Epithelial—mesenchymal and mesenchymal—epithelial transitions in carcinoma progression

Like a set of bookends, cellular, molecular, and genetic changes of the beginnings of life mirror those of one of the most common cause of death—metastatic cancer. Epithelial to mesenchymal transition (EMT) is an important change in cell phenotype which allows the escape of epithelial cells from the structural constraints imposed by tissue architecture, and was first recognized by Elizabeth Hay in the early to mid 1980's to be a central process in early embryonic morphogenesis. Reversals of these changes, termed mesenchymal to epithelial transitions (METs), also occur and are important in tissue construction in normal development. Over the last decade, evidence has mounted for EMT as the means through which solid tissue epithelial cancers invade and metastasize. However, demonstrating this potentially rapid and transient process in vivo has proven difficult and data connecting the relevance of this process to tumor progression is still somewhat limited and controversial. Evidence for an important role of MET in the development of clinically overt metastases is starting to accumulate, and model systems have been developed. This review details recent advances in the knowledge of EMT as it occurs in breast development and carcinoma and prostate cancer progression, and highlights the role that MET plays in cancer metastasis. Finally, perspectives from a clinical and translational viewpoint are discussed

Palliative care in undergraduate curricula : Results of a national scoping study

Background: We wished to explore the ways in which palliative care is included in undergraduate health services curricula in Australia and the barriers to, and opportunities for, such inclusion. Methods: A scoping study of current Australian undergraduate health care curricula, using an email survey of deans (or equivalent) of health faculties was designed utilising all Australian undergraduate courses that prepare medicine, nursing and allied health professionals for entry to practice. Participants were deans or faculty heads from health and related faculties which offered courses relevant to the project, identified from the Australian Government Department of Education, Science and Training website. Sixty-two deans (or equivalent) from 41 Australian universities were surveyed. A total of 42 completed surveys were returned (68% of deans). Main outcome measures were total hours, content, teaching and learning strategies and resources for palliative care education in undergraduate curricula; perceived gaps, barriers, and opportunities to support the inclusion of palliative care education in undergraduate curricula. Results: Forty-five percent of respondents reported the content of current curricula reflected the palliative approach to a large degree. More than half of the respondents reported that their course had palliative care components integrated to a minor degree and a further third to a moderate degree. The number of hours dedicated to palliative care and teaching and learning strategies varied across all respondents, although there was a high degree of commonality in content areas taught. Conclusion: Current Australian undergraduate courses vary widely in the nature and extent to which they provide education in palliative care.

The media and parliament

For decades, indeed centuries, the Scottish media have been a source of national pride. Alongside the education system, the Church of Scotland and the legal apparatus the media have been rightly viewed as a distinctive Scottish cultural institution, a key part of what makes Scotland a nation rather than a region. Scotland has long sustained, per capita, one of the richest and most diverse media systems in the world, encapsulating a heady mix of local newspapers such as the West Highland Free Press, national [i.e., Scotland-wide] newspapers and broadcast outlets such as BBC Scotland and the Scotsman, and UK-based media with Scottish editions such as the Sun and the Mail. These media have reflected and fuelled what is in turn a distinctive Scottish political identity separate from, though connected with that of the United Kingdom as a whole. There has, for example, been no major paper with a pro-Tory editorial line north of the border for longer than most of us can remember, reflecting (and perhaps contributing to) the Conservative Party’s poor showing in successive Scottish elections.

Developing a research method to test 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). The paper begins with an update on a key development in a new early/first-order procurement decision making model that deploys production cost/benefit theory and theories concerning transaction costs from the New Institutional Economics, in order to identify a procurement mode that is likely to deliver the best ratio of production costs and transaction costs to production benefits, and therefore deliver superior VfM relative to alternative procurement modes. In doing so, the new procurement model is also able to address the uncertainty concerning the relative merits of Public-Private Partnerships (PPP) and non-PPP procurement approaches. The main aim of the paper is to develop competition as a dependent variable/proxy for VfM and a hypothesis (overarching proposition), as well as developing a research method to test the new procurement model. Competition reflects both production costs and benefits (absolute level of competition) and transaction costs (level of realised competition) and is a key proxy for VfM. Using competition as a proxy for VfM, the overarching proposition is given as: When the actual procurement mode matches the predicted (theoretical) procurement mode (informed by the new procurement model), then actual competition is expected to match potential competition (based on actual capacity). To collect data to test this proposition, the research method that is developed in this paper combines a survey and case study approach. More specifically, data collection instruments for the surveys to collect data on actual procurement, actual competition and potential competition are outlined. Finally, plans for analysing this survey data are briefly mentioned, along with noting the planned use of analytical pattern matching in deploying the new procurement model and in order to develop the predicted (theoretical) procurement mode.

A learning-based approach to reactive security

Despite the conventional wisdom that proactive security is superior to reactive security, we show that reactive security can be competitive with proactive security as long as the reactive defender learns from past attacks instead of myopically overreacting to the last attack. Our game-theoretic model follows common practice in the security literature by making worst-case assumptions about the attacker: we grant the attacker complete knowledge of the defender’s strategy and do not require the attacker to act rationally. In this model, we bound the competitive ratio between a reactive defense algorithm (which is inspired by online learning theory) and the best fixed proactive defense. Additionally, we show that, unlike proactive defenses, this reactive strategy is robust to a lack of information about the attacker’s incentives and knowledge.

Osteopontin is a downstream effector of the PI3-kinase pathway in melanomas that is inversely correlated with functional PTEN

The tumor suppressor PTEN antagonizes phosphatidylinositol 3-kinase (PI3K), which contributes to tumorigenesis in many cancer types. While PTEN mutations occur in some melanomas, their precise mechanistic consequences have yet to be elucidated. We sought to identify novel downstream effectors of PI3K using a combination of genomic and functional tests. Microarray analysis of 53 melanoma cell lines identified 610 genes differentially expressed (P<0.05) between wild-type lines and those with PTEN aberrations. Many of these genes are known to be involved in the PI3K pathway and other signaling pathways influenced by PTEN. Validation of differential gene expression by qRT-PCR was performed in the original 53 cell lines and an independent set of 18 melanoma lines with known PTEN status. Osteopontin (OPN), a secreted glycophosphoprotein that contributes to tumor progression, was more abundant at both the mRNA and protein level in PTEN mutants. The inverse correlation between OPN and PTEN expression was validated (P<0.02) by immunohistochemistry using melanoma tissue microarrays. Finally, treatment of cell lines with the PI3K inhibitor LY294002 caused a reduction in expression of OPN. These data indicate that OPN acts downstream of PI3K in melanoma and provides insight into how PTEN loss contributes to melanoma development.

Mutation analysis of the CDKN2A promoter in Australian melanoma families

Approximately 50% of all melanoma families worldwide show linkage to 9p21-22, but only about half of these have been shown to contain germ line CDKN2A mutations. It has been hypothesized that a proportion of these families carry mutations in the noncoding regions of CDKN2A. Several Canadian families have been reported to carry a mutation in the 5' UTR, at position -34 relative to the start site, which gives rise to a novel AUG translation initiation codon that markedly decreases translation from the wild-type AUG (Liu et al., 1999). Haplotype sharing in these Canadian families suggested that this mutation is of British origin. We sequenced 1,327 base pairs (bp) of CDKN2A, making up 1,116 bp of the 5' UTR and promoter, all of exon 1, and 61 bp of intron 1, in at least one melanoma case from 110 Australian families with three or more affected members known not to carry mutations within the p16 coding region. In addition, 431 bp upstream of the start codon was sequenced in an additional 253 affected probands from two-case melanoma families for which the CDKN2A mutation status was unknown. Several known polymorphisms at positions -33, -191, -493, and -735 were detected, in addition to four novel variants at positions 120, -252, -347, and -981 relative to the start codon. One of the probands from a two-case family was found to have the previously reported Q50R mutation. No family member was found to carry the mutation at position -34 or any other disease-associated mutation. For further investigation of noncoding CDKN2A mutations that may affect transcription, allele-specific expression analysis was carried out in 31 of the families with at least three affected members who showed either complete or "indeterminate" 9p haplotype sharing without CDKN2A exonic mutations. Reverse transcription polymerase chain reaction and automated sequencing showed expression of both CDKN2A alleles in all family members tested. The lack of CDKN2A promoter mutations and the absence of transcriptional silencing in the germ line of this cohort of families suggest that mutations in the promoter and 5' UTR play a very limited role in melanoma predisposition.