Estrogen receptor-Beta activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNF-alpha mediated

Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are androgen-dependent diseases commonly treated by inhibiting androgen action. However, androgen ablation or castration fail to target androgen-independent cells implicated in disease etiology and recurrence. Mechanistically different to castration, this study shows beneficial proapoptotic actions of estrogen receptor–β (ERβ) in BPH and PCa. ERβ agonist induces apoptosis in prostatic stromal, luminal and castrate-resistant basal epithelial cells of estrogen-deficient aromatase knock-out mice. This occurs via extrinsic (caspase-8) pathways, without reducing serum hormones, and perturbs the regenerative capacity of the epithelium. TNFα knock-out mice fail to respond to ERβ agonist, demonstrating the requirement for TNFα signaling. In human tissues, ERβ agonist induces apoptosis in stroma and epithelium of xenografted BPH specimens, including in the CD133+ enriched putative stem/progenitor cells isolated from BPH-1 cells in vitro. In PCa, ERβ causes apoptosis in Gleason Grade 7 xenografted tissues and androgen-independent cells lines (PC3 and DU145) via caspase-8. These data provide evidence of the beneficial effects of ERβ agonist on epithelium and stroma of BPH, as well as androgen-independent tumor cells implicated in recurrent disease. Our data are indicative of the therapeutic potential of ERβ agonist for treatment of PCa and/or BPH with or without androgen withdrawal.

Varenicline, an alpha-4 beta-2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking

Abstract Alcohol dependence is a disease that impacts millions of individuals worldwide. There has been some progress with pharmacotherapy for alcohol-dependent individuals; however, there remains a critical need for the development of novel and additional therapeutic approaches. Alcohol and nicotine are commonly abused together, and there is evidence that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in both alcohol and nicotine dependence. Varenicline, a partial agonist at the alpha4beta2 nAChRs, reduces nicotine intake and was recently approved as a smoking cessation aid. We have investigated the role of varenicline in the modulation of ethanol consumption and seeking using three different animal models of drinking. We show that acute administration of varenicline, in doses reported to reduce nicotine reward, selectively reduced ethanol but not sucrose seeking using an operant self-administration drinking paradigm and also decreased voluntary ethanol but not water consumption in animals chronically exposed to ethanol for 2 months before varenicline treatment. Furthermore, chronic varenicline administration decreased ethanol consumption, which did not result in a rebound increase in ethanol intake when the varenicline was no longer administered. The data suggest that the alpha4beta2 nAChRs may play a role in ethanol-seeking behaviors in animals chronically exposed to ethanol. The selectivity of varenicline in decreasing ethanol consumption combined with its reported safety profile and mild side effects in humans suggest that varenicline may prove to be a treatment for alcohol dependence.

Mutations in exon 3 of the beta-catenin gene are rare in melanoma cell lines

Mutations in exon 3 of the CTNNB1 gene encoding beta-catenin have been reported in colorectal cancer cell lines and tumours. Although one study reported mutations or deletions affecting beta-catenin in 20% of melanoma cell lines, subsequent reports detected a much lower frequency of aberrations in uncultured melanomas. To determine whether this difference in mutation frequency reflected an in vitro culturing artefact, exon 3 of CTNNB1 was screened in a panel of 62 melanoma cell lines. In addition, reverse transcription-polymerase chain reaction (RT-PCR) was performed to detect intragenic deletions affecting exon 3. One out of 62 (1.6%) cell lines was found to carry a mutation, indicating that aberration of the Wnt-1/wingless pathway through activation of beta-catenin is a rare event, even in melanoma cell lines.

From margins to mainstream : how screen and creative industries developed in the Northern Rivers region of NSW : 2000–2010

This thesis explores the proposition that growth and development in the screen and creative industries is not confined to the major capital cities. Lifestyle considerations, combined with advances in digital technology, convergence and greater access to broadband are altering requirements for geographic location, and creative workers are being drawn away from the big metropolises to certain regional areas. Regional screen industry enclaves are emerging outside of London, in the Highlands and Islands of Scotland, in Nova Scotia in Canada and in New Zealand. In the Australian context, the proposition is tested in an area regarded as a ‘special case’ in creative industry expansion: the Northern Rivers region of NSW. A key feature of the ‘specialness’ of this region is the large number of experienced, credited producers who live and operate their businesses within the region. The development of screen and creative industries in the Northern Rivers over the decade 2000 – 2010 has implications for regional regeneration and offers new insights into the rapidly changing screen industry landscape. This development also has implications for creative industry discourse, especially the dominance of the urban in creative industries thought. The research is pioneering in a number of ways. Building on the work conducted for my Masters thesis in 2000, a second study was conducted during the research phase, adapting creative industries theory and mapping methods, which have been largely city and nation-centric, and applying them to a regional context. The study adopted an action research approach as an industry development strategy for screen industries, while at the same time developing fine-grained ground up methods for collecting primary quantitative data on the size and scope of the creative industries. In accordance with the action research framework, the researcher also acted in the dual roles of industry activist and screen industry producer in the region. The central focus of the research has been both to document and contribute to the growth and development of screen and creative industries over the past decade in the Northern Rivers region. These interventions, along with policy developments at both a local and national level, and broader global shifts, have had the effect of repositioning the sector from a marginal one to a priority area considered integral to the future economic and cultural life of the region. The research includes a detailed mapping study undertaken in 2005 with comparisons to an earlier 2000 study and to ABS data for 2001 and 2006 to reveal growth trends. It also includes two case studies of projects that developed from idea to production and completion in the region during the decade in question. The studies reveal the drivers, impediments and policy implications for sustaining the development of screen industries in a regional area. A major finding of the research was the large and increasing number of experienced producers who operate within the region and the leadership role they play in driving the development of the emerging local industry. The two case studies demonstrate the impact of policy decisions on local screen industry producers and their enterprises. A brief overview of research in other regional areas is presented, including two international examples, and what they reveal about regional regeneration. Implications are drawn for creative industries discourse and regional development policy challenges for the future.

Improved sensorimotor adaptation after exhaustive exercise is accompanied by altered brain activity

Acute exercise has been shown to exhibit different effects on human sensorimotor behavior; however, the causes and mechanisms of the responses are often not clear. The primary aim of the present study was to determine the effects of incremental running until exhaustion on sensorimotor performance and adaptation in a tracking task. Subjects were randomly assigned to a running group (RG), a tracking group (TG), or a running followed by tracking group (RTG), with 10 subjects assigned to each group. Treadmill running velocity was initially set at 2.0 m s− 1, increasing by 0.5 m s− 1 every 5 min until exhaustion. Tracking consisted of 35 episodes (each 40 s) where the subjects' task was to track a visual target on a computer screen while the visual feedback was veridical (performance) or left-right reversed (adaptation). Resting electroencephalographic (EEG) activity was recorded before and after each experimental condition (running, tracking, rest). Tracking performance and the final amount of adaptation did not differ between groups. However, task adaptation was significantly faster in RTG compared to TG. In addition, increased alpha and beta power were observed following tracking in TG but not RTG although exhaustive running failed to induce significant changes in these frequency bands. Our results suggest that exhaustive running can facilitate adaptation processes in a manual tracking task. Attenuated cortical activation following tracking in the exercise condition was interpreted to indicate cortical efficiency and exercise-induced facilitation of selective central processes during actual task demands.

Music selection using a touch screen interface : effect of auditory and visual feedback on driving and usability

This study aimed to examine the effects on driving, usability and subjective workload of performing music selection tasks using a touch screen interface. Additionally, to explore whether the provision of visual and/or auditory feedback offers any performance and usability benefits. Thirty participants performed music selection tasks with a touch screen interface while driving. The interface provided four forms of feedback: no feedback, auditory feedback, visual feedback, and a combination of auditory and visual feedback. Performance on the music selection tasks significantly increased subjective workload and degraded performance on a range of driving measures including lane keeping variation and number of lane excursions. The provision of any form of feedback on the touch screen interface did not significantly affect driving performance, usability or subjective workload, but was preferred by users over no feedback. Overall, the results suggest that touch screens may not be a suitable input device for navigating scrollable lists.

Broadband, the NBN and screen futures

It is important to try to come to grips with what content and applications are likely to be feasible, popular and beneficial on the National Broadband Network, which is being rolled out now. This short article looks at the three main types of content ('unmanaged', 'managed' and 'publicly supported' services), shows how creative content is being, or could be, deployed across all three, and discusses the policy opportunities and challenges for content industries in connecting with what Minister for Regional Australia, Regional Development and Local Government and Minister for the Arts Simon Crean calls 'the largest cultural infrastructure project Australia has ever seen'.

A screen for modifiers of epigenetic reprogramming

Epigenetic modifiers are the proteins involved in establishing and maintaining the epigenome of an organism. They are particularly important for development. Changes in epigenetic modifiers have been shown be lethal, or cause diseases. Our laboratory has developed an ENU mutagenesis screen to produce mouse mutants displaying altered epigenetic gene silencing. The screen relies on a GFP transgene that is expressed in red blood cells in a variegated manner. In the orginal transgenic FVB mice expression occurs in approximately 55% of red blood cells. During the course of my Masters, I characterised four different Mommes (Modifiers of murine metastable epiallele), MommeD32, MommeD33, MommeD35 and MommeD36. For each Momme, I identified the underlying mutation, and observed the corresponding phenotype. In MommeD32 the causative mutation is in Dnmt1, (DNA methyltransferase 1). This gene was previously identified in the screen, as MommeD2, and the new allele, MommeD32 has a change in the BAH domain of the protein. MommeD33 is the result of a change at the transgene itself. MommeD35 carries a mutation in Suv39h1 (suppressor of variegation 3-9 homolog 1). This gene has not previously been identified in the screen, but it is a known epigenetic modifier. MommeD36 had the same ENU treated sire as MommeD32, and I found that it has the same mutation as MommeD32. These mutant strains provide valuable tools that can be used to further our knowledge of epigenetic reprogramming. An example being the cancer study done with MommeD9 which has a mutation in Trim28. By crossing MommeD9+/- mutant mice with Trp53+/- mice, it can be seen if Trim28 has an effect on the rate of tumour genesis. However no clear effect of Trim28 haploinsufficiency can be observed in Trp53+/- mice.