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.

Second ESMO consensus conference on lung cancer : pathology and molecular biomarkers for non-small-cell lung cancer

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The Second ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on management of patients with nonsmall- cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, early stage disease, locally advanced disease and advanced (metastatic) disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on recommendations for pathology and molecular biomarkers in relation to the diagnosis of lung cancer, primarily non-small-cell carcinomas.

Tailored silica coated Ag nanoparticles for non-invasive surface enhanced Raman spectroscopy of biomolecular targets

Silica coated Ag nanoparticles with defined surface plasmon resonances are used to selectively detect and analyze protein cofactors in solution and on interfaces via surface enhanced resonance Raman spectroscopy. The silica coating has a surprisingly small effect on optical amplification but minimizes unwanted interactions between the protein and the nanoparticle.

Predicting the likelihood of non-healing : a venous leg ulcer risk assessment tool

This project developed, validated and tested reliability of a risk assessment tool to predict the risk of failure to heal of patients with venous leg ulcers within 24 weeks. The risk assessment tool will allow clinicians to be able to determine realistic outcomes for their patients, promote early healing and potentially avoid weeks of inappropriate therapy. The tool will also assist in addressing specific risk factors and guide decisions on early, alternative, tailored interventions.

The effect of the addition of hip strengthening exercises to a lumbopelvic exercise programme for the treatment of non-specific low back pain : a randomized controlled trial

Objectives To compare the efficacy of two exercise programs in reducing pain and disability for individuals with non-specific low back pain and to examine the underlying mechanical factors related to pain and disability for individuals with NSLBP. Design A single-blind, randomized controlled trial. Methods: Eighty participants were recruited from eleven community-based general medical practices and randomized into two groups completing either a lumbopelvic motor control or a combined lumbopelvic motor control and progressive hip strengthening exercise therapy program. All participants received an education session, 6 rehabilitation sessions including real time ultrasound training, and a home based exercise program manual and log book. The primary outcomes were pain (0-100mm visual analogue scale), and disability (Oswestry Disability Index V2). The secondary outcomes were hip strength (N/kg) and two-dimensional frontal plane biomechanics (°) measure during the static Trendelenburg test and while walking. All outcomes were measured at baseline and at 6-week follow up. Results There was no statistical difference in the change in pain (xˉ = -4.0mm, t= -1.07, p =0.29, 95%CI -11.5, 3.5) or disability (xˉ = -0.3%, t= -0.19, p =0.85, 95%CI -3.5, 2.8) between groups. Within group comparisons revealed clinically meaningful reductions in pain for both Group One (xˉ =-20.9mm, 95%CI -25.7, -16.1) and Group Two (xˉ =-24.9, 95%CI -30.8, -19.0). Conclusion Both exercise programs had similar efficacy in reducing pain. The addition of hip strengthening exercises to a motor control exercise program does not appear to result in improved clinical outcome for pain for individuals with non-specific low back pain.

Geochemistry-based coral palaeoclimate studies and the potential of ‘non-traditional’ (non-massive Porites) corals : recent developments and future progression

Understanding the natural variability of the Earth's climate system and accurately identifying potential anthropogenic influences requires long term, geographically distributed records of key climate indicators, such as temperature and precipitation that extend prior to the last 400. years of the Holocene. Reef corals provide an excellent source of high resolution climate records, and importantly represent the tropical marine environment where palaeoclimate data are urgently required. Recent decades have seen significant improvement in our understanding of coral biomineralisation, the associated uptake of geochemical proxies and methods of identifying and understanding the effects of both early and late, post depositional diagenetic alteration. These processes all have significant implications for interpreting geochemical proxies relevant to palaeoclimatic reconstructions. This paper reviews the current 'state of the art' in terms of coral based palaeoclimate reconstructions and highlights a key remaining problem. The majority of coral based palaeoclimate research has been derived from massive colonies of Porites. However, massive Porites are not globally abundant and may not provide material of a particular age of interest in those regions where they are present. Therefore, there is great potential for alternate coral genera to act as complimentary climate archives. While it remains critical to consider five key factors - vital effects, differential growth morphologies, geochemical heterogeneity in the skeletal ultrastructure, transfer equation selection and diagenetic screening of skeletal material - in order to allow the highest level of accuracy in coral palaeoclimate reconstructions, it is also important to develop alternate taxa for palaeoclimate studies in regions where Porites colonies are absent or rare. Currently as many as nine genera other than Porites have proven at least limited utility in palaeothermometry, most of which are found in the Atlantic/Caribbean region where massive Porites do not exist. Even branching taxa such as Acropora have significant potential to preserve environmental archives. Increasing this capability will greatly expand the number of potential geochemical archives available for longer term temporal records of palaeoclimate.

Understanding Uncertainties in Non-Linear Population Trajectories: A Bayesian Semi-Parametric Hierarchical Approach to Large-Scale Surveys of Coral Cover

Recently, attempts to improve decision making in species management have focussed on uncertainties associated with modelling temporal fluctuations in populations. Reducing model uncertainty is challenging; while larger samples improve estimation of species trajectories and reduce statistical errors, they typically amplify variability in observed trajectories. In particular, traditional modelling approaches aimed at estimating population trajectories usually do not account well for nonlinearities and uncertainties associated with multi-scale observations characteristic of large spatio-temporal surveys. We present a Bayesian semi-parametric hierarchical model for simultaneously quantifying uncertainties associated with model structure and parameters, and scale-specific variability over time. We estimate uncertainty across a four-tiered spatial hierarchy of coral cover from the Great Barrier Reef. Coral variability is well described; however, our results show that, in the absence of additional model specifications, conclusions regarding coral trajectories become highly uncertain when considering multiple reefs, suggesting that management should focus more at the scale of individual reefs. The approach presented facilitates the description and estimation of population trajectories and associated uncertainties when variability cannot be attributed to specific causes and origins. We argue that our model can unlock value contained in large-scale datasets, provide guidance for understanding sources of uncertainty, and support better informed decision making

Non-destructive DNA extraction from Chironomidae, including of fragile pupal exuviae, extends analysable collections and enhances vouchering

It is well established that the traditional taxonomy and nomenclature of Chironomidae relies on adult males whose usually characteristic genitalia provide evidence of species distinction. In the early days some names were based on female adults of variable distinctiveness – but females are difficult to identify (Ekrem et al. 2010) and many of these names remain dubious. In Russia especially, a system based on larval morphology grew in parallel to the conventional adult-based system. The systems became reconciled with the studies that underlay the production of the Holarctic generic keys to Chironomidae, commencing notably with the larval volume (Wiederholm, 1983). Ever since Thienemann’s pioneering studies, it has been evident that the pupa, notably the cast skins (exuviae) provide a wealth of features that can aid in identification (e.g. Wiederholm, 1986). Furthermore, the pupae can be readily associated with name-bearing adults when a pharate (‘cloaked’) adult stage is visible within the pupa. Association of larvae with the name-bearing later stages has been much more difficult, time-consuming and fraught with risk of failure. Yet it is identification of the larval stage that is needed by most applied researchers due to the value of the immature stages of the family in aquatic monitoring for water quality, although the pupal stage also has advocates (reviewed by Sinclair & Gresens, 2008). Few use the adult stage for such purposes as their provenance and association with the water body can be verified only by emergence trapping, and sampling of adults lies outside regular aquatic monitoring protocols.

Medical negligence, causation and liability for non-disclosure of risk : a post-wallace framework and critique

Through an examination of Wallace v Kam, this article considers and evaluates the law of causation in the specific context of a medical practitioner’s duty to provide information to patients concerning material risks of treatment. To supply a contextual background for the analysis which follows, Part II summarises the basic principles of causation law, while Part III provides an overview of the case and the reasoning adopted in the decisions at first instance and on appeal. With particular emphasis upon the reasoning in the courts of appeal, Part IV then examines the implications of the case in the context of other jurisprudence in this field and, in so doing, provides a framework for a structured consideration of causation issues in future non-disclosure cases under the Australian civil liability legislation. As will become clear, Wallace was fundamentally decided on the basis of policy reasoning centred upon the purpose behind the legal duty violated. Although the plurality in Rogers v Whitaker rejected the utility of expressions such as ‘the patient’s right of self-determination’ in this context, some Australian jurisprudence may be thought to frame the practitioner’s duty to warn in terms of promoting a patient’s autonomy, or right to decide whether to submit to treatment proposed. Accordingly, the impact of Wallace upon the protection of this right, and the interrelation between it and the duty to warn’s purpose, is investigated. The analysis in Part IV also evaluates the courts’ reasoning in Wallace by questioning the extent to which Wallace’s approach to liability and causal connection in non-disclosure of risk cases: depends upon the nature and classification of the risk(s) in question; and can be reconciled with the way in which patients make decisions. Finally, Part V adopts a comparative approach by considering whether the same decision might be reached if Wallace was determined according to English law.

In silico analyses reveal common cellular pathways affected by loss of heterozygosity (LOH) events in the lymphomagenesis of Non-Hodgkin’s lymphoma (NHL)

Background The analysis of cellular networks and pathways involved in oncogenesis has increased our knowledge about the pathogenic mechanisms that underlie tumour biology and has unmasked new molecular targets that may lead to the design of better anti-cancer therapies. Recently, using a high resolution loss of heterozygosity (LOH) analysis, we identified a number of potential tumour suppressor genes (TSGs) within common LOH regions across cases suffering from two of the most common forms of Non-Hodgkin’s lymphoma (NHL), Follicular Lymphoma (FL) and Diffuse Large B-cell Lymphoma (DLBCL). From these studies LOH of the protein tyrosine phosphatase receptor type J (PTPRJ) gene was identified as a common event in the lymphomagenesis of these B-cell lymphomas. The present study aimed to determine the cellular pathways affected by the inactivation of these TSGs including PTPRJ in FL and DLBCL tumourigenesis. Results Pathway analytical approaches identified that candidate TSGs located within common LOH regions participate within cellular pathways, which may play a crucial role in FL and DLBCL lymphomagenesis (i.e., metabolic pathways). These analyses also identified genes within the interactome of PTPRJ (i.e. PTPN11 and B2M) that when inactivated in NHL may play an important role in tumourigenesis. We also detected genes that are differentially expressed in cases with and without LOH of PTPRJ, such as NFATC3 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 3). Moreover, upregulation of the VEGF, MAPK and ERBB signalling pathways was also observed in NHL cases with LOH of PTPRJ, indicating that LOH-driving events causing inactivation of PTPRJ, apart from possibly inducing a constitutive activation of these pathways by reduction or abrogation of its dephosphorylation activity, may also induce upregulation of these pathways when inactivated. This finding implicates these pathways in the lymphomagenesis and progression of FL and DLBCL. Conclusions The evidence obtained in this research supports findings suggesting that FL and DLBCL share common pathogenic mechanisms. Also, it indicates that PTPRJ can play a crucial role in the pathogenesis of these B-cell tumours and suggests that activation of PTPRJ might be an interesting novel chemotherapeutic target for the treatment of these B-cell tumours.

A non-fullerene electron acceptor based on fluorene and diketopyrrolopyrrole building blocks for solution-processable organic solar cells with an impressive open-circuit voltage

A novel solution-processable non-fullerene electron acceptor 6,6′-(5,5′-(9,9-dioctyl-9H-fluorene-2,7-diyl)bis(thiophene-5,2-diyl))bis(2,5-bis(2-ethylhexyl)-3-(thiophen-2-yl)pyrrolo[3,4-c]pyrrole-1,4(2H,5H)-dione) (DPP1) based on fluorene and diketopyrrolopyrrole conjugated moieties was designed, synthesized and fully characterized. DPP1 exhibited excellent solubility and high thermal stability which are essential for easy processing. Upon using DPP1 as an acceptor with the classical electron donor poly(3-hexylthiophene), solution processable bulk-heterojunction solar cells afforded a power conversion efficiency of 1.2% with a high open-circuit voltage (1.1 V). As per our knowledge, this value of open circuit voltage is one of the highest values reported so far for a bulk-heterojunction device using DPP1 as a non-fullerene acceptor.

Sustainability Non-Price Incentives and Rewards: A Collaborative Procurement Perspective

Construction scholars suggest that procurement processes can be used as mechanisms to change construction industry practices. This paper discusses industry changes as a response to the calls for integration of sustainability ideals into construction practices. Because major infrastructure construction has been identified as a key producer of greenhouse gas emissions (GHGE), this study explores collaborative procurement models that have been used to facilitate mitigation of GHGE. The study focuses on the application of non-price incentives and rewards that work together as a binary mechanism. Data were collected using mixed-methods: government document content analysis was complemented with data collected through focus groups and individual interviews with both clients and contractors. This report includes examples of greening procurement agendas for three Australian road authorities relating to collaborative procurement project delivery models. Three collaborative procurement models, Alliance Consortium, Early Contractor Involvement and Public Private Partnerships provide evidence of construction projects that were completed early. It can also be argued that both clients and contractors are rewarded through collaborative project delivery. The incentive of early completion is rewarded with reduction of GHGE. This positive environmental outcome, based on a dual benefit and non-price sustainability criteria, suggests a step towards changed industry practices though the use of green procurement models.

Corporate governance quality, audit fees and non-audit services fees

This paper extends prior research on the relationship between governance quality and auditor remuneration.We examine the influence of audit committee effectiveness (ACE), a proxy for governance quality, on audit fees (AF) and non-audit services fees (NASF) using a new composite measure comprising audit committee independence, expertise, diligence and size. We find that after controlling for board of director characteristics, there is a significant positive association between ACE and AF only for larger clients. Our results indicate that effective audit committees undertake more monitoring which results in wider audit scope and higher audit fees. Contrary to our expectations, we find the association between ACE and NASF to be positive and significant, especially for larger clients. This suggests that larger clients are more likely to purchase non-audit services (NAS) even in the presence of effective audit committees probably due to the complexity of their activities. Overall, our findings support regulatory initiatives aimed at improving corporate governance quality.

Ross River virus disease activity associated with naturally occurring non-tidal flood events in Australia : A systematic review

Ross River virus (RRV) disease is the most common and widespread mosquito-borne disease in Australia, resulting in considerable health and economic cost to communities. While naturally occurring non-tidal flood events may enhance mosquito abundance, little is known about the impact of such events on RRV transmission. This paper critically reviews the existing evidence for an association between naturally occurring non-tidal flood events and RRV transmission. A systematic literature search was conducted on RRV transmission related to flooding and inundation from rain and riverine overflow. Overall, the evidence to support a positive association between flooding and RRV outbreaks is largely circumstantial, with the literature mostly reporting only coincidental occurrence between the two. However, for the Murray River, river flow and height (surrogates of flooding) were positively and significantly associated with RRV transmission. The association between non-tidal flooding and RRV transmission has not been studied comprehensively. More frequent flood events arising from climate change may result in increased outbreaks of RRV disease. Understanding the link between flood events and RRV transmission is necessary if resources for mosquito spraying and public health warnings are to be utilized more effectively and efficiently.

Delivering crushed tablets using thickened fluids : is drug diffusion into gastric fluids restricted?

Solid medications are often crushed and mixed with food or thickened water to aid drug delivery for those who cannot or prefer not to swallow whole tablets or capsules. Dysphagic patients have the added problem of being unable to safely swallow thin fluids so water thickened with polysaccharides is used to deliver crushed medications and ensure safe swallowing. It is postulated that these polysaccharide systems may restrict drug release by reducing the diffusion of the drug into gastric fluids. METHODS By using a vertical diffusion cell separated with a synthetic membrane, the diffusion of a model drug (atenolol) was studied from a donor system containing the drug dispersed into thickened water with xanthan gum (concentration range from 0.005%-2.2%) into a receptor system containing simulated gastric fluid (SGF) at 37°C. The amount of drug transferred was measured over 8 hours and diffusion coefficients estimated using the Higuchi model approach. RESULTS Atenolol diffusion decreased with increasing xanthan gum concentration up to 1.0%, above which diffusion remained around 300 μ2s-1. The rheological measurements captured the influence of the structure and conformation of the polysaccharide in water on the movement and availability of the drug in SGF. DISCUSSION Dose form administration for dysphagic patients’ needs special attention from general practitioners, pharmacist and patients. Improving drug release of crushed tablets from thickening agents requires a reduction in the diffusion pathway (e.g. by decreasing drop size radius). This approach could make the drug available in SGF in a short time without compromising the mechanical aspects of thickening agents that guarantee safe swallowing.