Analysis of the CDKN2A, CDKN2B and CDK4 genes in 48 Australian melanoma kindreds

Germline mutations within the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene and one of its targets, the cyclin dependent kinase 4 (CDK4) gene, have been identified in a proportion of melanoma kindreds. In the case of CDK4, only one specific mutation, resulting in the substitution of a cysteine for an arginine at codon 24 (R24C), has been found to be associated with melanoma. We have previously reported the identification of germline CDKN2A mutations in 7/18 Australian melanoma kindreds and the absence of the R24C CDK4 mutation in 21 families lacking evidence of a CDKN2A mutation. The current study represents an expansion of these efforts and includes a total of 48 melanoma families from Australia. All of these families have now been screened for mutations within CDKN2A and CDK4, as well as for mutations within the CDKN2A homolog and 9p21 neighbor, the CDKN2B gene, and the alternative exon 1 (E1beta) of CDKN2A. Families lacking CDKN2A mutations, but positive for a polymorphism(s) within this gene, were further evaluated to determine if their disease was associated with transcriptional silencing of one CDKN2A allele. Overall, CDKN2A mutations were detected in 3/30 (10%) of the new kindreds. Two of these mutations have been observed previously: a 24 bp duplication at the 5' end of the gene and a G to C transversion in exon 2 resulting in an M531 substitution. A novel G to A transition in exon 2, resulting in a D108N substitution was also detected. Combined with our previous findings, we have now detected germline CDKN2A mutations in 10/48 (21%) of our melanoma kindreds. In none of the 'CDKN2A-negative' families was melanoma found to segregate with either an untranscribed CDKN2A allele, an R24C CDK4 mutation, a CDKN2B mutation, or an E1beta mutation. The last three observations suggest that these other cell cycle control genes (or alternative gene products) are either not involved at all, or to any great extent, in melanoma predisposition.

Deletion mapping suggests that the 1p22 melanoma susceptibility gene is a tumor suppressor localized to a 9-Mb interval

Loss of the short arm of chromosome 1 is frequently observed in many tumor types, including melanoma. We recently localized a third melanoma susceptibility locus to chromosome band 1p22. Critical recombinants in linked families localized the gene to a 15-Mb region between D1S430 and D1S2664. To map the locus more finely we have performed studies to assess allelic loss across the region in a panel of melanomas from 1p22-linked families, sporadic melanomas, and melanoma cell lines. Eighty percent of familial melanomas exhibited loss of heterozygosity (LOH) within the region, with a smallest region of overlapping deletions (SRO) of 9 Mb between D1S207 and D1S435. This high frequency of LOH makes it very likely that the susceptibility locus is a tumor suppressor. In sporadic tumors, four SROs were defined. SRO1 and SRO2 map within the critical recombinant and familial tumor region, indicating that one or the other is likely to harbor the susceptibility gene. However, SRO3 may also be significant because it overlaps with the markers with the highest 2-point LOD score (D1S2776), part of the linkage recombinant region, and the critical region defined in mesothelioma. The candidate genes PRKCL2 and GTF2B, within SRO2, and TGFBR3, CDC7, and EVI5, in a broad region encompassing SRO3, were screened in 1p22-linked melanoma kindreds, but no coding mutations were detected. Allelic loss in melanoma cell lines was significantly less frequent than in fresh tumors, indicating that this gene may not be involved late in progression, such as in overriding cellular senescence, necessary for the propagation of melanoma cells in culture.

Towards testing the eclectic paradigm on multinational contracting: an approach to reviewing and analysing secondary data

In response to the need to leverage private finance and the lack of competition in some parts of the Australian public sector major infrastructure market, especially in very large economic infrastructure procured using Pubic Private Partnerships, the Australian Federal government has demonstrated its desire to attract new sources of in-bound foreign direct investment (FDI) into the Australian construction market. This paper aims to report on progress towards an investigation into the determinants of multinational contractors’ willingness to bid for Australian public sector major infrastructure projects and which is designed to give an improved understanding of matters surrounding FDI into the Australian construction sector. This research deploys Dunning’s eclectic theory for the first time in terms of in-bound FDI by multinational contractors and as head contractors bidding for Australian major infrastructure public sector projects. Elsewhere, the authors have developed Dunning’s principal hypothesis associated with his eclectic framework in order to suit the context of this research and to address a weakness arising in Dunning’s principal hypothesis that is based on a nominal approach to the factors in the eclectic framework and which fail to speak to the relative explanatory power of these factors. In this paper, an approach to reviewing and analysing secondary data, as part of the first stage investigation in this research, is developed and some illustrations given, vis-à-vis the selected sector (roads, bridges and tunnels) in Australia (as the host location) and using one of the selected home countries (Spain). In conclusion, some tentative thoughts are offered in anticipation of the completion of the first stage investigation - in terms of the extent to which this first stage based on secondary data only might suggest the relative importance of the factors in the eclectic framework. It is noted that more robust conclusions are expected following the future planned stages of the research and these stages including primary data are briefly outlined. Finally, and beyond theoretical contributions expected from the overall approach taken to developing and testing Dunning’s framework, other expected contributions concerning research method and practical implications are mentioned.

Performance load testing and structural adequacy evaluation of road bridge decks

Many ageing road bridges, particularly timber bridges, require urgent improvement due to the demand imposed by the recent version of the Australian bridge loading code, AS 5100. As traffic volume plays a key role in the decision of budget allocations for bridge refurbishment/ replacement, many bridges in low volume traffic network remain in poor condition with axle load and/ or speed restrictions, thus disadvantaging many rural communities. This thesis examines an economical and environmentally sensible option of incorporating disused flat rail wagons (FRW) in the construction of bridges in low volume, high axle load road network. The constructability, economy and structural adequacy of the FRW road bridge is reported in the thesis with particular focus of a demonstration bridge commissioned in regional Queensland. The demonstration bridge comprises of a reinforced concrete slab (RCS) pavement resting on two FRWs with custom designed connection brackets at regular intervals along the span of the bridge. The FRW-RC bridge deck assembly is supported on elastomeric rubber pads resting on the abutment. As this type of bridge replacement technology is new and its structural design is not covered in the design standards, the in-service structural performance of the FRW bridge subjected to the high axle loadings prescribed in AS 5100 is examined through performance load testing. Both the static and the moving load tests are carried out using a fully laden commonly available three-axle tandem truck. The bridge deck is extensively strain gauged and displacement at several key locations is measured using linear variable displacement transducers (LVDTs). A high speed camera is used in the performance test and the digital image data are analysed using proprietary software to capture the locations of the wheel positions on the bridge span accurately. The wheel location is thus synchronised with the displacement and strain time series to infer the structural response of the FRW bridge. Field test data are used to calibrate a grillage model, developed for further analysis of the FRW bridge to various sets of high axle loads stipulated in the bridge design standard. Bridge behaviour predicted by the grillage model has exemplified that the live load stresses of the FRW bridge is significantly lower than the yield strength of steel and the deflections are well below the serviceability limit state set out in AS 5100. Based on the results reported in this thesis, it is concluded that the disused FRWs are competent to resist high axle loading prescribed in AS 5100 and are a viable alternative structural solution of bridge deck in the context of the low volume road networks.

Errata supplement for QUT thesis 'Heavy vehicle suspensions : testing and analysis'

Errata supplement to QUT thesis: 'Heavy vehicle suspensions : testing and analysis'

Towards testing a new first-order decision making model for the procurement of public sector major infrastructure

Given global demand for new infrastructure, governments face substantial challenges in funding new infrastructure and simultaneously delivering Value for Money (VfM). As background to this challenge, a brief review is given of current practice in the selection of major public sector infrastructure in Australia, along with a review of the related literature concerning the Multi-Attribute Utility Approach (MAUA) and the effect of MAUA on the role of risk management in procurement selection. To contribute towards addressing the key weaknesses of MAUA, a new first-order procurement decision making model is mentioned. A brief summary is also given of the research method and hypothesis used to test and develop the new procurement model and which uses competition as the dependent variable and as a proxy for VfM. The hypothesis is given as follows: When the actual procurement mode matches the theoretical/predicted procurement mode (informed by the new procurement model), then actual competition is expected to match optimum competition (based on actual prevailing capacity vis-à-vis the theoretical/predicted procurement mode) and subject to efficient tendering. The aim of this paper is to report on progress towards testing this hypothesis in terms of an analysis of two of the four data components in the hypothesis. That is, actual procurement and actual competition across 87 road and health major public sector projects in Australia. In conclusion, it is noted that the Global Financial Crisis (GFC) has seen a significant increase in competition in public sector major road and health infrastructure and if any imperfections in procurement and/or tendering are discernible, then this would create the opportunity, through the deployment of economic principles embedded in the new procurement model and/or adjustments in tendering, to maintain some of this higher level post-GFC competition throughout the next business cycle/upturn in demand including private sector demand. Finally, the paper previews the next steps in the research with regard to collection and analysis of data concerning theoretical/predicted procurement and optimum competition.

The impact of high stakes testing: the Australian story

High stakes testing in Australia was introduced in 2008 by way of the National Assessment Program – Literacy and Numeracy (NAPLAN). Currently, every year all students in Years 3, 5, 7 and 9 are assessed on the same days using national tests in Reading, Writing, Language Conventions (Spelling, Grammar and Punctuation) and Numeracy. In 2010 the NAPLAN results were published on the Federal Government MySchool website. The impact of these high stakes tests on jurisdictions, school principals, parents and students is considered in this article. We draw on reported observations from the Australian Primary Principals Association during 2009–10 testing periods across the country and published Australian research on the impact of high stakes literacy and numeracy testing. We also examine alternative approaches that include the use of assessment evidence for learning improvement purposes and for accountability purposes. In considering alternatives to the current large-scale testing approach we draw on key insights from research on teacher judgement, achievement standards and social moderation in the context of national curriculum and assessment reform in support of the suggested directions forward.

Performance testing of road bridge deck containing flat rail wagons

A road bridge containing disused flatbed rail wagons as the primary deck superstructure was performance tested in a low volume, high axle load traffic road in Queensland, Australia; some key results are presented in this paper. A fully laden truck of total weight 28.88 % of the serviceability design load prescribed in the Australian bridge code was used; its wheel positions were accurately captured using a high speed camera and synchronised with the real‐time deflections and strains measured at the critical members of the flat rail wagons. The strains remained well below the yield and narrated the existence of composite action between the reinforced concrete slab pavement and the wagon deck. A three dimensional grillage model was developed and calibrated using the test data, which established the structural adequacy of the rail wagons and the positive contribution of the reinforced concrete slab pavement to resist high axle traffic loads on a single lane bridge in the low volume roads network.

Reducing aggression on our roads : testing a comprehensive model of aggressive driving

Background: Trauma resulting from traffic crashes poses a significant problem in highly motorised countries. Over a million people worldwide are killed annually and 50 million are critically injured as a result of traffic collisions. In Australia, road crashes cost an average of $17 billion annually in personal loss of income and quality of life, organisational losses in productivity and workplace quality, and health care costs. Driver aggression has been identified as a key factor contributing to crashes, and many motorists report experiencing mild forms of aggression (e.g., rude gestures, horn honking). However despite this concern, driver aggression has received relatively little attention in empirical research, and existing research has been hampered by a number of methodological and conceptual shortcomings. Specifically, there has been substantial disagreement regarding what constitutes aggressive driving and a failure to examine both the situational factors and the emotional and cognitive processes underlying driver aggression. To enhance current understanding of aggressive driving, a model of driver aggression that highlights the cognitive and emotional processes at play in aggressive driving incidents is proposed. Aims: The research aims to improve current understanding of the complex nature of driver aggression by testing and refining a model of aggressive driving that incorporates the person-related and situational factors and the cognitive and emotional appraisal processes fundamental to driver aggression. In doing so, the research will assist to provide a clear definition of what constitutes aggressive driving, assist to identify on-road incidents that trigger driver aggression, and identify the emotional and cognitive appraisal processes that underlie driver aggression. Methods: The research involves three studies. Firstly, to contextualise the model and explore the cognitive and emotional aspects of driver aggression, a diary-based study using self-reports of aggressive driving events will be conducted with a general population of drivers. This data will be supplemented by in-depth follow-up interviews with a sub-sample of participants. Secondly, to test generalisability of the model, a large sample of drivers will be asked to respond to video-based scenarios depicting driving contexts derived from incidents identified in Study 1 as inciting aggression. Finally, to further operationalise and test the model an advanced driving simulator will be used with sample of drivers. These drivers will be exposed to various driving scenarios that would be expected to trigger negative emotional responses. Results: Work on the project has commenced and progress on the first study will be reported.