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.

A pseudo-marginal sequential Monte Carlo algorithm for random effects models in Bayesian sequential design

A computationally efficient sequential Monte Carlo algorithm is proposed for the sequential design of experiments for the collection of block data described by mixed effects models. The difficulty in applying a sequential Monte Carlo algorithm in such settings is the need to evaluate the observed data likelihood, which is typically intractable for all but linear Gaussian models. To overcome this difficulty, we propose to unbiasedly estimate the likelihood, and perform inference and make decisions based on an exact-approximate algorithm. Two estimates are proposed: using Quasi Monte Carlo methods and using the Laplace approximation with importance sampling. Both of these approaches can be computationally expensive, so we propose exploiting parallel computational architectures to ensure designs can be derived in a timely manner. We also extend our approach to allow for model uncertainty. This research is motivated by important pharmacological studies related to the treatment of critically ill patients.

Pharmacokinetics and tumor disposition of PEGylated, methotrexate conjugated poly-l-lysine dendrimers

Dendrimers have potential for delivering chemotherapeutic drugs to solid tumours via the enhanced permeation and retention (EPR) effect. The impact of conjugation of hydrophobic anticancer drugs to hydrophilic PEGylated dendrimer surfaces, however, has not been fully investigated. The current study has therefore characterised the effect on dendrimer disposition of conjugating α-carboxyl protected methotrexate (MTX) to a series of PEGylated 3H-labelled poly-L-lysine dendrimers ranging in size from generation 3 (G3) to 5 (G5) in rats. Dendrimers contained 50% surface PEG and 50% surface MTX. Conjugation of MTX generally increased plasma clearance when compared to conjugation with PEG alone. Conversely, increasing generation reduced clearance, increased metabolic stability and reduced renal elimination of the administered radiolabel. For constructs with molecular weights >20 kDa increasing the molecular weight of conjugated PEG also reduced clearance and enhanced metabolic stability but had only a minimal effect on renal elimination. Tissue distribution studies revealed retention of MTX conjugated smaller (G3-G4) PEG570 dendrimers (or their metabolic products) in the kidneys. In contrast, the larger G5 dendrimer was concentrated more in the liver and spleen. The G5 PEG1100 dendrimer was also shown to accumulate in solid Walker 256 and HT1080 tumours and comparative disposition data in both rats (1 to 2% dose/g in tumour) and mice (11% dose/g in tumour) are presented. The results of this study further illustrate the potential utility of biodegradable PEGylated poly-L-lysine dendrimers as long circulating vectors for the delivery and tumour-targeting of hydrophobic drugs.

NADPH oxidases as regulators of tumor angiogenesis : current and emerging concepts

Significance Reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and peroxynitrite are generated ubiquitously by all mammalian cells and have been understood for many decades as inflicting cell damage and as causing cancer by oxidation and nitration of macromolecules, including DNA, RNA, proteins, and lipids. Recent Advances A current concept suggests that ROS can also promote cell signaling pathways triggered by growth factors and transcription factors that ultimately regulate cell proliferation, differentiation, and apoptosis, all of which are important hallmarks of tumor cell proliferation and angiogenesis. Moreover, an emerging concept indicates that ROS regulate the functions of immune cells that infiltrate the tumor environment and stimulate angiogenesis, such as macrophages and specific regulatory T cells. Critical Issues In this article, we highlight that the NADPH oxidase family of ROS-generating enzymes are the key sources of ROS and, thus, play an important role in redox signaling within tumor, endothelial, and immune cells thereby promoting tumor angiogenesis. Future Directions Knowledge of these intricate ROS signaling pathways and identification of the culprit NADPH oxidases is likely to reveal novel therapeutic opportunities to prevent angiogenesis that occurs during cancer and which is responsible for the revascularization after current antiangiogenic treatment.

Development and characterization of a novel, antimicrobial, sterile hydrogel dressing for burn wounds : single-step production with gamma irradiation creates silver nanoparticles and radical polymerization

Patients with burn wounds are susceptible to wound infection and sepsis. This research introduces a novel burn wound dressing that contains silver nanoparticles (SNPs) to treat infection in a 2-acrylamido-2-methylpropane sulfonic acid sodium salt (AMPS-Na(+) ) hydrogel. Silver nitrate was dissolved in AMPS-Na(+) solution and then exposed to gamma irradiation to form SNP-infused hydrogels. The gamma irradiation results in a cross-linked polymeric network of sterile hydrogel dressing and a reduction of silver ions to form SNPs infused in the hydrogel in a one-step process. About 80% of the total silver was released from the hydrogels after 72 h immersion in simulated body fluid solution; therefore, they could be used on wounds for up to 3 days. All the hydrogels were found to be nontoxic to normal human dermal fibroblast cells. The silver-loaded hydrogels had good inhibitory action against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. Results from a pilot study on a porcine burn model showed that the 5-mM silver hydrogel was efficient at preventing bacterial colonization of wounds, and the results were comparable to the commercially available silver dressings (Acticoat(TM) , PolyMem Silver(®) ). These results support its use as a potential burn wound dressing.

Supine to standing Cobb angle change in idiopathic scoliosis : the effect of endplate pre-selection

Background Supine imaging modalities provide valuable 3D information on scoliotic anatomy, but the altered spine geometry between the supine and standing positions affects the Cobb angle measurement. Previous studies report a mean 7°-10° Cobb angle increase from supine to standing, but none have reported the effect of endplate pre-selection or whether other parameters affect this Cobb angle difference. Methods Cobb angles from existing coronal radiographs were compared to those on existing low-dose CT scans taken within three months of the reference radiograph for a group of females with adolescent idiopathic scoliosis. Reformatted coronal CT images were used to measure supine Cobb angles with and without endplate pre-selection (end-plates selected from the radiographs) by two observers on three separate occasions. Inter and intra-observer measurement variability were assessed. Multi-linear regression was used to investigate whether there was a relationship between supine to standing Cobb angle change and eight variables: patient age, mass, standing Cobb angle, Risser sign, ligament laxity, Lenke type, fulcrum flexibility and time delay between radiograph and CT scan. Results Fifty-two patients with right thoracic Lenke Type 1 curves and mean age 14.6 years (SD 1.8) were included. The mean Cobb angle on standing radiographs was 51.9° (SD 6.7). The mean Cobb angle on supine CT images without pre-selection of endplates was 41.1° (SD 6.4). The mean Cobb angle on supine CT images with endplate pre-selection was 40.5° (SD 6.6). Pre-selecting vertebral endplates increased the mean Cobb change by 0.6° (SD 2.3, range −9° to 6°). When free to do so, observers chose different levels for the end vertebrae in 39% of cases. Multi-linear regression revealed a statistically significant relationship between supine to standing Cobb change and fulcrum flexibility (p = 0.001), age (p = 0.027) and standing Cobb angle (p < 0.001). The 95% confidence intervals for intra-observer and inter-observer measurement variability were 3.1° and 3.6°, respectively. Conclusions Pre-selecting vertebral endplates causes minor changes to the mean supine to standing Cobb change. There is a statistically significant relationship between supine to standing Cobb change and fulcrum flexibility such that this difference can be considered a potential alternative measure of spinal flexibility.

The effect of endplate preselection when measuring supine versus standing cobb angle change in idiopathic scoliosis

The primary aim of this study was to determine whether endplate pre-selection makes a difference to the Cobb Angle change between supine and standing which is known to occur in idiopathic scoliosis. A secondary aim of this study was to identify which (if any) patient characteristics were correlated with supine versus standing Cobb change. The study found that pre-selecting vertebral endplates causes only has a minor effect on supine to standing Cobb change in scoliosis. There is a statistically significant relationship between supine to standing Cobb Angle change and fulcrum flexibility. Therefore, supine to standing Cobb Angle change can be considered as a measure of spinal flexibility when both standing and supine images are clinically available.

Labour Law and Labour Market Regulation

The traditional boundaries of labour law are becoming outmoded in a modern world in which active labour market participants vastly outnumber “employees”, and the world of work extends way beyond the workplace gate. There is convergence with labour market regulation. The contract of employment remains central but is no longer the sole object of study.Labour Law and Labour Market Regulation reflects the dramatically different industrial, social, political and legislative contexts in which the law now operates and the intellectual revolution this is generating. Individual chapters contain studies of regulation within prescriptive government schemes, contract networks, specialist labour markets, the intersection between work and family, enterprise policies and practices, and the courts and tribunals. The book provides insights into areas that are, as arbitration declines, becoming increasingly important to their clients' interests. The most recent legislation and jurisprudence is discussed in many chapters including discrimination, dismissals, health and safety, immigration, social security, franchise, volunteer and contract law.

Regulating Occupational Health and Safety in a Changing Labour Market

The traditional boundaries of labour law are becoming outmoded in a modern world in which active labour market participants vastly outnumber “employees”, and the world of work extends way beyond the workplace gate. There is convergence with labour market regulation. The contract of employment remains central but is no longer the sole object of study.

Constitutive Regulation of the Firm: occupational health and safety, dismissal, discrimination and sexual harassment

As many other chapters in this book have noted, until recently labour lawyers have tended not to draaw on regulatory scholarship. In this chapter we look at certain areas of labour law through a particular kind of regulatory lens - regulation that requires firms to reconstitute their management processes and procedures, perhaps even their organisational cultures. In particular, we examine the kinds of regulatory demands made on firms by legal rules in four areas of labour law: (i) occupational health and safety (OHS)regulation; unfair dismissal law; equal opportunity (EO) and (iv) sexual harassment law.

New Dawn (Parts I & II)

New Dawn is a cross-media visual art project that comprises a multi–channel video work (Boxcopy ARI, Brisbane) and a series of sculptural works (MetroArts, Brisbane) both of which conflate the online spectacle of real events with virtual gaming. The purpose of this project is to question this new phenomenon and what are the political, social and economic repercussions for these new technological developments on our bodies and subjectivities. By doing this my work asks us to reflect on how we function as a society in response to these new spaces of interaction, how we might respond to the political dimensions of these expanded sites of inhabitation, and how they might also represent a more troubling scenario for the possibility of dissent or opposition in our media saturated culture. The work was shown at multiple venues simultaneously. One of the components of the work won the 2013 Sunshine Coast Art Prize for sculpture.

Better half-dead than read? The Mezzomorto cases and their implications for literary culture in the 1930s

This article focusses on the two libel cases arising from Brian Penton's review of Vivian Crockett's novel Mezzomorto for the Bulletin in 1934, viewing them as points of entry into Australian literary politics in the 1930s, and as windows on to one of the most enduring and interesting feuds in Australian literary culture, that between P.R. 'Inky' Stephensen, self-styled 'Bunyip Critic,' and Brian Penton, arch exponent of 'destructive criticism' and scourge of parochial pretension. The cases are particularly interesting for what they reveal about the evolving positions of two influential figures in Australian writing of the 1930s and 1940s. They also play in to contemporary debates about the state and status of 'literature' in Australia. And while Penton's biographer Patrick Buckridge avers that the cases did not impact on any of the larger contemporary literary issues (meaning censorship and free speech), a case may be made for the significance of the libel actions in the context of attempts to establish an industrial and cultural presence for a diverse range of Australian writing.

Deterrence of drug driving : the impact of the ACT drug driving legislation and detection techniques

Overarching Research Questions Are ACT motorists aware of roadside saliva based drug testing operations? What is the perceived deterrent impact of the operations? What factors are predictive of future intentions to drug drive? What are the differences between key subgroups

Using qualitative mixed methods to study small health care organizations while maximising trustworthiness and authenticity

Background The primary health care sector delivers the majority of health care in western countries through small, community-based organizations. However, research into these healthcare organizations is limited by the time constraints and pressure facing them, and the concern by staff that research is peripheral to their work. We developed Q-RARA—Qualitative Rapid Appraisal, Rigorous Analysis—to study small, primary health care organizations in a way that is efficient, acceptable to participants and methodologically rigorous. Methods Q-RARA comprises a site visit, semi-structured interviews, structured and unstructured observations, photographs, floor plans, and social scanning data. Data were collected over the course of one day per site and the qualitative analysis was integrated and iterative. Results We found Q-RARA to be acceptable to participants and effective in collecting data on organizational function in multiple sites without disrupting the practice, while maintaining a balance between speed and trustworthiness. Conclusions The Q-RARA approach is capable of providing a richly textured, rigorous understanding of the processes of the primary care practice while also allowing researchers to develop an organizational perspective. For these reasons the approach is recommended for use in small-scale organizations both within and outside the primary health care sector.