Kallikrein 14 is down-regulated by androgen receptor signalling and harbours genetic variation that is associated with prostate tumour aggressiveness

Kallikrein 14 (KLK14) has been proposed as a useful prognostic marker in prostate cancer, with expression reported to be associated with tumour characteristics such as higher stage and Gleason score. KLK14 tumour expression has also shown the potential to predict prostate cancer patients at risk of disease recurrence after radical prostatectomy. The KLKs are a remarkably hormone-responsive family of genes, although detailed studies of androgen regulation of KLK14 in prostate cancer have not been undertaken to date. Using in vitro studies, we have demonstrated that unlike many other prostatic KLK genes that are strictly androgen responsive, KLK14 is more broadly expressed and inversely androgen regulated in prostate cancer cells. Given these results and evidence that KLK14 may play a role in prostate cancer prognosis, we also investigated whether common genetic variants in the KLK14 locus are associated with risk and/or aggressiveness of prostate cancer in approximately 1200 prostate cancer cases and 1300 male controls. Of 41 single nucleotide polymorphisms assessed, three were associated with higher Gleason score (≥7): rs17728459 and rs4802765, both located upstream of KLK14, and rs35287116, which encodes a p.Gln33Arg substitution in the KLK14 signal peptide region. Our findings provide further support for KLK14 as a marker of prognosis in prostate cancer.

Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status

BACKGROUND: Melanoma is the most lethal form of skin cancer, but recent advances in molecularly targeted agents against the Ras/Raf/MAPK pathway demonstrate promise as effective therapies. Despite these advances, resistance remains an issue, as illustrated recently by the clinical experience with vemurafenib. Such acquired resistance appears to be the result of parallel pathway activation, such as PI3K, to overcome single-agent inhibition. In this report, we describe the cytotoxicity and anti-tumour activity of the novel MEK inhibitor, E6201, in a broad panel of melanoma cell lines (n = 31) of known mutational profile in vitro and in vivo. We further test the effectiveness of combining E6201 with an inhibitor of PI3K (LY294002) in overcoming resistance in these cell lines. RESULTS: The majority of melanoma cell lines were either sensitive (IC50 < 500 nM, 24/31) or hypersensitive (IC50 < 100 nM, 18/31) to E6201. This sensitivity correlated with wildtype PTEN and mutant BRAF status, whereas mutant RAS and PI3K pathway activation were associated with resistance. Although MEK inhibitors predominantly exert a cytostatic effect, E6201 elicited a potent cytocidal effect on most of the sensitive lines studied, as evidenced by Annexin positivity and cell death ELISA. Conversely, E6201 did not induce cell death in the two resistant melanoma cell lines tested. E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees, but a more pronounced anti-tumour effect was observed for cell lines that previously demonstrated a cytocidal response in vitro. In vitro combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested, as defined by a mean combination index < 1. CONCLUSIONS: Our data demonstrate that E6201 elicits a predominantly cytocidal effect in vitro and in vivo in melanoma cells of diverse mutational background. Resistance to E6201 was associated with disruption of PTEN and activation of downstream PI3K signalling. In keeping with these data we demonstrate that co-inhibition of MAPK and PI3K is effective in overcoming resistance inherent in melanoma.

Say goodbye to the fries : graduate careers in media, cultural and communication studies

This article addresses the paucity of systematic data on graduate careers in the arts and humanities in the broader context of enduring public and policy debates about the benefits of education to society, the relation between public and private good that is derivable from education, and the specific disciplinary angle that can be brought to bear on these questions from media, cultural and communication studies. We report findings from a survey of ten years of graduates from Queensland University of Technology’s courses in media, cultural and communication studies which indicate very high employment levels and generally positive accounts of the relevance of courses to working life. A major insight that can be drawn from the research is that media, cultural and communication studies deliver capabilities, skills and orientations which are themselves strongly aligned with the kinds of transferable generic attributes which facilitate transition into the workplace.

More is not necessarily better. A biomechanical study on distal screw numbers in volar locking distal radius plates

INTRODUCTION: Currently available volar locking plates for the treatment of distal radius fractures incorporate at least two distal screw rows for fixation of the metaphyseal fragment and have a variable-angle locking mechanism which allows placement of the screws in various directions There is, however no evidence that these plates translate into better outcomes or have superior biomechanical properties to first generation plates, which had a single distal screw row and fixed-angle locking. The aim of our biomechanical study was to compare fixed-angle single-row plates with variable-angle multi-row plates to clarify the optimal number of locking screws. MATERIALS AND METHODS: Five different plate-screw combinations of three different manufacturers were tested, each group consisting of five synthetic fourth generation distal radius bones. An AO type C2 fracture was created and the fractures were plated according to each manufacturer's recommendations. The specimens then underwent cyclic and load-to-failure testing. An optical motion analysis system was used to detect displacement of fragments. RESULTS: No significant differences were detected after cyclic loading as well as after load-to-failure testing, neither in regard to axial deformation, implant rigidity or maximum displacement. The fixed-angle single-row plate showed the highest pre-test rigidity, least increase in post-testing rigidity and highest load-to-failure rigidity and least radial shortening. The radial shortening of plates with two distal screw rows was 3.1 and 4.3 times higher, respectively, than that of the fixed-angle single-row plate. CONCLUSION: The results of our study indicate that two distal screw rows do not add to construct rigidity and resistance against loss of reduction. Well conducted clinical studies based on the findings of biomechanical studies are necessary to determine the optimal number of screws necessary to achieve reproducibly good results in the treatment of distal radius fractures.

Setting up a platform for plant-based influenza virus vaccine production in South Africa

Background During a global influenza pandemic, the vaccine requirements of developing countries can surpass their supply capabilities, if these exist at all, compelling them to rely on developed countries for stocks that may not be available in time. There is thus a need for developing countries in general to produce their own pandemic and possibly seasonal influenza vaccines. Here we describe the development of a plant-based platform for producing influenza vaccines locally, in South Africa. Plant-produced influenza vaccine candidates are quicker to develop and potentially cheaper than egg-produced influenza vaccines, and their production can be rapidly upscaled. In this study, we investigated the feasibility of producing a vaccine to the highly pathogenic avian influenza A subtype H5N1 virus, the most generally virulent influenza virus identified to date. Two variants of the haemagglutinin (HA) surface glycoprotein gene were synthesised for optimum expression in plants: these were the full-length HA gene (H5) and a truncated form lacking the transmembrane domain (H5tr). The genes were cloned into a panel of Agrobacterium tumefaciens binary plant expression vectors in order to test HA accumulation in different cell compartments. The constructs were transiently expressed in tobacco by means of agroinfiltration. Stable transgenic tobacco plants were also generated to provide seed for stable storage of the material as a pre-pandemic strategy. Results For both transient and transgenic expression systems the highest accumulation of full-length H5 protein occurred in the apoplastic spaces, while the highest accumulation of H5tr was in the endoplasmic reticulum. The H5 proteins were produced at relatively high concentrations in both systems. Following partial purification, haemagglutination and haemagglutination inhibition tests indicated that the conformation of the plant-produced HA variants was correct and the proteins were functional. The immunisation of chickens and mice with the candidate vaccines elicited HA-specific antibody responses. Conclusions We managed, after synthesis of two versions of a single gene, to produce by transient and transgenic expression in plants, two variants of a highly pathogenic avian influenza virus HA protein which could have vaccine potential. This is a proof of principle of the potential of plant-produced influenza vaccines as a feasible pandemic response strategy for South Africa and other developing countries.

The evolutionary value of recombination is constrained by genome modularity

Genetic recombination is a fundamental evolutionary mechanism promoting biological adaptation. Using engineered recombinants of the small single-stranded DNA plant virus, Maize streak virus (MSV), we experimentally demonstrate that fragments of genetic material only function optimally if they reside within genomes similar to those in which they evolved. The degree of similarity necessary for optimal functionality is correlated with the complexity of intragenomic interaction networks within which genome fragments must function. There is a striking correlation between our experimental results and the types of MSV recombinants that are detectable in nature, indicating that obligatory maintenance of intragenome interaction networks strongly constrains the evolutionary value of recombination for this virus and probably for genomes in general.

The capsid protein of beak and feather disease virus binds to the viral DNA and is responsible for transporting the replication-associated protein into the nucleus

Circoviruses lack an autonomous DNA polymerase and are dependent on the replication machinery of the host cell for de novo DNA synthesis. Accordingly, the viral DNA needs to cross both the plasma membrane and the nuclear envelope before replication can occur. Here we report on the subcellular distribution of the beak and feather disease virus (BFDV) capsid protein (CP) and replication-associated protein (Rep) expressed via recombinant baculoviruses in an insect cell system and test the hypothesis that the CP is responsible for transporting the viral genome, as well as Rep, across the nuclear envelope. The intracellular localization of the BFDV CP was found to be directed by three partially overlapping bipartite nuclear localization signals (NLSs) situated between residues 16 and 56 at the N terminus of the protein. Moreover, a DNA binding region was also mapped to the N terminus of the protein and falls within the region containing the three putative NLSs. The ability of CP to bind DNA, coupled with the karyophilic nature of this protein, strongly suggests that it may be responsible for nuclear targeting of the viral genome. Interestingly, whereas Rep expressed on its own in insect cells is restricted to the cytoplasm, coexpression with CP alters the subcellular localization of Rep to the nucleus, strongly suggesting that an interaction with CP facilitates movement of Rep into the nucleus. Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Is it time to revisit the problem young driver?

For decades there have been two young driver concepts: the „young driver problem‟ where the driver cohort represents a key problem for road safety; and the „problem young driver‟ where a sub-sample of drivers represents the greatest road safety problem. Given difficulties associated with identifying and then modifying the behaviour of the latter group, broad countermeasures such as graduated driver licensing (GDL) have generally been relied upon to address the young driver problem. GDL evaluations reveal general road safety benefits for young drivers, yet they continue to be overrepresented in fatality and injury statistics. Therefore it is timely for researchers revisit the problem young driver concept to assess its potential countermeasure implications. Personal characteristics, behaviours and attitudes of 378 Queensland novice drivers aged 17-25 years were explored during their pre-, Learner and Provisional 1 (intermediate) licence as part of a larger longitudinal research project. Self-reported risky driving was measured by the Behaviour of Young Novice Drivers Scale (BYNDS), and five subscale scores were used to cluster the drivers into three groups (high risk n = 49, medium risk n = 163, low risk n = 166). High risk „problem young‟ drivers were characterised by self-reported pre-Licence driving, unsupervised Learner driving, and speeding, driving errors, risky driving exposure, crash involvement, and offence detection during the Provisional period. Medium risk drivers were also characterised by more risky road use behaviours than the low risk group. Interestingly problem young drivers appear to have some insight into their high-risk driving, and they report significantly greater intentions to bend road rules in future driving. The results suggest that in addition to broad countermeasures such as GDL which target the young driver problem, tailored intervention efforts may need to target problem young drivers. Driving behaviours and crash-involvement could be used to identify these drivers as pre-intervention screening measures.

Living a life with a physical impairment in Taiwan : "It is more than just the impairment"

This thesis is concerned with understanding what it is like to live with a physical impairment in Taiwan. Constructionism was used as the epistemological stance to guide the study and Heideggerian interpretive phenomenology was used as the theoretical perspective. Information was gained through a series of in-depth interviews with seven Taiwanese adults with a physical impairment living in the community. They were recruited from Yunlin and Tainan Counties in Taiwan. Study participants were seen as research partners who had expertise in understanding disability, and the researcher was seen as a learner. Grounded theory principles were used to develop the theory "it is more than just the impairment" from the information provided by the participants. According to their descriptions of how they lived their lives, participants are grouped into three clusters. These are ‘fortress ladies’, ‘social networkers’ and ‘the mind man’. The grounded theory developed portrays their lives, providing a vivid picture of living a life with a physical impairment in Taiwan. The study’s findings contribute to three main areas. First, as an occupational therapist and with my growing understanding of disability learned from the study participants, I recognize the agency of people with an impairment and their expertise in disability. Thus, I argue the need for health professionals to build alliances with them, and suggest ways to achieve such a relationship. Second, I propose the developed conceptual framework is suitable for exploring lived experience in other research areas; I discuss the implications of the subtle interactions between impaired people’s body and mind; I also present three impressive lived experiences provided by study participants as exemplars of the findings, and these form the foundation for discussion. Finally, the development of "it is more than just the impairment" provides a basis from which to theorize disability in a more holistic way.

The 'variety effect' is anticipated in meal planning

The 'variety effect' describes the greater consumption that is observed when multiple foods with different sensory characteristics are presented either simultaneously or sequentially. Variety increases the amount of food consumed in test of ad libitum intake. However, outside the laboratory, meals are often planned in advance and then consumed in their entirety. We sought to explore the extent to which the variety effect is anticipated in this pre-meal planning. Participants were shown two food images, each representing a first or a second course of a hypothetical meal. The two courses were either, i) exactly the same food, ii) different foods from the same sensory category (sweet or savoury) or, iii) different foods from a different sensory category. In Study 1 (N = 30) these courses comprised typical ‘main meal’ foods and in Study 2 (N = 30) they comprised snack foods. For each pair of images, participants rated their expected liking of the second course and selected ideal portion sizes, both for the second course and the first and second course, combined. In both studies, as the difference between the courses (from (i) same to (ii) similar to (iii) different) increased, the second course was selected in a larger portion and it was rated as more pleasant. To our knowledge, these are the first studies to show that the variety effect is evident in the energy content of self-selected meals. This work shows that effects of variety are learned and anticipated. This extends our characterisation beyond a passive process that develops towards the end of a meal.