Integrated genomic characterization of endometrial carcinoma

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.

Sustainable knowledge community precincts : lessons from global best practices

In the era of global knowledge economy, urban regions—seeking to increase their competitive edge, become destinations for talent and investment, and provide prosperity and quality of life to their inhabitants—have little chance achieving their development goals without forming effective knowledge-based urban development (KBUD) strategies. KBUD paradigm suggests that the economic future of cities increasingly depends on the capacity to attract, generate, retain and foster creativity, knowledge and innovation—and make space and place for knowledge generation and knowledge communities. Thus, the paper aims to shed light on the planning and development processes of the KBUD phenomenon with respect to the construction of sustainable knowledge community precincts (KCPs) aimed at making space for knowledge generation and place for knowledge communities—and provide useful lessons for the developing country cities seeking such sustainable and KBUD.

Response to chemotherapy is predictive in relation to longer overall survival in an individual patient combined-analysis with pleural mesothelioma

Background: There is currently no early predictive marker of survival for patients receiving chemotherapy for malignant pleural mesothelioma (MPM). Tumour response may be predictive for overall survival (OS), though this has not been explored. We have thus undertaken a combined-analysis of OS, from a 42 day landmark, of 526 patients receiving systemic therapy for MPM. We also validate published progression-free survival rates (PFSRs) and a progression-free survival (PFS) prognostic-index model. Methods: Analyses included nine MPM clinical trials incorporating six European Organisation for Research and Treatment of Cancer (EORTC) studies. Analysis of OS from landmark (from day 42 post-treatment) was considered regarding tumour response. PFSR analysis data included six non-EORTC MPM clinical trials. Prognostic index validation was performed on one non-EORTC data-set, with available survival data. Results: Median OS, from landmark, of patients with partial response (PR) was 12·8 months, stable disease (SD), 9·4 months and progressive disease (PD), 3·4 months. Both PR and SD were associated with longer OS from landmark compared with disease progression (both p < 0·0001). PFSRs for platinum-based combination therapies were consistent with published significant clinical activity ranges. Effective separation between PFS and OS curves provided a validation of the EORTC prognostic model, based on histology, stage and performance status. Conclusion: Response to chemotherapy is associated with significantly longer OS from landmark in patients with MPM. © 2012 Elsevier Ltd. All rights reserved.

Development of a computer based 1D-2D dynamic flood model. Case study of the Pagsangaan river basin in Leyte, the Philippines

Floods are among the most devastating events that affect primarily tropical, archipelagic countries such as the Philippines. With the current predictions of climate change set to include rising sea levels, intensification of typhoon strength and a general increase in the mean annual precipitation throughout the Philippines, it has become paramount to prepare for the future so that the increased risk of floods on the country does not translate into more economic and human loss. Field work and data gathering was done within the framework of an internship at the former German Technical Cooperation (GTZ) in cooperation with the Local Government Unit of Ormoc City, Leyte, The Philippines, in order to develop a dynamic computer based flood model for the basin of the Pagsangaan River. To this end, different geo-spatial analysis tools such as PCRaster and ArcGIS, hydrological analysis packages and basic engineering techniques were assessed and implemented. The aim was to develop a dynamic flood model and use the development process to determine the required data, availability and impact on the results as case study for flood early warning systems in the Philippines. The hope is that such projects can help to reduce flood risk by including the results of worst case scenario analyses and current climate change predictions into city planning for municipal development, monitoring strategies and early warning systems. The project was developed using a 1D-2D coupled model in SOBEK (Deltares Hydrological modelling software package) and was also used as a case study to analyze and understand the influence of different factors such as land use, schematization, time step size and tidal variation on the flood characteristics. Several sources of relevant satellite data were compared, such as Digital Elevation Models (DEMs) from ASTER and SRTM data, as well as satellite rainfall data from the GIOVANNI server (NASA) and field gauge data. Different methods were used in the attempt to partially calibrate and validate the model to finally simulate and study two Climate Change scenarios based on scenario A1B predictions. It was observed that large areas currently considered not prone to floods will become low flood risk (0.1-1 m water depth). Furthermore, larger sections of the floodplains upstream of the Lilo- an’s Bridge will become moderate flood risk areas (1 - 2 m water depth). The flood hazard maps created for the development of the present project will be presented to the LGU and the model will be used to create a larger set of possible flood prone areas related to rainfall intensity by GTZ’s Local Disaster Risk Management Department and to study possible improvements to the current early warning system and monitoring of the basin section belonging to Ormoc City; recommendations about further enhancement of the geo-hydro-meteorological data to improve the model’s accuracy mainly on areas of interest will also be presented at the LGU.

Bayesian P-splines with a multiplicative term in EMG trace data

A method is proposed to describe force or compound muscle action potential (CMAP) trace data collected in an electromyography study for motor unit number estimation (MUNE). Experimental data was collected using incre- mental stimulation at multiple durations. However, stimulus information, vital for alternate MUNE methods, is not comparable for multiple duration data and therefore previous methods of MUNE (Ridall et al., 2006, 2007) cannot be used with any reliability. Hypothesised ring combinations of motor units are mod- elled using a multiplicative factor and Bayesian P-spline formulation. The model describes the process for force and CMAP in a meaningful way.

Energy-based positioning control of underactuated vehicles using manifold regulation

In this paper, we consider the problem of position regulation of a class of underactuated rigid-body vehicles that operate within a gravitational field and have fully-actuated attitude. The control objective is to regulate the vehicle position to a manifold of dimension equal to the underactuation degree. We address the problem using Port-Hamiltonian theory, and reduce the associated matching PDEs to a set of algebraic equations using a kinematic identity. The resulting method for control design is constructive. The point within the manifold to which the position is regulated is determined by the action of the potential field and the geometry of the manifold. We illustrate the performance of the controller for an unmanned aerial vehicle with underactuation degree two-a quadrotor helicopter.

On evaluation of robust autonomy for uninhabited vehicles and systems

This paper discusses a method to quantify robust autonomy of Uninhabited Vehicles and Systems (UVS) in aerospace, marine, or land applications. Based on mission-vehicle specific performance criteria, we define an system utility function that can be evaluated using simulation scenarios for an envelope of environmental conditions. The results of these evaluations are used to compute a figure of merit or measure for operational efectiveness (MOE). The procedure is then augmented to consider faults and the performance of mechanisms to handle these faulty operational modes. This leads to a measure of robust autonomy (MRA). The objective of the proposed figures of merit is to assist in decision making about vehicle performance and reliability at both vehicle development stage (using simulation models) and at certification stage (using hardware-in-the-loop testing). Performance indices based on dynamic and geometric tasks associated with vehicle manoeuvring problems are proposed, and an example of a two- dimensional y scenario is provided to illustrate the use of the proposed figures of merit.

Parameter estimation of thrust models of uninhabited airborne systems

This paper presents a method for the estimation of thrust model parameters of uninhabited airborne systems using specific flight tests. Particular tests are proposed to simplify the estimation. The proposed estimation method is based on three steps. The first step uses a regression model in which the thrust is assumed constant. This allows us to obtain biased initial estimates of the aerodynamic coeficients of the surge model. In the second step, a robust nonlinear state estimator is implemented using the initial parameter estimates, and the model is augmented by considering the thrust as random walk. In the third step, the estimate of the thrust obtained by the observer is used to fit a polynomial model in terms of the propeller advanced ratio. We consider a numerical example based on Monte-Carlo simulations to quantify the sampling properties of the proposed estimator given realistic flight conditions.

Multiple criteria-based real-time decision making by autonomous city vehicles

This paper addresses the topic of real-time decision making for autonomous city vehicles, i.e. the autonomous vehicles’ ability to make appropriate driving decisions in city road traffic situations. After decomposing the problem into two consecutive decision making stages, and giving a short overview about previous work, the paper explains how Multiple Criteria Decision Making (MCDM) can be used in the process of selecting the most appropriate driving maneuver.

Reason of state and a new notion of fortune : Historicising the risk society

Since the 1980s the concept of risk has produced a large and diverse volume of sociological research. Ulrich Beck’s groundbreaking risk society thesis provides a particularly engaging contribution, since it seems that nearly every sociological account of risk engages with this work. For Beck, we are living in second modernity – a new epoch that breaks with pre-modernity and industrial society due to the centrality, incalculability and reflexivity of globalised risk. While Beck’s theory is compelling, a reading of other theorists such as Foucault (2007[1978]) and Hacking (1975,1990) suggests that a difficulty with Beck’s work is that in attempting to explain what is novel about risk in contemporary times, he too quickly passes over the complexities and ruptures of historical change that impact on the history and contingency of risk. This paper begins by presenting a brief analysis of the present state of risk by introducing Beck’s historical narrative of risk from pre-modernity to the risk society; it then outlines the challenges with the “risk as epoch” argument by considering a range of literature, which suggests risk has a more complex history than proposed by Beck; and finally it highlights the value in examining strategies of statecraft in early modern Europe, specifically Machiavelli’s The Prince (2008[1513]) and Giovanni Botero’s political treatise, Della Ragion di Stato (1956[1589]) – as a means of more thoroughly understanding how our current concept of risk emerges. In doing so, this paper seeks to open up new trajectories in the historicisation of risk for other interested scholars.

The role of knowledge integration in innovation and capability development

Purpose This paper investigates the interrelationships between knowledge integration (KI), product innovation and capability development to enhance our understanding of how firms can develop capability at the firm level, which in turn enhances their performance. One of the critical underlying mechanisms for capability building identified in the literature is the role of knowledge integration, which operates within product innovation projects and contributes to dynamic capability development. Therefore, the main research question is “how does the integration of knowledge across product innovation projects lead to the development of capability?” Design/methodology/approach We adopted a case-based approach and investigated the case of a successful firm that was able to sustain its performance through a series of product innovation projects. In particular this research focused on the role of KI and firm-level capability development over the course of four projects, during which the firm successfully managed the transformation of its product base and renewal of its competitive advantage. For this purpose an in-depth case study of capability development was undertaken at the Iran Khodro Company (IKCO), the key player in the Iranian auto industry transformation. Originality/value This research revealed that along with changes at each level of product architecture “design knowledge” and “design capability” have been developed at the same level of product architecture, leading to capability development at that level. It can be argued that along the step by step maturation of radical innovation across the four case projects, architectural knowledge and capability have been developed at the case company, resulting in the gradual emergence of a modular product and capability architecture across different levels of product architecture. Such findings basically add to extensive emphasis in the literature on the interrelationship of the concept of modularity with knowledge management and capability development. Practical implications Findings of this study indicate that firms manage their knowledge in accordance with the level of specialization in knowledge and capability. Furthermore, firms design appropriate knowledge integration mechanisms within and among functions in order dynamically align knowledge processes at different levels of the product architecture. Accordingly, the outcomes of this study may guide practitioners in managing their knowledge processes, through dynamically employing knowledge integration modes step-by-step and from the part level to the architectural level of product architecture across a sequence of product innovation projects to encourage learning and radical innovation.

Brief report: Intestinal dysbiosis in ankylosing spondylitis

Objective Ankylosing spondylitis (AS) is a common, highly heritable immune-mediated arthropathy that occurs in genetically susceptible individuals exposed to an unknown but likely ubiquitous environmental trigger. There is a close relationship between the gut and spondyloarthritis, as exemplified in patients with reactive arthritis, in whom a typically self-limiting arthropathy follows either a gastrointestinal or urogenital infection. Microbial involvement in AS has been suggested; however, no definitive link has been established. The aim of this study was to determine whether the gut in patients with AS carries a distinct microbial signature compared with that in the gut of healthy control subjects. Methods Microbial profiles for terminal ileum biopsy specimens obtained from patients with recent-onset tumor necrosis factor antagonist-naive AS and from healthy control subjects were generated using culture-independent 16S ribosomal RNA gene sequencing and analysis techniques. Results Our results showed that the terminal ileum microbial communities in patients with AS differ significantly (P < 0.001) from those in healthy control subjects, driven by a higher abundance of 5 families of bacteria (Lachnospiraceae [P = 0.001], Ruminococcaceae [P = 0.012], Rikenellaceae [P = 0.004], Porphyromonadaceae [P = 0.001], and Bacteroidaceae [P = 0.001]) and a decrease in the abundance of 2 families of bacteria (Veillonellaceae [P = 0.01] and Prevotellaceae [P = 0.004]). Conclusion We show evidence for a discrete microbial signature in the terminal ileum of patients with AS compared with healthy control subjects. The microbial composition was demonstrated to correlate with disease status, and greater differences were observed between disease groups than within disease groups. These results are consistent with the hypothesis that genes associated with AS act, at least in part, through effects on the gut microbiome.

Nitrogen-doped graphene films from chemical vapor deposition of pyridine: Influence of process parameters on the electrical and optical properties

Graphene films were produced by chemical vapor deposition (CVD) of pyridine on copper substrates. Pyridine-CVD is expected to lead to doped graphene by the insertion of nitrogen atoms in the growing sp2 carbon lattice, possibly improving the properties of graphene as a transparent conductive film. We here report on the influence that the CVD parameters (i.e., temperature and gas flow) have on the morphology, transmittance, and electrical conductivity of the graphene films grown with pyridine. A temperature range between 930 and 1070 °C was explored and the results were compared to those of pristine graphene grown by ethanol-CVD under the same process conditions. The films were characterized by atomic force microscopy, Raman and X-ray photoemission spectroscopy. The optical transmittance and electrical conductivity of the films were measured to evaluate their performance as transparent conductive electrodes. Graphene films grown by pyridine reached an electrical conductivity of 14.3 × 105 S/m. Such a high conductivity seems to be associated with the electronic doping induced by substitutional nitrogen atoms. In particular, at 930 °C the nitrogen/carbon ratio of pyridine-grown graphene reaches 3%, and its electrical conductivity is 40% higher than that of pristine graphene grown from ethanol-CVD.