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.

Investigation of the CACNA1A gene as a candidate for typical migraine susceptibility

Typical migraine is a complex neurological disorder comprised of two main subtypes: migraine with (MA) and without aura (MO). The disease etiology is still unclear, but family studies provide strong evidence that defective genes play an important role. Familial hemiplegic migraine (FHM) is a very rare and severe subtype of MA. It has been proposed that FHM and MA may have a similar genetic etiology. Therefore, genetic studies on FHM provide a useful model for investigating the more prevalent types of typical migraine. FHM in some families has been shown to be caused by mutations in a brain-specific P/Q-type calcium channel alpha1 subunit gene (CACNA1A) on chromosome 19p13. There has also been a report of a CACNA1A mutation being associated with MA in a patient from a family with predominant FHM. We have previously demonstrated suggestive linkage of typical migraine in a large Australian family to the FHM region on chromosome 19p13. These findings suggest that CACNA1A may also be implicated in the etiology of typical migraine in this pedigree. To investigate this possibility, we sequenced two patients carrying the critical susceptibility haplotype surrounding CACNA1A. No disease-causing mutations or polymorphisms were revealed in any of the 47 exons screened. To determine whether the CACNA1A gene was implicated in typical migraine susceptibility in the general Caucasian population, we also analyzed 82 independent pedigrees and a large case control group. We did not detect any linkage or association in these groups and conclude that if CACNA1A plays a role in typical migraine, it does not confer a major effect on the disease.

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.

Implementation of a better choice healthy food and drink supply strategy for staff and visitors in government owned health facilities in Queensland, Australia

Objective The present paper reports on a quality improvement activity examining implementation of A Better Choice Healthy Food and Drink Supply Strategy for Queensland Health Facilities (A Better Choice). A Better Choice is a policy to increase supply and promotion of healthy foods and drinks and decrease supply and promotion of energy-dense, nutrient-poor choices in all food supply areas including food outlets, staff dining rooms, vending machines, tea trolleys, coffee carts, leased premises, catering, fundraising, promotion and advertising. Design An online survey targeted 278 facility managers to collect self-reported quantitative and qualitative data. Telephone interviews were sought concurrently with the twenty-five A Better Choice district contact officers to gather qualitative information. Setting Public sector-owned and -operated health facilities in Queensland, Australia. Subjects One hundred and thirty-four facility managers and twenty-four district contact officers participated with response rates of 48·2 % and 96·0 %, respectively. Results Of facility managers, 78·4 % reported implementation of more than half of the A Better Choice requirements including 24·6 % who reported full strategy implementation. Reported implementation was highest in food outlets, staff dining rooms, tea trolleys, coffee carts, internal catering and drink vending machines. Reported implementation was more problematic in snack vending machines, external catering, leased premises and fundraising. Conclusions Despite methodological challenges, the study suggests that policy approaches to improve the food and drink supply can be implemented successfully in public-sector health facilities, although results can be limited in some areas. A Better Choice may provide a model for improving food supply in other health and workplace settings.

Experience of being an advanced practice nurse within Australian acute care settings : a systematic review of qualitative evidence

Background Nationally and internationally, advanced practice nurses are working under various titles and in different contexts to address gaps within healthcare systems. Analysis of advanced practice roles in different countries has been undertaken, but due to variations in cultural, geographical and professional factors, it is difficult and perhaps ineffectual to compare roles between countries. Contextual factors may also affect the actual experience of being an advanced practice nurse. A systematic review was therefore undertaken of qualitative evidence on the experience of being an advanced practice nurse in Australia, to provide deeper understanding of the role in the defined context. Methods The review followed the method for qualitative synthesis as per the Joanna Briggs Institute. An extensive search was undertaken of databases and online resources to find published and unpublished studies. Papers from 1990 to October 2011 which met specified inclusion criteria were appraised using the Joanna Briggs Institute Qualitative Assessment and Review Instrument. Results Three published studies and one unpublished dissertation were included in the review. From these studies, 216 findings were extracted and these were formed into 18 categories. Six meta-syntheses grouped under the headings of expert knowledge, confidence, education, relationships, negative experiences and patient-centred experience were created. Organisational factors impact greatly on the experience, professionally and personally. Conclusions Heterogeneity of role titles makes synthesis a difficult process, but contextualising the population provides a pragmatic approach to informing the status of the advanced practice nurse discourse. The review identifies positive and negative experiences of being an advanced practice nurse in Australian acute care settings with overlapping and intertwining findings that reinforce the complexity of the role.

Resistance to exercise-induced weight loss : compensatory behavioral adaptations

In many interventions that are based on an exercise program intended to induce weight loss, the mean weight loss observed is modest and sometimes far less than what the individual expected. The individual responses are also widely variable, with some individuals losing a substantial amount of weight, others maintaining weight, and a few actually gaining weight. The media have focused on the subpopulation that loses little weight, contributing to a public perception that exercise has limited utility to cause weight loss. The purpose of the symposium was to present recent, novel data that help explain how compensatory behaviors contribute to a wide discrepancy in exercise-induced weight loss. The presentations provide evidence that some individuals adopt compensatory behaviors, that is, increased energy intake and/or reduced activity, that offset the exercise energy expenditure and limit weight loss. The challenge for both scientists and clinicians is to develop effective tools to identify which individuals are susceptible to such behaviors and to develop strategies to minimize their effect.

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.

Synthesis of novel inhibitors blocking Wnt signaling downstream of β-Catenin

Large scale screening of libraries consisting of natural and small molecules led to the identification of many small molecule inhibitors repressing Wnt/β-Catenin signaling. However, targeted synthesis of novel Wnt pathway inhibitors has been rarely described. We developed a modular and expedient way to create the aromatic ring system with an aliphatic ring in between. Our synthesis opens up the possibility, in principle, to substitute all positions at the ring system with any desired substituent. Here, we tested five different haloquinone analogs carrying methoxy- and hydroxy-groups at different positions. Bona fide Wnt activity assays in cell culture and in Xenopus embryos revealed that two of these compounds act as potent inhibitors of aberrant activated Wnt/β-Catenin signaling.

Effect of Al content on the structure of Al-substituted goethite : a micro-Raman spectroscopic study

The characterization of X-ray diffraction, X-ray fluorescence, and field emission scanning electron microscope were used to confirm the successful preparation of Al-substituted goethite with different Al content. The micro-Raman spectroscopy was utilized to investigate the effect of Al content on the goethite lattice. The results show that all the feature bands of goethite shifted to high wavenumbers after the occurrence of Al substitution for Fe in the structure of goethite. The shift of wavenumber shows a good linear relationship as a function of increasing Al content especially for the band at 299 cm−1 (R2 = 0.9992). The in situ Raman spectroscopy of thermally treated goethite indicated that the Al substitution not only hinders the transformation of goethite, but also retarded the crystallization of thermally formed hematite. All the results indicated that Raman spectrum displayed an excellent performance in characterizing Al-substituted goethite, which implied the promising application in other substituted metal oxides or hydroxides.

Composite SaaS scaling in cloud computing using a hybrid genetic algorithm

A Software-as-a-Service or SaaS can be delivered in a composite form, consisting of a set of application and data components that work together to deliver higher-level functional software. Components in a composite SaaS may need to be scaled – replicated or deleted, to accommodate the user’s load. It may not be necessary to replicate all components of the SaaS, as some components can be shared by other instances. On the other hand, when the load is low, some of the instances may need to be deleted to avoid resource underutilisation. Thus, it is important to determine which components are to be scaled such that the performance of the SaaS is still maintained. Extensive research on the SaaS resource management in Cloud has not yet addressed the challenges of scaling process for composite SaaS. Therefore, a hybrid genetic algorithm is proposed in which it utilises the problem’s knowledge and explores the best combination of scaling plan for the components. Experimental results demonstrate that the proposed algorithm outperforms existing heuristic-based solutions.