Students' perceptions of teacher biases : experimental economics in schools

We put forward a new experimental economics design with monetary incentives to estimate students’ perceptions of grading discrimination. We use this design in a large field experiment which involved 1,200 British students in grade 8 classrooms across 29 schools. In this design, students are given an endowment they can invest on a task where payoff depends on performance. The task is a written verbal test which is graded non anonymously by their teacher, in a random half of the classrooms, and graded anonymously by an external examiner in the other random half of the classrooms. We find significant evidence that students’ choices reflect perceptions of biases in teachers’ grading practices. Our results show systematic gender interaction effects: male students invest less with female teachers than with male teachers while female students invest more with male teachers than with female teachers. Interestingly, female students’ perceptions are not in line with actual discrimination: Teachers tend to give better grades to students of their own gender. Results do not suggest that ethnicity and socioeconomic status play a role. .

Monster factory : International dynamics of the Australian horror movie industry

From the early-to-mid 2000s, the Australian horror film production sector has achieved growth and prosperity of a kind not seen since its heyday of the 1980s. Australian horror films can be traced back to the early 1970s, when they experienced a measure of commercial success. However, throughout the twenty-first-century Australian horror gained levels of international recognition that have surpassed the cult status enjoyed by some of the films in the 1970s and 1980s. In recent years, Australia has emerged as a significant producer of breakout, cult, and solid B-grade horror films, which have circulated in markets worldwide. Australian horror’s recent successes have been driven by one of its distinguishing features: its international dimensions. As this chapter argues, the Australian horror film production sector is an export-oriented industry that relies heavily on international partnerships and presales (the sale of distribution rights prior to a film’s completion), and on its relationships with overseas distributors. Yet, these traits vary from film to film as the sector is comprised of several distinct domains of production activity, from guerrilla films destined for niche video markets like specialist cult video stores and online mail-order websites to high(er)-end pictures made for theatrical markets. Furthermore, the content and style of Australian horror movies has often been tailored for export. While some horror filmmakers have sought to play up the Australianness of their product, others have attempted to pass off their films as faux-American or as placeless films effaced of national reference points.

Urban transit quality of service : user perception and behaviour

Despite its potential multiple contributions to sustainable policy objectives, urban transit is generally not widely used by the public in terms of its market share compared to that of automobiles, particularly in affluent societies with low-density urban forms like Australia. Transit service providers need to attract more people to transit by improving transit quality of service. The key to cost-effective transit service improvements lies in accurate evaluation of policy proposals by taking into account their impacts on transit users. If transit providers knew what is more or less important to their customers, they could focus their efforts on optimising customer-oriented service. Policy interventions could also be specified to influence transit users’ travel decisions, with targets of customer satisfaction and broader community welfare. This significance motivates the research into the relationship between urban transit quality of service and its user perception as well as behaviour. This research focused on two dimensions of transit user’s travel behaviour: route choice and access arrival time choice. The study area chosen was a busy urban transit corridor linking Brisbane central business district (CBD) and the St. Lucia campus of The University of Queensland (UQ). This multi-system corridor provided a ‘natural experiment’ for transit users between the CBD and UQ, as they can choose between busway 109 (with grade-separate exclusive right-of-way), ordinary on-street bus 412, and linear fast ferry CityCat on the Brisbane River. The population of interest was set as the attendees to UQ, who travelled from the CBD or from a suburb via the CBD. Two waves of internet-based self-completion questionnaire surveys were conducted to collect data on sampled passengers’ perception of transit service quality and behaviour of using public transit in the study area. The first wave survey is to collect behaviour and attitude data on respondents’ daily transit usage and their direct rating of importance on factors of route-level transit quality of service. A series of statistical analyses is conducted to examine the relationships between transit users’ travel and personal characteristics and their transit usage characteristics. A factor-cluster segmentation procedure is applied to respodents’ importance ratings on service quality variables regarding transit route preference to explore users’ various perspectives to transit quality of service. Based on the perceptions of service quality collected from the second wave survey, a series of quality criteria of the transit routes under study was quantitatively measured, particularly, the travel time reliability in terms of schedule adherence. It was proved that mixed traffic conditions and peak-period effects can affect transit service reliability. Multinomial logit models of transit user’s route choice were estimated using route-level service quality perceptions collected in the second wave survey. Relative importance of service quality factors were derived from choice model’s significant parameter estimates, such as access and egress times, seat availability, and busway system. Interpretations of the parameter estimates were conducted, particularly the equivalent in-vehicle time of access and egress times, and busway in-vehicle time. Market segmentation by trip origin was applied to investigate the difference in magnitude between the parameter estimates of access and egress times. The significant costs of transfer in transit trips were highlighted. These importance ratios were applied back to quality perceptions collected as RP data to compare the satisfaction levels between the service attributes and to generate an action relevance matrix to prioritise attributes for quality improvement. An empirical study on the relationship between average passenger waiting time and transit service characteristics was performed using the service quality perceived. Passenger arrivals for services with long headways (over 15 minutes) were found to be obviously coordinated with scheduled departure times of transit vehicles in order to reduce waiting time. This drove further investigations and modelling innovations in passenger’ access arrival time choice and its relationships with transit service characteristics and average passenger waiting time. Specifically, original contributions were made in formulation of expected waiting time, analysis of the risk-aversion attitude to missing desired service run in the passengers’ access time arrivals’ choice, and extensions of the utility function specification for modelling passenger access arrival distribution, by using complicated expected utility forms and non-linear probability weighting to explicitly accommodate the risk of missing an intended service and passenger’s risk-aversion attitude. Discussions on this research’s contributions to knowledge, its limitations, and recommendations for future research are provided at the concluding section of this thesis.

Attitudes of future special education teachers toward gifted students and their education

Saudi Arabian education is undergoing substantial reform in the context of a nation transitioning from a resource-rich economy to a knowledge economy. Gifted students are important human resources for such developing countries. However, there are some concerns emanating from the international literature that gifted students have been neglected in many schools due to teachers’ attitudes toward them. The literature shows that future teachers also hold similar negative attitudes, especially those in Special Education courses who, as practicing teachers, are often responsible for supporting the gifted education process. The purpose of this study was to explore whether these attitudes are held by future special education teachers in Saudi Arabia, and how the standard gifted education course, delivered as part of their program, impacts on their attitudes toward gifted students. The study was strongly influenced by the Theory of Reasoned Action (Ajzen, 1980, 2012) and the Theory of Personal Knowledge (Polanyi, 1966), which both suggest that attitudes are related to people’s (i.e. teachers’) beliefs. A mixed methods design was used to collect quantitative and qualitative data from a cohort of students enrolled in a teacher education program at a Saudi Arabian university. The program was designed for students majoring in special education. The quantitative component of the study involved an investigation of a cohort of future special education teachers taking a semester-long course in gifted education. The data were primarily sourced from a standard questionnaire instrument modified in the Arabic language, and supplemented with questions that probed the future teachers’ attitudes toward gifted children. The participants, 90 special education future teachers, were enrolled in an introductory course about gifted education. The questionnaire contained 34 items from the "Opinions about the Gifted and Their Education" (Gagné, 1991) questionnaire, utilising a five-point Likert scale. The quantitative data were analysed through the use of descriptive statistics, Spearman correlation Coefficients, Paired Samples t-test, and Multiple Linear Regression. The qualitative component focussed on eight participants enrolled in the gifted education course. The primary source of the qualitative data was informed by individual semi-structured interviews with each of these participants. The findings, based on both the quantitative and qualitative data, indicated that the majority of future special education teachers held, overall, slightly positive attitudes toward gifted students and their education. However, the participants were resistant to offering special services for the gifted within the regular classroom, even when a comparison was made on equity grounds with disabled students. While the participants held ambivalent attitudes toward ability grouping, their attitudes were positive toward grade acceleration. Further, the majority agreed that gifted students are likely to be rejected by their teachers. Despite such judgments, they considered the gifted to be a valuable resource for Saudi society. Differences within the cohort were found when two variables emerged as potential predictors of attitude: age, experience, and participants’ hometown. The younger (under 25 years old) future special education teachers, with no internship or school practice experience, held more positive attitudes toward the gifted students, with respect to their general needs, than did the older participants with previous school experiences. Additionally, participants from a rural region were more resistant toward gifted education than future teachers from urban areas. The findings also indicated that the attitudes of most of the participants were significantly improved, as a result of the course, toward ability grouping such as special classes and schools, but remained highly concerned about differentiation within regular classrooms with either elitism or time pressure. From the findings, it can be confirmed that a lectured-based course can serve as a starting point from which to focus future teachers’ attention on the varied needs of the gifted, and as a conduit for learning about special services for the gifted. However, by itself, the course appears to have minimal influence on attitudes toward differentiation. As a consequence, there is merit in its redevelopment, and the incorporation of more practical opportunities for future teachers to experience the teaching of the gifted.

Shear-critical impact response of biaxially loaded reinforced concrete circular columns

A study on the vulnerability of biaxially loaded reinforced concrete (RC) circular columns in multi-story buildings under low- to medium-velocity impacts at shear-critical locations is presented. The study is based on a previously validated nonlinear explicit dynamic finite element (FE) modeling technique developed by the authors. The impact is simulated using force pulses generated from full-scale vehicle impact tests abundantly found in the literature with a view to quantifying the sensitivity of the design parameters of the RC columns under the typical impacts that are representative of the general vehicle population. The design parameters considered include the diameter and height of the column, the vertical steel ratio, the concrete grade, and the confinement effects. From the results of the simulations, empirical equations to quantify the critical impulses for the simplified design of the short, circular RC columns under the risk of shear-critical impacts are developed.

Towards a model for student selection in clinical psychology

Background Selection of candidates for clinical psychology programmes is arguably the most important decision made in determining the clinical psychology workforce. However, there are few models to inform the development of selection tools to support selection procedures. The study, using a factor analytic structure, has operationalised the model predicting applicants' capabilities. Method Eighty-eight clinical applicants for entry into a postgraduate clinical psychology programme were assessed on a series of tasks measuring eight capabilities: guided reflection, communication skills, ethical decision making, writing, conceptual reasoning, empathy, and awareness of mind and self-observation. Results Factor analysis revealed three capabilities: labelled “awareness” accounting for 35.71% of variance; “reflection” accounting for 20.56%; and “reasoning” accounting for 18.24% of variance. Fourth year grade point average (GPA) did not correlate with performance on any of the selection capabilities other than a weak correlation with performance on the ethics capability. Conclusions Eight selection capabilities are identified for the selection of candidates independent of GPA. While the model is tentative, it is hoped that the findings will stimulate the development and validation of assessment procedures with good predictive validity which will benefit the training of clinical psychologists and, ultimately, effective service delivery.

Semaphorin–plexin signalling genes associated with human breast tumourigenesis

Introduction Gene expression profiling has enabled us to demonstrate the heterogeneity of breast cancers. The potential of a tumour to grow and metastasise is partly dependant on its ability to initiate angiogenesis or growth and remodelling of new blood vessels, usually from a pre-existing vascular network, to ensure delivery of oxygen, nutrients, and growth factors to rapidly dividing transformed cells along with access to the systemic circulation. Cell–cell signalling of semaphorin ligands through interaction with their plexin receptors is important for the homeostasis and morphogenesis of many tissues and has been widely studied for a role in neural connectivity, cancer, cell migration and immune responses. This study investigated the role of four semaphorin/plexin signalling genes in human breast cancers in vivo and in vitro. Materials and methods mRNA was extracted from formalin fixed paraffin embedded archival breast invasive ductal carcinoma tissue samples of progressive grades (grades I–III) and compared to tissue from benign tumours. Gene expression profiles were determined by microarray using the Affymetrix GeneChip® Human Genome U133 Plus 2.0 Arrays and validated by Q-PCR using a Corbett RotorGene 6000. Following validation, the gene expression profile of the identified targets was correlated with those of the human breast cancer cell lines MCF-7 and MDA-MD-231. Results The array data revealed that 888 genes were found to be significantly (p ≤ 0.05) differentially expressed between grades I and II tumours and 563 genes between grade III and benign tumours. From these genes, we identified four genes involved in semaphorin–plexin signalling including SEMA4D which has previously been identified as being involved in increased angiogenesis in breast cancers, and three other genes, SEMA4F, PLXNA2 and PLXNA3, which in the literature were associated with tumourigenesis, but not directly in breast tumourigenesis. The microarray analysis revealed that SEMA4D was significantly (P = 0.0347) down-regulated in the grade III tumours compared to benign tumours; SEMA4F, was significantly (P = 0.0159) down-regulated between grades I and II tumours; PLXNA2 was significantly (P = 0.036) down-regulated between grade III and benign tumours and PLXNA3 significantly (P = 0.042) up-regulated between grades I and II tumours. Gene expression of SEMA4D was validated using Q-PCR, demonstrating the same expression profile in both data sets. When the sample set was increased to incorporate more cases, SEMA4D continued to follow the same expression profile, including statistical significance for the differences observed and small standard deviations. In vitro the same pattern was present where expression for SEMA4D was significantly higher in MDA-MB-231 cells when compared to MCF-7 cells. The expression of SEMA4F, PLXNA2 and PLXNA3 could not be validated using Q-PCR, however in vitro analysis of these three genes revealed that both SEMA4F and PLXNA3 followed the microarray trend in expression, although they did not reach significance. In contrast, PLXNA2 demonstrated statistical significance and was in concordance with the literature. Discussion We, and others, have proposed SEMA4D to be a gene with a potentially protective effect in benign tumours that contributes to tumour growth and metastatic suppression. Previous data supports a role for SEMA4F as a tumour suppressor in the peripheral nervous system but our data seems to indicate that the gene is involved in tumour progression in breast cancer. Our in vitro analysis of PLXNA2 revealed that the gene has higher expression in more aggressive breast cancer cell types. Finally, our in vitro analysis on PLXNA3 also suggest that this gene may have some form of growth suppressive role in breast cancer, in addition to a similar role for the gene previously reported in ovarian cancer. From the data obtained in this study, SEMA4D may have a role in more aggressive and potentially metastatic breast tumours. Conclusions Semaphorins and their receptors, the plexins, have been implicated in numerous aspects of neural development, however their expression in many other epithelial tissues suggests that the semaphorin–plexin signalling system also contributes to blood vessel growth and development. These findings warrant further investigation of the role of semaphorins and plexins and their role in normal and tumour-induced angiogenesis in vivo and in vitro. This may represent a new front of attack in anti-angiogenic therapies of breast and other cancers.

Progesterone, glucocorticoid, but not estrogen receptor mRNA is altered in breast cancer stroma

Our laboratory has previously found that anti-mitogenic nuclear receptor mRNA is elevated in late stage tumours and this study was performed to scrutinize the possibility of cancer-stroma crosstalk using hormone signaling in these tissues. RNA levels in stromal tissue were examined for the estrogen α, estrogen β, androgen, progesterone and glucocorticoid nuclear receptors by a semi-quantitative PCR. Significant differences in expression between the cancer stroma and control tissue were seen, analyzing for both cancer grade and estrogen receptor status. Stroma and control tissue were significantly different for the progesterone and glucocorticoid nuclear receptors (p = 5.908 × 10−7 and 2.761 × 10−5, respectively). Glucocorticoid receptor also showed a significant increase to mRNA levels in the stroma of estrogen receptor negative tumours (p = 5.85 × 10−5). By contrast, the estrogen receptors α and β, those most closely associated with breast tissue growth, showed no significant change in mRNA (p = 0.372 and 0.655, respectively). Androgen receptor mRNA also remained unaffected (p = 0.174).

Detection of mRNA levels for the estrogen alpha, estrogen beta and androgen nuclear receptor genes in archival breast cancer tissue

Previous studies in our laboratory have shown association of nuclear receptor expression and histological breast cancer grade. To further investigate these findings, it was the objective of this study to determine if expression levels of the estrogen alpha, estrogen beta and androgen nuclear receptor genes varied in different breast cancer grades. RNA extracted from paraffin embedded archival breast tumour tissue was converted into cDNA and cDNA underwent PCR to enable quantitation of mRNA expression. Expression data was normalised against the 18S ribosomal gene multiplex and analysed using ANOVA. Analysis indicated a significant alteration of expression for the androgen receptor in different cancer grades (P=0.014), as well as in tissues that no longer possess estrogen receptor alpha proteins (P=0.025). However, expression of estrogen receptors alpha and beta did not vary significantly with cancer grade (P=0.057 and 0.622, respectively). Also, the expression of estrogen receptor alpha or beta did not change, regardless of the presence of estrogen receptor alpha protein in the tissue (P=0.794 and 0.716, respectively). Post-hoc tests indicate that the expression of the androgen receptor is increased in estrogen receptor negative tissue as well as in grade 2 and grade 3 tumours, compared to control tissue. This increased expression in late stage breast tumours may have implications to the treatment of breast tumours, particularly those lacking expression of other nuclear receptor genes.

Detection of mRNA for nuclear receptor co-activators 1 and 3 in archival breast cancer tissue and surrounding stroma : a tissue expression study

Before the age of 75 years, approximately 10% of women will be diagnosed with breast cancer, one of the most common malignancies and a leading cause of death among women. The objective of this study was to determine if expression of the nuclear receptor coactivators 1 and 3 (NCoA1 and NCoA3) varied in breast cancer grades. RNA was extracted from 25 breast tumours and transcribed into cDNA which underwent semi-quantitative polymerase chain reaction, normalised using 18S. Analysis indicated that an expression change for NCoA1 in cancer grades and estrogen receptor alpha negative tissue (P= 0.028 and 0.001 respectively). NCoA1 expression increased in grade 3 and estrogen receptor alpha negative tumours, compared to controls. NCoA3 showed a similar, but not significant, trend in grade and a non-significant decrease in estrogen receptor alpha negative tissues. Expression of NCoA1 in late stage and estrogen receptor alpha negative breast tumours may have implications to breast cancer treatment, particularly in the area of manipulation of hormone signalling systems in advanced tumours.

Expression of glucocorticoid and progesterone nuclear receptor genes in archival breast cancer tissue.

BACKGROUND: Previous studies in our laboratory have shown associations of specific nuclear receptor gene variants with sporadic breast cancer. In order to investigate these findings further, we conducted the present study to determine whether expression levels of the progesterone and glucocorticoid nuclear receptor genes vary in different breast cancer grades. METHODS: RNA was extracted from paraffin-embedded archival breast tumour tissue and converted into cDNA. Sample cDNA underwent PCR using labelled primers to enable quantitation of mRNA expression. Expression data were normalized against the 18S ribosomal gene multiplex and analyzed using analysis of variance. RESULTS: Analysis of variance indicated a variable level of expression of both genes with regard to breast cancer grade (P = 0.00033 for glucocorticoid receptor and P = 0.023 for progesterone receptor). CONCLUSION: Statistical analysis indicated that expression of the progesterone nuclear receptor is elevated in late grade breast cancer tissue.

The effects of risk factors and protective factors on influencing engagement in risky behaviours and injury experiences for high-risk adolescents

High-risk adolescents are most vulnerable to the negative outcomes of risk taking behaviour, such as injury. It has been theorised by Jessor (1987) that adolescent risk behaviours (e.g. violence, alcohol use) can be predicted by assessing the risk factors (e.g. peer models for violence) and protective factors (e.g. school connectedness) in a young person’s life. The aim of this research is to examine the influence of risk factors and protective factors on the proneness of high-risk adolescents to engage in risky behaviour. 2,521 Grade 9 students (13-14 years of age) from 35 schools in Queensland, Australia participated in this study. The findings examine the influence of risk factors and protective factors on self-reported risky behaviour and injury experiences for adolescents who have been categorized as high-risk. Thereby, providing insight that may be used to target preventive interventions aimed at high-risk adolescents.

The function and mechanisms of action of ghrelin and obestatin in ovarian cancer

In this study, we have demonstrated that the preproghrelin derived hormones, ghrelin and obestatin, may play a role in ovarian cancer. Ghrelin and obestatin stimulated an increase in cell migration in ovarian cancer cell lines and may play a role in cancer progression. Ovarian cancer is the leading cause of death among gynaecological cancers and is the sixth most common cause of cancer-related deaths in women in developed countries. As ovarian cancer is difficult to diagnose at a low tumour grade, two thirds of ovarian cancers are not diagnosed until the late stages of cancer development resulting in a poor prognosis for the patient. As a result, current treatment methods are limited and not ideal. There is an urgent need for improved diagnostic markers, as well better therapeutic approaches and adjunctive therapies for this disease. Ghrelin has a number of important physiological effects, including roles in appetite regulation and the stimulation of growth hormone release. It is also involved in regulating the immune, cardiovascular and reproductive systems and regulates sleep, memory and anxiety, and energy metabolism. Over the last decade, the ghrelin axis, (which includes the hormones ghrelin and obestatin and their receptors), has been implicated in the pathogenesis of many human diseases and it may t may also play an important role in the development of cancer. Ghrelin is a 28 amino acid peptide hormone that exists in two forms. Acyl ghrelin (usually referred to as ghrelin), has a unique n-octanoic acid post-translational modification (which is catalysed by ghrelin O-acyltransferase, GOAT), and desacyl ghrelin, which is a non-octanoylated form. Octanoylated ghrelin acts through the growth hormone secretagogue receptor type 1a (GHSR1a). GHSR1b, an alternatively spliced isoform of GHSR, is C-terminally truncated and does not bind ghrelin. Ghrelin has been implicated in the pathophysiology of a number of diseases Obestatin is a 23 amino acid, C-terminally amidated peptide which is derived from preproghrelin. Although GPR39 was originally thought to be the obestatin receptor this has been disproven, and its receptor remains unknown. Obestatin may have as diverse range of roles as ghrelin. Obestatin improves memory, inhibits thirst and anxiety, increases pancreatic juice secretion and has cardioprotective effects. Obestatin also has been shown to regulate cell proliferation, differentiation and apoptosis in some cell types. Prior to this study, little was known regarding the functions and mechanisms of action ghrelin and obestatin in ovarian cancer. In this study it was demonstrated that the full length ghrelin, GHSR1b and GOAT mRNA transcripts were expressed in all of the ovarian-derived cell lines examined (SKOV3, OV-MZ-6 and hOSE 17.1), however, these cell lines did not express GHSR1a. Ovarian cancer tissue of varying stages and normal ovarian tissue expressed the coding region for ghrelin, obestatin, and GOAT, but not GHSR1a, or GHSR1b. No correlations between cancer grade and the level of expression of these transcripts were observed. This study demonstrated for the first time that both ghrelin and obestatin increase cell migration in ovarian cancer cell lines. Treatment with ghrelin (for 72 hours) significantly increased cell migration in the SKOV3 and OV-MZ-6 ovarian cancer cell lines. Ghrelin (100 nM) stimulated cell migration in the SKOV3 (2.64 +/- 1.08 fold, p <0.05) and OV-MZ-6 (1.65 +/- 0.31 fold, p <0.05) ovarian cancer cell lines, but not in the representative normal cell line hOSE 17.1. This increase in migration was not accompanied by an increase in cell invasion through Matrigel. In contrast to other cancer types, ghrelin had no effect on proliferation. Ghrelin treatment (10nM) significantly decreased attachment of the SKOV3 ovarian cancer cell line to collagen IV (24.7 +/- 10.0 %, p <0.05), however, there were no changes in attachment to the other extracellular matrix molecules (ECM) tested (fibronectin, vitronectin and collagen I), and there were no changes in attachment to any of the ECM molecules in the OV-MZ-6 or hOSE 17.1 cell lines. It is, therefore, unclear if ghrelin plays a role in cell attachment in ovarian cancer. As ghrelin has previously been demonstrated to signal through the ERK1/2 pathway in cancer, we investigated ERK1/2 signalling in ovarian cancer cell lines. In the SKOV3 ovarian cancer cell line, a reduction in ERK1/2 phosphorylation (0.58 fold +/- 0.23, p <0.05) in response to 100 nM ghrelin treatment was observed, while no significant change in ERK1/2 signalling was seen in the OV-MZ-6 cell line with treatment. This suggests that this pathway is unlikely to be involved in mediating the increased migration seen in the ovarian cancer cell lines with ghrelin treatment. In this study ovarian cancer tissue of varying stages and normal ovarian tissue expressed the coding region for obestatin, however, no correlation between cancer grade and level of obestatin transcript expression was observed. In the ovarian-derived cell lines studied (SKOV3, OV-MZ-6 and hOSE 17.1) it was demonstrated that the full length preproghrelin mRNA transcripts were expressed in all cell lines, suggesting they have the ability to produce mature obestatin. This is the first study to demonstrate that obestatin stimulates cell migration and cell invasion. Obestatin induced a significant increase in migration in the SKOV3 ovarian cancer cell line with 10 nM (2.80 +/- 0.52 fold, p <0.05) and 100 nM treatments (3.12 +/- 0.68 fold, p <0.05) and in the OV-MZ-6 cancer cell line with 10 nM (2.04 +/- 0.10 fold, p <0.01) and 100 nM treatments (2.00 +/- 0.37 fold, p <0.05). Obestatin treatment did no affect cell migration in the hOSE 17.1normal ovarian epithelial cell line. Obestatin treatment (100 nM) also stimulated a significant increase in cell invasion in the OV-MZ-6 ovarian cancer cell line (1.45 fold +/- 0.13, p <0.05) and in the hOSE17.1 normal ovarian cell line cells (1.40 fold +/- 0.04 and 1.55 fold +/- 0.05 respectively, p <0.01) with 10 nM and 100 nM treatments. Obestatin treatment did not stimulate cell invasion in the SKOV3 ovarian cancer cell line. This lack of obestatin-stimulated invasion in the SKOV3 cell line may be a cell line specific result. In this study, obestatin did not stimulate cell proliferation in the ovarian cell lines and it has previously been shown to have no effect on cell proliferation in the BON-1 pancreatic neuroendocrine and GC rat somatotroph tumour cell lines. In contrast, obestatin has been shown to affect cell proliferation in gastric and thyroid cancer cell lines, and in some normal cell lines. Obestatin also had no effect on attachment of any of the cell lines to any of the ECM components tested (fibronectin, vitronectin, collagen I and collagen IV). The mechanism of action of obestatin was investigated further using a two dimensional-difference in gel electrophoresis (2D-DIGE) proteomic approach. After treatment with obestating (0, 10 and 100 nM), SKOV3 ovarian cancer and hOSE 17.1 normal ovarian cell lines were collected and 2D-DIGE analysis and mass spectrometry were performed to identify proteins that were differentially expressed in response to treatment. Twenty-six differentially expressed proteins were identified and analysed using Ingenuity Pathway Analysis (IPA). This linked 16 of these proteins in a network. The analysis suggested that the ERK1/2 MAPK pathway was a major mediator of obestatin action. ERK1/2 has previously been shown to be associated with obestatin-stimulated cell proliferation and with the anti-apoptotic effects of obestatin. Activation of the ERK1/2 signalling pathway by obestatin was, therefore, investigated in the SKOV3 and OV-MZ-6 ovarian cancer cell lines using anti-active antibodies and Western immunoblots. Obestatin treatment significantly decreased ERK1/2 phosphorylation at higher obestatin concentrations in both the SKOV3 (100 nM and 1000 nM) and OV-MZ-6 (1000 nM) cell lines compared to the untreated controls. Currently, very little is known about obestatin signalling in cancer. This thesis has demonstrated for the first time that the ghrelin axis may play a role in ovarian cancer migration. Ghrelin and obestatin increased cell migration in ovarian cancer cell lines, indicating that they may be a useful target for therapies that reduce ovarian cancer progression. Further studies investigating the role of the ghrelin axis using in vivo ovarian cancer metastasis models are warranted.

The association of single nucleotide polymorphisms with endometrial cancer risk and prognosis

Endometrial cancer is one of the most common female diseases in developed nations and is the most commonly diagnosed gynaecological cancer in Australia. The disease is commonly classified by histology: endometrioid or non-endometrioid endometrial cancer. While non-endometrioid endometrial cancers are accepted to be high-grade, aggressive cancers, endometrioid cancers (comprising 80% of all endometrial cancers diagnosed) generally carry a favourable patient prognosis. However, endometrioid endometrial cancer patients endure significant morbidity due to surgery and radiotherapy used for disease treatment, and patients with recurrent disease have a 5-year survival rate of less than 50%. Genetic analysis of women with endometrial cancer could uncover novel markers associated with disease risk and/or prognosis, which could then be used to identify women at high risk and for the use of specialised treatments. Proteases are widely accepted to play an important role in the development and progression of cancer. This PhD project hypothesised that SNPs from two protease gene families, the matrix metalloproteases (MMPs, including their tissue inhibitors, TIMPs) and the tissue kallikrein-related peptidases (KLKs) would be associated with endometrial cancer susceptibility and/or prognosis. In the first part of this study, optimisation of the genotyping techniques was performed. Results from previously published endometrial cancer genetic association studies were attempted to be validated in a large, multicentre replication set (maximum cases n = 2,888, controls n = 4,483, 3 studies). The rs11224561 progesterone receptor SNP (PGR, A/G) was observed to be associated with increased endometrial cancer risk (per A allele OR 1.31, 95% CI 1.12-1.53; p-trend = 0.001), a result which was initially reported among a Chinese sample set. Previously reported associations for the remaining 8 SNPs investigated for this section of the PhD study were not confirmed, thereby reinforcing the importance of validation of genetic association studies. To examine the effect of SNPs from the MMP and KLK families on endometrial cancer risk, we selected the most significantly associated MMP and KLK SNPs from genome-wide association study analysis (GWAS) to be genotyped in the GWAS replication set (cases n = 4,725, controls n = 9,803, 13 studies). The significance of the MMP24 rs932562 SNP was unchanged after incorporation of the stage 2 samples (Stage 1 per allele OR 1.18, p = 0.002; Combined Stage 1 and 2 OR 1.09, p = 0.002). The rs10426 SNP, located 3' to KLK10 was predicted by bioinformatic analysis to effect miRNA binding. This SNP was observed in the GWAS stage 1 result to exhibit a recessive effect on endometrial cancer risk, a result which was not validated in the stage 2 sample set (Stage 1 OR 1.44, p = 0.007; Combined Stage 1 and 2 OR 1.14, p = 0.08). Investigation of the regions imputed surrounding the MMP, TIMP and KLK genes did not reveal any significant targets for further analysis. Analysis of the case data from the endometrial cancer GWAS to identify genetic variation associated with cancer grade did not reveal SNPs from the MMP, TIMP or KLK genes to be statistically significant. However, the representation of SNPs from the MMP, TIMP and KLK families by the GWAS genotyping platform used in this PhD project was examined and observed to be very low, with the genetic variation of four genes (MMP23A, MMP23B, MMP28 and TIMP1) not captured at all by this technique. This suggests that comprehensive candidate gene association studies will be required to assess the role of SNPs from these genes with endometrial cancer risk and prognosis. Meta-analysis of gene expression microarray datasets curated as part of this PhD study identified a number of MMP, TIMP and KLK genes to display differential expression by endometrial cancer status (MMP2, MMP10, MMP11, MMP13, MMP19, MMP25 and KLK1) and histology (MMP2, MMP11, MMP12, MMP26, MMP28, TIMP2, TIMP3, KLK6, KLK7, KLK11 and KLK12). In light of these findings these genes should be prioritised for future targeted genetic association studies. Two SNPs located 43.5 Mb apart on chromosome 15 were observed from the GWAS analysis to be associated with increased endometrial cancer grade, results that were validated in silico in two independent datasets. One of these SNPs, rs8035725 is located in the 5' untranslated region of a MYC promoter binding protein DENND4A (Stage 1 OR 1.15, p = 9.85 x 10P -5 P, combined Stage 1 and in silico validation OR 1.13, p = 5.24 x 10P -6 P). This SNP has previously been reported to alter the expression of PTPLAD1, a gene involved in the synthesis of very long fatty acid chains and in the Rac1 signaling pathway. Meta-analysis of gene expression microarray data found PTPLAD1 to display increased expression in the aggressive non-endometrioid histology compared with endometrioid endometrial cancer, suggesting that the causal SNP underlying the observed genetic association may influence expression of this gene. Neither rs8035725 nor significant SNPs identified by imputation were predicted bioinformatically to affect transcription factor binding sites, indicating that further studies are required to assess their potential effect on other regulatory elements. The other grade- associated SNP, rs6606792, is located upstream of an inferred pseudogene, ELMO2P1 (Stage 1 OR 1.12, p = 5 x 10P -5 P; combined Stage 1 and in silico validation OR 1.09, p = 3.56 x 10P -5 P). Imputation of the ±1 Mb region surrounding this SNP revealed a cluster of significantly associated variants which are predicted to abolish various transcription factor binding sites, and would be expected to decrease gene expression. ELMO2P1 was not included on the microarray platforms collected for this PhD, and so its expression could not be investigated. However, the high sequence homology of ELMO2P1 with ELMO2, a gene important to cell motility, indicates that ELMO2 could be the parent gene for ELMO2P1 and as such, ELMO2P1 could function to regulate the expression of ELMO2. Increased expression of ELMO2 was seen to be associated with increasing endometrial cancer grade, as well as with aggressive endometrial cancer histological subtypes by microarray meta-analysis. Thus, it is hypothesised that SNPs in linkage disequilibrium with rs6606792 decrease the transcription of ELMO2P1, reducing the regulatory effect of ELMO2P1 on ELMO2 expression. Consequently, ELMO2 expression is increased, cell motility is enhanced leading to an aggressive endometrial cancer phenotype. In summary, these findings have identified several areas of research for further study. The results presented in this thesis provide evidence that a SNP in PGR is associated with risk of developing endometrial cancer. This PhD study also reports two independent loci on chromosome 15 to be associated with increased endometrial cancer grade, and furthermore, genes associated with these SNPs to be differentially expressed according in aggressive subtypes and/or by grade. The studies reported in this thesis support the need for comprehensive SNP association studies on prioritised MMP, TIMP and KLK genes in large sample sets. Until these studies are performed, the role of MMP, TIMP and KLK genetic variation remains unclear. Overall, this PhD study has contributed to the understanding of genetic variation involvement in endometrial cancer susceptibility and prognosis. Importantly, the genetic regions highlighted in this study could lead to the identification of novel gene targets to better understand the biology of endometrial cancer and also aid in the development of therapeutics directed at treating this disease.

Engineering based problem solving in the middle school : design and construction with simple machines

Incorporating engineering concepts into middle school curriculum is seen as an effective way to improve students’ problem-solving skills. A selection of findings is reported from a science, technology, engineering and mathematics (STEM)-based unit in which students in the second year (grade 8) of a three-year longitudinal study explored engineering concepts and principles pertaining to the functioning of simple machines. The culminating activity, the focus of this paper, required the students to design, construct, test, and evaluate a trebuchet catapult. We consider findings from one of the schools, a co-educational school, where we traced the design process developments of four student groups from two classes. The students’ descriptions and explanations of the simple machines used in their catapult design are examined, together with how they rated various aspects of their engineering designs. Included in the findings are students’ understanding of how their simple machines were simulated by the resources supplied and how the machines interacted in forming a complex machine. An ability to link physical materials with abstract concepts and an awareness of design constraints on their constructions were apparent, although a desire to create a ‘‘perfect’’ catapult despite limitations in the physical materials rather than a prototype for testing concepts was evident. Feedback from teacher interviews added further insights into the students’ developments as well as the teachers’ professional learning. An evolving framework for introducing engineering education in the pre-secondary years is proposed.