Integrin αvβ3 mediates upregulation of epidermal growth-factor receptor expression and activity in human ovarian cancer cells

Upon overexpression of integrin αvβ3 and its engagement by vitronectin, we previously showed enhanced adhesion, proliferation, and motility of human ovarian cancer cells. By studying differential expression of genes possibly related to these tumor biological events, we identified the epidermal growth-factor receptor (EGF-R) to be under control of αvβ3 expression levels. Thus in the present study we characterized αvβ3-dependent changes of EGF-R and found significant upregulation of its expression and activity which was reflected by prominent changes of EGF-R promoter activity. Upon disruption of DNA-binding motifs for the transcription factors p53, ETF, the repressor ETR, p50, and c-rel, respectively, we sought to identify DNA elements contributing to αvβ3-mediated EGF-R promoter induction. Both, the p53- and ETF-mutant, while exhibiting considerably lower EGF-R promoter activity than the wild type promoter, retained inducibility by αvβ3. Mutation of the repressor motif ETR, as expected, enhanced EGF-R promoter activity with a further moderate increase upon αvβ3 elevation. The p50-mutant displayed EGF-R promoter activity almost comparable to that of the wild type promoter with no impairment of induction by αvβ3. However, the activity of an EGF-R promoter mutant displaying a disrupted c-rel-binding motif did not only prominently decline, but, moreover, was not longer responsive to enhanced αvβ3, involving this DNA element in αvβ3-dependent EGF-R upregulation. Moreover, αvβ3 did not only increase the EGF-R but, moreover, also led to obvious co-clustering on the cancer cell surface. By studying αvβ3/EGF-R-effects on the focal adhesion kinase (FAK) and the mitogen activated protein kinases (MAPK) p44/42 (erk−1/erk−2), having important functions in synergistic crosstalk between integrins and growth-factor receptors, we found for both significant enhancement of expression and activity upon αvβ3/VN interaction and cell stimulation by EGF. Upregulation of the EGF-R by integrin αvβ3, both receptor molecules with a well-defined role as targets for cancer treatment, might represent an additional mechanism to adapt synergistic receptor signaling and crosstalk in response to an altered tumor cell microenvironment during ovarian cancer progression.

Fostering rapid transitions to education for sustainable development through a whole-system approach to curriculum and organizational change

Despite decades of attempts to embed sustainability within higher education, literature clearly suggests that highly regulated disciplines such as engineering have been relatively slow to incorporate sustainability knowledge and skill areas, and are generally poorly prepared to do so. With current efforts, it is plausible that sustainability could take another two decades to be embedded within the curriculum. Within this context, this paper presents a whole system approach to implement systematic, intentional and timely curriculum renewal that is responsive to emerging challenges and opportunities, encompassing curriculum and organizational change. The paper begins by considering the evolution of curriculum renewal processes, documenting a number of whole system considerations that have been empirically distilled from literature, case studies, pilot trials, and a series of workshops with built environment educators from around the world over the last decade. The paper outlines a whole-of-institution curriculum renewal approach to embedding sustainability knowledge and skills within the DNA of the institutional offerings. The paper concludes with a discussion of research and practice implications for the field of education research, within and beyond higher education.

Working with Behavioural and Emotional Problems in Young People

This chapter outlines specific issues relating to behavioural and emotional problems in Aboriginal and Torres Strait Islander young people. It describes the most common disorders and their consequences, and how young Aboriginal people are at higher risk for developing such problems than other young Australians. The chapter also discusses the importance of psychosocial, cultural and environmental issues that need to be recognised in assessing and treating Aboriginal young people with behavioural and emotional problems. Issues concerning the delivery of both universal and culturally responsive prevention and intervention programs to address social and emotional wellbeing and mental health are discussed and possible interventions to enhance student engagement at school are provided. Finally, a range of mental health services for Aboriginal families which offer a culturally responsive approach to mental health treatment are listed.

Informing engineering education for sustainable development using a deliberative dynamic model for curriculum renewal

Literature from around the world clearly suggests that engineering education has been relatively slow to incorporate significant knowledge and skill areas, including the rapidly emerging area of sustainable development. Within this context, this paper presents the findings of research that questioned how engineering educators could consistently implement systematic and intentional curriculum renewal that is responsive to emerging engineering challenges and opportunities. The paper presents a number of elements of systematic and intentional curriculum renewal that have been empirically distilled from a qualitative multiple-method iterative research approach including literature review, narrative enquiry, pilot trials and peer-review workshops undertaken by the authors with engineering educators from around the world. The paper also presents new knowledge arising from the research, in the form of a new model that demonstrates a dynamic and deliberative mechanism for strategically accelerating for curriculum renewal efforts. Specifically the paper discusses implications of this model to achieve education for sustainable development, across all disciplines of engineering. It concludes with broader research and practice implications for the field of education research.

Pandemic planning as risk management : how fared the Australian Federation?

The role of law in managing public health challenges such as influenza pandemics poses special challenges. This article reviews Australian plans in the context of the H1N1 09 experience to assess whether risk management was facilitated or inhibited by the "number" of levels or phases of management, the degree of prescriptive detail for particular phases, the number of plans, the clarity of the relationship between them, and the role of the media. Despite differences in the content and form of the plans at the time of the H1N1 09 emerging pandemic, the article argues that in practice, the plans proved to be responsive and robust bases for managing pandemic risks. It is suggested that this was because the plans proved to be frameworks for coordination rather than prescriptive straitjackets, to be only one component of the regulatory response, and to offer the varied tool box of possible responses, as called for by the theory of responsive regulation. Consistent with the principle of subsidiarity, it is argued that the plans did not inhibit localised responses such as selective school closures or rapid responses to selected populations such as cruise ship passengers.

Dark Cartographies

‘Dark Cartographies’ is a slowly evolving meditation upon seasonal change, life after light and the occluding shadows of human influence. Through creating experiences of the many ‘times of a night’ the work allows participants to experience deep engagement with rich spectras of hidden place and sound. By amplifying and shining light upon a myriad of lives lived in blackness, ‘Dark Cartographies’ tempts us to re-understand seasonal change as actively-embodied temporality, inflected by our climate-changing disturbances. ‘Dark Cartographies’ uses custom interactive systems, illusionary techniques and real time spatial audio that draw upon a rich array of media, including seasonal, nocturnal field recordings sourced in the Far North Queensland region and detailed observations of foliage & flowering phases. By drawing inspiration from the subtle transitions between what Europeans named ‘Summer’ and ‘Autumn’, and by including the body and its temporal disturbances within the work, ‘Dark Cartographies’ creates compellingly immersive environments that wrap us in atmospheres beyond sight and hearing. ‘Dark Cartographies’ is a dynamic new installation directed & choreographed by environmental cycles; alluding to a new framework for making works that we call ‘Seasonal’. This powerful, responsive & experiential work draws attention to that which will disappear when biodiverse worlds have descended into an era of permanent darkness – an ‘extinction of human experience’. By tapping into the deeply interlocking seasonal cycles of environments that are themselves intimately linked with social, geographical & political concerns, participating audiences are therefore challenged to see the night, their locality & ecologies in new ways through extending their personal limits of perception, imagery & comprehension.

Challenges for integrated design and delivery solutions

A new approach of integrated design and delivery solutions (IDDS) aims to radically improve the performance of the construction industries. IDDS builds upon recent trends in the construction industries that have seen the widespread adoption of technologies such as building information modelling (BIM) and innovative processes such as integrated project delivery. However, these innovations are seen to develop in isolation, with little consideration of the overarching interactions between people, process and technology. The IDDS approach is holistic in that it recognizes that it is only through a combination of initiatives such as skill development, process re-engineering, responsive information technology, enhanced interoperability and integrating knowledge management, among others, that radical change can be achieved. To implement IDDS requires step changes in many project aspects, and this gap between current performance and that required for IDDS is highlighted. The research required to bridge the gaps is identified in four major aspects of collaborative processes, workforce skills, integrated information and knowledge management.

Transcriptional regulation of flavonoid biosynthesis in nectarine (Prunus persica) by a set of R2R3 MYB transcription factors

Background Flavonoids such as anthocyanins, flavonols and proanthocyanidins, play a central role in fruit colour, flavour and health attributes. In peach and nectarine (Prunus persica) these compounds vary during fruit growth and ripening. Flavonoids are produced by a well studied pathway which is transcriptionally regulated by members of the MYB and bHLH transcription factor families. We have isolated nectarine flavonoid regulating genes and examined their expression patterns, which suggests a critical role in the regulation of flavonoid biosynthesis. Results In nectarine, expression of the genes encoding enzymes of the flavonoid pathway correlated with the concentration of proanthocyanidins, which strongly increases at mid-development. In contrast, the only gene which showed a similar pattern to anthocyanin concentration was UDP-glucose-flavonoid-3-O-glucosyltransferase (UFGT), which was high at the beginning and end of fruit growth, remaining low during the other developmental stages. Expression of flavonol synthase (FLS1) correlated with flavonol levels, both temporally and in a tissue specific manner. The pattern of UFGT gene expression may be explained by the involvement of different transcription factors, which up-regulate flavonoid biosynthesis (MYB10, MYB123, and bHLH3), or repress (MYB111 and MYB16) the transcription of the biosynthetic genes. The expression of a potential proanthocyanidin-regulating transcription factor, MYBPA1, corresponded with proanthocyanidin levels. Functional assays of these transcription factors were used to test the specificity for flavonoid regulation. Conclusions MYB10 positively regulates the promoters of UFGT and dihydroflavonol 4-reductase (DFR) but not leucoanthocyanidin reductase (LAR). In contrast, MYBPA1 trans-activates the promoters of DFR and LAR, but not UFGT. This suggests exclusive roles of anthocyanin regulation by MYB10 and proanthocyanidin regulation by MYBPA1. Further, these transcription factors appeared to be responsive to both developmental and environmental stimuli.

Regulating small things : genes, gametes and nanotechnology

Biotechnology and nanotechnology both intersect with other technologies in ways that open new possibilities for further technological progress. The potential for increased convergence between technological fields highlights the need for regulatory frameworks to be integrated, flexible and responsive. Within a federal legal system such as Australia’s, there is a need to ensure that we adopt a coordinated national approach to the crafting of regulatory solutions. In addition, there is a need for global cooperation in the development of international standards and regulatory harmonisation. Finally, this article considers the role that law plays in negotiating risk in relation to new technologies.

Developing agency in the creative career : a design-based framework for work integrated learning

Research shows that approximately half of creative practitioners operate as embedded creatives by securing gainful employment within organisations located in the field beyond their core discipline. This foregrounds the significance of having the skills necessary to successfully cross the disciplinary boundaries in order to negotiate a professional role. The multiple implications of such reframing for emerging creative practitioners who navigate uncertain professional boundaries include developing a skill of identifying and successfully targeting the shifting professional and industry coordinates while remaining responsive to changes. A further implication involves creative practitioners engaging in a continuous cycle of re-negotiation of their professional identity making the management of multiple professional selves - along with creating and recreating a meaningful frame of references such as the language around their emerging practice - a necessary skill. This chapter presents a case study of a set of Work Integrated Learning subjects designed to develop in creative industries practitioners the skills to manage their emerging professional identities in response to the shifts in the professional world.

Modulation of breast cancer progression and differentiation by the gp30/neregulin

In the last decade we have come to understand that the growth of cancer cells in general and of breast cancer in particular depends, in many cases, upon growth factors that will bind to and activate their receptors. One of these growth factor receptors is the erbB-2 protein which plays an important role in the prognosis of breast cancer and is overexpressed in nearly 30% of human breast cancer patients. While evidence accumulates to support the relationship between erbB-2 overexpression and poor overall survival in breast cancer, understanding of the biological consequence(s) of erbB-2 overexpression remains elusive. Our recent discovery of the gp30 has allowed us to identify a number of related but distinct biological endpoints which appear responsive to signal transduction through the erbB-2 receptor. These endpoints of growth, invasiveness, and differentiation have clear implications for the emergence, maintenance and/or control of malignancy, and represent established endpoints in the assessment of malignant progression in breast cancer. We have shown that gp30 induces a biphasic growth effect on cells with erbB-2 over-expression. We have recently determined the protein sequence of gp30 and cloned its full length cDNA sequence. We have also cloned two additional forms to the ligand, that are believed to be different isoforms. We are currently expressing the different forms in order to determine their biological effects. To elucidate the cellular mechanisms underlying cell growth inhibition by gp30, we tested the effect of this ligand on cell growth and differentiation of the human breast cancer cells which overexpress erbB-2 and cells which express low levels of this protooncogene. High concentrations of ligand induced differentiation of cells overexpressing erbB-2, as measured by inhibition of cell growth, and increased synthesis of milk components, and modulation of E-cadherin and up- regulation of c-jun and c-fos. These findings indicate that ligand-induced growth inhibition in cells overexpressing erbB-2 is associated with an apparent induction of differentiation. The availability of gp30 derived synthetic peptides and its full cDNAs provides tools necessary to acquire a better understanding of the mechanism of action of the this ligands and the erbB-2 receptor in breast cancer.

Taxation determinations as de facto regulation : private equity exits in Australia

The Australian Taxation Office (AT)) attempted to challenge both the private equity fund reliance on double tax agreements and the assertion that profits were capital in nature in its dispute with private equity group TPG. Failure to resolve the dispute resulted in the ATO issuing two taxation determinations: TD 2010/20 which states that the general anti-avoidance provisions can apply to arrangements designed to alter the intended effect of Australia's international tax agreements net; and TD 2010/21 which states that the profits on the sale of shares in a company group acquired in a leveraged buyout is assessable income. The purpose of this article is to determine the effectiveness of the administrative rulings regime as a regulatory strategy. This article, by using the TPG-Myer scenario and subsequent tax determinations as a case study, collects qualitative data which is then analysed (and triangulated) using tonal and thematic analysis. Contemporaneous commentary of private equity stakeholders, tax professionals, and media observations are analysed and evaluated within a framework of responsive regulation and utilising the current ATO compliance model. Contrary to the stated purpose of the ATO rulings regime to alleviate complexities in Australian taxation law and provide certainty to taxpayers, and despite the de facto law status afforded these rulings, this study found that the majority of private equity stakeholders and their advisors perceived that greater uncertainty was created by the two determinations. Thus, this study found that in the context of private equity fund investors, a responsive regulation measure in the form of taxation determinations was not effective.

MCF7/LCC2: A 4-hydroxytamoxifen resistant human breast cancer variant that retains sensitivity to the steroidal antiestrogen ICI 182,780

The development of resistance to the antiestrogen tamoxifen occurs in a high percentage of initially responsive patients. We have developed a new model in which to investigate acquired resistance to triphenylethylenes. A stepwise in vitro selection of the hormone-independent human breast cancer variant MCF-7/LCC1 against 4-hydroxytamoxifen produced a stable resistant population designated MCF7/LCC2. MCF7/LCC2 cells retain levels of estrogen receptor expression comparable to the parental MCF7/LCC1 and MCF-7 cells. Progesterone receptor expression remains estrogen inducible in MCF7/LCC2 cells, although to levels significantly lower than observed in MCF-7 and MCF7/LCC1 cells. MCF7/ LCC2 cells form tumors in ovariectomized nude mice without estrogen supplementation, and these tumors are tamoxifen resistant but can be tstrogen stimulated. Significantly, MCF7/LCC2 cells have retained sensitivity to the steroidal antiestrogen ICI 182,780. These data suggest that some breast cancer patients who acquire resistance to tamoxifen may not develop cross-resistance to treatment with steroidal antiestrogens.

A securities market operator's use of the "please explain" price query and its impact on compliance

Market operators in New Zealand and Australia, such as the New Zealand Exchange (NZX) and the Australian Securities Exchange (ASX), have the regulatory power in their listing rules to issue queries to their market participants to explain unusual fluctuations in trading price and/or volume in the market. The operator will issue a price query where it believes that the market has not been fully informed as to price relevant information. Responsive regulation theory has informed much of the regulatory debate in securities laws in the region. Price queries map onto the lower level of the enforcement pyramid envisaged by responsive regulation and are one strategy that a market operator can use in communicating its compliance expectations to its stakeholders. The issue of a price query may be a precursor to more severe enforcement activities. The aim of this study is to investigate whether increased use of price queries by the securities market operator in New Zealand corresponded with an increase in disclosure frequency by all participating companies. The study finds that an increased use of price queries did correspond with an increase in disclosure frequency. A possible explanation for this finding is that price queries are an effective means of appealing to the factors that motivate corporations, and the individuals who control them, to comply with the law and regulatory requirements. This finding will have implications for both the NZX and the ASX as well as for regulators and policy makers generally.

Paracrine interactions between LNCaP prostate cancer cells and bioengineered bone in 3D in vitro culture reflect molecular changes during bone metastasis

As microenvironmental factors such as three-dimensionality and cell–matrix interactions are increasingly being acknowledged by cancer biologists, more complex 3D in vitro models are being developed to study tumorigenesis and cancer progression. To better understand the pathophysiology of bone metastasis, we have established and validated a 3D indirect co-culture model to investigate the paracrine interactions between prostate cancer (PCa) cells and human osteoblasts. Co-culture of the human PCa, LNCaP cells embedded within polyethylene glycol hydrogels with human osteoblasts in the form of a tissue engineered bone construct (TEB), resulted in reduced proliferation of LNCaP cells. LNCaP cells in both monoculture and co-culture were responsive to the androgen analog, R1881, as indicated by an increase in the expression (mRNA and/or protein induction) of androgen-regulated genes including prostate specific antigen and fatty acid synthase. Microarray gene expression analysis further revealed an up-regulation of bone markers and other genes associated with skeletal and vasculature development and a significant activation of transforming growth factor β1 downstream genes in LNCaP cells after co-culture with TEB. LNCaP cells co-cultured with TEB also unexpectedly showed similar changes in classical androgen-responsive genes under androgen-deprived conditions not seen in LNCaP monocultures. The molecular changes of LNCaP cells after co-culturing with TEBs suggest that osteoblasts exert a paracrine effect that may promote osteomimicry and modulate the expression of androgen-responsive genes in LNCaP cells. Taken together, we have presented a novel 3D in vitro model that allows the study of cellular and molecular changes occurring in PCa cells and osteoblasts that are relevant to metastatic colonization of bone. This unique in vitro model could also facilitate cancer biologists to dissect specific biological hypotheses via extensive genomic or proteomic assessments to further our understanding of the PCa-bone crosstalk.