Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells

One mechanism of resistance of prostate cancer (PCa) to enzalutamide (MDV3100) treatment is the increased expression of AR variants lacking the ligand binding-domain, the best characterized of which is AR-V7. We have previously reported that Phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), is a lipid kinase that links to CDK1 and AR pathways. The discovery of PIP5Kα inhibitor highlight the potential of PIP5K1α as a drug target in PCa. In this study, we show that AR-V7 expression positively correlates with PIP5K1α in tumor specimens from PCa patients. Overexpression of AR-V7 increases PIP5K1α, promotes rapid growth of PCa in xenograft mice, whereas inhibition of PIP5K1α by its inhibitor ISA-2011B suppresses the growth and invasiveness of xenograft tumors overexpressing AR-V7. PIP5K1α is a key co-factor for both AR-V7 and AR, which are present as protein-protein complexes predominantly in the nucleus of PCa cells. In addition, PIP5K1α and CDK1 influence AR-V7 expression also through AKT-associated mechanism dependent on PTEN-status. ISA-2011B disrupts protein stabilization of AR-V7 which is dependent on PIP5K1α, leading to suppression of invasive growth of AR-V7-high tumors in xenograft mice. Our study suggests that combination of enzalutamide and PIP5K1α may have a significant impact on refining therapeutic strategies to circumvent resistance to antiandrogen therapies

The feasibility and acceptability of a web-based alcohol management intervention in community sports clubs: a cross-sectional study

BACKGROUND: The implementation of comprehensive alcohol management strategies can reduce excessive alcohol use and reduce the risk of alcohol-related harm at sporting venues. Supporting sports venues to implement alcohol management strategies via the Web may represent an effective and efficient means of reducing harm caused by alcohol in this setting. However, the feasibility and acceptability of such an approach is unknown. OBJECTIVE: This study aimed to identify (1) the current access to and use of the Web and electronic devices by sports clubs; (2) the perceived usefulness, ease of use, and intention to use a Web-based program to support implementation of alcohol management policies in sports clubs; (3) the factors associated with intention to use such a Web-based support program; and (4) the specific features of such a program that sports clubs would find useful. METHODS: A cross-sectional survey was conducted with club administrators of community football clubs in the state of New South Wales, Australia. Perceived usefulness, ease of use and intention to use a hypothetical Web-based alcohol management support program was assessed using the validated Technology Acceptance Model (TAM) instrument. Associations between intention to use a Web-based program and club characteristics as well as perceived ease of use and usefulness was tested using Fisher\u27s exact test and represented using relative risk (RR) for high intention to use the program. RESULTS: Of the 73 football clubs that were approached to participate in the study, 63 consented to participate and 46 were eligible and completed the survey. All participants reported having access to the Web and 98% reported current use of electronic devices (eg, computers, iPads/tablets, smartphones, laptops, televisions, and smartboards). Mean scores (out of a possible 7) for the TAM constructs were high for intention to use (mean 6.25, SD 0.87), perceived ease of use (mean 6.00, SD 0.99), and perceived usefulness (mean 6.17, SD 0.85). Intention to use the Web-based alcohol management program was significantly associated with perceived ease of use (P=.02, RR 1.4, CI 1.0-2.9), perceived usefulness (P=.03, RR 1.5, CI 1.0-6.8) and club size (P=.02, RR 0.8, CI 0.5-0.9). The most useful features of such a program included the perceived ability to complete program requirements within users\u27 own time, complete program accreditation assessment and monitoring online, develop tailored action plans, and receive email reminders and prompts to complete action. CONCLUSIONS: A Web-based alcohol management approach to support sports clubs in the implementation of recommended alcohol management policies appears both feasible and acceptable. Future research should aim to determine if such intended use leads to actual use and club implementation of alcohol management policies

"Reassurance that you're doing okay, or guidance if you're not": A qualitative descriptive study of pregnant first time mothers' expectations and information needs about postnatal care in England

To explore what first time mothers in England expect from postnatal care while they are pregnant, what they would ideally like, where they get their information on postnatal care, and their views on the sufficiency of this information. A qualitative descriptive interview-based study. England PARTICIPANTS: A maximum variation sample of 40 women who were currently in the third trimester of pregnancy; aged 16 or over; planning to give birth in England and had not given birth previously. Semi structured interviews were carried out between October 2017 and March 2018, by telephone (n = 32) and face to face (n = 8). Interviews were analysed using thematic analysis. There were six themes and twelve subthemes. The themes were: (1) 'Piecing together snippets of information' containing subthemes 'Incomplete official sources' and 'Other mothers' stories'; (2) 'Planning ahead or going with the flow' containing subthemes 'Wanting more information' and 'Postnatal care not a priority'; (3) 'Judgement or reassurance' containing subthemes 'Real: Being judged', 'Ideal: Reassurance and non-judgmental advice'; (4) 'Focus of care' containing subthemes 'Real: A focus on checks and feeding', 'Ideal: More focus on mother's wellbeing'; (5) 'A system under pressure' containing subthemes 'Real: Busy midwives, reactive care', 'Ideal: Reliable, proactive information'; (6) 'Deciding about discharge', containing subthemes 'Real: Confusion about decision-making', 'Ideal: More control over length of hospital stay'. First time mothers' experience of the transition to parenthood could be improved by antenatal access to comprehensive information about the timing, location, content and purpose of postnatal care. Information should take a woman-centred perspective and cover all settings (hospitals, birth centres, home, community), including the roles and responsibilities of all the professionals who may be involved. Clear and comprehensive information about postnatal care should be provided to all women in ways that are accessible at any stage of pregnancy or the postnatal period. As women pregnant for the first time worry about being judged if they seek professional advice and reassurance postnatally, information about postnatal care should aim to address this. [Abstract copyright: Copyright © 2020. Published by Elsevier Ltd.

Dealing with Alcohol-related problems in the Night-Time Economy: A Study Protocol for Mapping trends in harm and stakeholder views surrounding local community level interventions

<p>Abstract</p> <p>Background</p> <p>This project will provide a comprehensive investigation into the prevalence of alcohol-related harms and community attitudes in the context of community-based interventions being implemented to reduce harm in two regional centres of Australia. While considerable experimentation and innovation to address these harms has occurred in both Geelong and Newcastle, only limited ad-hoc documentation and analysis has been conducted on changes in the prevalence of harm as a consequence, leaving a considerable gap in terms of a systematic, evidence-based analysis of changes in harm over time and the need for further intervention. Similarly, little evidence has been reported regarding the views of key stakeholder groups, industry, government agencies, patrons or community regarding the need for, and the acceptability of, interventions to reduce harms. This project will aim to provide evidence regarding the impact and acceptability of local initiatives aimed at reducing alcohol-related harms.</p> <p>Methods/Design</p> <p>This study will gather existing police data (assault, property damage and drink driving offences), Emergency Department presentations and Ambulance attendance data. Further, the research team will conduct interviews with licensed venue patrons and collect observational data of licensed venues. Key informant interviews will assess expert knowledge from key industry and government stakeholders, and a community survey will assess community experiences and attitudes towards alcohol-related harm and harm-reduction strategies. Overall, the project will assess: the extent of alcohol-related harm in the context of harm-reduction interventions, and the need for and acceptability of further intervention.</p> <p>Discussion</p> <p>These findings will be used to improve evidence-based practice both nationally and internationally.</p> <p>Ethical Approval</p> <p>This project has been approved by Deakin University HREC.</p

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Food fairness Illawarra: Factors enabling an effective coalition to ensure a fair food future

Food security, access to appropriate, nutritious food on a regular, reliable basis, is a human right and core to Australia’s future. However, it is increasingly recognised that groups in the Australian community are food insecure, including \u3e6% of Illawarra residents. In recognition of this, Food Fairness Illawarra formed as a community alliance to promote a fair food future for residents. Collaborative community partnerships and coalitions are a core Ottawa Charter strategy for enhancing health. It is important therefore to evaluate the effectiveness of such coalitions in promoting community food security. The effectiveness of Food Fairness Illawarra as a community coalition to enhance food security can be measured in terms of outcomes and processes. The coalition has been successful in a wide range of outcomes at a number of strategic levels to promote and enhance local food security. In addition, the coalition has surveyed members regularly concerning satisfaction, communication and capacity building to ensure that the coalition has appropriate processes for continuing effectiveness. This discussion will present the outcome and process measures used by Food Fairness Illawarra to demonstrate its effectiveness and highlight the factors contributing to the success of this community coalition in promoting community food security

Food security: mapping the environmental determinants for urban planning and infrastructure development.

Food security, access to appropriate, nutritious food on a regular and reliable basis, using socially and culturally acceptable means to acquire it, is a human right. There are groups in the Australian community who are food insecure, including low income families with children, the elderly, and other marginalised and disadvantaged groups. However, low income does not equate to food insecurity and urban infrastructure can ameliorate or exacerbate food access issues. This paper describes environmental aspects of urban food access in Wollongong NSW, using GIS software. It presents layered data on food outlets by type, food aid distributors, sociodemographic profiles (including SEIFA indices and other ABS data), transport routes, and aspects of the social and built environments. Through the use of mapping, clear differences within similar sociodemographic areas were identified that challenge simplistic interpretations linking food security and socioeconomic data. The visual demonstration of infrastructural aspects of the environment can be used to advocate to local government for consideration of infrastructure and planning impacts on food access and health. Mapping also can provide information to local food aid providers in planning for the appropriate distribution of food aid and as an advocacy tool through comparison with other Australian data. In addition, this project has acted as an important focal point for collaborative partnerships between the university and other agencies, including South Eastern Sydney Illawarra Health (NSW Health), NGOs, and the private sector, to develop sustainable action to promote health

Alcohol management practices in community football clubs: association with risky drinking at the club and overall hazardous alcohol consumption

Across the world, it has been estimated that approximately 270 million people participate in community football clubs. However, the community sports club setting is associated with high levels of risky alcohol consumption. The study examined if sporting club alcohol management practices are associated with risky consumption of alcohol by club members while at the club, and also whether such consumption is directly and indirectly associated with club member overall hazardous alcohol consumption