Thymidylate synthase expression and outcome of patients receiving pemetrexed for advanced nonsquamous non-small-cell lung cancer in a prospective blinded assessment phase II clinical trial

INTRODUCTION In retrospective analyses of patients with nonsquamous non-small-cell lung cancer treated with pemetrexed, low thymidylate synthase (TS) expression is associated with better clinical outcomes. This phase II study explored this association prospectively at the protein and mRNA-expression level. METHODS Treatment-naive patients with nonsquamous non-small-cell lung cancer (stage IIIB/IV) had four cycles of first-line chemotherapy with pemetrexed/cisplatin. Nonprogressing patients continued on pemetrexed maintenance until progression or maximum tolerability. TS expression (nucleus/cytoplasm/total) was assessed in diagnostic tissue samples by immunohistochemistry (IHC; H-scores), and quantitative reverse-transcriptase polymerase chain reaction. Cox regression was used to assess the association between H-scores and progression-free/overall survival (PFS/OS) distribution estimated by the Kaplan-Meier method. Maximal χ analysis identified optimal cutpoints between low TS- and high TS-expression groups, yielding maximal associations with PFS/OS. RESULTS The study enrolled 70 patients; of these 43 (61.4%) started maintenance treatment. In 60 patients with valid H-scores, median (m) PFS was 5.5 (95% confidence interval [CI], 3.9-6.9) months, mOS was 9.6 (95% CI, 7.3-15.7) months. Higher nuclear TS expression was significantly associated with shorter PFS and OS (primary analysis IHC, PFS: p < 0.0001; hazard ratio per 1-unit increase: 1.015; 95%CI, 1.008-1.021). At the optimal cutpoint of nuclear H-score (70), mPFS in the low TS- versus high TS-expression groups was 7.1 (5.7-8.3) versus 2.6 (1.3-4.1) months (p = 0.0015; hazard ratio = 0.28; 95%CI, 0.16-0.52; n = 40/20). Trends were similar for cytoplasm H-scores, quantitative reverse-transcriptase polymerase chain reaction and other clinical endpoints (OS, response, and disease control). CONCLUSIONS The primary endpoint was met; low TS expression was associated with longer PFS. Further randomized studies are needed to explore nuclear TS IHC expression as a potential biomarker of clinical outcomes for pemetrexed treatment in larger patient cohorts. © 2013 by the International Association for the Study of Lung Cancer.

Hydrogel microwell arrays allow the assessment of protease-associated enhancement of cancer cell aggregation and survival

Current routine cell culture techniques are only poorly suited to capture the physiological complexity of tumor microenvironments, wherein tumor cell function is affected by intricate three-dimensional (3D), integrin-dependent cell-cell and cell-extracellular matrix (ECM) interactions. 3D cell cultures allow the investigation of cancer-associated proteases like kallikreins as they degrade ECM proteins and alter integrin signaling, promoting malignant cell behaviors. Here, we employed a hydrogel microwell array platform to probe using a high-throughput mode how ovarian cancer cell aggregates of defined size form and survive in response to the expression of kallikreins and treatment with paclitaxel, by performing microscopic, quantitative image, gene and protein analyses dependent on the varying microwell and aggregate sizes. Paclitaxel treatment increased aggregate formation and survival of kallikrein-expressing cancer cells and levels of integrins and integrin-related factors. Cancer cell aggregate formation was improved with increasing aggregate size, thereby reducing cell death and enhancing integrin expression upon paclitaxel treatment. Therefore, hydrogel microwell arrays are a powerful tool to screen the viability of cancer cell aggregates upon modulation of protease expression, integrin engagement and anti-cancer treatment providing a micro-scaled yet high-throughput technique to assess malignant progression and drug-resistance.

Quantitative fit analysis of orthopedic bone plates : methods, criteria and approach

Studies on quantitative fit analysis of precontoured fracture fixation plates emerged within the last few years and therefore, there is a wide research gap in this area. Quantitative fit assessment facilitates the measure of the gap between a fracture fixation plate and the underlying bone, and specifies the required plate fit criteria. For clinically meaningful fit assessment outcome, it is necessary to establish the appropriate criteria and parameter. The present paper studies this subject and recommends using multiple fit criteria and the maximum distance between the plate and underlying bone as fit parameter for clinically relevant outcome. We also propose the development of a software tool for automatic plate positioning and fit assessment for the purpose of implant design validation and optimization in an effort to provide better fitting implant that can assist proper fracture healing. The fundamental specifications of the software are discussed.

Assessment of gene expression of intracellular calcium channels, pumps and exchangers with epidermal growth factor-induced epithelial-mesenchymal transition in a breast cancer cell line

Background Epithelial-mesenchymal transition (EMT) is a process implicated in cancer metastasis that involves the conversion of epithelial cells to a more mesenchymal and invasive cell phenotype. In breast cancer cells EMT is associated with altered store-operated calcium influx and changes in calcium signalling mediated by activation of cell surface purinergic receptors. In this study, we investigated whether MDA-MB-468 breast cancer cells induced to undergo EMT exhibit changes in mRNA levels of calcium channels, pumps and exchangers located on intracellular calcium storing organelles, including the Golgi, mitochondria and endoplasmic reticulum (ER). Methods Epidermal growth factor (EGF) was used to induce EMT in MDA-MB-468 breast cancer cells. Serum-deprived cells were treated with EGF (50 ng/mL) for 12 h and gene expression was assessed using quantitative RT-PCR. Results and conclusions These data reveal no significant alterations in mRNA levels of the Golgi calcium pump secretory pathway calcium ATPases (SPCA1 and SPCA2), or the mitochondrial calcium uniporter (MCU) or Na+/Ca2+ exchanger (NCLX). However, EGF-induced EMT was associated with significant alterations in mRNA levels of specific ER calcium channels and pumps, including (sarco)-endoplasmic reticulum calcium ATPases (SERCAs), and inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RYR) calcium channel isoforms. The most prominent change in gene expression between the epithelial and mesenchymal-like states was RYR2, which was enriched 45-fold in EGF-treated MDA-MB-468 cells. These findings indicate that EGF-induced EMT in breast cancer cells may be associated with major alterations in ER calcium homeostasis.

Development of a dose assessment tool for the auditing of radiotherapy treatment dosimetric quality

The reporting and auditing of patient dose is an important component of radiotherapy quality assurance. The manual extraction of dose-volume metrics is time consuming and undesirable when auditing the dosimetric quality of a large cohort of patient plans. A dose assessment application was written to overcome this, allowing the calculation of various dose-volume metrics for large numbers of plans exported from treatment planning systems. This application expanded on the DICOM-handling functionality of the MCDTK software suite. The software extracts dose values in the volume of interest by using a ray casting point-in-polygon algorithm, where the polygons have been defined by the contours in the RTSTRUCT file...

Accurately defining the reference condition for summary biotic metrics: A comparison of four approaches

Protocols for bioassessment often relate changes in summary metrics that describe aspects of biotic assemblage structure and function to environmental stress. Biotic assessment using multimetric indices now forms the basis for setting regulatory standards for stream quality and a range of other goals related to water resource management in the USA and elsewhere. Biotic metrics are typically interpreted with reference to the expected natural state to evaluate whether a site is degraded. It is critical that natural variation in biotic metrics along environmental gradients is adequately accounted for, in order to quantify human disturbance-induced change. A common approach used in the IBI is to examine scatter plots of variation in a given metric along a single stream size surrogate and a fit a line (drawn by eye) to form the upper bound, and hence define the maximum likely value of a given metric in a site of a given environmental characteristic (termed the 'maximum species richness line' - MSRL). In this paper we examine whether the use of a single environmental descriptor and the MSRL is appropriate for defining the reference condition for a biotic metric (fish species richness) and for detecting human disturbance gradients in rivers of south-eastern Queensland, Australia. We compare the accuracy and precision of the MSRL approach based on single environmental predictors, with three regression-based prediction methods (Simple Linear Regression, Generalised Linear Modelling and Regression Tree modelling) that use (either singly or in combination) a set of landscape and local scale environmental variables as predictors of species richness. We compared the frequency of classification errors from each method against set biocriteria and contrast the ability of each method to accurately reflect human disturbance gradients at a large set of test sites. The results of this study suggest that the MSRL based upon variation in a single environmental descriptor could not accurately predict species richness at minimally disturbed sites when compared with SLR's based on equivalent environmental variables. Regression-based modelling incorporating multiple environmental variables as predictors more accurately explained natural variation in species richness than did simple models using single environmental predictors. Prediction error arising from the MSRL was substantially higher than for the regression methods and led to an increased frequency of Type I errors (incorrectly classing a site as disturbed). We suggest that problems with the MSRL arise from the inherent scoring procedure used and that it is limited to predicting variation in the dependent variable along a single environmental gradient.

An experimental based assessment of the deviation of the bearing characteristic frequencies

Slippage in the contact roller-races has always played a central role in the field of diagnostics of rolling element bearings. Due to this phenomenon, vibrations triggered by a localized damage are not strictly periodic and therefore not detectable by means of common spectral functions as power spectral density or discrete Fourier transform. Due to the strong second order cyclostationary component, characterizing these signals, techniques such as cyclic coherence, its integrated form and square envelope spectrum have proven to be effective in a wide range of applications. An expert user can easily identify a damage and its location within the bearing components by looking for particular patterns of peaks in the output of the selected cyclostationary tool. These peaks will be found in the neighborhood of specific frequencies, that can be calculated in advance as functions of the geometrical features of the bearing itself. Unfortunately the non-periodicity of the vibration signal is not the only consequence of the slippage: often it also involves a displacement of the damage characteristic peaks from the theoretically expected frequencies. This issue becomes particularly important in the attempt to develop highly automated algorithms for bearing damage recognition, and, in order to correctly set thresholds and tolerances, a quantitative description of the magnitude of the above mentioned deviations is needed. This paper is aimed at identifying the dependency of the deviations on the different operating conditions. This has been possible thanks to an extended experimental activity performed on a full scale bearing test rig, able to reproduce realistically the operating and environmental conditions typical of an industrial high power electric motor and gearbox. The importance of load will be investigated in detail for different bearing damages. Finally some guidelines on how to cope with such deviations will be given, accordingly to the expertise obtained in the experimental activity.

The Catlin Seaview Survey – kilometre-scale seascape assessment, and monitoring of coral reef ecosystems

1.Marine ecosystems provide critically important goods and services to society, and hence their accelerated degradation underpins an urgent need to take rapid, ambitious and informed decisions regarding their conservation and management. 2.The capacity, however, to generate the detailed field data required to inform conservation planning at appropriate scales is limited by time and resource consuming methods for collecting and analysing field data at the large scales required. 3.The ‘Catlin Seaview Survey’, described here, introduces a novel framework for large-scale monitoring of coral reefs using high-definition underwater imagery collected using customized underwater vehicles in combination with computer vision and machine learning. This enables quantitative and geo-referenced outputs of coral reef features such as habitat types, benthic composition, and structural complexity (rugosity) to be generated across multiple kilometre-scale transects with a spatial resolution ranging from 2 to 6 m2. 4.The novel application of technology described here has enormous potential to contribute to our understanding of coral reefs and associated impacts by underpinning management decisions with kilometre-scale measurements of reef health. 5.Imagery datasets from an initial survey of 500 km of seascape are freely available through an online tool called the Catlin Global Reef Record. Outputs from the image analysis using the technologies described here will be updated on the online repository as work progresses on each dataset. 6.Case studies illustrate the utility of outputs as well as their potential to link to information from remote sensing. The potential implications of the innovative technologies on marine resource management and conservation are also discussed, along with the accuracy and efficiency of the methodologies deployed.

Development of an online role-play assessment initiative for nursing students in their bioscience studies

Devising assessment tasks for large units that embrace academic goals of authenticity and assessment variety can be a challenge. We developed an online Role-Play Assessment Initiative for first year nursing students in bioscience. Students responded to a case study by preparing two role-play dialogues: as a nurse with the patient, and between two nurses. The aims were to assess whether the students could: 1) understand the underlying disease process (pathophysiology) and relate it to clinical practice; 2) use language appropriate for lay and medical conversation; and 3) apply information using active learning. We conducted a student survey using quantitative questions (Likert scale: 1=strongly disagree to 5=strongly agree), and qualitative questions. 65 completed surveys were received. 80% of respondents agreed (includes agree or strongly agree) that it was a useful way to learn and understand pathophysiology of the case study. 86% agreed that it was useful to apply pathophysiology from lectures to a clinical setting. Overall, students found it enjoyable, which is beneficial for enhanced student engagement, and agreed that it allowed them to work well in a group (74% and 85%, respectively). Most qualitative suggestions for improvement related to group work, despite the encouraging response to group work in quantitative questions. Most positive comments surrounded different communication with a nurse compared with a patient. These results demonstrate that students developed deeper understanding of pathophysiology through active learning and were able to expand their nursing career skills during the role-play. Learning using role-play to simulate the workforce has fostered active learning.

Development of health risk-based metrics for defining a heatwave : a time series study in Brisbane, Australia

Background: This study attempted to develop health risk-based metrics for defining a heatwave in Brisbane, Australia. Methods: Poisson generalised additive model was performed to assess the impact of heatwaves on mortality and emergency hospital admissions (EHAs) in Brisbane. Results: In general, the higher the intensity and the longer the duration of a heatwave, the greater the health impacts. There was no apparent difference in EHAs risk during different periods of a warm season. However, there was a greater risk of mortality in the second half of a warm season than that in the first half. While elderly (>75 years)were particularly vulnerable to both the EHA and mortality effects of a heatwave, the risk for EHAs also significantly increased for two other age groups (0-64 years and 65-74 years) during severe heatwaves. Different patterns between cardiorespiratory mortality and EHAs were observed. Based on these findings, we propose the use of a teiered heat warning system based on the health risk of heatwave. Conclusions: Health risk-based metrics are a useful tool for the development of local heatwave definitions. thsi tool may have significant implications for the assessment of heatwave-related health consequences and development of heatwave response plans and implementation strategies.

Comparison of visual inspection and structural-health monitoring as bridge condition assessment methods

This paper presents the results of a research project aimed at examining the capabilities and challenges of two distinct but not mutually exclusive approaches to in-service bridge assessment: visual inspection and installed monitoring systems. In this study, the intended functionality of both approaches was evaluated on its ability to identify potential structural damage and to provide decision-making support. Inspection and monitoring are compared in terms of their functional performance, cost, and barriers (real and perceived) to implementation. Both methods have strengths and weaknesses across the metrics analyzed, and it is likely that a hybrid evaluation technique that adopts both approaches will optimize efficiency of condition assessment and ultimately lead to better decision making.

Positive development and assessment

Purpose – There has been a tendency in sustainability science to be passive. The purpose of this paper is to introduce an alternative positive framework for a more active and direct approach to sustainable design and assessment that de-couples environmental impacts and economic growth. Design/methodology/approach – This paper deconstructs some systemic gaps that are critical to sustainability in built environment management processes and tools, and reframes negative “sustainable” decision making and assessment frameworks into their positive counterparts. In particular, it addresses the omission of ecology, design and ethics in development assessment. Findings – Development can be designed to provide ecological gains and surplus “eco-services,” but assessment tools and processes favor business-as-usual. Despite the tenacity of the dominant paradigm (DP) in sustainable development institutionalized by the Brundtland Report over 25 years ago, these omissions are easily corrected. Research limitations/implications – The limitation is that the author was unable to find exceptions to the omissions cited here in the extensive literature on urban planning and building assessment tools. However, exceptions prove the rule. The implication is that it is not too late for eco-positive retrofitting of cities to increase natural and social capital. The solutions are just as applicable in places like China and India as the USA, as they pay for themselves. Originality/value – Positive development (PD) is a fundamental paradigm shift that reverses the negative models, methods and metrics of the DP of sustainable development. This paper provides an example of how existing “negative” concepts and practices can be converted into positive ones through a PD prism. Through a new form of bio-physical design, development can be a sustainability solution.

Social Media Audience Metrics as a New Form of TV Audience Measurement

Digital media have contributed to significant disruptions in the business of audience measurement. Television broadcasters have long relied on simple and authoritative measures of who is watching what. The demand for ratings data, as a common currency in transactions involving advertising and program content, will likely remain, but accompanying measurements of audience engagement with media content would also be of value. Today's media environment increasingly includes social media and second-screen use, providing a data trail that affords an opportunity to measure engagement. If the limitations of using social media to indicate audience engagement can be overcome, social media use may allow for quantitative and qualitative measures of engagement. Raw social media data must be contextualized, and it is suggested that tools used by sports analysts be incorporated to do so. Inspired by baseball's Sabremetrics, the authors propose Telemetrics in an attempt to separate actual performance from contextual factors. Telemetrics facilitates measuring audience activity in a manner controlling for factors such as time slot, network, and so forth. It potentially allows both descriptive and predictive measures of engagement.

A Bayesian Framework for the Assessment of Vision-based Weed and Fruit Detection and Classification Algorithms

This paper proposes new metrics and a performance-assessment framework for vision-based weed and fruit detection and classification algorithms. In order to compare algorithms, and make a decision on which one to use fora particular application, it is necessary to take into account that the performance obtained in a series of tests is subject to uncertainty. Such characterisation of uncertainty seems not to be captured by the performance metrics currently reported in the literature. Therefore, we pose the problem as a general problem of scientific inference, which arises out of incomplete information, and propose as a metric of performance the(posterior) predictive probabilities that the algorithms will provide a correct outcome for target and background detection. We detail the framework through which these predicted probabilities can be obtained, which is Bayesian in nature. As an illustration example, we apply the framework to the assessment of performance of four algorithms that could potentially be used in the detection of capsicums (peppers).

Evaluation of hospital preparedness for public health emergencies in Sichuan (China)

The aim of this research was to develop a set of reliable, valid preparedness metrics, built around a comprehensive framework for assessing hospital preparedness. This research used a combination of qualitative and quantitative methods which included interview and a Delphi study as well as a survey of hospitals in the Sichuan Province of China. The resultant framework is constructed around the stages of disaster management and includes nine key elements. Factor Analysis identified four contributing factors. The comparison of hospitals' preparedness using these four factors, revealed that tertiary-grade, teaching and general hospitals performed better than secondary-grade, non-teaching and non-general hospitals.