Relationship between EGFR expression, EGFR mutation status, and the efficacy of chemotherapy plus cetuximab in FLEX study patients with advanced non-small-cell lung cancer

INTRODUCTION: The phase III FLEX study (NCT00148798) in advanced non-small-cell lung cancer indicated that the survival benefit associated with the addition of cetuximab to cisplatin and vinorelbine was limited to patients whose tumors expressed high levels of epidermal growth factor receptor (EGFR) (immunohistochemistry score of >/=200; scale 0-300). We assessed whether the treatment effect was also modulated in FLEX study patients by tumor EGFR mutation status. METHODS: A tumor mutation screen of EGFR exons 18 to 21 included 971 of 1125 (86%) FLEX study patients. Treatment outcome in low and high EGFR expression groups was analyzed across efficacy endpoints according to tumor EGFR mutation status. RESULTS: Mutations in EGFR exons 18 to 21 were detected in 133 of 971 tumors (14%), 970 of which were also evaluable for EGFR expression level. The most common mutations were exon 19 deletions and L858R (124 of 133 patients; 93%). In the high EGFR expression group (immunohistochemistry score of >/=200), a survival benefit for the addition of cetuximab to chemotherapy was demonstrated in patients with EGFR wild-type (including T790M mutant) tumors. Although patient numbers were small, those in the high EGFR expression group whose tumors carried EGFR mutations may also have derived a survival benefit from the addition of cetuximab to chemotherapy. Response data suggested a cetuximab benefit in the high EGFR expression group regardless of EGFR mutation status. CONCLUSIONS: The survival benefit associated with the addition of cetuximab to first-line chemotherapy for advanced non-small-cell lung cancer expressing high levels of EGFR is not limited by EGFR mutation status.

Learning-based Relevance Feedback for Web-based Relation Completion

In a pilot application based on web search engine calledWeb-based Relation Completion (WebRC), we propose to join two columns of entities linked by a predefined relation by mining knowledge from the web through a web search engine. To achieve this, a novel retrieval task Relation Query Expansion (RelQE) is modelled: given an entity (query), the task is to retrieve documents containing entities in predefined relation to the given one. Solving this problem entails expanding the query before submitting it to a web search engine to ensure that mostly documents containing the linked entity are returned in the top K search results. In this paper, we propose a novel Learning-based Relevance Feedback (LRF) approach to solve this retrieval task. Expansion terms are learned from training pairs of entities linked by the predefined relation and applied to new entity-queries to find entities linked by the same relation. After describing the approach, we present experimental results on real-world web data collections, which show that the LRF approach always improves the precision of top-ranked search results to up to 8.6 times the baseline. Using LRF, WebRC also shows performances way above the baseline.

Current status and future trends of school counseling in Australia

School counselling in Australia is presently in a state of flux and adaptation. Within this period of change and adjustment, three key points are acknowledged. First structural and organisational change is a constant in the field of school counselling in the Australian context. Second, despite this, the nature of the school counselling role tends to remain the same but with new areas of need being added, such as self harm and cyberbullying. Third, each state and territory in Australia has differing role statements and training requirements for its school counsellors. This paper initially reviews the historical context of school counselling in Australia, including changes and developments in qualifications and training programs. A description is then provided of the current status of school counselling including the differences among the state systems. Issues such as work intensification, uncertainty of tenure, supervision, ethical issues and online counselling are discussed. The scant research into the effectiveness of the profession is outlined, followed by future recommendations.

The effect of topical adrenergic and anticholinergic agents on the choroidal thickness of young healthy adults

The human choroid is capable of rapidly changing its thickness in response to a variety of stimuli. However little is known about the role of the autonomic nervous system in the regulation of the thickness of the choroid. Therefore, we investigated the effect of topical parasympatholytic and sympathomimetic agents upon the choroidal thickness and ocular biometrics of young healthy adult subjects. Fourteen subjects (mean age 27.9 ± 4 years) participated in this randomized, single-masked, placebo-controlled study. Each subject had measurements of choroidal thickness (ChT) and ocular biometrics of their right eye taken before, and then 30 and 60 min following the administration of topical pharmacological agents. Three different drugs: 2% homatropine hydrobromide, 2.5% phenylephrine hydrochloride and a placebo (0.3% hydroxypropyl methylcellulose) were tested in all subjects; each on different days (at the same time of the day) in randomized order. Participants were masked to the pharmacological agent being used at each testing session. The instillation of 2% homatropine resulted in a small but significant increase in subfoveal ChT at 30 and 60 min after drug instillation (mean change 7 ± 3 μm and 14 ± 2 μm respectively; both p < 0.0001). The parafoveal choroid also exhibited a similar magnitude, significant increase in thickness with time after 2% homatropine (p < 0.001), with a mean change of 7 ± 0.3 μm and 13 ± 1 μm (in the region located 0.5 mm from the fovea center), 6 ± 1 μm and 12.5 ± 1 μm (1 mm from the fovea center) and 6 ± 2 μm and 12 ± 2 μm (1.5 mm from the fovea center) after 30 and 60 min respectively. Axial length decreased significantly 60 min after homatropine (p < 0.01). There were also significant changes in lens thickness (LT) and anterior chamber depth (ACD) (p < 0.05) associated with homatropine instillation. No significant changes in choroidal thickness, or ocular biometrics were found after 2.5% phenylephrine or placebo at any examination points (p > 0.05). In human subjects, significant increases in subfoveal and parafoveal choroidal thickness occurred after administration of 2% homatropine and this implies an involvement of the parasympathetic system in the control of choroidal thickness in humans.

Children's emotions and multimodal appraisal of places : walking with the camera

This sensory ethnography explores the affordances and constraints of multimodal design to represent emotions and appraisal associated with experiencing local places. Digital video production, walking with the camera, and the use of a think-aloud protocol to reflect on the videos, provided an opportunity for the primary school children to represent their emotions and appraisal of places multimodally. Applying a typology from Martin and White's (2005) framework for the Language of Evaluation, children's multimodal emotional responses to places in this study tended toward happiness, security, and satisfaction. The findings demonstrate an explicit connection between children's emotions in response to local places through video, while highlighting the potential for teachers to use digital filmmaking to allow children to reflect actively on their placed experiences and represent their emotional reactions to places through multiple modes.

Large scale multiuser digital mind mapping tool : a study in usability

Project work can involve multiple people from varying disciplines coming together to solve problems as a group. Large scale interactive displays are presenting new opportunities to support such interactions with interactive and semantically enabled cooperative work tools such as intelligent mind maps. In this paper, we present a novel digital, touch-enabled mind-mapping tool as a first step towards achieving such a vision. This first prototype allows an evaluation of the benefits of a digital environment for a task that would otherwise be performed on paper or flat interactive surfaces. Observations and surveys of 12 participants in 3 groups allowed the formulation of several recommendations for further research into: new methods for capturing text input on touch screens; inclusion of complex structures; multi-user environments and how users make the shift from single- user applications; and how best to navigate large screen real estate in a touch-enabled, co-present multi-user setting.

Morphometric analysis of telencephalic structure in a variety of neognath and paleognath bird species reveals regional differences associated with specific behavioral traits

Birds exhibit a huge array of behavior, ecology and physiology, and occupy nearly every environment on earth, ranging from the desert outback of Australia to the tropical rain forests of Panama. Some birds have adopted a fully nocturnal lifestyle, such as the barn owl and kiwi, while others, such as the albatross, spend nearly their entire life flying over the ocean. Each species has evolved unique adaptations over millions of years to function in their respective niche. In order to increase processing power or network efficiency, many of these adaptations require enlargements and/or specializations of the brain as a whole or of specific brain regions. In this study, we examine the relative size and morphology of 9 telencephalic regions in a number of Paleognath and Neognath birds and relate the findings to differences in behavior and sensory ecology. We pay particular attention to those species that have undergone a relative enlargement of the telencephalon to determine whether this relative increase in telencephalic size is homogeneous across different brain regions or whether particular regions have become differentially enlarged. The analysis indicates that changes in the relative size of telencephalic regions are not homogeneous, with every species showing hypertrophy or hypotrophy of at least one of them. The three-dimensional structure of these regions in different species was also variable, in particular that of the mesopallium in kiwi. The findings from this study provide further evidence that the changes in relative brain size in birds reflect a process of mosaic evolution.

Changing views of culture, learning, teaching, and knowledge : Fiji in-service primary teachers

This paper explores in-service primary teachers' views and beliefs about culture, learning, teaching and knowledge. Fifty Bachelor of Education in-service primary teachers at a university in Fiji participated in the study. The analysis reveals a mix of old and new beliefs about culture, learning teaching and knowledge. The influence of globalization of technology is a contributing factor towards changing views. To keep the indigenous epistemologies alive and valued like the Western epistemologies, more effort is needed to integrate these in formal education. This has implications for the future professional preparation of pre-service and in-service teachers.

Process considerations related to the microencapsulation of plasmid DNA via ultrasonic atomization

An effective means of facilitating DNA vaccine delivery to antigen presenting cells is through biodegradable microspheres. Microspheres offer distinct advantages over other delivery technologies by providing release of DNA vaccine in its bioactive form in a controlled fashion. In this study, biodegradable poly(D,L-lactide-coglycolide) (PLGA) microspheres containing polyethylenimine (PEI) condensed plasmid DNA (pDNA) were prepared using a 40 kHz ultrasonic atomization system. Process synthesis parameters, which are important to the scale-up of microspheres that are suitable for nasal delivery (i.e., less than 20 μm), were studied. These parameters include polymer concentration; feed flowrate; volumetric ratio of polymer and pDNA-PEI (plasmid DNA-polyethylenimine) complexes; and nitrogen to phosphorous (N/P) ratio. PDNA encapsulation efficiencies were predominantly in the range 82-96%, and the mean sizes of the particle were between 6 and 15 μm. The ultrasonic synthesis method was shown to have excellent reproducibility. PEI affected morphology of the microspheres, as it induced the formation of porous particles that accelerate the release rate of pDNA. The PLGA microspheres displayed an in vitro release of pDNA of 95-99% within 30 days and demonstrated zero order release kinetics without an initial spike of pDNA. Agarose electrophoresis confirmed conservation of the supercoiled form of pDNA throughout the synthesis and in vitro release stages. It was concluded that ultrasonic atomization is an efficient technique to overcome the key obstacles in scaling-up the manufacture of encapsulated vaccine for clinical trials and ultimately, commercial applications.

The pragmatic approach : the myriad gene patents before the Australian courts

The Full Court of the Federal Court of Australia in D'Arcy v Myriad Genetics [2014] FCAFC 115 recently upheld the validity of Myriad Genetics' Australian BRCA1 gene patent over isolated DNA sequences.

Speaking too soon : the sabotage of bail reform in New South Wales

Within just over one month of coming into operation in May 2014, the new Bail Act 2013 (NSW), a product of long-term law reform consideration, was reviewed and then amended after talk-back radio ‘shock jock’ and tabloid newspaper outcry over three cases. This article examines the media triggers, the main arguments of the review conducted by former New South Wales (NSW) Attorney General John Hatzistergos, and the amendments, with our analysis of the judicial interpretation of the Act thus far providing relevant background. We argue that the amendments are premature, unnecessary, create complexity and confusion, and, quite possibly, will have unintended consequences: in short, they are a mess. The whole process of reversal is an example of law and order politics driven by the shock jocks and tabloid media, the views of which, are based on fundamental misconceptions of the purpose of bail and its place in the criminal process, resulting in a conflation of accusation, guilt and punishment. Other consequences of the review and amendments process recognised in this article include the denigration of judicial expertise and lack of concern with evidence and process; the disproportionate influence of the shock jocks, tabloids and Police Association of NSW on policy formation; the practice of using retired politicians to produce ‘quick fix’ reviews; and the political failure to understand and defend fundamental legal principles that benefit us all and are central to the maintenance of a democratic society and the rule of law. The article concludes with some discussion of ways in which media and political debate might be conducted to produce more balanced outcomes.

Study of the novel non-xanthine heterocyclic compound GU 285 as a potent non-selective adenosine receptor antagonist in the rat

The novel pyrazolo[3,4-d]pyrimidine compound GU285 (4-amino-6-alpha-carbamoylethylthio-1- phenylpyrazolo[3,4-d]pyrimidine, CAS 134896-40-5) was examined for its ability (1) to inhibit binding of adenosine (ADO) receptor ligands in rat brain membranes, (2) to antagonise functional responses to ADO agonists in rat right and left atria and coronary resistance vessels, and (3) to reduce the fall in heart rate and arterial blood pressure produced by the ADO A1 agonist N6-cyclopentyladenosine (CPA) in the intact, anaesthetized rat. GU285 competitively inhibited binding of the ADO A1 agonist [3H]-R-N6-phenylisopropyladenosine (R-PIA) yielding a Ki value of 11 (7-18) nmol.l-1 (geometric mean +/- 95% Cl). When assayed against the ADO A2A selective agonist [3H]-2-[p-(2-carboxyethyl)- phenethylamino]-5'-N-ethylcarboxamidoadenosine, (CGS21680), a Ki of 15 (10-24) nmol.l-1 was obtained. In spontaneously beating right atria, GU285 competitively antagonized negative chronotropic effects of R-PIA with a pA2 of 8.7 +/- 0.3 and in electrically paced left atria, GU285 competitively antagonized negative inotropic effects of R-PIA with a pA2 of 9.0 +/- 0.1. In the potassium-arrested, perfused rat heart GU285 (1 mumol.l-1) antagonized only the high sensitivity, ADO A2B mediated component of the biphasic relaxation of the coronary vasculature produced by NECA. The low sensitivity component was unchanged. GU285 (1 mumol.kg-1) antagonized the negative chronotropic and hypotensive effects of the adenosine A1 agonist CPA in anaesthetized rats, producing a 10-fold rightward shift in the dose-response relationship. These data demonstrate that in the rat, GU285 is a potent, non-selective adenosine receptor antagonist that maintains its activity in vivo.

Evolutionary game design : automated game design comes of age

The "Humies" awards are an annual competition held in conjunction with the Genetic and Evolutionary Computation Conference (GECCO), in which cash prizes totalling $10,000 are awarded to the most human-competitive results produced by any form of evolutionary computation published in the previous year. This article describes the gold medal-winning entry from the 2012 "Humies" competition, based on the LUDI system for playing, evaluating and creating new board games. LUDI was able to demonstrate human-competitive results in evolving novel board games that have gone on to be commercially published, one of which, Yavalath, has been ranked in the top 2.5% of abstract board games ever invented. Further evidence of human-competitiveness was demonstrated in the evolved games implicitly capturing several principles of good game design, outperforming human designers in at least one case, and going on to inspire a new sub-genre of games.

An internet of social things

The Internet of Things is a vision for a world of interconnected smart devices. We present an alternative vision based on a review of literature that emphasizes the importance and role of objects in social relations. We situate this work in relation to a conceptual understanding of objects and sociality, and note some methodological implications of a more object-centred sociality that may suggest design opportunities alongside the emerging Internet of Things.