Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia

We show that imatinib, nilotinib, and dasatinib possess weak off-target activity against RAF and, therefore, drive paradoxical activation of BRAF and CRAF in a RAS-dependent manner. Critically, because RAS is activated by BCR-ABL, in drug-resistant chronic myeloid leukemia (CML) cells, RAS activity persists in the presence of these drugs, driving paradoxical activation of BRAF, CRAF, MEK, and ERK, and leading to an unexpected dependency on the pathway. Consequently, nilotinib synergizes with MEK inhibitors to kill drug-resistant CML cells and block tumor growth in mice. Thus, we show that imatinib, nilotinib, and dasatinib drive paradoxical RAF/MEK/ERK pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug-resistant CML cells in vitro and in vivo.

Transition Pedagogy Handbook : A Good Practice Guide for Policy and Practice in the First Year Experience at QUT

This Handbook has been specifically designed for academic and professional staff responsible for managing first year students and curriculum and co-curricular programs at QUT. As well as presenting examples of good practice, the handbook provides a brief overview of QUT’s First Year Experience Program, a summary of QUT’s First Year Experience and Retention Policy and the Transition Pedagogy that frames both curricular and co-curricular activities. We hope you find this resource both useful and informative.

Intravitreal drug delivery in retinal disease : are we out of our depth?

Introduction With the ever-increasing global burden of retinal disease, there is an urgent need to vastly improve formulation strategies that enhance posterior eye delivery of therapeutics. Despite intravitreal administration having demonstrated notable superiority over other routes in enhancing retinal drug availability, there still exist various significant physical/biochemical barriers preventing optimal drug delivery into the retina. A further complication lies with an inability to reliably translate laboratory-based retinal models into a clinical setting. Several formulation approaches have recently been evaluated to improve intravitreal therapeutic outcomes, and our aim in this review is to highlight strategies that hold the most promise. Areas covered We discuss the complex barriers faced by the intravitreal route and examine how formulation strategies including implants, nanoparticulate carriers, viral vectors and sonotherapy have been utilized to attain both sustained delivery and enhanced penetration through to the retina. We conclude by highlighting the advances and limitations of current in vitro, ex vivo and in vivo retinal models in use by researchers globally. Expert opinion Various nanoparticle compositions have demonstrated the ability to overcome the retinal barriers successfully; however, their utility is limited to the laboratory setting. Optimization of these formulations and the development of more robust experimental retinal models are necessary to translate success in the laboratory into clinically efficacious outcomes.

A policy model for access control using building information models

Building information models have created a paradigm shift in how buildings are built and managed by providing a dynamic repository for building data that is useful in many new operational scenarios. This change has also created an opportunity to use building information models as an integral part of security operations and especially as a tool to facilitate fine-grained access control to building spaces in smart buildings and critical infrastructure environments. In this paper, we identify the requirements for a security policy model for such an access control system and discuss why the existing policy models are not suitable for this application. We propose a new policy language extension to XACML, with BIM specific data types and functions based on the IFC specification, which we call BIM-XACML.

Chinese EFL students' response to an assessment policy change

In light of its documented potential for enhancing learning, formative assessment has been adopted across a range of educational contexts to improve the quality of education. The assessment innovation that the Chinese Ministry of Education (CMoE) proposed to College English in 2007 via the College English Curriculum Requirements (CECR) (CMoE, 2007), is an initiative of this kind. Considering the acknowledged influence of assessment on students’ learning, it is instructive to explore the ways in which Chinese university students respond to an assessment policy change of this magnitude, particularly as it positions them as more active learners, having the potential for increased agency and engagement in their English language learning and assessment practices. In order to explore the response of students to this assessment initiative, a case study was conducted in the context of a College English classroom. Data included an interview with a College English teacher and four students from her classes, and classroom observations and a survey of her two classes of 100 students. Analysis of the data reveals that Chinese students’ responses to the assessment policy change are influenced by a variety of sociocultural factors, including their previous English language learning and assessment experience and the extent to which they are willing to play the ‘assessment game’. These findings have implications for policy and practice.

Synthesis and toxicological evaluation of a chitosan‑L‑leucine conjugate for pulmonary drug delivery applications

Herein are reported the synthesis of a conjugate of chitosan with L-leucine, the preparation of nanoparticles from both chitosan and the conjugate for use in pulmonary drug delivery, and the in vitro evaluation of toxicity and inflammatory effects of both the polymers and their nanoparticles on the bronchial epithelial cell line, BEAS-2B. The nanoparticles, successfully prepared both from chitosan and the conjugate, had a diameter in the range of 10−30 nm. The polymers and their nanoparticles were tested for their effects on cell viability by MTT assay, on trans-epithelial permeability by using sodium fluorescein as a fluid phase marker, and on IL-8 secretion by ELISA. The conjugate nanoparticles had a low overall toxicity (IC50 = 2 mg/mL following 48 h exposure; no induction of IL-8 release at 0.5 mg/mL concentration), suggesting that they may be safe for pulmonary drug delivery applications.

Colloidal drug probe : Method development and validation for adhesion force measurement using Atomic Force Microscopy

This study demonstrates a novel technique of preparing drug colloid probes to determine the adhesion force between a model drug salbutamol sulphate (SS) and the surfaces of polymer microparticles to be used as carriers for the dispersion of drug particles from dry powder inhaler (DPI) formulations. Model silica probes of approximately 4 lm size, similar to a drug particle used in DPI formulations, were coated with a saturated SS solution with the aid of capillary forces acting between the silica probe and the drug solution. The developed method of ensuring a smooth and uniform layer of SS on the silica probe was validated using X-ray Photoelectron Spectroscopy (XPS) and Scanning Electron Microscopy (SEM). Using the same technique, silica microspheres pre-attached on the AFM cantilever were coated with SS. The adhesion forces between the silica probe and drug coated silica (drug probe) and polymer surfaces (hydrophilic and hydrophobic) were determined. Our experimental results showed that the technique for preparing the drug probe was robust and can be used to determine the adhesion force between hydrophilic/ hydrophobic drug probe and carrier surfaces to gain a better understanding on drug carrier adhesion forces in DPI formulations.

Engineered microenvironments provide new insights into ovarian and prostate cancer progression and drug responses

Tissue engineering technologies, which have originally been designed to reconstitute damaged tissue structure and function, can mimic not only tissue regeneration processes but also cancer development and progression. Bioengineered approaches allow cell biologists to develop sophisticated experimentally and physiologically relevant cancer models to recapitulate the complexity of the disease seen in patients. Tissue engineering tools enable three-dimensionality based on the design of biomaterials and scaffolds that re-create the geometry, chemistry, function and signalling milieu of the native tumour microenvironment. Three-dimensional (3D) microenvironments, including cell-derived matrices, biomaterial-based cell culture models and integrated co-cultures with engineered stromal components, are powerful tools to study dynamic processes like proteolytic functions associated with cancer progression, metastasis and resistance to therapeutics. In this review, we discuss how biomimetic strategies can reproduce a humanised niche for human cancer cells, such as peritoneal or bone-like microenvironments, addressing specific aspects of ovarian and prostate cancer progression and therapy response.

Economic Analysis and Policy moves forward

As Editor of Economic Analysis and Policy (EAP) I am delighted to announce that EAP is now published by Elsevier. EAP is the journal of the Economic Society of Australia (Queensland branch). As a result of this move, four issues of EAP will be published per year instead of the current three. This will include special issues. EAP will now receive wider coverage in the relevant abstracting and indexing services...

Work Health and Safety Law and Policy

The third edition of Work Health and Safety Law and Policy continues to provide a plain English approach to explaining and analysing the law which regulates work health and safety in Australia. Providing broad coverage, this book focuses on the role that legal regulation plays in preventing work-related injury and disease, as well as the way in which the law contributes to rehabilitating and compensating injured and ill workers. This third edition focuses on the national model Work Health and Safety Bill 2009. The provisions of the model Bill are outlined, along with court decisions and other documentation that help interpret the provisions in new legislation enacting the model Bill. There is also a chapter in the book examining the national model Work Health and Safety Regulations 2011, and model codes of practice. The book includes three chapters on common law, statutory workers’ compensation provisions and rehabilitation. Tables summarising the key legal provisions of the major Australian Commonwealth, State and Territory workers’ compensation statutes have been updated and give quick and easy reference to points of legislation.

Leader vision and diffusion of HR policy during change

Purpose – This paper utilizes diffusion of innovation theory in order to investigate and understand the relationships between HR policies on employee change-related outcomes. In addition, the aim is to explore the role of leader vision at different hierarchical levels in the organization in terms of the relationship of HR policy with employee change-related outcomes. Design/methodology/approach – This quantitative study was conducted in one large Australian government department undergoing major restructuring and cultural change. Data from 624 employees were analyzed in relation to knowledge of HR policies (awareness and clarity), leader vision (organizational and divisional), and change-related outcomes. Findings –Policy knowledge (awareness and clarity) does not have a direct impact on employee change-related outcomes. It is the implementation of policies through the divisional leader that begins to enable favorable employee outcomes. Research limitations/implications – Future research should employ a longitudinal design to investigate relationships over time, and also examine the importance of communication medium and individual preferences in relation to leader vision. Originality/value - This research extends the application of diffusion of innovation theory and leader vision theory to investigate the relationship between HR policy, leader vision, and employees’ change-related outcomes.

Indigenous livelihoods policy reference group: Research priorities identified from the first meeting, 28th April 2010

The CSIRO Indigenous Livelihoods Project sought to work with Indigenous communities, government and non-government stakeholders to bring together western science and Indigenous knowledge in order to understand the potential livelihood benefits of enterprises based on natural resource management. The research focus was to enhance livelihood opportunities for Indigenous communities derived from new enterprises and activities based on natural resource management in regional and remote Australia. Underpinning outcomes were: · Identification of effective policy and institutional arrangements required to establish and maintain sustainable livelihoods; · Improved systems understanding of factors that enhance or inhibit sustainable livelihoods based on natural resource management; · Tools and methods for measuring the livelihood benefits of natural resource management; · Education, training, employment and capacity building for Indigenous communities and researchers.

Evaluation of Indigenous justice programs.: final report / Project D, Safe Aboriginal Youth Patrol Programs in New South Wales and Northbridge Policy and Juvenile Aid Group in Western Australia

The Australian Government has provided funding to evaluate the effectiveness of Indigenous law and justice programs across five subject areas to identify the best approaches to tackling crime and justice issues and better inform government funding decisions in the future. This report presents the findings of subject area "D", which examined two different approaches to delivering community and night patrol services for young people: the Safe Aboriginal Youth Patrol programs in New South Wales, and the Northbridge Policy project (the Young People in Northbridge project), in Western Australia. Night patrols can address crime either directly or indirectly, by prevention work or by addressing the social causes of crime through community development.