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.

Using GPS and accelerometry to assess older adults' driving behaviours and performance : challenges and future directions

With the projected increase in older adults, the older driver population is estimated to be the fastest growing cohort of drivers among many developed countries. The increased physical fragility associated with the aging process make older adults who drive private automobiles a vulnerable road user group. Much of the current research on older drivers’ behaviours and practices rely on self-report data. This paper explores the utility of in-vehicle devices (Global Positioning Systems and recording accelerometers) in assessing older drivers’ habitual driving behaviours. Seventy-eight older drivers (above 65 years of age), from the Australian Capital Territory, Australia, participated in the current study. The driving behaviours and practices of these participants were prospectively assessed over a two-week period. The use of combined GPS and recording accelerometers to improve understanding of older drivers’ driving behaviours show promise within the current study. The challenges of using multiple in-vehicle devices in assessing driving beahaviours and performances within this cohort will be discussed. Based on the current findings, recommendations for future research regarding the use of in-vehicle devices among the older driver cohort are proposed.

Review essay : Crime, risk and money : "The Currency of Justice : Fines and Damages in Consumer Societies" and "Crime and Risk", both by Pat O'Malley

Sharing some closely related themes and a common theoretical orientation based on the governmentality analytic, these are nevertheless two very different contributions to criminological knowledge and theory. The first, The Currency of Justice: Fines and Damages in Consumer Societies (COJ), is a sustained and highly original analysis of that most pervasive yet overlooked feature of modern legal orders; their reliance on monetary sanctions. Crime and Risk (CAR), on the other hand, is a short synoptic overview of the many dimensions and trajectories of risk in contemporary debate and practice, both the practices of crime and the governance of crime. It is one of the first in a new series by Sage, 'Compact Criminology', in which authors survey in little more than a hundred pages some current field of debate. With this small gem, Pat O'Malley has set the bar very high for those who follow. For all its brevity, CAR traverses a massive expanse of research, debates and issues, while also opening up new and challenging questions around the politics of risk and the relationship between criminal risk-taking and the governance of risk and crime. The two books draw together various threads of O'Malley's rich body of work on these issues, and once again demonstrate that he is one of the foremost international scholars of risk inside and outside criminology.

Validation of an instrument to measure governance and performance on collaborative infrastructure projects

Collaborative infrastructure projects use hybrid formal and informal governance structures to manage transactions. Based on previous desk-top research, the authors identified the key mechanisms underlying project governance, and posited the performance implications of the governance (Chen et al. 2012). The current paper extends that qualitative research by testing the veracity of those findings using data from 320 Australian construction organisations. The results provide, for the first time, reliable and valid scales to measure governance and performance of collaborative projects, and the relationship between them. The results confirm seven of seven hypothesised governance mechanisms; 30 of 43 hypothesised underlying actions; eight of eight hypothesised key performance indicators; and the dual importance of formal and informal governance. A startling finding of the study was that the implementation intensity of informal mechanisms (non-contractual conditions) is a greater predictor of project performance variance than that of formal mechanisms (contractual conditions). Further, contractual conditions do not directly impact project performance; instead their impact is mediated by the non-contractual features of a project. Obligations established under the contract are not sufficient to optimise project performance.

Strategies and solutions for housing sustainability : building information files and performance certificates

The overall aim of this research project was to provide a broader range of value propositions (beyond upfront traditional construction costs) that could transform both the demand side and supply side of the housing industry. The project involved gathering information about how building information is created, used and communicated and classifying building information, leading to the formation of an Information Flow Chart and Stakeholder Relationship Map. These were then tested via broad housing industry focus groups and surveys. The project revealed four key relationships that appear to operate in isolation to the whole housing sector and may have significant impact on the sustainability outcomes and life cycle costs of dwellings over their life cycle. It also found that although a lot of information about individual dwellings does already exist, this information is not coordinated or inventoried in any systematic manner and that national building information files of building passports would present value to a wide range of stakeholders.

Organizational factors impacting on patient satisfaction : a cross sectional examination of service climate and linkages to nurses' effort and performance

Background Patient satisfaction is influenced by the setting in which patients are treated and the employees providing care. However, to date, limited research has explained how health care organizations or nurses influence patient satisfaction. Objectives The purpose of this study was to test the model that service climate would increase the effort and performance of nursing groups and, in turn, increase patient satisfaction. Method This study incorporated data from 156 nurses, 28 supervisors, and 171 patients. A cross-sectional design was utilized to examine the relationship between service climate, nurse effort, nurse performance and patient satisfaction. Structural equation modeling was conducted to test the proposed relationships. Results Service climate was associated with the effort that nurses directed towards technical care and extra-role behaviors. In turn, the effort that nurses exerted predicted their performance, as rated by their supervisors. Finally, task performance was a significant predictor of patient satisfaction. Conclusions This study suggests that both hospital management and nurses play a role in promoting patient satisfaction. By focusing on creating a climate for service, health care managers can improve nursing performance and patient satisfaction with care.

Service quality and performance measurement : evidence from the Indian Water Sector

The conventional measures of benchmarking focus mainly on the water produced or water delivered, and ignore the service quality, and as a result the 'low-cost and low-quality' utilities are rated as efficient units. Benchmarking must credit utilities for improvements in service delivery. This study measures the performance of 20 urban water utilities using data from an Asian Development Bank survey of Indian water utilities in 2005. It applies data envelopment analysis to measure the performance of utilities. The results reveal that incorporation of a quality dimension into the analysis significantly increases the average performance of utilities. The difference between conventional quantity-based measures and quality-adjusted estimates implies that there are significant opportunity costs of maintaining the quality of services in water delivery.

The contribution of sport and performance psychology to coaching

The role of the sport and performance psychologists offers an historical base to many of the conceptualizations, strategies and tools currently utilized by coaches and coaching psychologists. The world of elite sport and performance offers little room for negativity, little tolerance for cognitions, emotions and behaviours that are less than optimal; in an environment that sets high expectation, makes obvious comparisons and is driven by competition; all within inflexible timelines and with harsh consequences for those that don’t make the grade. From this context the presenters will reflect on their development, challenges and expertise; offering ideas and tools that translate into the coaching arena.

The impact of work-family programs on the relationship between gender diversity and performance

Work–family programs signal an employer's perspective on gender diversity to employees, and can influence whether the effects of diversity on performance are positive or negative. This article tests the interactive effects of nonmanagement gender diversity and work–family programs on productivity, and management gender diversity and work–family programs on financial performance. The predictions were tested in 198 Australian publicly listed organizations using primary (survey) and secondary (publicly available) data based on a two-year time lag between diversity and performance. The findings indicate that nonmanagement gender diversity leads to higher productivity in organizations with many work–family programs, and management gender diversity leads to lower financial performance in organizations with few work–family programs. The results suggest different business cases at nonmanagement and management levels for the adoption of work–family programs in gender-diverse organizations.

Investigation on characteristics and performance of recycled concrete aggregates as granular materials for unbound pavements

This research was a step forward in investigating the characteristics of recycled concrete aggregates to use as an unbound pavement material. The results present the guidelines for successfully application of recycled concrete aggregates in high traffic volume roads. Outcomes of the research create more economical and environmental benefits through reducing the depletion of natural resources and effectively manage the generated concrete waste before disposal as land fill.

Modelling and performance of an active heave compensator for offshore operations

The development of offshore oil and gas fields require the placement of different equipment on the sea floor. This is done by deploying the equipment from vessels operating in dynamic positioning on the surface. The deployment operation has different phases, and in higher sea states, it may require wave-load synchronization, when the load is going through the splash zone, and heave compensation when the load is close to the sea floor. In this paper, we analyse the performance of a particular type of hardware operating in a heave compensation mode. We derive a comprehensive model, analyse limits of performance and evaluate a control strategy.

Academic honors and performance

Despite the social importance of awards, they have been largely disregarded by academic research in economics. This paper investigates whether receiving prestigious academic awards—the John Bates Clark Medal and the Fellowship of the Econometric Society—is associated with higher subsequent research productivity and status compared to a synthetic control group of non-recipient scholars with similar previous research performance. Our results suggest statistically significant positive publication and citation differences after award receipt.

Dynamic capabilities and performance : an empirical study of audiovisual producers in Europe

This study tests Teece’s conceptualization of dynamic capabilities in the context of small and medium sized firms competing in creative industries, i.e. the European audio-visual production industry. This industry is characterized by immature and evolving markets where firms’ dynamic capabilities are expected to lead to superior innovative performance. Using survey data from audio-visual producers in ten European countries we find that both sensing and seizing capabilities have a positive effect on firms' innovative performance. The effect however, is curvilinear and positive effects appear only when capabilities overcome a threshold level.