Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling

Activating mutations in genes of the Ras-mitogen-activated protein kinase (MAPK) pathway occur in approximately 30% of all human cancers; however, mutation of Ras alone is rarely sufficient to induce tumour development. Scribble is a polarity regulator recently isolated from a Drosophila screen for events that cooperate with Ras mutation to promote tumour progression and cell invasion. In mammals, Scribble regulates directed cell migration and wound healing in vivo; however, no role has been identified for mammalian Scribble in oncogenic transformation. Here we show that in human epithelial cells expressing oncogenic Ras or Raf, loss of Scribble promotes invasion of cells through extracellular matrix in an organotypic culture system. Further, we show that the mechanism by which this occurs is in the regulation of MAPK signalling by Scribble. The suppression of MAPK signalling is a highly conserved function of Scribble as it also prevents Raf-mediated defects in Drosophila wing development. Our data identify Scribble as an important mediator of MAPK signalling and provide a molecular basis for the observation that Scribble expression is decreased in many invasive human cancers. © 2008 Macmillan Publishers Limited All rights reserved

SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia

Loss of cellular polarity is a hallmark of epithelial cancers, raising the possibility that regulators of polarity have a role in suppressing tumorigenesis. The Scribble complex is one of at least three interacting protein complexes that have a critical role in establishing and maintaining epithelial polarity. In human colorectal, breast, and endometrial cancers, expression of the Scribble complex member SCRIB is often mislocalized and deregulated. Here, we report that Scrib is indispensable for prostate homeostasis in mice. Scrib heterozygosity initiated prostate hyperplasia, while targeted biallelic Scrib loss predisposed mice to prostate intraepithelial neoplasia. Mechanistically, Scrib was shown to negatively regulate the MAPK cascade to suppress tumorigenesis. Further analysis revealed that prostate-specific loss of Scrib in mice combined with expression of an oncogenic Kras mutation promoted the progression of prostate cancer that recapitulated the human disease. The clinical significance of the work in mice was highlighted by our observation that SCRIB deregulation strongly correlated with poor survival in human prostate cancer. These data suggest that the polarity network could provide a new avenue for therapeutic intervention

Broker roles in open innovation

Knowledge brokers play a crucial role in open innovation. We use exponential random graph models and qualitative analysis of semi-structured interview data to contrast knowledge brokerage in three open innovation partnerships. Our analysis considers both tacit and explicit knowledge exchanges. Significant broker role effects occur mainly in tacit knowledge-sharing networks. This result implies that brokerage in open innovation is primarily about connecting know-how rather than know-what. We see that trust is crucial for both tacit and explicit knowledge sharing. Adding broker roles to exponential random graph models offers a more nuanced explanation of the observed network structure

A modelling analysis of financial incentives for hepatitis C testing and treatment uptake delivered through a community-based testing campaign

Financial incentives may reduce opportunity costs associated with people who become lost to follow-up in hepatitis C treatment programs. We estimated the impact that different financial incentive amounts would need to have on retention in care to maintain the same unit cost per (1) RNA-positive person completing testing (defined as awareness of RNA status) and (2) RNA diagnosed person initiating treatment. Costing data were obtained from a 2019 community-based testing campaign focused on engaging people who inject drugs. For different financial incentive amounts, we modelled the corresponding improvements in retention in care that would be needed to maintain the same overall (1) unit cost per testing completion and (2) unit cost per treatment initiation. In the testing campaign, the unit cost per RNA-positive person completing testing was A$3215 and the unit cost per RNA diagnosed person initiating treatment was A$1055. Modelling found that an incentive of A$500 per RNA-positive person completing testing would result in more people completing testing for the same unit cost if the percentage of attendees receiving their test results increased from 63$200 per RNA diagnosed person initiating treatment would result in more people initiating treatment for the same unit cost if the percentage initiating treatment increased from 67% to 83%. Monetary incentives for completing testing and initiating treatment may be an effective way to increase retention in care without increasing the overall unit cost of completing testing/initiating treatment

Scrib heterozygosity predisposes to lung cancer and cooperates with KRas hyperactivation to accelerate lung cancer progression in vivo

Lung cancer is the leading cause of cancer deaths worldwide with non small-cell lung cancer (NSCLC) accounting for 80% of all lung cancers. Although activating mutations in genes of the RAS-MAPK pathway occur in up to 30% of all NSCLC, the cooperating genetic lesions that are required for lung cancer initiation and progression remain poorly understood. Here we identify a role for the cell polarity regulator Scribble (Scrib) in NSCLC. A survey of genomic databases reveals deregulation of SCRIB in human lung cancer and we show that Scrib+/− mutant mice develop lung cancer by 540 days with a penetrance of 43%. To model NSCLC development in vivo, we used the extensively characterized LSL-KRasG12D murine model of NSCLC. We show that loss of Scrib and activated oncogenic KRas cooperate in vivo, resulting in more aggressive lung tumors, likely due to a synergistic elevation in RAS–MAPK signaling. Finally, we provide data consistent with immune infiltration having an important role in the acceleration of tumorigenesis in KRasG12D lung tumors following Scrib loss

A community-based co-designed genetic health service model for Aboriginal Australians

© 2020 Elsum et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Aboriginal and Torres Strait Islander people experience a greater burden of disease and die younger than non-Indigenous Australians, with Aboriginal people living in remote areas of the Northern Territory of Australia having the lowest life expectancy estimates. Despite a high burden of chronic disease among Aboriginal and Torres Strait Islander people, access to specialist health services remains low and models of care that increase engagement, may improve health outcomes. Methods We describe client and staff perspectives of a model of clinical genetics services provided by the MJD Foundation (MJDF) in geographically and culturally complex contexts within the Northern Territory of Australia. We seek to understand the MJDF model’s success in supporting Aboriginal families with the familial, neurodegenerative condition Machado-Joseph disease and how it could be applied in the provision of other specialist services. Thematic analysis was undertaken on semi-structured interviews with primary health care staff (n = 2), Non-Aboriginal MJDF Staff (n = 7) and Aboriginal MJDF Clients / Community workers (n = 13). Results Four key themes regarding the MJDF model of service delivery were identified with the service being; 1) client led 2) accepting of various understandings of genetic disease causation 3) focused on relationships, continuity and trust between the service provider and the clients, and 4) committed to incorporating an inclusive whole-of-family practice. The MJDF model takes a community-based, person-and family-centred approach to successfully deliver effective specialist genetic health services in remote community settings. We propose that these approaches have broad application in the future design and delivery of specialist health services particularly in culturally complex settings

Exploring hepatitis C virus testing and treatment engagement over time in Melbourne, Australia: a study protocol for a longitudinal cohort study (EC-Experience Cohort study)

INTRODUCTION: The advent of direct acting antiviral therapy for hepatitis C virus (HCV) means the elimination of HCV is possible but requires sustained effort to achieve. Between 2016 and 2019, 44% of those living with HCV were treated in Australia. However, treatment uptake has declined significantly. In Australia, people who inject drugs (PWID) are the population most at risk of HCV acquisition. Eliminating HCV in Australia will require nuanced understanding of the barriers to HCV treatment experienced by PWID and tailored interventions to address these barriers. The EC-Experience Cohort study aims to explore the barriers and enablers reported by PWID to engagement in HCV care. METHODS AND ANALYSIS: The EC-Experience Cohort study is a prospective cohort of PWID, established in Melbourne, Australia in 2018. Participants are assigned into three study groups: (1) those not currently engaged in HCV testing; (2) those diagnosed with HCV but not currently engaged in treatment and (3) those completed treatment. Participants complete a total of four interviews every 6 months across an 18-month study period. Predictors of experience of key outcome events along the HCV care cascade will be explored over time. ETHICS AND DISSEMINATION: Ethical approval for the EC-Experience Cohort study was obtained by the Alfred Hospital Ethics Committee in Melbourne, Australia (Project Number: HREC/16/Alfred/164). All eligible participants are assessed for capacity to consent and partake in a thorough informed consent process. Results from the EC-Experience Cohort study will be disseminated via national and international scientific and public health conferences and peer-reviewed journal publications. Data from the EC-Experience Cohort study will improve the current understanding of the barriers to HCV care for PWID and guide the tailoring of service provision for specific subgroups. Understanding the barriers and how to increase engagement in care of PWID is critical to achieve HCV elimination goals

A community-based co-designed genetic health service model for Aboriginal Australians

© 2020 Elsum et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Aboriginal and Torres Strait Islander people experience a greater burden of disease and die younger than non-Indigenous Australians, with Aboriginal people living in remote areas of the Northern Territory of Australia having the lowest life expectancy estimates. Despite a high burden of chronic disease among Aboriginal and Torres Strait Islander people, access to specialist health services remains low and models of care that increase engagement, may improve health outcomes. Methods We describe client and staff perspectives of a model of clinical genetics services provided by the MJD Foundation (MJDF) in geographically and culturally complex contexts within the Northern Territory of Australia. We seek to understand the MJDF model’s success in supporting Aboriginal families with the familial, neurodegenerative condition Machado-Joseph disease and how it could be applied in the provision of other specialist services. Thematic analysis was undertaken on semi-structured interviews with primary health care staff (n = 2), Non-Aboriginal MJDF Staff (n = 7) and Aboriginal MJDF Clients / Community workers (n = 13). Results Four key themes regarding the MJDF model of service delivery were identified with the service being; 1) client led 2) accepting of various understandings of genetic disease causation 3) focused on relationships, continuity and trust between the service provider and the clients, and 4) committed to incorporating an inclusive whole-of-family practice. The MJDF model takes a community-based, person-and family-centred approach to successfully deliver effective specialist genetic health services in remote community settings. We propose that these approaches have broad application in the future design and delivery of specialist health services particularly in culturally complex settings

Quality of life among people living with HIV aged 50 years and over in Australia: Identifying opportunities to support better ageing

Objectives: Improved life expectancy has led to an ageing population of people living with HIV in most countries. Research on ageing among people living with HIV has predominantly focused on physical and health-related quality of life rather than multidimensional quality of life. We measured quality of life among older people living with HIV in Australia and identified opportunities to guide the development and implementation of appropriate interventions. Methods: In a national health and wellbeing survey of Australian people living with HIV, participants aged ≥50 years completed additional questions relevant to ageing. Quality of life was measured using PozQoL, a validated multidimensional instrument assessing quality of life among people living with HIV (range 1–5). Exploratory bivariate analyses aimed to identify sociodemographic characteristics associated with quality of life. Adjusted linear regressions aimed to assess changes in PozQoL score associated with recent experiences (last 12 months) of four exposures: food insecurity, HIV-related stigma, isolation from the HIV community, and difficulties accessing non-HIV health services. Results: Among 319 older people living with HIV, the mean PozQol score was 3.30 (95% confidence interval [CI] 3.20–3.39). In bivariate analyses, PozQol scores were significantly higher among participants who were older (p = 0.006), had higher educational attainment (p = 0.009), were in a relationship (p = 0.005), were employed (p = 0.005), and had a higher income (p = 0.001). In adjusted regression models, PozQoL scores were lower among participants who reported recent experiences of food insecurity (β −0.49; 95% CI −0.74 to −0.24), stigma (β −0.53; 95% CI −0.73 to −0.33), isolation from the HIV community (β −0.49; 95% CI −0.70 to −0.29), and difficulties accessing non-HIV health services (β −0.50; 95% CI −0.71 to −0.30). Conclusions: Overall, older people living with HIV in this study had a moderate quality of life. Our findings suggest that HIV services should integrate programmes to support economic security and foster connections within the HIV community and across health services