Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244)

Selumetinib (AZD6244, ARRY-142886) is a selective, non-ATP-competitive inhibitor of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-1/2. The range of antitumor activity seen preclinically and in patients highlights the importance of identifying determinants of response to this drug. In large tumor cell panels of diverse lineage, we show that MEK inhibitor response does not have an absolute correlation with mutational or phospho-protein markers of BRAF/MEK, RAS, or phosphoinositide 3-kinase (PI3K) activity. We aimed to enhance predictivity by measuring pathway output through coregulated gene networks displaying differential mRNA expression exclusive to resistant cell subsets and correlated to mutational or dynamic pathway activity. We discovered an 18-gene signature enabling measurement of MEK functional output independent of tumor genotype. Where the MEK pathway is activated but the cells remain resistant to selumetinib, we identified a 13-gene signature that implicates the existence of compensatory signaling from RAS effectors other than PI3K. The ability of these signatures to stratify samples according to functional activation of MEK and/or selumetinib sensitivity was shown in multiple independent melanoma, colon, breast, and lung tumor cell lines and in xenograft models. Furthermore, we were able to measure these signatures in fixed archival melanoma tumor samples using a single RT-qPCR-based test and found intergene correlations and associations with genetic markers of pathway activity to be preserved. These signatures offer useful tools for the study of MEK biology and clinical application of MEK inhibitors, and the novel approaches taken may benefit other targeted therapies.

Demonstration of regulatory cross-talk between P fimbriae and type 1 fimbriae in uropathogenic Escherichia coli

The majority of Escherichia coli strains isolated from urinary tract infections have the potential to express multiple fimbriae. Two of the most common fimbrial adhesins are type 1 fimbriae and pyelonephritis-associated pili (Pap). Previous research has shown that induced, plasmid-based expression of a Pap regulator, papB, and its close homologues can prevent inversion of the fim switch controlling the expression of type 1 fimbriae. The aim of the present study was to determine if this cross-regulation occurs when PapB is expressed from its native promoter in the chromosome of E. coli K-12 and clinical isolates. The regulation was examined in three ways: (1) mutated alleles of the pap regulatory region, including papB and papI, that maintain the pap promoter in either the off or the on phase were exchanged into the chromosome of both E. coli K-12 and the clinical isolate E. coli CFT073, and the effect on type 1 fimbrial expression was measured; (2) type 1 fimbrial expression was determined using a novel fimS : : gfp+ reporter system in mutants of the clinical isolate E. coli 536 in which combinations of complete fimbrial clusters had been deleted; (3) type 1 fimbrial expression was determined in a range of clinical isolates and compared with both the number of P clusters and their expression. All three approaches demonstrated that P expression represses type 1 fimbrial expression. Using a number of novel genetic approaches, this work extends the initial finding that PapB inhibits FimB recombination to the impact of this regulation in clinical isolates.

Cartels – What are they and how to avoid being part of one : the implications of University fee deregulation

Universities supply a range of services to students. These include most obviously, tuition services in relation to undergraduate and postgraduate courses; research supervision services in relation to research degrees; as well as consultancy services in relation to Government and industry work. For the purposes of the CCA, universities are trading corporations. They engage in trade or commerce through the provision of a range of services for reward. As such Universities are subject to the same rules and regulations that govern the conduct of other trading corporations, such Coles and Woolworths. As senior officers and managers of a trading corporation you need to acquire some basic understanding of the rules that govern competition in the education sector. In other sectors, companies generally undertake a risk assessment of those areas where they are most at risk of contravening the CCA; to ascertain in advance how problems might arise so that they can put in place strategies to mitigate the risk of inadvertent contraventions.

Chinese TEFL teachers’ perceptions about research and influences on their research endeavours

English has always occupied a key position in China’s education. The quality of English education depends largely on the quality of the English teaching force. Improving the overall quality of Teaching English as a Foreign Language (TEFL) teachers entails advancing both their teaching and research competence. This study, with its focus on Chinese TEFL teachers working in a higher education institution, was set up in a context where Chinese higher education colleges are being transformed into universities and research is becoming a crucial aspect of all teachers’ work. This small-scale case study investigated a group of Chinese TEFL teachers’ perceptions about research and their individual and workplace characteristics that influenced their research endeavours. The findings revealed that Chinese TEFL teachers recognised the significance of research for teaching, professional growth and career advancement. However, lack of individual characteristics such as research and disciplinary knowledge, confidence in research and intrinsic motivation impeded their research efforts. Their institution and departments seemed to encourage research; yet, more specific financial and academic support to start and sustain their research endeavours is required. This study’s findings provide implications for both individual teachers and their institutions to engage TEFL teachers more actively in research.

Citizen’s right to the digital city: Urban interfaces, activism, and placemaking

Edited by thought leaders of the fields of urban informatics and urban interaction design, this book brings together case studies and examples from around the world to discuss the role that urban Interfaces, citizen action, and city making play in the quest to create and maintain not only secure and resilient, but productive, sustainable, and liveable urban environments. The book debates the impact of these trends on theory, policy, and practice. The chapters in this book are sourced from blind peer reviewed contributions by leading researchers working at the intersection of the social / cultural, technical / digital, and physical / spatial domains of urbanism scholarship. The book appeals not only to research colleagues and students, but also to a vast number of practitioners in the private and public sector interested in accessible accounts that clearly and rigorously analyse the affordances and possibilities of urban interfaces, mobile technology, and location-based services to engage people towards open, smart and participatory urban environments.

Development of a new regulatory model for occupational health and safety in the New South Wales coal industry: an issues paper for the New South Wales Department of Mineral Resources

This paper addresses the regulatory issues arising in developing a new regulatory model for the New South Wales Coal Industry. As such, it identifies the relevant literature on this subject, the options available for reform, and the experience of Australian and key international bodies responsible for the development of regulatory standards in this area. In particular it: Identifies the main shortcomings in the existing regulatory approach; Identifies the potential roles/main strengths and weaknesses of different types of standards (eg specification, performance, process and systems-based rules) and potential “best practice’ combinations of standards; Examines the appropriateness of the current regulatory regime whereby the general OHS legislation (including the general duty provisions) applies to mining in addition to the large body of regulation which is specific to mining; Identifies the importance of, and possible means of addressing, issues of worker participation within the coal mining industry; Draws on the literature on what motivates companies and individuals for the purpose of recommending key provisions for inclusion in new legislation to provide appropriate personal and organisational incentives; Draws on the literature on major hazards facilities to suggest the appropriate roles for OHS management systems and safety reports or comparable approaches (eg mine safety management plans); Draws on the United Kingdom (UK) and United States of America (USA) experience of coal mine safety and its regulation for comparative purposes, and for insights as to what sort of regulation most effectively reduces work related injury and disease in coal mining; Examines the relevant roles of International Labour Organisation (ILO) Conventions; Examines the extent to which different regulatory regimes would be appropriate to open cut and underground coal mining; and Examines options for reform. This paper is focussed specifically on the issues identified above.

Kumarina and bidders voting in transfer schemes

Transfer schemes are an alternative means of acquiring control of a company to making a takeover bid under the provisions in Ch 6 of the Corporations Act 2001 (Cth). The recent decision Re Kumarina Resources Ltd [2013] FCA 549 overturned long-standing practice in relation to a certain type of transfer scheme. If followed, the decision would allow a “bidder” to vote at scheme meetings where the scheme consideration for the acquisition of the target shares are shares in another company, and the scheme results in a merger. But the bidder is not allowed to vote where the scheme consideration is cash. The article points out the difficulties arising from this decision and argues that it should not be followed. In providing a “no objection” statement, the Australian Securities and Investments Commission (ASIC) has created uncertainty as to the approach it will take towards the bidders being allowed to vote at scheme meetings where the scheme consideration for the acquisition of target shares are shares in another company. The article also points out that in providing the no objection statement in Kumarina, ASIC appears to have ignored breaches of s 606(1) of the Corporations Act. There is a pressing need for ASIC to clarify its position and, in particular, whether or not it will provide a no objection statement in respect of future transfer schemes where a bidder (or its parent company) votes at the scheme meeting.

“Do I really need a nap?”: The role of sleep science in informing sleep practices in early childhood education and care settings

A compelling body of studies identifies the importance of sleep for children’s learning, behavioral regulation, and health. These studies have primarily focused on nighttime sleep or on total sleep duration. The independent contribution of daytime sleep, or napping, in childhood is an emerging research focus. Daytime sleep is particularly pertinent to the context of early childhood education and care (ECEC) where, internationally, allocation of time for naps is commonplace through to the time of school entry. The biological value of napping varies with neurological maturity and with individual circumstance. Beyond the age of 3 years, when monophasic sleep patterns become typical, there is an increasing disjuncture between children’s normative sleep requirements and ECEC practice. At this time, research evidence consistently identifies an association between napping and decreased quality and duration of night sleep. We assess the implications of this evidence for educational practice and health policy. We identify the need to distinguish the functions of napping from those of rest, and assert the need for evidence-based guidelines on sleep–rest practices in ECEC settings to accommodate individual variation in sleep needs. Given both the evidence on the impact of children’s nighttime sleep on long-term trajectories of health and well-being and the high rates of child attendance in ECEC programs, we conclude that policy and practice regarding naptime have significant implications for child welfare and ongoing public health.

Non-market use and non-use values for preserving ecosystem services over time : a choice experiment application to coral reef ecosystems in New Caledonia

Non-use values (i.e. economic values assigned by individuals to ecosystem goods and services unrelated to current or future uses) provide one of the most compelling incentives for the preservation of ecosystems and biodiversity. Assessing the non-use values of non-users is relatively straightforward using stated preference methods, but the standard approaches for estimating non-use values of users (stated decomposition) have substantial shortcomings which undermine the robustness of their results. In this paper, we propose a pragmatic interpretation of non-use values to derive estimates that capture their main dimensions, based on the identification of a willingness to pay for ecosystem protection beyond one's expected life. We empirically test our approach using a choice experiment conducted on coral reef ecosystem protection in two coastal areas in New Caledonia with different institutional, cultural, environmental and socio-economic contexts. We compute individual willingness to pay estimates, and derive individual non-use value estimates using our interpretation. We find that, a minima, estimates of non-use values may comprise between 25 and 40% of the mean willingness to pay for ecosystem preservation, less than has been found in most studies.

Individuals, Innovation, and the Internet : Why Access is Essential

As each day passes, and as new and better devices and services are developed, more and more government and private services are being moved to an online format. This movement makes access to the internet an essential for 21st Century life. The internet has become so integrated in our lives that many of us cannot imagine how we could operate without it. This omnipresent ‘being’ affects all forms of ‘normal’ social and economic activity and does so in ways that we do not realize. Those with access are able to engage with government, business, and family and friends more easily, which can lead to an improved standard of living. For the disadvantaged, however – those with the desire but without the capacity – a lack of access can be socially isolating. "Between the idea And the reality Between the motion And the act Falls the Shadow – T. S. Elliott. “The Hollow Men” Engagement in the internet economy requires both physical access and the individual to have the necessary finances and skills to make and sustain their use. If governments and the international community want a fully functioning internet economy this requires that all individuals must be operating in it. That not all individuals do so means, very simply, that the internet economy is not fully functioning. The text contextualizes for policy makers and legislatures why it is essential to ensure that individuals have appropriate access to the internet and what can be done to achieve it. The interrelationship/overlap between why access is essential, how it can be achieved and the central role of the individual to the internet economy is explored and translated into the concept of connectedness. From this, solutions for ensuring connectedness for all individuals are developed. It is Dr Cradduck’s hope that in the not too distant future readers will puzzle over why texts such as this needed to be written.

Australian DOCAs versus UK pre-packs and CVAs : sifting through the ashes of comparative dividend returns

This article is something of a brief extension of recent research into deeds of company arrangement (DOCAs) under Pt 5.3A of the Corporations Act 2001 (Cth), conducted with the support of the Australian Restructuring Insolvency & Turnaround Association’s (ARITA’s) Terry Taylor Scholarship (TTS). This article presents some of the findings of that research (namely, the dividend outcomes delivered by sampled Australian DOCAs) in a manner consistent with reports which have recently emerged from similar research conducted in the UK. In so doing, a basic comparison can be made of the performance of Australian DOCAs against analogous UK procedures.

Crash involvement patterns of unlicensed drivers: Literature review. Report to Queensland Department of Transport and Main Roads

There is a lack of definitive evidence available relating to the extent and nature of unlicensed driving. Analysis of the crash involvement of unlicensed drivers provides an opportunity to better understand the behaviours of this group. This paper reviews the available literature relating to crash involvement patterns of unlicensed drivers. Key areas discussed include the prevalence of unlicensed driving as indicated by studies of crashes involving this group and associations between unlicensed driving and higher levels of risk-taking on the road. This paper also notes differences found in the characteristics and on-road behaviour of unlicensed drivers and the degree to which these factors, in particular alcohol and drug misuse, may influence crash involvement patterns. Drawing on Australian and international studies, this paper consolidates the available research evidence and identifies gaps in current knowledge relating to crash involvement patterns of unlicensed drivers.

Sneak peek: Dance audience relationships during open rehearsals

Over the past decade there has been a surge of interest in behind-the-scenes events from mainstream dance companies and audiences alike. Online videos, open classes, open rehearsals, and backstage tours all provide insights for audiences about daily life in a dance company and how dance work is made. This article focuses on the use of open rehearsals in studio sites and investigates audience experience and relationship with dancers during these events. Applying Clare Dyson’s (2010) scales of audience engagement, I analyse two open rehearsal models that I observed as an audience participant in 2013: Friends Open Days with English National Ballet (London), and Inner Workings with Chunky Move (Melbourne). Through this analysis, open rehearsals emerge as an experience with elements reminiscent of both the traditional presentation paradigm and non-traditional presentation models. Elements such as close audience-dancer proximity, authenticity, and experiences in liminal sites, such as staircases and green rooms, present the possibility of new audience-dancer relationship within the mainstream dance company context.

Breakfast at Tiffany's': eBay Inc., trade mark law, and counterfeiting

In an exploration of intellectual property and fashion, this article examines the question of the intermediary liability of online auction-houses for counterfeiting. In the United States, the illustrious jewellery store, Tiffany & Co, brought a legal action against eBay Inc, alleging direct trademark infringement, contributory trademark infringement, false advertising, unfair competition and trademark dilution. The luxury store depicted the online auction-house as a pirate bazaar, a flea-market and a haven for counterfeiting. During epic litigation, eBay Inc successfully defended itself against these allegations in a United States District Court and the United States Court of Appeals for the Second Circuit. Tiffany & Co made a desperate, unsuccessful effort to appeal the matter to the Supreme Court of the United States. The matter featured a number of interventions from amicus curiae — Tiffany was supported by Coty, the Fashion Designer's Guild, and the International Anticounterfeiting Coalition, while eBay was defended by publicly-spirited civil society groups such as Electronic Frontier Foundation, Public Citizen, and Public Knowledge as well as Yahoo!, Google Inc, Amazon.com, and associations representing telecommunications carriers and internet service providers. The litigation in the United States can be counterpointed with the fusillade of legal action against eBay in the European Union. In contrast to Tiffany & Co, Louis Vuitton triumphed over eBay in the French courts — claiming its victory as vindication of the need to protect the commercial interests and cultural heritage of France. However, eBay has fared somewhat better in a dispute with L’Oréal in Great Britain and the European Court of Justice. It is argued that, in a time of flux and uncertainty, Australia should follow the position of the United States courts in Tiffany & Co v eBay Inc. The final part examines the ramifications of this litigation over online auction-houses for trade mark law reform and consumer rights; parallel disputes over intermediary liability and safe harbours in the field of copyright law and the Anti-Counterfeiting Trade Agreement 2010. The conclusion calls for a revision of trade mark law, animated by a respect for consumers’ rights and interests in the electronic marketplace.

The Jean Chretien Pledge to Africa act: Patent law and humanitarian aid

This article evaluates the implementation of the WTO General Council Decision in 2003, which resolved that developed nations could export patented pharmaceutical drugs to member states in order to address public health issues - such as HIV/AIDS, tuberculosis, malaria and other epidemics. The Jean Chretien Pledge to Africa Act 2004 (Canada) provides authorisation for the export of pharmaceutical drugs from Canada to developing countries to address public health epidemics. The European Union has issued draft regulations governing the export of pharmaceutical drugs. A number of European countries - including Norway, the Netherlands, France, and Switzerland - are seeking to pass domestic legislation to give force to the WTO General Council Decision. Australia has shown little initiative in seeking to implement such international agreements dealing with access to essential medicines. It is argued that Australia should implement humanitarian legislation to embody the WTO General Council Decision, emulating models in Canada, Norway, and the European Union. Ideally, there should be no right of first refusal; the list of pharmaceutical drugs should be open-ended; and the eligible importing countries should not be limited to members of the WTO.