The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib and ponatinib ATP-competitive inhibitors

We sought to identify fibroblast growth factor receptor 2 (FGFR2) kinase domain mutations that confer resistance to the pan-FGFR inhibitor, dovitinib, and explore the mechanism of action of the drug-resistant mutations. We cultured BaF3 cells overexpressing FGFR2 in high concentrations of dovitinib and identified fourteen dovitinib-resistant mutations, including the N550K mutation observed in 25% of FGFR2mutant endometrial cancers (EC). Structural and biochemical in vitro kinase analyses, together with BaF3 proliferation assays, showed that the resistance mutations elevate the intrinsic kinase activity of FGFR2. BaF3 lines were used to assess the ability of each mutation to confer cross-resistance to PD173074 and ponatinib. Unlike PD173074, ponatinib effectively inhibited all the dovitinib-resistant FGFR2 mutants except the V565I gatekeeper mutation, suggesting ponatinib but not dovitinib targets the active conformation of FGFR2 kinase. EC cell lines expressing wild-type FGFR2 were relatively resistant to all inhibitors. Whereas EC cell lines expressing mutated FGFR2 showed differential sensitivity. Within the FGFR2mutant cell lines, 3/7 showed marked resistance to PD173074 and relative resistance to dovitinib and ponatinib. This suggests that alternative mechanisms distinct from kinase domain mutations are responsible for intrinsic resistance in these three EC lines. Finally, overexpression of FGFR2N550K in JHUEM-2 cells (FGFR2C383R) conferred resistance (~5 fold) to PD173074, providing independent data that FGFR2N550K can be associated with drug resistance. Biochemical in vitro kinase analyses also shows ponatinib is more effective than dovitinib at inhibiting FGFR2N550K. We propose tumors harboring mutationally activated FGFRs should be treated with FGFR inhibitors that specifically bind the active kinase.

Achieving high reliability for ambiguity resolutions with multiple GNSS constellations

Global Navigation Satellite Systems (GNSS)-based observation systems can provide high precision positioning and navigation solutions in real time, in the order of subcentimetre if we make use of carrier phase measurements in the differential mode and deal with all the bias and noise terms well. However, these carrier phase measurements are ambiguous due to unknown, integer numbers of cycles. One key challenge in the differential carrier phase mode is to fix the integer ambiguities correctly. On the other hand, in the safety of life or liability-critical applications, such as for vehicle safety positioning and aviation, not only is high accuracy required, but also the reliability requirement is important. This PhD research studies to achieve high reliability for ambiguity resolution (AR) in a multi-GNSS environment. GNSS ambiguity estimation and validation problems are the focus of the research effort. Particularly, we study the case of multiple constellations that include initial to full operations of foreseeable Galileo, GLONASS and Compass and QZSS navigation systems from next few years to the end of the decade. Since real observation data is only available from GPS and GLONASS systems, the simulation method named Virtual Galileo Constellation (VGC) is applied to generate observational data from another constellation in the data analysis. In addition, both full ambiguity resolution (FAR) and partial ambiguity resolution (PAR) algorithms are used in processing single and dual constellation data. Firstly, a brief overview of related work on AR methods and reliability theory is given. Next, a modified inverse integer Cholesky decorrelation method and its performance on AR are presented. Subsequently, a new measure of decorrelation performance called orthogonality defect is introduced and compared with other measures. Furthermore, a new AR scheme considering the ambiguity validation requirement in the control of the search space size is proposed to improve the search efficiency. With respect to the reliability of AR, we also discuss the computation of the ambiguity success rate (ASR) and confirm that the success rate computed with the integer bootstrapping method is quite a sharp approximation to the actual integer least-squares (ILS) method success rate. The advantages of multi-GNSS constellations are examined in terms of the PAR technique involving the predefined ASR. Finally, a novel satellite selection algorithm for reliable ambiguity resolution called SARA is developed. In summary, the study demonstrats that when the ASR is close to one, the reliability of AR can be guaranteed and the ambiguity validation is effective. The work then focuses on new strategies to improve the ASR, including a partial ambiguity resolution procedure with a predefined success rate and a novel satellite selection strategy with a high success rate. The proposed strategies bring significant benefits of multi-GNSS signals to real-time high precision and high reliability positioning services.

Adsorption of reactive dye on seawater-neutralised bauxite refinery residue

This investigation has demonstrated the need for thermal treatment of seawater neutralised red mud (SWRM) in order to obtain reasonable adsorption of Reactive Blue dye 19 (RB 19). Thermal treatment results in a greater surface area, which results in an increased adsorption capacity due to more available adsorption sites. Adsorption of RB 19 has been found to be best achieved in acidic conditions using SWNRM400 (heated to 400 �C) with an adsorption capacity of 416.7 mg/g compared to 250.0 mg/g for untreated SWNRM. Kinetic studies indicate a pseudosecond-order reaction mechanism is responsible for the adsorption of RB 19 using SWNRM, which indicates adsorption occurs by electrostatic interactions.

Settling sexual harassment complaints through conciliation : what complaints settle and what complaints don’t?

This paper explores why some complaints of sexual harassment lodged under Australian anti-discrimination laws might settle during the conciliation process while others do not. It draws on an analysis of data collected from files of sexual harassment complaints lodged with all state, territory and federal human rights agencies in the area of employment over a six month period. The analysis suggests that complaints that conform with the stereotypical image of sexual harassment, where a woman is physically sexually harassed by a senior man, are more likely to settle as are complaints where the complainant is in full-time, secure employment and where complainants are not legally represented. However, sustained Australian research, including by human rights agencies, is vital is to further explore these issues.

Unravelling (e-)government channel selection: A quantitative analysis of individual customer preferences in Germany and Australia

The purpose of this study is to identify the impact of individual differences on service channel selection for e-government services. In a comparative survey of citizens in Germany and Australia (n=1205), we investigate the impact of age, gender, and mobility issues on the selection of personal or mobile communication as channels for service consumption. The results suggest that Australians are more likely to want to use new technology-oriented channels as internet or mobile applications while Germans tend to use classical channels as telephone or in person. Moreover, differences with respect to age, gender, and mobility exist. Implications for practice and issues for future research are discussed.

Immunodeficiency-associated lymphomas

This article covers lymphoproliferative disorders in patients with primary or acquired immunodeficiencies. Primary immunodeficiences include Ataxia Telangiectasia and X-linked disorders such as Wiskott-Aldrich syndrome. Acquired immunodeficiencies predominantly occur in the setting of infection with the Human Immunodeficiency Virus or arise following immunosuppressive therapy administered after organ transplantation. The rising incidence of HIV throughout the world and the dramatic increase in transplant surgery since the 1990's suggest that these lymphomas will remain an important health problem. Evidence for lymphoma developing as a result of treatment with methotrexate or Tumour Necrosis Factor Antagonists for autoimmune entities will also be reviewed. The lymphoproliferations that occur with immunodeficiency are extremely heterogenous. In part this reflects the diversity of the causal immune defect. The most striking clinical characteristic is the high frequency of extranodal disease. Frequently, these lymphomas are driven by viruses such as Epstein-Barr virus (EBV), although the lack of EBV in a proportion indicates that alternate pathways must also be involved in the pathogenesis. Lastly, discussion will centre on mechanisms utilized by lymphomas in the immunodeficient as these may have applications to lymphomas in the "immunocompetent", by serving as a paradigm for the altered immunoregulatory environment present in many lymphoma sub-types.

Standard preanalytical coding for biospecimens: Review and implementation of the Sample PREanalytical Code (SPREC)

The first version of the Standard PREanalytical Code (SPREC) was developed in 2009 by the International Society for Biological and Environmental Repositories (ISBER) Biospecimen Science Working Group to facilitate documentation and communication of the most important preanalytical quality parameters of different types of biospecimens used for research. This same Working Group has now updated the SPREC to version 2.0, presented here, so that it contains more options to allow for recent technological developments. Existing elements have been fine tuned. An interface to the Biospecimen Reporting for Improved Study Quality (BRISQ) has been defined, and informatics solutions for SPREC implementation have been developed. A glossary with SPRECrelated definitions has also been added.

Contemporary research on parenting: conceptual, methodological, and translational issues.

Researchers over the last decade have documented the association between general parenting style and numerous factors related to childhood obesity (e.g., children's eating behaviors, physical activity, and weight status). Many recent childhood obesity prevention programs are family focused and designed to modify parenting behaviors thought to contribute to childhood obesity risk. This article presents a brief consideration of conceptual, methodological, and translational issues that can inform future research on the role of parenting in childhood obesity. They include: (1) General versus domain specific parenting styles and practices; (2) the role of ethnicity and culture; (3) assessing bidirectional influences; (4) broadening assessments beyond the immediate family; (5) novel approaches to parenting measurement, and; (6) designing effective interventions. Numerous directions for future research are offered.

Fabrication and electrocatalytic properties of polyaniline/Pt nanoparticle composites

Polyaniline (PANI)/Pt nanoparticle composites can be prepared by the spontaneous redox reaction of K2PtCl4 with PANI, to yield thin films that show electrocatalytic properties in both acidic and neutral aqueous media.

Formation of polyaniline/Pt nanoparticle composite films and their electrocatalytic properties

Polyaniline (PANI) thin films modified with platinum nanoparticles have been prepared by several methods, characterised and assessed in terms of electrocatalytic properties. These composite materials have been prepared by the in situ reduction of a platinum salt (K2PtCl4) by PANI, in a variety of solvents, resulting in the formation of platinum nanoparticles and clusters of different sizes. The further deposition of platinum clusters at spin cast thin films of PANI/Pt composites from a neutral aqueous solution of K2PtCl4 has also been demonstrated. Thin-film electrodes prepared from these materials have been investigated for their electrocatalytic activity by studying hydrazine oxidation and dichromate reduction. The properties of the composite materials have been determined using UV–visible spectroscopy, atomic force microscopy and transmission electron microscopy. The nature of the material formed is strongly dependent on the solvent used to dissolve PANI, the method of preparation of the PANI/Pt solution and the composition of the spin cast thin film before subsequent deposition of platinum from the aqueous solution of K2PtCl4.

Settlement outcomes in sexual harassment complaints

This article examines the dispute resolution process of conciliation through a detailed study of Australian workplace sexual harassment complaints. It links two data sets: settlement details of a census of conciliated complaints lodged under all federal, State, and Territory anti-discrimination laws in a six-month period; and interviews undertaken with 71 professionals who have extensive, first-hand experience of conciliation processes in anti-discrimination jurisdictions. The article provides a critique of the effectiveness of conciliation as a form of ADR within the individualised constraints of current anti-discrimination laws.

Superior piezoelectric composite films : taking advantage of carbon nanomaterials

Piezoelectric composites comprising an active phase of ferroelectric ceramic and a polymer matrix have recently attracted numerous sensory applications. However, it remains a major challenge to further improve their electromechanical response for advanced applications such as precision control and monitoring systems. We hereby investigated the incorporation of graphene platelets (GnPs) and multi-walled carbon nanotubes (MWNTs), each with various weight fractions, into PZT (lead zirconate titanate)/epoxy composites to produce three-phase nanocomposites. The nanocomposite films show markedly improved piezoelectric coefficients and electromechanical responses (50%) besides an enhancement of ~200% in stiffness. Carbon nanomaterials strengthened the impact of electric field on the PZT particles by appropriately raising the electrical conductivity of epoxy. GnPs have been proved far more promising in improving the poling behavior and dynamic response than MWNTs. The superior dynamic sensitivity of GnP-reinforced composite may be caused by GnPs’ high load transfer efficiency arising from their two-dimensional geometry and good compatibility with the matrix. Reduced acoustic impedance mismatch resulted from the improved thermal conductance may also contribute to the higher sensitivity of GnP-reinforced composite. This research pointed out the potential of employing GnPs to develop highly sensitive piezoelectric composites for sensing applications.

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.

A review of the removal of anions and oxyanions of the halogen elements from aqueous solution by layered double hydroxides

The application of layered double hydroxides (LDHs) and thermally activated LDHs for the removal of various fluorine (F-, BF-4), chlorine (Cl-,ClO-4), bromine (Br-, BrO-3) and iodine (I-, IO-3) species from aqueous solutions has been reviewed in this article. LDHs and thermally activated LDHs were able to significantly reduce the concentration of selected anions in laboratory scale experiments. The M2+:M3+ cation ratio of the LDH adsorbent was an important factor which influenced anion uptake. Though LDHs were able to remove some target anion species through anion exchange and surface adsorption thermal activation and reformation generally produced better results. The presence of competing anions including carbonate, phosphate and sulphate had a significant impact on uptake of the target anion as LDHs typically exhibit lower affinity towards monovalent anions compared to anions with multiple charges. The removal of fluoride and perchlorate from aqueous solution by a continuous flow system utilising fixed bed columns packed with LDH adsorbents has also been investigated. The adsorption capacity of the columns at breakpoint was heavily dependent on the flow rate and lower than result reported for the corresponding batch methods. There is still considerable scope for future research on numerous topics summarised in this article.