EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer : analysis of data from the phase 3 FLEX study

Background: Findings from the phase 3 First-Line ErbituX in lung cancer (FLEX) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone (hazard ratio [HR] 0·871, 95% CI 0·762-0·996; p=0·044) in patients with advanced non-small-cell lung cancer (NSCLC). To define patients benefiting most from cetuximab, we studied the association of tumour EGFR expression level with clinical outcome in FLEX study patients. Methods: We used prospectively collected tumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0-300. We used response data to select an outcome-based discriminatory threshold immunohistochemistry score for EGFR expression of 200. Treatment outcome was analysed in patients with low (immunohistochemistry score <200) and high (≥200) tumour EGFR expression. The primary endpoint in the FLEX study was overall survival. We analysed patients from the FLEX intention-to-treat (ITT) population. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798. Findings: Tumour EGFR immunohistochemistry data were available for 1121 of 1125 (99·6%) patients from the FLEX study ITT population. High EGFR expression was scored for 345 (31%) evaluable patients and low for 776 (69%) patients. For patients in the high EGFR expression group, overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group (median 12·0 months [95% CI 10·2-15·2] vs 9·6 months [7·6-10·6]; HR 0·73, 0·58-0·93; p=0·011), with no meaningful increase in side-effects. We recorded no corresponding survival benefit for patients in the low EGFR expression group (median 9·8 months [8·9-12·2] vs 10·3 months [9·2-11·5]; HR 0·99, 0·84-1·16; p=0·88). A treatment interaction test assessing the difference in the HRs for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression (p=0·044). Interpretation: High EGFR expression is a tumour biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC. Assessment of EGFR expression could offer a personalised treatment approach in this setting. Funding: Merck KGaA. © 2012 Elsevier Ltd.

RanGTPase : a candidate for myc-mediated cancer progression

Background Ras-related nuclear protein (Ran) is required for cancer cell survival in vitro and human cancer progression, but the molecular mechanisms are largely unknown. Methods We investigated the effect of the v-myc myelocytomatosis viral oncogene homolog (Myc) on Ran expression by Western blot, chromatin immunoprecipitation, and luciferase reporter assays and the effects of Myc and Ran expression in cancer cells by soft-agar, cell adhesion, and invasion assays. The correlation between Myc and Ran and the association with patient survival were investigated in 14 independent patient cohorts (n = 2430) and analyzed with Spearman's rank correlation and Kaplan-Meier plots coupled with Wilcoxon-Gehan tests, respectively. All statistical tests were two-sided. Results Myc binds to the upstream sequence of Ran and transactivates Ran promoter activity. Overexpression of Myc upregulates Ran expression, whereas knockdown of Myc downregulates Ran expression. Myc or Ran overexpression in breast cancer cells is associated with cancer progression and metastasis. Knockdown of Ran reverses the effect induced by Myc overexpression in breast cancer cells. In clinical data, a positive association between Myc and Ran expression was revealed in 288 breast cancer and 102 lung cancer specimens. Moreover, Ran expression levels differentiate better or poorer survival in Myc overexpressing breast (χ2 = 24.1; relative risk [RR] = 9.1, 95% confidence interval [CI] = 3.3 to 24.7, P <. 001) and lung (χ2 = 6.04; RR = 2.8, 95% CI = 1.2 to 6.3; P =. 01) cancer cohorts. Conclusions Our results suggest that Ran is required for and is a potential therapeutic target of Myc-driven cancer progression in both breast and lung cancers. © 2013 The Author.

Influence of stop position on spectacle magnification

Purpose To develop and use equations of spectacle magnification when the limiting stop is either the entrance pupil of the eye or an artificial pupil in front of a lens. Methods Spectacle magnification was determined for ophthalmic lenses in air and for water environments. The reference was the retinal image for an uncorrected eye in air with a natural pupil. Results When an artificial pupil is placed in front of lenses, spectacle magnification is hardly affected by lens power, unlike the usual situation where the natural pupil is used. The water environment provides interesting influences in which spectacle magnification is highly sensitive to the distance between the cornea and eye entrance pupil. In water, retinal images are approximately 18% bigger than in air. Wearing air-filled goggles in water increases retinal image size by about 13% compared with that when they are not worn. Conclusions The equations extend earlier understanding of spectacle magnification and should be useful for those wishing to determine magnification of ophthalmic lens systems when artificial pupils and environments such as water are used.

The adaptive metabolic response to exercise-induced weight loss influences both energy expenditure and energy intake

BACKGROUND/OBJECTIVEs A decline in resting energy expenditure (REE) beyond that predicted from changes in body composition has been noted following dietary-induced weight loss. However, it is unknown whether a compensatory downregulation in REE also accompanies exercise (EX)-induced weight loss, or whether this adaptive metabolic response influences energy intake (EI). SUBJECTS/METHODS Thirty overweight and obese women (body mass index (BMI)=30.6±3.6 kg/m2) completed 12 weeks of supervised aerobic EX. Body composition, metabolism, EI and metabolic-related hormones were measured at baseline, week 6 and post intervention. The metabolic adaptation (MA), that is, difference between predicted and measured REE was also calculated post intervention (MApost), with REE predicted using a regression equation generated in an independent sample of 66 overweight and obese women (BMI=31.0±3.9 kg/m2). RESULTS Although mean predicted and measured REE did not differ post intervention, 43% of participants experienced a greater-than-expected decline in REE (−102.9±77.5 kcal per day). MApost was associated with the change in leptin (r=0.47; P=0.04), and the change in resting fat (r=0.52; P=0.01) and carbohydrate oxidation (r=−0.44; P=0.02). Furthermore, MApost was also associated with the change in EI following EX (r=−0.44; P=0.01). CONCLUSIONS Marked variability existed in the adaptive metabolic response to EX. Importantly, those who experienced a downregulation in REE also experienced an upregulation in EI, indicating that the adaptive metabolic response to EX influences both physiological and behavioural components of energy balance.

Response of a buried tunnel to surface blast using different numerical techniques

This paper presents a comparative study on the response of a buried tunnel to surface blast using the arbitrary Lagrangian-Eulerian (ALE) and smooth particle hydrodynamics (SPH) techniques. Since explosive tests with real physical models are extremely risky and expensive, the results of a centrifuge test were used to validate the numerical techniques. The numerical study shows that the ALE predictions were faster and closer to the experimental results than those from the SPH simulations which over predicted the strains. The findings of this research demonstrate the superiority of the ALE modelling techniques for the present study. They also provide a comprehensive understanding of the preferred ALE modelling techniques which can be used to investigate the surface blast response of underground tunnels.

An interactive planning and scheduling framework for optimising pits-to-crushers operations

In this paper, an interactive planning and scheduling framework are proposed for optimising operations from pits to crushers in ore mining industry. Series of theoretical and practical operations research techniques are investigated to improve the overall efficiency of mining systems due to the facts that mining managers need to tackle optimisation problems within different horizons and with different levels of detail. Under this framework, mine design planning,mine production sequencing and mine transportation scheduling models are integrated and interacted within a whole optimisation system. The proposed integrated framework could be used by mining industry for reducing equipment costs, improving the production efficiency and maximising the net present value.

The promise of justice reinvestment

Abstract: This article examines the notion and practice of Justice Reinvestment (‘JR’), an emerging approach addressing the high social and economic costs of soaring incarceration rates. JR invests in public safety by reallocating dollars from corrections budgets to finance education, housing, healthcare, and jobs in high-crime communities. Key distinguishing features of JR (including justice and asset mapping, budgetary devolution and localism, and the desirability of bipartisanship) are briefly outlined, followed by discussion of its recent emergence and application in the United States, and to a lesser extent in the United Kingdom. The prospects for the adoption of JR approaches in Australia are then considered, with particular reference to the high imprisonment rates of Indigenous people. If JR is to be promoted in the Australian context it is important that it be subject to critical scrutiny and therefore some of the key problems are briefly outlined, before a conclusion which emphasizes the potential benefits of JR.

A randomized controlled trial of a 10 percent CPP-ACP cream to reduce mutans streptococci colonization

Purpose The purpose of this study was to investigate the effectiveness of a 10 percent casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) cream to reduce mutans streptococci (MS) colonization and prevent early childhood caries. Methods The cohort was randomized at mean age of 11 days old to receive once-daily CPP-ACP cream (n=102) or no product (comparison group; n=89) from the time of first tooth eruption. All mothers were contacted by telephone at six, 12, and 18 months and advised to brush their children's teeth twice daily with low-dose fluoride toothpaste. At 24 months, all children were examined at a community clinic. Results At 24 months old, one out of 65 (2 percent) children in the CPP-ACP group had caries vs. four out of 58 (seven percent) in the comparison group (difference not statistically significant). There were fewer MS-positive children in the CPP-ACP group (26 percent) vs. the comparison group (47 percent; P=.02). A dose-response effect of CPP-ACP usage on MS was observed, where MS was present in eight percent of regular CPP-ACP users, 28 percent of irregular users, and 47 percent of non-users (P<.02). Conclusions CPP-ACP reduced the percentages of mutans streptococci-positive 24-month-old children, although it did not reduce caries prevalence.

Crime, justice, and inequality : Oh Canada, where art thou?

Since Canada’s colonial beginnings, it has become increasingly riddled with classism, racism,sexism, and other damaging outcomes of structured social inequality. In 2006, however,many types of social injustice were turbo‐charged under the federal leadership of the Harper government. For example, a recent southern Ontario study shows that less than half of working people between the ages of 25 and 65 have full‐time jobs with benefits. The main objective of this paper is to critique the dominant Canadian political economic order and the pain and suffering it has caused for millions of people. Informed by left realism and other progressive ways of knowing, I also suggest some ways of turning the tide.

Beat-mixing rock music

Electronic dance music (EDM) has the capacity of producing not simply individual recordings but also a medium to create new soundtracks through live manipulation of these recordings by disc jockeys (DJs). This immediacy in dance music is in contrast with recorded rock music continuing to be presented in a static form. Research was undertaken to explore the proposition that EDM’s beat-mixing function can be implemented to create immediacy in rock music. The term used in this thesis to refer to the application of beat-mixing in rock music is ‘ClubRock’. Through collaboration between a number of disk jockeys and rock music professionals the research applied the process of beat-mixing standard rock compositions to produce a continuous rock set. DJ techniques created immediacy in the recordings and transformed static renditions into a fluid creative work.

Co-thought gestures : supporting students to successfully navigate map tasks

This study considers the role and nature of co-thought gestures when students process map-based mathematics tasks. These gestures are typically spontaneously produced silent gestures which do not accompany speech and are represented by small movements of the hands or arms often directed toward an artefact. The study analysed 43 students (aged 10–12 years) over a 3-year period as they solved map tasks that required spatial reasoning. The map tasks were representative of those typically found in mathematics classrooms for this age group and required route finding and coordinate knowledge. The results indicated that co-thought gestures were used to navigate the problem space and monitor movements within the spatial challenges of the respective map tasks. Gesturing was most influential when students encountered unfamiliar tasks or when they found the tasks spatially demanding. From a teaching and learning perspective, explicit co-thought gesturing highlights cognitive challenges students are experiencing since students tended to not use gesturing in tasks where the spatial demands were low.

Extensions of the cube attack based on low degree annihilators

At Crypto 2008, Shamir introduced a new algebraic attack called the cube attack, which allows us to solve black-box polynomials if we are able to tweak the inputs by varying an initialization vector. In a stream cipher setting where the filter function is known, we can extend it to the cube attack with annihilators: By applying the cube attack to Boolean functions for which we can find low-degree multiples (equivalently annihilators), the attack complexity can be improved. When the size of the filter function is smaller than the LFSR, we can improve the attack complexity further by considering a sliding window version of the cube attack with annihilators. Finally, we extend the cube attack to vectorial Boolean functions by finding implicit relations with low-degree polynomials.

The Language : Rationale and Fundamentals

The Business Process Management domain has evolved at a dramatic pace over the past two decades and the notion of the business process has become a ubiquitous part of the modern business enterprise. Most organizations now view their operations in terms of business processes and manage these business processes in the same way as other corporate assets. In recent years, an increasingly broad range of generic technology has become available for automating business processes. This is part of a growing trend in the software engineering field throughout the past 40 years, where aspects of functionality that are potentially reusable on a widespread basis have coalesced into generic software components. Figure 2.1 illustrates this trend and shows how software systems have evolved from the monolithic applications of the 1960s developed in their entirety often by a single development team to today’s offerings that are based on the integration of a range of generic technologies with only a small component of the application actually being developed from scratch. In the 1990s, generic functionality for the automation of business processes first became commercially available in the form of workflow technology and subsequently evolved in the broader field of business process management systems (BPMS). This technology alleviated the necessity to develop process support within applications from scratch and provided a variety of off-the-shelf options on which these requirements could be based. The demand for this technology was significant and it is estimated that by 2000 there were well over 200 distinct workflow offerings in the market, each with a distinct conceptual foundation. Anticipating the difficulties that would be experienced by organizations seeking to utilize and integrate distinct workflow offerings, the Workflow Management Coalition (WfMC), an industry group formed to advance technology in this area, proposed a standard reference model for workflow technology with an express desire to seek a common platform for achieving workflow interoperation.

Joint identification of infinite-frequency added mass and fluid-memory models of marine structures

This paper addresses the problem of joint identification of infinite-frequency added mass and fluid memory models of marine structures from finite frequency data. This problem is relevant for cases where the code used to compute the hydrodynamic coefficients of the marine structure does not give the infinite-frequency added mass. This case is typical of codes based on 2D-potential theory since most 3D-potential-theory codes solve the boundary value associated with the infinite frequency. The method proposed in this paper presents a simpler alternative approach to other methods previously presented in the literature. The advantage of the proposed method is that the same identification procedure can be used to identify the fluid-memory models with or without having access to the infinite-frequency added mass coefficient. Therefore, it provides an extension that puts the two identification problems into the same framework. The method also exploits the constraints related to relative degree and low-frequency asymptotic values of the hydrodynamic coefficients derived from the physics of the problem, which are used as prior information to refine the obtained models.