Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma

PURPOSE: Hreceptor (VEGFR) and FGF receptor (FGFR) signaling pathways. EXPERIMENTAL DESIGN: Six different s.c. patient-derived HCC xenografts were implanted into mice. Tumor growth was evaluated in mice treated with brivanib compared with control. The effects of brivanib on apoptosis and cell proliferation were evaluated by immunohistochemistry. The SK-HEP1 and HepG2 cells were used to investigate the effects of brivanib on the VEGFR-2 and FGFR-1 signaling pathways in vitro. Western blotting was used to determine changes in proteins in these xenografts and cell lines. RESULTS: Brivanib significantly suppressed tumor growth in five of six xenograft lines. Furthermore, brivanib-induced growth inhibition was associated with a decrease in phosphorylated VEGFR-2 at Tyr(1054/1059), increased apoptosis, reduced microvessel density, inhibition of cell proliferation, and down-regulation of cell cycle regulators. The levels of FGFR-1 and FGFR-2 expression in these xenograft lines were positively correlated with its sensitivity to brivanib-induced growth inhibition. In VEGF-stimulated and basic FGF stimulated SK-HEP1 cells, brivanib significantly inhibited VEGFR-2, FGFR-1, extracellular signal-regulated kinase 1/2, and Akt phosphorylation. CONCLUSION: This study provides a strong rationale for clinical investigation of brivanib in patients with HCC.

Intermittent access to 20% ethanol induces high ethanol consumption in Long-Evans and Wistar rats

BACKGROUND: There has been some difficulty getting standard laboratory rats to voluntarily consume large amounts of ethanol without the use of initiation procedures. It has previously been shown that standard laboratory rats will voluntarily consume high levels of ethanol if given intermittent-access to 20% ethanol in a 2-bottle-choice setting [Wise, Psychopharmacologia 29 (1973), 203]. In this study, we have further characterized this drinking model. METHODS: Ethanol-naïve Long-Evans rats were given intermittent-access to 20% ethanol (three 24-hour sessions per week). No sucrose fading was needed and water was always available ad libitum. Ethanol consumption, preference, and long-term drinking behaviors were investigated. Furthermore, to pharmacologically validate the intermittent-access 20% ethanol drinking paradigm, the efficacy of acamprosate and naltrexone in decreasing ethanol consumption were compared with those of groups given continuous-access to 10 or 20% ethanol, respectively. Additionally, ethanol consumption was investigated in Wistar and out-bred alcohol preferring (P) rats following intermittent-access to 20% ethanol. RESULTS: The intermittent-access 20% ethanol 2-bottle-choice drinking paradigm led standard laboratory rats to escalate their ethanol intake over the first 5 to 6 drinking sessions, reaching stable baseline consumption of high amounts of ethanol (Long-Evans: 5.1 +/- 0.6; Wistar: 5.8 +/- 0.8 g/kg/24 h, respectively). Furthermore, the cycles of excessive drinking and abstinence led to an increase in ethanol preference and increased efficacy of both acamprosate and naltrexone in Long-Evans rats. P-rats initiate drinking at a higher level than both Long-Evans and Wistar rats using the intermittent-access 20% ethanol paradigm and showed a trend toward a further escalation in ethanol intake over time (mean ethanol intake: 6.3 +/- 0.8 g/kg/24 h). CONCLUSION: Standard laboratory rats will voluntarily consume ethanol using the intermittent-access 20% ethanol drinking paradigm without the use of any initiation procedures. This model promises to be a valuable tool in the alcohol research field.

An approach to access control under uncertainty

In dynamic and uncertain environments such as healthcare, where the needs of security and information availability are difficult to balance, an access control approach based on a static policy will be suboptimal regardless of how comprehensive it is. The uncertainty stems from the unpredictability of users’ operational needs as well as their private incentives to misuse permissions. In Role Based Access Control (RBAC), a user’s legitimate access request may be denied because its need has not been anticipated by the security administrator. Alternatively, even when the policy is correctly specified an authorised user may accidentally or intentionally misuse the granted permission. This paper introduces a novel approach to access control under uncertainty and presents it in the context of RBAC. By taking insights from the field of economics, in particular the insurance literature, we propose a formal model where the value of resources are explicitly defined and an RBAC policy (entailing those predictable access needs) is only used as a reference point to determine the price each user has to pay for access, as opposed to representing hard and fast rules that are always rigidly applied.

Optimal budget allocation in budget-based access control

In dynamic and uncertain environments, where the needs of security and information availability are difficult to balance, an access control approach based on a static policy will be suboptimal regardless of how comprehensive it is. Risk-based approaches to access control attempt to address this problem by allocating a limited budget to users, through which they pay for the exceptions deemed necessary. So far the primary focus has been on how to incorporate the notion of budget into access control rather than what or if there is an optimal amount of budget to allocate to users. In this paper we discuss the problems that arise from a sub-optimal allocation of budget and introduce a generalised characterisation of an optimal budget allocation function that maximises organisations expected benefit in the presence of self-interested employees and costly audit.

Cloning and characterization of a novel human gene related to vascular endothelial growth factor

This paper describes the cloning and characterization of a new member of the vascular endothelial growth factor (VEGF) gene family, which we have designated VRF for VEGF-related-factor. Sequencing of cDNAs from a human fetal brain library and RT-PCR products from normal and tumor tissue cDNA pools indicate two alternatively spliced messages with open reading frames of 621 and 564 bp, respectively. The predicted proteins differ at their carboxyl ends resulting from a shift in the open reading frame. Both isoforms show strong homology to VEGF at their amino termini, but only the shorter isoform maintains homology to VEGF at its carboxyl terminus and conserves all 16 cysteine residues of VEGF165. Similarity comparisons of this isoform revealed overall protein identity of 48% and conservative substitution of 69% with VEGF189. VRF is predicted to contain a signal peptide, suggesting that it may be a secreted factor. The VRF gene maps to the D11S750 locus at chromosome band 11q13, and the protein coding region, spanning approximately 5 kb, is comprised of 8 exons that range in size from 36 to 431 bp. Exons 6 and 7 are contiguous and the two isoforms of VRF arise through alternate splicing of exon 6. VRF appears to be ubiquitously expressed as two transcripts of 2.0 and 5.5 kb; the level of expression is similar among normal and malignant tissues.

Understanding the legal implications of data sharing, access and reuse in the Australian research landscape

Researchers are increasingly involved in data-intensive research projects that cut across geographic and disciplinary borders. Quality research now often involves virtual communities of researchers participating in large-scale web-based collaborations, opening their earlystage research to the research community in order to encourage broader participation and accelerate discoveries. The result of such large-scale collaborations has been the production of ever-increasing amounts of data. In short, we are in the midst of a data deluge. Accompanying these developments has been a growing recognition that if the benefits of enhanced access to research are to be realised, it will be necessary to develop the systems and services that enable data to be managed and secured. It has also become apparent that to achieve seamless access to data it is necessary not only to adopt appropriate technical standards, practices and architecture, but also to develop legal frameworks that facilitate access to and use of research data. This chapter provides an overview of the current research landscape in Australia as it relates to the collection, management and sharing of research data. The chapter then explains the Australian legal regimes relevant to data, including copyright, patent, privacy, confidentiality and contract law. Finally, this chapter proposes the infrastructure elements that are required for the proper management of legal interests, ownership rights and rights to access and use data collected or generated by research projects.

Access to protection for 'Offshore Entry Persons' aka asylum seekers

In 2001, amendments to the Migration Act 1958 (Cth) made possible the offshore processing of protection claims. The same amendments also foreshadowed the processing of claims by ‘offshore entry persons’ in Australia according to non-statutory procedures. After disbanding offshore processing the then Rudd Labor Government commenced processing of protection claims by ‘offshore entry persons’ in Australia under the Refugee Status Assessment process (RSA). The RSA process sought to substitute well established legislative criteria for the grant of a protection visa, as interpreted by the courts, with administrative guidelines and decision-making immune from judicial review. This approach was rejected by the High Court in the cases M61 and M69. This article analyses these developments in light of Australia’s international protection obligations, as well as considering the practical obstacles that continue to confront offshore entry persons as they pursue judicial review of adverse refugee status determinations after the High Court’s decision.

Nurses driving change to improve access to education and quality in lcinical teaching : A partnership between Australia and Viet Nam

In Viet Nam, standards of nursing care fail to meet international competency standards. This increases risks to patient safety (eg. hospital acquired infection), consequently the Ministry of Health identified the need to strengthen nurse education in Viet Nam. This paper presents experiences of a piloted clinical teaching model developed in Ha Noi, to strengthen nurse led institutional capacity for in-service education and clinical teaching. Historically 90% of nursing education was conducted by physicians and professional development in hospitals for nurses was limited. There was minimal communication between hospitals and nursing schools about expectations of students and assessment and quality of the learning experience. As a result when students came to the clinical sites, no-one understood how to plan their learning objectives and utilise teaching and learning approaches appropriate to their level. Therefore student learning outcomes were variable. They focussed on procedures and techniques and “learning how to do” rather than learning how to plan, implement and evaluate patient care. This project is part of a multi-component capacity building program designed to improve nurse education in Viet Nam. The project was funded jointly by Queensland University of Technology (QUT) and the Australian Agency for International Development. Its aim was to develop a collaborative clinically-based model of teaching to create an environment that encourages evidence-based, student-centred clinical learning. Accordingly, strategies introduced promoted clinical teaching of competency based nursing practice utilising the regionally endorsed nurse core competency standards. Thirty nurse teachers from Viet Duc University Hospital and Hanoi Medical College participated in the program. These nurses and nurse teachers undertook face to face education in three workshops, and completed three assessment items. Assessment was applied, where participants integrated the concepts learned in each workshop and completed assessment tasks related to planning, implementing and evaluating teaching in the clinical area. Twenty of these participants were then selected to undertake a two week study tour in Brisbane, Australia where the clinical teaching model was refined and an action plan developed to integrate into both organisations with possible implementation across Viet Nam. Participants on this study tour also experienced clinical teaching and learning at QUT by attending classes held at the university, and were able to visit selected hospitals to experience clinical teaching in these settings as well. Effectiveness of the project was measured throughout the implementation phase and in follow up visits to the clinical site. To date changes have been noted on an individual and organisational level. There is also significant planning underway to incorporate the clinical teaching model developed across the organisation and how this may be implemented in other regions. Two participants have also been involved in disseminating aspects of this approach to clinical teaching in Ho Chi Minh, with further plans for more in-depth dissemination to occur throughout the country.

Using mobile phones to improve offline access to online information : distributed content delivery

Mobile phones are now powerful and pervasive making them ideal information browsers. The Internet has revolutionized our lives and is a major knowledge sharing media. However, many mobile phone users cannot access the Internet (for financial or technical reasons) and so the mobile Internet has not been fully realized. We propose a novel content delivery network based on both a factual and speculative analysis of today’s technology and analyze its feasibility. If adopted people living in remote regions without Internet will be able to access essential (static) information with periodic updates.