Phosphoprotein pathway mapping: Akt/Mammalian target of rapamycin activation is negatively associated with childhood rhabdomyosarcoma survival

Mapping of protein signaling networks within tumors can identify new targets for therapy and provide a means to stratify patients for individualized therapy. Despite advances in combination chemotherapy, the overall survival for childhood rhabdomyosarcoma remains ∼60%. A critical goal is to identify functionally important protein signaling defects associated with treatment failure for the 40% nonresponder cohort. Here, we show, by phosphoproteomic network analysis of microdissected tumor cells, that interlinked components of the Akt/mammalian target of rapamycin (mTOR) pathway exhibited increased levels of phosphorylation for tumors of patients with short-term survival. Specimens (n = 59) were obtained from the Children's Oncology Group Intergroup Rhabdomyosarcoma Study (IRS) IV, D9502 and D9803, with 12-year follow-up. High phosphorylation levels were associated with poor overall and poor disease-free survival: Akt Ser473 (overall survival P < 0.001, recurrence-free survival P < 0.0009), 4EBP1 Thr37/46 (overall survival P < 0.0110, recurrence-free survival P < 0.0106), eIF4G Ser1108 (overall survival P < 0.0017, recurrence-free survival P < 0.0072), and p70S6 Thr389 (overall survival P < 0.0085, recurrence-free survival P < 0.0296). Moreover, the findings support an altered interrelationship between the insulin receptor substrate (IRS-1) and Akt/mTOR pathway proteins (P < 0.0027) for tumors from patients with poor survival. The functional significance of this pathway was tested using CCI-779 in a mouse xenograft model. CCI-779 suppressed phosphorylation of mTOR downstream proteins and greatly reduced the growth of two different rhabdomyosarcoma (RD embryonal P = 0.00008; Rh30 alveolar P = 0.0002) cell lines compared with controls. These results suggest that phosphoprotein mapping of the Akt/mTOR pathway should be studied further as a means to select patients to receive mTOR/IRS pathway inhibitors before administration of chemotherapy.

Network-targeted combination therapy : a new concept in cancer treatment

Toxicity is a major concern for anti-neoplastic drugs, with much of the existing pharmacopoeia being characterized by a very narrow therapeutic index. 'Network-targeted' combination therapy is a promising new concept in cancer therapy, whereby therapeutic index might be improved by targeting multiple nodes in a cell's signaling network, rather than a single node. Here, we examine the potential of this novel approach, illustrating how therapeutic benefit could be achieved with smaller doses of the necessary agents.

One-stop shopping : some notes on the concept and some Australian initiatives

This paper aims to review the notion of the one-stop shop, particularly as it has developed in Australia. It has three main components. The first focuses on a significant initiative taken by the Coombs Royal Commission on Australian Government Administration as a form of action research in the mid-1970s. The second highlights the associated work on access theory by the late Bernard Schaffer and his associates and explains why this work was of fundamental importance for the development of the idea of the one-stop shop. The third deals with subsequent Australian understandings and a pp lications of the idea.

Non-invasive techniques for imaging in-vivo human corneal sub basal nerve mapping and migration rate in diabetic neuropathy

Purpose Corneal confocal microscopy (CCM) is a rapid non-invasive ophthalmic technique, which has been shown to diagnose and stratify the severity of diabetic neuropathy. Current morphometric techniques assess individual static images of the subbasal nerve plexus; this work explores the potential for non-invasive assessment of the wide-field morphology and dynamic changes of this plexus in vivo. Methods In this pilot study, laser scanning CCM was used to acquire maps (using a dynamic fixation target and semi-automated tiling software) of the central corneal sub-basal nerve plexus in 4 diabetic patients with and 6 without neuropathy and in 2 control subjects. Nerve migration was measured in an additional 7 diabetic patients with neuropathy, 4 without neuropathy and in 2 control subjects by repeating a modified version of the mapping procedure within 2-8 weeks, thus facilitating re-identification of distinctive nerve landmarks in the 2 montages. The rate of nerve movement was determined from these data and normalised to a weekly rate (µm/week), using customised software. Results Wide-field corneal nerve fibre length correlated significantly with the Neuropathy Disability Score (r = -0.58, p < 0.05), vibration perception (r = -0.66, p < 0.05) and peroneal conduction velocity (r = 0.67, p < 0.05). Central corneal nerve fibre length did not correlate with any of these measures of neuropathy (p > 0.05 for all). The rate of corneal nerve migration was 14.3 ± 1.1 µm/week in diabetic patients with neuropathy, 19.7 ± 13.3µm/week in diabetic patients without neuropathy, and 24.4 ± 9.8µm/week in control subjects; however, these differences were not significantly different (p = 0.543). Conclusions Our data demonstrate that it is possible to capture wide-field images of the corneal nerve plexus, and to quantify the rate of corneal nerve migration by repeating this procedure over a number of weeks. Further studies on larger sample sizes are required to determine the utility of this approach for the diagnosis and monitoring of diabetic neuropathy.

China's "Responsible Protection" concept : re-interpreting the Responsibility to Protect (R2P) and military intervention for humanitarian purposes

This article assesses the extent to which the recently formulated Chinese concept of “Responsible Protection” (RP) offers a valuable contribution to the normative debate over R2P’s third pillar following the controversy over military intervention in Libya. While RP draws heavily on previous proposals such as the original 2001 ICISS report and Brazil’s “Responsibility while Protecting” (RwP), by amalgamating and re-packaging these earlier ideas in a more restrictive form the initiative represents a new and distinctive interpretation of R2P. However, some aspects of RP are framed too narrowly to provide workable guidelines for determining the permissibility of military intervention for civilian protection purposes, and should therefore be clarified and refined. Nevertheless, the Chinese proposal remains significant because it offers important insights into Beijing’s current stance on R2P. More broadly, China’s RP and Brazil’s RwP initiatives illustrate the growing willingness of rising, non-Western powers to assert their own normative preferences on sovereignty, intervention and global governance.

Vision-based simultaneous localization and mapping in changing outdoor environments

For robots operating in outdoor environments, a number of factors, including weather, time of day, rough terrain, high speeds, and hardware limitations, make performing vision-based simultaneous localization and mapping with current techniques infeasible due to factors such as image blur and/or underexposure, especially on smaller platforms and low-cost hardware. In this paper, we present novel visual place-recognition and odometry techniques that address the challenges posed by low lighting, perceptual change, and low-cost cameras. Our primary contribution is a novel two-step algorithm that combines fast low-resolution whole image matching with a higher-resolution patch-verification step, as well as image saliency methods that simultaneously improve performance and decrease computing time. The algorithms are demonstrated using consumer cameras mounted on a small vehicle in a mixed urban and vegetated environment and a car traversing highway and suburban streets, at different times of day and night and in various weather conditions. The algorithms achieve reliable mapping over the course of a day, both when incrementally incorporating new visual scenes from different times of day into an existing map, and when using a static map comprising visual scenes captured at only one point in time. Using the two-step place-recognition process, we demonstrate for the first time single-image, error-free place recognition at recall rates above 50% across a day-night dataset without prior training or utilization of image sequences. This place-recognition performance enables topologically correct mapping across day-night cycles.

Efficiently capturing large, complex cultural heritage sites with a handheld mobile 3D laser mapping system

Accurate three-dimensional representations of cultural heritage sites are highly valuable for scientific study, conservation, and educational purposes. In addition to their use for archival purposes, 3D models enable efficient and precise measurement of relevant natural and architectural features. Many cultural heritage sites are large and complex, consisting of multiple structures spatially distributed over tens of thousands of square metres. The process of effectively digitising such geometrically complex locations requires measurements to be acquired from a variety of viewpoints. While several technologies exist for capturing the 3D structure of objects and environments, none are ideally suited to complex, large-scale sites, mainly due to their limited coverage or acquisition efficiency. We explore the use of a recently developed handheld mobile mapping system called Zebedee in cultural heritage applications. The Zebedee system is capable of efficiently mapping an environment in three dimensions by continually acquiring data as an operator holding the device traverses through the site. The system was deployed at the former Peel Island Lazaret, a culturally significant site in Queensland, Australia, consisting of dozens of buildings of various sizes spread across an area of approximately 400 × 250 m. With the Zebedee system, the site was scanned in half a day, and a detailed 3D point cloud model (with over 520 million points) was generated from the 3.6 hours of acquired data in 2.6 hours. We present results demonstrating that Zebedee was able to accurately capture both site context and building detail comparable in accuracy to manual measurement techniques, and at a greatly increased level of efficiency and scope. The scan allowed us to record derelict buildings that previously could not be measured because of the scale and complexity of the site. The resulting 3D model captures both interior and exterior features of buildings, including structure, materials, and the contents of rooms.

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.

Teachers using annotations to engage students in assessment conversations : recontextualising knowledge

Assessment for Learning practices with students such as feedback, and self- and peer assessment are opportunities for teachers and students to develop a shared understanding of how to create quality learning performances. Quality is often represented through achievement standards. This paper explores how primary school teachers in Australia used the process of annotating work samples to develop shared understanding of achievement standards during their curriculum planning phase, and how this understanding informed their teaching so that their students also developed this understanding. Bernstein's concept of the pedagogic device is used to identify the ways teachers recontextualised their assessment knowledge into their pedagogic practices. Two researchers worked alongside seven primary school teachers in two schools over a year, gathering qualitative data through focus groups and interviews. Three general recontextualising approaches were identified in the case studies; recontextualising standards by reinterpreting the role of rubrics, recontextualising by replicating the annotation process with the students and recontextualising by reinterpreting practices with students. While each approach had strengths and limitations, all of the teachers concluded that annotating conversations in the planning phase enhanced their understanding, and informed their practices in helping students to understand expectations for quality.

Convergence in European corporate governance : the audit committee concept

This paper analyses recent corporate governance codes issued by 20 countries for evidence of convergence in corporate governance systems in Europe. The analysis shows that there has been a degree of convergence towards an Anglo-Saxon model of corporate governance as the audit committee concept is widely accepted in countries with both unitary and two-tier governance systems. Further, the latest audit committee recommendations in countries that have issued several governance codes show a strengthening of the recommendations for an audit committee over time in line with the Anglo-Saxon audit committee concept and convergence with the debate in the US and UK on issues such as the independence and financial expertise of members. However, consistent with the literature on the convergence of European corporate governance systems, at an operational level there is limited consistency in the recommended structure and role of audit committees.

The legal concept of work-related injury and disease in Australian OHS and workers' compensation systems

This paper analyses the concept of ‘work-relatedness’ in Australian workers’ compensation and occupational health and safety (OHS) systems. The concept of work-relatedness is important because it is a crucial element circumscribing the limits of the protection afforded to workers under the preventative OHS statutes, and is a threshold element which has to be satisfied before an injured or ill worker can recover statutory compensation. While the preventive and compensatory regimes do draw on some similar concepts of work-relatedness, as this paper will illustrate, there are significant differences both between, and within, these regimes.

Component modeling for SCADA network mapping

Supervisory Control and Data Acquisition systems (SCADA) are widely used to control critical infrastructure automatically. Capturing and analyzing packet-level traffic flowing through such a network is an essential requirement for problems such as legacy network mapping and fault detection. Within the framework of captured network traffic, we present a simple modeling technique, which supports the mapping of the SCADA network topology via traffic monitoring. By characterizing atomic network components in terms of their input-output topology and the relationship between their data traffic logs, we show that these modeling primitives have good compositional behaviour, which allows complex networks to be modeled. Finally, the predictions generated by our model are found to be in good agreement with experimentally obtained traffic.

Public relations and engagement : theoretical imperatives of a multidimensional concept

Engagement has emerged as important concept in public relations, as stakeholders challenge the discourse of organizational primacy and organizations prioritize the need for authentic stakeholder involvement. As a multidimensional concept, engagement offers a foundation for building organizational relationships, and provides a means to facilitate community–organization interaction. This special issue on engagement and public relations presents a body of work that both explicates and expands the theoretical foundations of engagement, and contributes to scholarly understanding of its contexts, processes, and outcomes.