Pharmacogenetics of migraine : genetic variants and their potential role in migraine therapy

Migraine is a paroxysmal neurological disorder affecting up to 6% of males and 18% of females in the general population, and has been demonstrated to have a strong, but complex, genetic component. Genetic investigation of migraine provides hope that new targets for medications and individual specific therapy will be developed. The identification of polymorphisms or genetic biomarkers for disease susceptibility and treatment should aid in providing a better understanding of migraine pathology and, consequently, more appropriate and efficient treatment for migraineurs. In this review, we will discuss results investigating genetic biomarkers for migraine and their potential role in future therapy planning.

Association analysis of somatostatin receptor (SSTR1 and SSTR2) polymorphisms in breast cancer and solar keratosis

The presence of somatostatin receptors (SSTR1-5) in tumour cells indicates a potential for somatostatin to bind and suppress growth, as well as allowing for therapeutic treatment with somatostatin analogues. The genes for SSTR1 and SSTR2 have been shown to contain dinucleotide repeat polymorphisms. We have performed association studies on breast cancer and solar keratosis populations to determine whether these genes play a role in the development of these conditions. Results showed that there was no significant difference between SSTR1 and SSTR2 polymorphism frequencies in the tested breast cancer population (P = 0.59 and P = 0.54, respectively) nor the solar keratosis population (P = 0.10 and P = 0.883, respectively) as compared to unaffected populations. Hence, these studies do not support a role for these receptor genes in either breast cancer or solar keratosis lesions.

The influence of oxygenated organic aerosols (OOA) on the oxidative potential of diesel and biodiesel particulate matter

Generally, the magnitude of pollutant emissions from diesel engines running on biodiesel fuel is ultimately coupled to the structure of respective molecules that constitutes the fuel. Previous studies demonstrated the relationship between organic fraction of PM and its oxidative potential. Herein, emissions from a diesel engine running on different biofuels were analysed in more detail to explore the role different organic fractions play in the measured oxidative potential. In this work, a more detailed chemical analysis of biofuel PM was undertaken using a compact Time of Flight Aerosol Mass Spectrometer (c-ToF AMS). This enabled a better identification of the different organic fractions that contribute to the overall measured oxidative potentials. The concentration of reactive oxygen species (ROS) was measured using a profluorescent nitroxide molecular probe 9-(1,1,3,3-tetramethylisoindolin-2-yloxyl-5-ethynyl)-10-(phenylethynyl)anthracene (BPEAnit). Therefore the oxidative potential of the PM, measured through the ROS content, although proportional to the total organic content in certain cases shows a much higher correlation with the oxygenated organic fraction as measured by the c-ToF AMS. This highlights the importance of knowing the surface chemistry of particles for assessing their health impacts. It also sheds light onto new aspects of particulate emissions that should be taken into account when establishing relevant metrics for assessing health implications of replacing diesel with alternative fuels.

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.

Pten and Ndufb8 aberrations in cervical cancer tissue

Cervical cancer is one of the world's major health issues. Despite many studies in this field, the carcinogenetic events of malignant conversion in cervical tumours have not been significantly characterised. The first aim of this project was to investigate the mutation status of the tumour suppressor gene- Phosphatase and Tension Homolog (PTEN)- in cervical cancer tissue. The second aim of this study was the analysis in the same cervical cancer tissue for aberrations in the mitochondrial electron transport chain subunit gene NDUFB8, which is localised to the same chromosomal contig as PTEN. The third aim was the evaluation of the potential therapeutic anti-cancer drug 2,4-Thiazolidinediones (TZDs) and its affect in regulating the PTEN protein in a cervical cancer cell line (HeLa). To approach the aims, paraffin-embedded cancerous cervical tissue and non-cancerous cervical tissue were obtained. DNA recovered from those tissues was then used to investigate the putative genomic changes regarding the NDUFB8 gene utilising SYBR Green I Real-Time PCR. The PTEN gene was studied via Dual-Labelled probe Real-Time PCR. To investigate the protein expression change of the PTEN protein, HeLa cells were firstly treated with different concentrations of 2,4-Thiazolidinediones and the level of PTEN protein expression was then observed utilising standard protein assays. Results indicated that there were putative copy-number changes between the cancerous cervical tissue and non-cancerous cervical tissue, with regard to the PTEN locus. This implies a potential gain of the PTEN gene in cancerous cervical tissue. With regards to normal cervical tissue versus cancerous cervical tissue no significant melting temperature differences were observed with the SYBR Green I Real-Time PCR in respect to the NDUFB8 gene. A putative up-regulation of PTEN protein was observed in TZD treated HeLa cells. © 2008 Springer Science+Business Media, LLC.

High performance liquid chromatography determined alkamide levels in Australian-grown Echinacea spp.

Extracts of Echinacea spp. are widely used as therapeutic immunostimulants with such activity being attributed in part to the alkamide fractions of these plants. Using high performance liquid chromatography, the levels of 8 alkamides, including 2 tetraene alkamides (dodeca-2E, 4E, 8Z, 10E/Z-tetraenoic acid isobutylamide), were quantitatively determined in 2 Australian-grown Echinacea spp. Overall, the levels of alkamides in Australian-grown E. angustifolia were found to be comparable with levels obtained in this study and other studies for USA and European Echinacea spp. However, results obtained for one sample of E. angustifolia suggested that it may have been mislabelled and that it was most likely a sample of E. pallida. Levels of tetraene alkamides in Australian-grown E. purpurea were also similar to, if not higher, than levels which have been reported for the same species grown in Germany and the USA. Preliminary studies on the stability of alkamide compounds in E. angustifolia indicated that they are susceptible to degradation, with a 13% loss of alkamide level over 2 months. Overall, results indicate that there is considerable potential to develop Echinacea as a viable crop in Australia.

The intervening role of Agreeableness in the relationship between trait emotional intelligence and Machiavellianism : reassessing the potential dark side of EI

Previous research into the potential ‘dark’ side of trait emotional intelligence (EI) has repeatedly demonstrated that trait EI is negatively associated with Machiavellianism. In this study, we reassess the potential dark side of trait EI, by testing whether Agreeableness mediates and/or moderates the relationship between trait EI and Machiavellianism. Hypothesized mediation and moderation effects were tested using a large sample of 884 workers who completed several self-report questionnaires. Results provide support for both hypotheses; Agreeableness was found to mediate and moderate the relationship between trait EI and Machiavellianism. Overall, results indicate that individuals high in trait EI tend to have low levels of Machiavellianism because they generally have a positive nature (i.e. are agreeable) and not because they are emotionally competent per se. Results also indicate that individuals high in ‘perceived emotional competence’ have the potential to be high in Machiavellianism, particularly when they are low in Agreeableness.

Making the train : an examination of five perspectives of rail access and how they resonate with existing and potential passengers

Rail operators recognize a need to increase ridership in order to improve the economic viability of rail service, and to magnify the role that rail travel plays in making cities feel liveable. This study extends previous research that used cluster analysis with a small sample of rail passengers to identify five salient perspectives of rail access (Zuniga et al, 2013). In this project stage, we used correlation techniques to determine how those perspectives would resonate with two larger study populations, including a relatively homogeneous sample of university students in Brisbane, Australia and a diverse sample of rail passengers in Melbourne, Australia. Findings from Zuniga et al. (2013) described a complex typology of current passengers that was based on respondents’ subjective attitudes and perceptions rather than socio-demographic or travel behaviour characteristics commonly used for segmentation analysis. The typology included five qualitative perspectives of rail travel. Based on the transport accessibility literature, we expected to find that perspectives from that study emphasizing physical access to rail stations would be shared by current and potential rail passengers who live further from rail stations. Other perspectives might be shared among respondents who live nearby, since the relevance of distance would be diminished. The population living nearby would thus represent an important target group for increasing ridership, since making rail travel accessible to them does not require expansion of costly infrastructure such as new lines or stations. By measuring the prevalence of each perspective in a larger respondent pool, results from this study provide insight into the typical socio-demographic and travel behaviour characteristics that correspond to each perspective of intra-urban rail travel. In several instances, our quantitative findings reinforced Zuniga et al.’s (2013) qualitative descriptions of passenger types, further validating the original research. This work may directly inform rail operators’ approach to increasing ridership through marketing and improvements to service quality and station experience. Operators in other parts of Australia and internationally may also choose to replicate the study locally, to fine-tune understanding of diverse customer bases. Developing regional and international collaboration would provide additional opportunities to evaluate and benchmark service and station amenities as they address the various access dimensions.

An exploratory study of the potential of resurfacing articular cartilage with synthetic phospholipids

This thesis is aimed at further understanding the uppermost lipid-filled membranous layer (i.e. surface amorphous layer (SAL)) of articular cartilage and to develop a scientific framework for re-introducing lipids onto the surface of lipid-depleted articular cartilage (i.e. "resurfacing"). The outcome will potentially contribute to knowledge that will facilitate the repair of the articular surface of cartilage where degradation is limited to the loss of the lipids of the SAL only. The surface amorphous layer is of utmost importance to the effective load-spreading, lubrication, and semipermeability (which controls its fluid management, nutrient transport and waste removal) of articular cartilage in the mammalian joints. However, because this uppermost layer of cartilage is often in contact during physiological function, it is prone to wear and tear, and thus, is the site for damage initiation that can lead to the early stages of joint condition like osteoarthritis, and related conditions that cause pain and discomfort leading to low quality of life in patients. It is therefore imperative to conduct a study which offers insight into remedying this problem. It is hypothesized that restoration (resurfacing) of the surface amorphous layer can be achieved by re-introducing synthetic surface-active phospholipids (SAPL) into the joint space. This hypothesis was tested in this thesis by exposing cartilage samples whose surface lipids had been depleted to individual and mixtures of synthetic saturated and unsaturated phospholipids. The surfaces of normal, delipidized, and relipidized samples of cartilage were characterized for their structural integrity and functionality using atomic force microscope (AFM), confocal microscope (COFM), Raman spectroscopy, magnetic resonance imaging (MRI) with image processing in the MATLAB® environment and mechanical loading experiments. The results from AFM imaging, confocal microscopy, and Raman spectroscopy revealed a successful deposition of new surface layer on delipidized cartilage when incubated in synthetic phospholipids. The relipidization resulted in a significant improvement in the surface nanostructure of the artificially degraded cartilage, with the complete SAPL mixture providing better outcomes in comparison to those created with the single SAPL components (palmitoyl-oleoyl-phosphatidylcholine, POPC and dipalmitoyl-phosphatidylcholine, DPPC). MRI analysis revealed that the surface created with the complete mixture of synthetic lipids was capable of providing semipermeability to the surface layer of the treated cartilage samples relative to the normal intact surface. Furthermore, deformation energy analysis revealed that the treated samples were capable of delivering the elastic properties required for load bearing and recovery of the tissue relative to the normal intact samples, with this capability closer between the normal and the samples incubated in the complete lipid mixture. In conclusion, this thesis has established that it is possible to deposit/create a potentially viable layer on the surface of cartilage following degradation/lipid loss through incubation in synthetic lipid solutions. However, further studies will be required to advance the ideas developed in this thesis, for the development of synthetic lipid-based injections/drugs for treatment of osteoarthritis and other related joint conditions.

Zeta-potential and morphology of electrospun nano- and microfibers from biopolymers and their blends used as scaffolds in tissue engineering

Electrostatic spinning or electrospinning is a fiber spinning technique driven by a high-voltage electric field that produces fibers with diameters in a submicrometer to nanometer range.1 Nanofibers are typical one-dimensional colloidal objects with an increased tensile strength, whose length can achieve a few kilometers and the specific surface area can be 100 m2 g–1 or higher.2 Nano- and microfibers from biocompatible polymers and biopolymers have received much attention in medical applications3 including biomedical structural elements (scaffolding used in tissue engineering,2,4–6 wound dressing,7 artificial organs and vascular grafts8), drug and vaccine delivery,9–11 protective shields in speciality fabrics, multifunctional membranes, etc. Other applications concern superhydrophobic coatings,12 encapsulation of solid materials,13 filter media for submicron particles in separation industry, composite reinforcement and structures for nano-electronic machines.

Heat-producing crust regulation of subsurface temperatures : a stochastic model re-evaluation of the geothermal potential in western Queensland, Australia

A large subsurface, elevated temperature anomaly is well documented in Central Australia. High Heat Producing Granites (HHPGs) intersected by drilling at Innamincka are often assumed to be the dominant cause of the elevated subsurface temperatures, although their presence in other parts of the temperature anomaly has not been confirmed. Geological controls on the temperature anomaly remain poorly understood. Additionally, methods previously used to predict temperature at 5 km depth in this area are simplistic and possibly do not give an accurate representation of the true distribution and magnitude of the temperature anomaly. Here we re-evaluate the geological controls on geothermal potential in the Queensland part of the temperature anomaly using a stochastic thermal model. The results illustrate that the temperature distribution is most sensitive to the thermal conductivity structure of the top 5 km. Furthermore, the results indicate the presence of silicic crust enriched in heat producing elements between and 40 km.

From production to purpose : using design led innovation to Build Strategic Potential in a Family-Owned SME

There is an evident need to develop the strategic capabilities of companies from within, to ensure competitive competence in a time where strategy is a necessity. This paper is based on the first 4 months of a longitudinal embedded case study of a family-owned Australian small to medium enterprise, in their journey towards design integration. The first author was embedded as a ‘Design Innovation Catalyst’ to collaborate on overcoming early barriers of strategic development, using design led innovation. Action research methodology, semi-structured interviews with seven out of eight employees and a reflective journal revealed the absence of a shared vision, conflicting drivers and a focus on operational efficiency rather than strategy. Through the Catalyst’s facilitation, a company vision, general awareness, practice and knowledge in strategic development have emerged as the first steps to generating strategic design competence within the firm.

Controlling whole blood activation and resultant clot properties on various material surfaces : a possible therapeutic approach for enhancing bone healing

Injured bone initiates the healing process by forming a blood clot at the damaged site. However, in severe damage, synthetic bone implants are used to provide structural integrity and restore the healing process. The implant unavoidably comes into direct contact with whole blood, leading to a blood clot formation on its surface. Despite this, most research in bone tissue engineering virtually ignores the important role of a blood clot in supporting healing. Surface chemistry of a biomaterial is a crucial property in mediating blood-biomaterials interactions, and hence the formation of the resultant blood clot. Surfaces presenting mixtures of functional groups carboxyl (–COOH) and methyl (–CH3) have been shown to enhance platelet response and coagulation activation, leading to the formation of fibrin fibres. In addition, it has been shown that varying the compositions of these functional groups and the length of alkyl groups further modulate the immune complement response. In this study, we hypothesised that a biomaterial surface with mixture of –COOH/–CH3(methyl), –CH2CH3 (ethyl) or –(CH2)3CH3 (butyl) groups at different ratios would modulate blood coagulation and complement activation, and eventually tailor the structural and functional properties of the blood clot formed on the surface, which subsequently impacts new bone formation. Firstly, we synthesised a series of materials composed of acrylic acid (AA), and methyl (MMA), ethyl (EMA) or butyl methacrylates (BMA) at different ratios and coated on the inner surfaces of incubation vials. Our surface analysis showed that the amount of –COOH groups on the surface coatings was lower than the ratios of AA prepared in the materials even though the surface content of –COOH groups increased with increasing in AA ratios. It was indicated that the surface hydrophobicity increased with increasing alkyl chain length: –CH 3 > –CH2CH3 > –(CH2)3CH3, and decreased with increasing –COOH groups. No significant differences in surface hydrophobicity was found on surfaces with –CH3 and –CH2CH3 groups in the presence of –COOH groups. The material coating was as smooth as uncoated glass and without any major flaws. The average roughness of material-coated surface (3.99 ± 0.54 nm) was slightly higher than that of uncoated glass surface (2.22 ± 0.29 nm). However, no significant differences in surface average roughness was found among surfaces with the same functionalities at different –COOH ratios nor among surfaces with different alkyl groups but the same –COOH ratios. These suggested that the surface functional groups and their compositions had a combined effect on modulating surface hydrophobicity but not surface roughness. The second part of our study was to investigate the effect of surface functional groups and their compositions on blood cascade activation and structural properties of the formed clots. It was found that surfaces with –COOH/–(CH2)3CH3 induced a faster coagulation activation than those with –COOH/–CH3 and –CH2CH3, regardless of the –COOH ratios. An increase in –COOH ratios on –COOH/–CH3 and –CH2CH3 surfaces decreased the rate of activation. Moreover, all material-coated surfaces markedly reduced the complement activation compared to uncoated glass surfaces, and the pattern of complement activation was entirely similar to that of surface-induced coagulation, suggesting there is an interaction between two cascades. The clots formed on material-coated surfaces had thicker fibrin with a tighter network at the exterior when compared to uncoated glass surfaces. Compared to the clot exteriors, thicker fibrins with a loose network were found in clot interiors. Coated surfaces resulted in more rigid clots with a significantly slower fibrinolysis after 1 h of lysis when compared to uncoated glass surfaces. Significant differences in fibrinolysis after 1 h of lysis among clots on material-coated surfaces correlated well with the differences in fibrin thickness and density at clot exterior. In addition, more growth factors were released during clot formation than during clot lysis. From an intact clot, there was a correlation between the amount of PDGF-AB release and fibrin density. Highest amount of PDGF-AB was released from clots formed on surfaces with 40% –COOH/60% –CH 3 (i.e. 65MMA). During clot lysis, the release of PDGF-AB also correlated with the fibrinolytic rate while the release of TGF-â1 was influenced by the fibrin thickness. This suggested that different clot structures led to different release profiles of growth factors in clot intact and degrading stages. We further validated whether the clots formed on material-coatings provide the microenvironment for improved bone healing by using a rabbit femoral defect model. In this pilot study, the implantation of clots formed on 65MMA coatings significantly increased new bone formation with enhanced chondrogenesis, osteoblasts activity and vascularisation, but decreased inflammatory macrophage number at the defects after 4 weeks when compared to commercial bone grafts ChronOSTM â-TCP granules. Empty defects were observed when blood clot formation was inhibited. In summary, our study demonstrated that surface functional groups and their relative ratios on material coatings synergistically modulate activation of blood cascades, resultant fibrin architecture, rigidity, susceptibility to fibrinolysis as well as growth factor release of the formed clots, which ultimately alter the healing microenvironment of injured bones.

Gene expression profiling in human breast cancer – toward personalised therapeutics?

The most integrated approach toward understanding the multiple molecular events and mechanisms by which cancer may develop is the application of gene expression profiling using microarray technologies. As molecular alterations in breast cancer are complex and involve cross-talk between multiple cellular signalling pathways, microarray technology provides a means of capturing and comparing the expression patterns of the entire genome across multiple samples in a high throughput manner. Since the development of microarray technologies, together with the advances in RNA extraction methodologies, gene expression studies have revolutionised the means by which genes suitable as targets for drug development and individualised cancer treatment can be identified. As of the mid-1990s, expression microarrays have been extensively applied to the study of cancer and no cancer type has seen as much genomic attention as breast cancer. The most abundant area of breast cancer genomics has been the clarification and interpretation of gene expression patterns that unite both biological and clinical aspects of tumours. It is hoped that one day molecular profiling will transform diagnosis and therapeutic selection in human breast cancer toward more individualised regimes. Here, we review a number of prominent microarray profiling studies focussed on human breast cancer and examine their strengths, their limitations, clinical implications including prognostic relevance and gene signature significance along with potential improvements for the next generation of microarray studies.

Whole genome and exome sequencing of melanoma

Melanoma has historically been refractive to traditional therapeutic approaches. As such, the development of novel drug strategies has been needed to improve rates of overall survival in patients with melanoma, particularly those with late stage or disseminated disease. Recent success with molecularly based targeted drugs, such as Vemurafenib in BRAF-mutant melanomas, has now made “personalized medicine” a reality within some oncology clinics. In this sense, tailored drugs can be administered to patients according to their tumor “mutation profiles.” The success of these drug strategies, in part, can be attributed to the identification of the genetic mechanisms responsible for the development and progression of metastatic melanoma. Recently, the advances in sequencing technology have allowed for comprehensive mutation analysis of tumors and have led to the identification of a number of genes involved in the etiology of metastatic melanoma. As the methodology and costs associated with next-generation sequencing continue to improve, this technology will be rapidly adopted into routine clinical oncology practices and will significantly impact on personalized therapy. This review summarizes current and emerging molecular targets in metastatic melanoma, discusses the potential application of next-generation sequencing within the paradigm of personalized medicine, and describes the current limitations for the adoption of this technology within the clinic.