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.

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.

Neoproterozoic glacial deposits of the Kimberly Region and northwestern Northern Territory, Australia

Neoproterozoic glacigenic formations are preserved in the Kimberley region and northwestern Northern Territory of northern Australia. They are distributed in the west Kimberley adjacent to the northern margins of the King Leopold Orogen, the Mt Ramsay area at the junction of the King Leopold and Halls Creek Orogens, and the east Kimberley, adjacent to the eastern margin of the Halls Creek Orogen. Small outlier glacigenic deposits are preserved in the Litchfield Province, Northern Territory (Uniya Formation) and Georgina Basin, western Queensland (Little Burke Formation). Glacigenic strata comprise diamictite, conglomerate, sandstone and pebbly mudstone and characterize the Walsh, Landrigan and Fargoo/Moonlight Valley formations. Thin units of laminated dolomite sit conformably at the top of the Walsh, Landrigan and Moonlight Valley formations. Glacigenic units are also interbedded with the carbonate platform deposits of the Egan Formation and Boonall Dolomite. δ13C data are available for all carbonate units. There is no direct chronological constraint on these successions. Dispute over regional correlation of the Neoproterozoic succession has been largely resolved through biostratigraphic, chemostratigraphic and lithostratigraphic analysis. However, palaeomagnetic results from the Walsh Formation are inconsistent with sedimentologically based correlations. Two stratigraphically defined glaciations are preserved in northwestern Australia: the ‘Landrigan Glaciation’, characterized by southwest-directed continental ice-sheet movement and correlated with late Cryogenian glaciation elsewhere in Australia and the world; and, the ‘Egan Glaciation’, a more localized glaciation of the Ediacaran Period. Future research focus should include chronology, palaeomagnetic constraint and tectonostratigraphic controls on deposition.

Mesoporous bioactive glass scaffolds for efficient delivery of vascular endothelial growth factor

In this article, we, for the first time, investigated mesoporous bioactive glass scaffolds for the delivery of vascular endothelial growth factor. We have found that mesoporous bioactive glass scaffolds have significantly higher loading efficiency and more sustained release of vascular endothelial growth factor than non-mesoporous bioactive glass scaffolds. In addition, vascular endothelial growth factor delivery from mesoporous bioactive glass scaffolds has improved the viability of endothelial cells. The study has suggested that mesopore structures in mesoporous bioactive glass scaffolds play an important role in improving the loading efficiency, decreasing the burst release, and maintaining the bioactivity of vascular endothelial growth factor, indicating that mesoporous bioactive glass scaffolds are an excellent carrier of vascular endothelial growth factor for potential bone tissue engineering applications.

Reclaiming professionalism for geography education : defending our own territory

In a world where governments increasingly attempt to impose regulation on all professional activities, this paper advocates that professional standards for teachers be developed ‘by the profession for the profession’. Foucauldian archaeology is applied to two teacher standards documents recently published in Australia, one developed at national governmental level and the other by geography teachers through their professional associations. The excavation reveals that both students and geography teachers themselves are better served when teachers assert their own definition of professionalism and thus reclaim their professional territory, rather than being compliant with generic governmental agendas. Whilst we use Australia as an illustrative example, our findings are applicable to all other countries where governments attempt to impose external professional standards on the teaching profession.

Discriminating stromatolite formation modes using rare earth element geochemistry: Trapping and binding versus in situ precipitation of stromatolites from the Neoproterozoic Bitter Springs Formation, Northern Territory, Australia

Stromatolites consist primarily of trapped and bound ambient sediment and/or authigenic mineral precipitates, but discrimination of the two constituents is difficult where stromatolites have a fine texture. We used laser ablation-inductively coupled plasma-mass spectrometry to measure trace element (rare earth element – REE, Y and Th) concentrations in both stromatolites (domical and branched) and closely associated particulate carbonate sediment in interspaces (spaces between columns or branches) from bioherms within the Neoproterozoic Bitter Springs Formation, central Australia. Our high resolution sampling allows discrimination of shale-normalised REE patterns between carbonate in stromatolites and immediately adjacent, fine-grained ambient particulate carbonate sediment from interspaces. Whereas all samples show similar negative La and Ce anomalies, positive Gd anomalies and chondritic Y/Ho ratios, the stromatolites and non-stromatolite sediment are distinguishable on the basis of consistently elevated light REEs (LREEs) in the stromatolitic laminae and relatively depleted LREEs in the particulate sediment samples. Additionally, concentrations of the lithophile element Th are higher in ambient sediment samples than in stromatolites, consistent with accumulation of some fine siliciclastic detrital material in the ambient sediment but a near absence in the stromatolites. These findings are consistent with the stromatolites consisting dominantly of in situ carbonate precipitates rather than trapped and bound ambient sediment. Hence, high resolution trace element (REE + Y, Th) geochemistry can discriminate fine-grained carbonates in these stromatolites from coeval non-stromatolitic carbonate sediment and demonstrates that the sampled stromatolites formed primarily from in situ precipitation, presumably within microbial mats/biofilms, rather than by trapping and binding of ambient sediment. Identification of the source of fine carbonate in stromatolites is significant, because if it is not too heavily contaminated by trapped ambient sediment, it may contain geochemical biosignatures and/or direct evidence of the local water chemistry in which the precipitates formed.

Phenomenography : opening a new territory for library and information science research

Phenomenography is a research approach devised to allow the investigation of varying ways in which people experience aspects of their world. Whilst growing attention is being paid to interpretative research in LIS, it is not always clear how the outcomes of such research can be used in practice. This article explores the potential contribution of phenomenography in advancing the application of phenomenological and hermeneutic frameworks to LIS theory, research and practice. In phenomenography we find a research toll which in revealing variation, uncovers everyday understandings of phenomena and provides outcomes which are readily applicable to professional practice. THe outcomes may be used in human computer interface design, enhancement, implementation and training, in the design and evaluation of services, and in education and training for both end users and information professionals. A proposed research territory for phenomenography in LIS includes investigating qualitative variation in the experienced meaning of: 1) information and its role in society 2) LIS concepts and principles 3) LIS processes and; 4) LIS elements.

An evaluation of the Australian Capital Territory Sexual Assault Reform Program (SARP): Final Report

In 2005 the Australian Capital Territory (ACT) Office of the Director of Public Prosecutions (DPP) and the Australian Federal Police (AFP) produced a report, Responding to sexual assault: The challenge of change (DPP & AFP 2005), which made 105 recommendations for reforming the way sexual offence cases are handled by the ACT’s criminal justice system. The Sexual Assault Reform Program (SARP) is one key initiative developed in response to these recommendations. Managed by the ACT Justice and Community Safety Directorate (JACS), SARP’s main objective is to improve aspects of the criminal justice system relating to: processes and support for victims of sexual offences as they progress through the system; attrition in sexual offence matters in the criminal justice system; and coordination and collaboration among the agencies involved. In November 2007 the ACT Attorney-General announced $4 million of funding for several SARP reforms. This funding provided for additional victim support staff; a dedicated additional police officer, prosecutor and legal policy officer; and an upgrade of equipment for the Supreme Court and Magistrates Court, including improvements in technology to assist witnesses in giving evidence, and the establishment of an off-site facility to allow witnesses to give evidence from a location outside of the court. In addition, the reform agenda included a number of legislative amendments that changed how evidence can be given by victims of sexual and family violence offences, children and other vulnerable witnesses. The primary objectives of these legislative changes are to provide an unintimidating, safe environment for vulnerable witnesses (including sexual offence complainants) to give evidence and to obtain prompt statements from witnesses to improve the quality of evidence captured (DPP 2009: 13). The current evaluation The funding for SARP reforms also provided for a preliminary evaluation of the reforms; this report outlines findings from the evaluation. The evaluation sought to address whether the program has met its key objectives: better support for victims, lower attrition rates and improved coordination and collaboration among agencies involved in administering SARP. The evaluation was conducted in two stages and involved a mixed-methods approach. During stage 1 key indicators for the evaluation were developed with stakeholders. During stage 2 quantitative data were collected by stakeholders and provided to the AIC for analysis. Qualitative interviews were also conducted with service delivery providers, and with a small number (n=5) of victim/survivors of sexual offences whose cases had recently been resolved in the ACT criminal justice system. The current evaluation is preliminary in nature. As the SARP reforms will take time to become entrenched within the ACT’s criminal justice system, some of the impacts of the reforms may not yet be evident. Nonetheless, this evaluation provides an insight into how well the SARP reforms have been implemented to date, as well as key areas that could be addressed in the future. Key findings from the preliminary evaluation are outlined briefly below.