree, of which 76 were affected with migraine, were analysed. Although no SNP reached chromosome-wide significance (empirical α = 1×10−5) ranking by P-value revealed two primary clusters of SNPs in the top 25. A 10 SNP cluster represents a novel migraine susceptibility locus at Xq12 whilst a 11 SNP cluster represents a previously identified migraine susceptibility locus at Xq27. The strongest association at Xq12 was seen for rs599958 (OR = 1.75, P = 8.92×10−4), whilst at Xq27 the strongest association was for rs6525667 (OR = 1.53, P = 1.65×10−4). Further analysis of SNPs at these loci was performed in 5,122 migraineurs from the Women’s Genome Health Study and provided additional evidence for association at the novel Xq12 locus (P<0.05). Overall, this study provides evidence for a novel migraine susceptibility locus on Xq12. The strongest effect SNP (rs102834, joint P = 1.63×10−5) is located within the 5′UTR of the HEPH gene, which is involved in iron homeostasis in the brain and may represent a novel pathway for involvement in migraine pathogenesis.

Complete mitochondrial genome sequencing reveals novel haplotypes in a Polynesian population

The high risk of metabolic disease traits in Polynesians may be partly explained by elevated prevalence of genetic variants involved in energy metabolism. The genetics of Polynesian populations has been shaped by island hoping migration events which have possibly favoured thrifty genes. The aim of this study was to sequence the mitochondrial genome in a group of Maoris in an effort to characterise genome variation in this Polynesian population for use in future disease association studies. We sequenced the complete mitochondrial genomes of 20 non-admixed Maori subjects using Affymetrix technology. DNA diversity analyses showed the Maori group exhibited reduced mitochondrial genome diversity compared to other worldwide populations, which is consistent with historical bottleneck and founder effects. Global phylogenetic analysis positioned these Maori subjects specifically within mitochondrial haplogroup - B4a1a1. Interestingly, we identified several novel variants that collectively form new and unique Maori motifs – B4a1a1c, B4a1a1a3 and B4a1a1a5. Compared to ancestral populations we observed an increased frequency of non-synonymous coding variants of several mitochondrial genes in the Maori group, which may be a result of positive selection and/or genetic drift effects. In conclusion, this study reports the first complete mitochondrial genome sequence data for a Maori population. Overall, these new data reveal novel mitochondrial genome signatures in this Polynesian population and enhance the phylogenetic picture of maternal ancestry in Oceania. The increased frequency of several mitochondrial coding variants makes them good candidates for future studies aimed at assessment of metabolic disease risk in Polynesian populations.

Detection of a novel mutation in the CACNA1A gene

Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. It is divided into three subtypes FHM1, FHM2 and FHM3, which are caused by mutations in the CACNA1A, ATP1A2 and SCN1A genes respectively. As part of a regular diagnostic service, we investigated 168 patients with FHM symptoms. Samples were tested for mutations contained within the CACNA1A gene. Some tested samples (4.43%) showed an FHM1 mutation, with five of the mutations found in exon 5, one mutation in exon 16 and one in exon 17. Four polymorphisms were also detected, one of which occurred in a large percentage of samples (14.88%). The exon 16 2094G>A polymorphism, however, has been found to occur in healthy Caucasian control populations up to a frequency of 16% and is not considered to be significantly associated with FHM. A finding of significance, found in a single patient, was the detection of a novel mutation in exon 5 that results in a P225H change. The affected individual was an 8-year-old female. The exact phenotypic effect of this mutation is unknown, and further studies are needed to understand the pathophysiology of this mutation in FHM1. New information will allow for diagnostic procedures to be constantly updated, thus improving accuracy of diagnosis. It is possible that new information will also aid the development of new therapeutic agents for the treatment of FHM.