Clinical and testing protocols for the analysis of epidermal growth factor receptor mutations in East Asian patients with non-small cell lung cancer:a combined clinical-molecular pathological approach

Several randomized phase III studies in advanced stage non-small cell lung cancer (NSCLC) confirmed the superior response rate and progression-free survival of using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor as first-line therapy compared with chemotherapy in patients with activating EGFR mutations. Despite the need for EGFR mutation tests to guide first-line therapy in East Asian NSCLC, there are no current standard clinical and testing protocols.

MIXED-MODEL PRODUCTION SYSTEM DESIGN FOR AIRCRAFT ASSEMBLY

With the advancement of flexible fixture and flexible tooling, mixed production has become possible for aircraft assembly as the manufacturing processes of different aircraft/sub-assembly models are similar. However, it is a great challenge to model the problem and provide a practical solution due to the low volume and complex constraints of aircraft assemblies. To tackle this problem, this work proposes a methodology for designing the mixed production system, and a new scheduling approach is proposed by combined backward and forward scheduling methods. These methods are validated through a real-life industrial case study. Simulation results show that the number of workstations and the cycle time for making a fuselage can be reduced by 50% and 39% respectively with the newly designed mixed-model system.

AXL Is a Key Regulator of Inherent and Chemotherapy-Induced Invasion and Predicts a Poor Clinical Outcome in Early-Stage Colon Cancer

Purpose: Despite the use of 5-fluorouracil (5-FU)–based adjuvant treatments, a large proportion of patients with high-risk stage II/III colorectal cancer will relapse. Thus, novel therapeutic strategies are needed for early-stage colorectal cancer. Residual micrometastatic disease from the primary tumor is a major cause of patient relapse.

Experimental Design: To model colorectal cancer tumor cell invasion/metastasis, we have generated invasive (KRASMT/KRASWT/+chr3/p53-null) colorectal cancer cell subpopulations. Receptor tyrosine kinase (RTK) screens were used to identify novel proteins that underpin the migratory/invasive phenotype. Migration/invasion was assessed using the XCELLigence system. Tumors from patients with early-stage colorectal cancer (N = 336) were examined for AXL expression.

Results: Invasive colorectal cancer cell subpopulations showed a transition from an epithelial-to-mesenchymal like phenotype with significant increases in migration, invasion, colony-forming ability, and an attenuation of EGF receptor (EGFR)/HER2 autocrine signaling. RTK arrays showed significant increases in AXL levels in all invasive sublines. Importantly, 5-FU treatment resulted in significantly increased migration and invasion, and targeting AXL using pharmacologic inhibition or RNA interference (RNAi) approaches suppressed basal and 5-FU–induced migration and invasion. Significantly, high AXL mRNA and protein expression were found to be associated with poor overall survival in early-stage colorectal cancer tissues.

Conclusions: We have identified AXL as a poor prognostic marker and important mediator of cell migration/invasiveness in colorectal cancer. These findings provide support for the further investigation of AXL as a novel prognostic biomarker and therapeutic target in colorectal cancer, in particular in the adjuvant disease in which EGFR/VEGF–targeted therapies have failed.

Understanding macroalgal dispersal in a complex hydrodynamic environment: a combined population genetic and physical modelling approach

Gene flow in macroalgal populations can be strongly influenced by spore or gamete dispersal. This, in turn, is influenced by a convolution of the effects of current flow and specific plant reproductive strategies. Although several studies have demonstrated genetic variability in macroalgal populations over a wide range of spatial scales, the associated current data have generally been poorly resolved spatially and temporally. In this study, we used a combination of population genetic analyses and high-resolution hydrodynamic modelling to investigate potential connectivity between populations of the kelp Laminaria digitata in the Strangford Narrows, a narrow channel characterized by strong currents linking the large semi-enclosed sea lough, Strangford Lough, to the Irish Sea. Levels of genetic structuring based on six microsatellite markers were very low, indicating high levels of gene flow and a pattern of isolation-by-distance, where populations are more likely to exchange migrants with geographically proximal populations, but with occasional long-distance dispersal. This was confirmed by the particle tracking model, which showed that, while the majority of spores settle near the release site, there is potential for dispersal over several kilometres. This combined population genetic and modelling approach suggests that the complex hydrodynamic environment at the entrance to Strangford Lough can facilitate dispersal on a scale exceeding that proposed for L. digitata in particular, and the majority of macroalgae in general. The study demonstrates the potential of integrated physical–biological approaches for the prediction of ecological changes resulting from factors such as anthropogenically induced coastal zone changes.

Assessing parenting capacity in child protection: towards a knowledge-based model

The assessment of parenting capacity continues to engender public concern in cases of suspected harm to children. This paper outlines a model for approaching this task based on the application of three key domains of knowledge in social work relating to facts, theory and practice wisdom. The McMaster Model of Family Assessment is identified out of this process and reworked to give it a sharper focus on parenting roles and responsibilities. Seven formative dimensions of parenting are then elicited and combined with an analytical process of identifying strengths, concerns, prospects for growth and impact on child outcomes. The resulting assessment framework, it is argued, adds rigour to professional judgements about parenting capacity and enhances formulations on risk in child protection.

Three dimensional morphology and compressive behaviour of sintered biodegradable composite scaffolds

Porous poly-L-lactide acid (PLA) scaffolds are prepared using polymer sintering and porogen leaching method. Different weight fractions of the Hydroxyapatite (HA) are added to the PLA to control the acidity and degradation rate. The three dimensional morphology and surface porosity are tested using micro CT, optical microscopy and scanning electron microscopy (SEM). Results indicate that the surface porosity does not change by addition of HA. The micro Ct examinations show slight decrease in the pore size and increase in wall thickness accompanied with reduced anisotropy for the scaffolds containing HA. SEM micrographs show detectable interconnected pores for the scaffold with pure PLA. Addition of the HA results in agglomeration of the HA which blocks some of the pores. Compression tests of the scaffold identify three stages in the stress-strain curve. The addition of HA adversely affects the modulus of the scaffold at the first stage, but this was reversed for the second and third stages of the compression. The results of these tests are compared with the cellular material model. The manufactured scaffold have acceptable properties for a scaffold, however improvement to the mixing of the phases of PLA and HA is required to achieve better integrity of the composite scaffolds.

A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

Background: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies.

Patients and methods: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload.

Results: A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival.

Conclusions: Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.

Analysis of the compressive behaviour of the three-dimensional printed porous titanium for dental implants using a modified cellular solid model

A set of cylindrical porous titanium test samples were produced using the three-dimensional printing and sintering method with samples sintered at 900 °C, 1000 °C, 1100 °C, 1200 °C or 1300 °C. Following compression testing, it was apparent that the stress-strain curves were similar in shape to the curves that represent cellular solids. This is despite a relative density twice as high as what is considered the threshold for defining a cellular solid. As final sintering temperature increased, the compressive behaviour developed from being elastic-brittle to elastic-plastic and while Young's modulus remained fairly constant in the region of 1.5 GPa, there was a corresponding increase in 0.2% proof stress of approximately 40-80 MPa. The cellular solid model consists of two equations that predict Young's modulus and yield or proof stress. By fitting to experimental data and consideration of porous morphology, appropriate changes to the geometry constants allow modification of the current models to predict with better accuracy the behaviour of porous materials with higher relative densities (lower porosity).

The changing university business model: a stakeholder perspective

Universities are in a current state of transition, whereby they are expected to develop a wide range of relationships with stakeholders in order to enhance regional innovation systems. However, despite external environmental pressures commonly regarded as one of the main drivers of business model evolution, there is a lack of studies that explore business model innovation as a result of multiple stakeholder influences. Accordingly, the aim of this paper is to examine the changing university business model within a region of the United Kingdom, using a stakeholder perspective that will aid theoretical development and refinement in both the business model and stakeholder fields. This examination is aided by consideration of the university business model as an activity system. Repeat interviews, combined with stakeholder theory, have been used to show how the changing university business model–stakeholder relationship has progressed through different stakeholder stages with resultant changes in content, structure and governance. Furthermore, conflicting objectives between each of the stakeholder groups (i.e. academics, industry liaison staff, technology transfer office staff and government support agency representatives) have led to the university business model evolving not as a process of co-creation but rather in a series of transitions whereby multiple stakeholders are continually shaping the university business model through strategies that are dependent upon their salience. Finally, this paper contributes to the development and refinement of business model innovation research, in that the use of stakeholder constructs can illustrate the impact of multiple stakeholders' power and influence on business model innovation.

Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification

Aims/hypothesis: Diabetic nephropathy is a major diabetic complication, and diabetes is the leading cause of end-stage renal disease (ESRD). Family studies suggest a hereditary component for diabetic nephropathy. However, only a few genes have been associated with diabetic nephropathy or ESRD in diabetic patients. Our aim was to detect novel genetic variants associated with diabetic nephropathy and ESRD. Methods: We exploited a novel algorithm, ‘Bag of Naive Bayes’, whose marker selection strategy is complementary to that of conventional genome-wide association models based on univariate association tests. The analysis was performed on a genome-wide association study of 3,464 patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study and subsequently replicated with 4,263 type 1 diabetes patients from the Steno Diabetes Centre, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK collection (UK–Republic of Ireland) and the Genetics of Kidneys in Diabetes US Study (GoKinD US). Results: Five genetic loci (WNT4/ZBTB40-rs12137135, RGMA/MCTP2-rs17709344, MAPRE1P2-rs1670754, SEMA6D/SLC24A5-rs12917114 and SIK1-rs2838302) were associated with ESRD in the FinnDiane study. An association between ESRD and rs17709344, tagging the previously identified rs12437854 and located between the RGMA and MCTP2 genes, was replicated in independent case–control cohorts. rs12917114 near SEMA6D was associated with ESRD in the replication cohorts under the genotypic model (p < 0.05), and rs12137135 upstream of WNT4 was associated with ESRD in Steno. Conclusions/interpretation: This study supports the previously identified findings on the RGMA/MCTP2 region and suggests novel susceptibility loci for ESRD. This highlights the importance of applying complementary statistical methods to detect novel genetic variants in diabetic nephropathy and, in general, in complex diseases.

Incorporating Severity and Risk as Factors to the Fardal Cost-Effectiveness Model to Create a Cost-Benefit Model for Periodontal Treatment

Background: A previously described economic model was based on average values for patients diagnosed with chronic periodontitis (CP). However, tooth loss varies among treated patients and factors for tooth loss include CP severity and risk. The model was refined to incorporate CP severity and risk to determine the cost of treating a specific level of CP severity and risk that is associated with the benefit of tooth preservation.

Methods: A population that received and another that did not receive periodontal treatment were used to determine treatment costs and tooth loss. The number of teeth preserved was the difference of the number of teeth lost between the two populations. The cost of periodontal treatment was divided by the number of teeth preserved for combinations of CP severity and risk.

Results: The cost of periodontal treatment divided by the number of teeth preserved ranged from (US) $ 1,405 to $ 4,895 for high or moderate risk combined with any severity of CP and was more than $ 8,639 for low risk combined with mild CP. The cost of a three-unit bridge was $ 3,416, and the cost of a single-tooth replacement was $ 4,787.

Conclusion: Periodontal treatment could be justified on the sole basis of tooth preservation when CP risk is moderate or high regardless of disease severity.

The nucleus of Comet 67P/Churyumov-Gerasimenko. A new shape model and thermophysical analysis

Context. Comet 67P/Churyumov-Gerasimenko is the target of the European Space Agency Rosetta spacecraft rendez-vous mission. Detailed physical characteristation of the comet before arrival is important for mission planning as well as providing a test bed for ground-based observing and data-analysis methods. Aims: To conduct a long-term observational programme to characterize the physical properties of the nucleus of the comet, via ground-based optical photometry, and to combine our new data with all available nucleus data from the literature. Methods: We applied aperture photometry techniques on our imaging data and combined the extracted rotational lightcurves with data from the literature. Optical lightcurve inversion techniques were applied to constrain the spin state of the nucleus and its broad shape. We performed a detailed surface thermal analysis with the shape model and optical photometry by incorporating both into the new Advanced Thermophysical Model (ATPM), along with all available Spitzer 8-24 μm thermal-IR flux measurements from the literature. Results: A convex triangular-facet shape model was determined with axial ratios b/a = 1.239 and c/a = 0.819. These values can vary by as much as 7% in each axis and still result in a statistically significant fit to the observational data. Our best spin state solution has Psid = 12.76137 ± 0.00006 h, and a rotational pole orientated at Ecliptic coordinates λ = 78°(±10°), β = + 58°(±10°). The nucleus phase darkening behaviour was measured and best characterized using the IAU HG system. Best fit parameters are: G = 0.11 ± 0.12 and HR(1,1,0) = 15.31 ± 0.07. Our shape model combined with the ATPM can satisfactorily reconcile all optical and thermal-IR data, with the fit to the Spitzer 24 μm data taken in February 2004 being exceptionally good. We derive a range of mutually-consistent physical parameters for each thermal-IR data set, including effective radius, geometric albedo, surface thermal inertia and roughness fraction. Conclusions: The overall nucleus dimensions are well constrained and strongly imply a broad nucleus shape more akin to comet 9P/Tempel 1, rather than the highly elongated or "bi-lobed" nuclei seen for comets 103P/Hartley 2 or 8P/Tuttle. The derived low thermal inertia of

3D Morphable Model Construction for Robust Ear and Face Recognition

Recent work suggests that the human ear varies significantly between different subjects and can be used for identification. In principle, therefore, using ears in addition to the face within a recognition system could improve accuracy and robustness, particularly for non-frontal views. The paper describes work that investigates this hypothesis using an approach based on the construction of a 3D morphable model of the head and ear. One issue with creating a model that includes the ear is that existing training datasets contain noise and partial occlusion. Rather than exclude these regions manually, a classifier has been developed which automates this process. When combined with a robust registration algorithm the resulting system enables full head morphable models to be constructed efficiently using less constrained datasets. The algorithm has been evaluated using registration consistency, model coverage and minimalism metrics, which together demonstrate the accuracy of the approach. To make it easier to build on this work, the source code has been made available online.

Classification the geographical origin of corn distillers dried grains with solubles by near infrared reflectance spectroscopy combined with chemometrics: A feasibility study

In this study, 137 corn distillers dried grains with solubles (DDGS) samples from a range of different geographical origins (Jilin Province of China, Heilongjiang Province of China, USA and Europe) were collected and analysed. Different near infrared spectrometers combined with different chemometric packages were used in two independent laboratories to investigate the feasibility of classifying geographical origin of DDGS. Base on the same dataset, one laboratory developed a partial least square discriminant analysis model and another laboratory developed an orthogonal partial least square discriminant analysis model. Results showed that both models could perfectly classify DDGS samples from different geographical origins. These promising results encourage the development of larger scale efforts to produce datasets which can be used to differentiate the geographical origin of DDGS and such efforts are required to provide higher level food security measures on a global scale.

Advanced Modelling and Optimization of Infared Oven in Injection Stretch Blow-moulding for Energy Saving

In the production process of polyethylene terephthalate (PET) bottles, the initial temperature of preforms plays a central role on the final thickness, intensity and other structural properties of the bottles. Also, the difference between inside and outside temperature profiles could make a significant impact on the final product quality. The preforms are preheated by infrared heating oven system which is often an open loop system and relies heavily on trial and error approach to adjust the lamp power settings. In this paper, a radial basis function (RBF) neural network model, optimized by a two-stage selection (TSS) algorithm combined with partial swarm optimization (PSO), is developed to model the nonlinear relations between the lamp power settings and the output temperature profile of PET bottles. Then an improved PSO method for lamp setting adjustment using the above model is presented. Simulation results based on experimental data confirm the effectiveness of the modelling and optimization method.