Fine-mapping the HOXB region detects common variants tagging a rare coding allele : evidence for synthetic association in prostate cancer

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer

The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4), and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a) was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic), whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p<0.05. MiR-21 and miR-146a expression was significantly increased in MyD88 negative cancers (p<0.05), indicating their participation in regulation. Significant alterations in MyD88 mRNA expression were observed between chemosensitive and chemoresistant cells and tissue. Knockdown of TLR4 in SKOV-3 ovarian cells recovered chemosensitivity. Knockdown of MyD88 alone did not. MyD88 expression was down-regulated in differentiated embryonal carcinoma (NTera2) cells, supporting the MyD88+ cancer stem cell hypothesis. Our findings demonstrate that expression of MyD88 is associated with significantly reduced patient survival and altered microRNA levels and suggest an intact/functioning TLR4/MyD88 pathway is required for acquisition of the chemoresistant phenotype. Ex vivo manipulation of ovarian cancer stem cell (CSC) differentiation can decrease MyD88 expression, providing a potentially valuable CSC model for ovarian cancer.

Critical linguistics in the early years : exploring functions of language through sophisticated picture books and process drama strategies

In this chapter we describe a critical fairytales unit taught to 4.5 to 5.5 year olds in a context of intensifying pressure to raise literacy achievement. The unit was infused with lessons on reinterpreted fairytales followed by process drama activities built around a sophisticated picture book, Beware of the Bears (MacDonald, 2004). The latter entailed a text analytic approach to critical literacy derived from systemic functional linguistics (Halliday, 1978; Halliday & Matthiessen, 2004). This approach provides a way of analysing how words and discourse are used to represent the world in a particular way and shape reader relations with the author in a particular field (Janks, 2010).

The United Nations Guiding Principles on Business and Human Rights : Putting Accounting for Human Rights into Practice

The “Guiding Principles on Business and Human Rights: Implementing the United Nations ‘Protect, Respect and Remedy Framework’” (the Guiding Principles), endorsed by The United Nations Human Rights Council on 16 June 2011, outline obligations for nation states that currently exist under international law and provide the first authoritative reference point for corporations’ human rights responsibilities. Of the 30 principles endorsed, half relate directly to business. The Guiding Principles have far-reaching implications for all businesses, both small and large, and represent one of the most significant developments in corporate governance this century. In response to a recognition of the potential impacts of the Guiding Principles on corporate governance, the Institute of Chartered Accountants in Australia provided La Trobe Business School with grant funding to undertake groundbreaking research on the implications of the Guiding Principles for management and accounting systems within corporate Australia. This report represents the outcome of the study.

Development of health risk-based metrics for defining a heatwave : a time series study in Brisbane, Australia

Background: This study attempted to develop health risk-based metrics for defining a heatwave in Brisbane, Australia. Methods: Poisson generalised additive model was performed to assess the impact of heatwaves on mortality and emergency hospital admissions (EHAs) in Brisbane. Results: In general, the higher the intensity and the longer the duration of a heatwave, the greater the health impacts. There was no apparent difference in EHAs risk during different periods of a warm season. However, there was a greater risk of mortality in the second half of a warm season than that in the first half. While elderly (>75 years)were particularly vulnerable to both the EHA and mortality effects of a heatwave, the risk for EHAs also significantly increased for two other age groups (0-64 years and 65-74 years) during severe heatwaves. Different patterns between cardiorespiratory mortality and EHAs were observed. Based on these findings, we propose the use of a teiered heat warning system based on the health risk of heatwave. Conclusions: Health risk-based metrics are a useful tool for the development of local heatwave definitions. thsi tool may have significant implications for the assessment of heatwave-related health consequences and development of heatwave response plans and implementation strategies.

Analyzing the impact of learning inputs on near-to-far terrain traversability estimation

With the increasing need to adapt to new environments, data-driven approaches have been developed to estimate terrain traversability by learning the rover’s response on the terrain based on experience. Multiple learning inputs are often used to adequately describe the various aspects of terrain traversability. In a complex learning framework, it can be difficult to identify the relevance of each learning input to the resulting estimate. This paper addresses the suitability of each learning input by systematically analyzing the impact of each input on the estimate. Sensitivity Analysis (SA) methods provide a means to measure the contribution of each learning input to the estimate variability. Using a variance-based SA method, we characterize how the prediction changes as one or more of the input changes, and also quantify the prediction uncertainty as attributed from each of the inputs in the framework of dependent inputs. We propose an approach built on Analysis of Variance (ANOVA) decomposition to examine the prediction made in a near-to-far learning framework based on multi-task GP regression. We demonstrate the approach by analyzing the impact of driving speed and terrain geometry on the prediction of the rover’s attitude and chassis configuration in a Marsanalogue terrain using our prototype rover Mawson.