Q fever prevention: Perspectives from university animal science and veterinary students and livestock farmers.

OBJECTIVE: To explore animal science and veterinary students' and livestock farmers' perceptions concerning Q fever prevention. DESIGN: An online survey with an open-ended question seeking knowledge and perceptions about Q fever prevention was distributed among participants during March-September 2019. We applied thematic analysis to identify emerging themes. SETTING: Animal science and veterinary students enrolled at the University of Adelaide and members of Livestock South Australia representing cattle, sheep and goat farmers in South Australia. PARTICIPANTS: A total of56 animal science and veterinary students and 154 livestock farmers responded to the open-ended question. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Perceived challenges and opportunities for a coordinated Q fever prevention approach including human vaccination reported by the participants. RESULTS: Two major themes arose in each group. Students and farmers viewed Q fever vaccination as important. However, excessive cost for students was a barrier and for farmers, it was general practitioners' lack of knowledge of Q fever and access to an accredited immunisation provider. Similarly, both groups highlighted the need for education and increasing public and community awareness of Q fever. CONCLUSION: Our findings underscore that a sector-wide approach involving community awareness programmes, education and training for general practitioners, and subsidised vaccination as well as commitment from government and industry partners may contribute to reducing the burden of Q fever among at-risk populations.

Documenting plans for care: advance care directives and the 7-step pathway in the acute care context.

BACKGROUND: Advance care planning involves the discussion and documentation of an individual's values and preferences to guide their future healthcare should they lose capacity to make or communicate treatment decisions. Advance care planning can involve the individual's completion of an Advance Care Directive (ACD), a legislated and common-law instrument which may include appointment of a substitute decision-maker and binding refusals of treatment. In South Australia, ACDs intersect in the acute-care context with the Resuscitation Plan 7-Step Pathway (7-SP), an integrated care plan written for and by clinicians, designed to organise and improve patients' end-of-life care through the use of structured documentation. Here, we examine the perspectives of healthcare professionals (HCPs) within a hospital setting on the practical integration of ACDs and the 7-SP, exploring the perceived role, function, and value of each as they intersect to guide end-of-life care in an Australian hospital setting. METHODS: Qualitative data were collected via eight focus groups with a total of 74 HCPs (acute care, and oncology specialists; medical intern; general and emergency nurses; social workers) across two hospitals. Audio recordings were transcribed and thematically analysed. RESULTS: HCPs viewed ACDs as a potentially valuable means of promoting patient autonomy, but as rarely completed and poorly integrated into hospital systems. Conversely, the process and documentation of the 7-SP was perceived as providing clarity about clinicians' responsibilities, and as a well-understood, integrated resource. Participants sometimes exhibited uncertainty around which document takes precedence if both were present. Sometimes, the routinisation of the 7-SP meant it was understood as the 'only way' to determine patient wishes and provide optimal end-of-life care. When this occurs, the perceived authority of ACDs, or of patients' choice not to participate in end-of-life discussions, may be undermined. CONCLUSIONS: The intersection of ACDs and the 7-SP appears problematic within acute care. Clinicians' uncertainty as to whether an ACD or 7-SP takes precedence, and when it should do so, suggests a need for further clarity and training on the roles of these documents in guiding clinical practice, the legislative context within which specific documentation is embedded, and the dynamics associated with collaborative decision-making in end-of-life care.

A scoping review of Aboriginal and Torres Strait Islander health promotion programs focused on modifying chronic disease risk factors.

ISSUE ADDRESSED: Noncommunicable chronic disease underlies much of the life expectancy gap experienced by Aboriginal and Torres Strait Islander people. Modifying contributing risk factors; tobacco smoking, nutrition, alcohol consumption, physical activity, social and emotional wellbeing (SNAPS) could help close this disease gap. This scoping review identified and describes SNAPS health promotion programs implemented for Aboriginal and Torres Strait Islander people in Australia. METHODS: Databases PubMed, CINAHL, Informit (Health Collection and Indigenous Peoples Collection), Scopus, Trove and relevant websites and clearing houses were searched for eligible studies until June 2015. To meet the inclusion criteria the program had to focus on modifying one of the SNAPS risk factors and the majority of participants had to identify as being of Aboriginal and/or Torres Strait Islander heritage. RESULTS: The review identified 71 health promotion programs, described in 83 publications. Programs were implemented across a range of health and community settings and included all Australian states and territories, from major cities to remote communities. The SNAPS factor addressed most commonly was nutrition. Some programs included the whole community, or had multiple key audiences, whilst others focused solely on one subgroup of the population such as chronic disease patients, pregnant women or youth. Fourteen of the programs reported no outcome assessments. CONCLUSIONS: Health promotion programs for Aboriginal and Torres Strait Islander people have not been adequately evaluated. The majority of programs focused on the development of individual skills and changing personal behaviours without addressing the other health promotion action areas, such as creating supportive environments or reorienting health care services. SO WHAT?: This scoping review provides a summary of the health promotion programs that have been delivered in Australia for Aboriginal and Torres Strait Islander people to prevent or manage chronic disease. These programs, although many are limited in quality, should be used to inform future programs. To improve evidence-based health promotion practice, health promotion initiatives need to be evaluated and the findings published publicly.

Intersectoral collaboration to implement school-based health programmes: Australian perspectives.

Understanding the processes and the factors influencing intersectoral collaboration is vital for the ongoing success of programmes that rely on effective partnerships between sectors, such as the school-based immunization programme, the school dental health programme and health promotion interventions delivered in school settings. We studied school-based health programmes delivered by partnerships between health, education and the local government sectors. We used purposive sampling to identify 19 people working in school-based health programmes and interviewed them about the barriers and enablers of successful collaboration. Data were analysed thematically. We found that collaboration between complex systems was a skilled endeavour which relied on a strong foundation of communication and interpersonal professional relationships. Understanding the core business, operational context and intersectoral point-of-view of collaborative partners was important both for establishing good intersectoral programmes and sustaining them as contexts and personnel changed. Aligning divergent sectoral agendas early in the collaborative process was essential for ensuring that all partners could meet their core business needs while also delivering the programme outcomes.

Improving management of student clinical placements: insights from activity theory.

BACKGROUND: An approach to improve management of student clinical placements, the Building Teams for Quality Learning project, was trialed in three different health services. In a previous paper the authors explored in some detail the factors associated with considerable success of this approach at one of these services. In this paper, the authors extend this work with further analysis to determine if the more limited outcomes observed with participants at the other two services could be explained by application of activity theory and in particular the expansive learning cycle. METHODS: Staff at three health services participated in the Building Teams for Quality Learning project: a dental clinic, a community aged care facility and a rural hospital. At each site a team of seven multi-disciplinary staff completed the project over 9 to 12 months (total 21 participants). Evaluation data were collected through interviews, focus groups and direct observation of staff and students. Following initial thematic analysis, further analysis was conducted to compare the processes and outcomes at each participating health service drawing on activity theory and the expansive learning cycle. RESULTS: Fifty-one interview transcripts, 33 h of workplace observation and 31 sets of workshop field notes (from 36 h of workshops) were generated. All participants were individually supportive of, and committed to, high quality student learning experiences. As was observed with staff at the dental clinic, a number of potentially effective strategies were discussed at the aged care facility and the rural hospital workshops. However, participants in these two health services could not develop a successful implementation plan. The expansive learning cycle element of modeling and testing new solutions was not achieved and participants were unable, collectively to reassess and reinterpret the object of their activities. CONCLUSION: The application of activity theory and the expansive learning cycle assisted a deeper understanding of the differences in outcomes observed across the three groups of participants. This included identifying specific points in the expansive learning cycle at which the three groups diverged. These findings support some practical recommendations for health services that host student clinical placements.

Ethical Challenges in School-Based Immunization Programs for Adolescents: A Qualitative Study.

OBJECTIVES: We investigated ethical issues in school-based immunization programs for adolescents and how they are addressed. METHODS: We used qualitative methods and an ethnographic approach to observe 9 secondary schools on immunization days in South Australia in 2011; concurrently, we conducted 9 focus groups with female secondary school students, 6 semistructured interviews with parents, and 10 interviews with nurses and teachers. We explored ethical challenges from the perspective of these groups. RESULTS: We identified ethical challenges for the delivery of adolescent immunization in a school-based setting in 3 main areas: informed consent, restrictions on privacy, and harm to students in the form of fear and anxiety. CONCLUSIONS: We found areas in which the design and delivery of school-based immunization programs can be improved. Information about immunization should be provided in ways that are appropriate to young people and their parents, and privacy protections should be enhanced when possible. Involving young people in the design and delivery of programs would assist with making these improvements.

Rethinking attitudes to student clinical supervision and patient care: a change management success story.

BACKGROUND: The aim of this project was to explore the process of change in a busy community dental clinic following a team development intervention designed to improve the management of student supervision during clinical placements. METHODS: An action research model was used. Seven members of a community dental clinic team (three dentists, two dental therapists, one dental assistant and the clinic manager), together with the university clinical placement supervisor participated in the team development intervention. The intervention consisted of two profiling activities and associated workshops spread six months apart. These activities focused on individual work preferences and overall team performance with the aim of improving the functioning of the clinic as a learning environment for dental students. Evaluation data consisted of 20 participant interviews, fourteen hours of workplace observation and six sets of field notes. Following initial thematic analysis, project outcomes were re-analysed using activity theory and expansive learning as a theoretical framework. RESULTS: At project commencement students were not well integrated into the day-to-day clinic functioning. Staff expressed a general view that greater attention to student supervision would compromise patient care. Following the intervention greater clinical team cohesion and workflow changes delivered efficiencies in practice, enhanced relationships among team members, and more positive attitudes towards students. The physical layout of the clinic and clinical workloads were changed to achieve greater involvement of all team members in supporting student learning. Unexpectedly, these changes also improved clinic functioning and increased the number of student placements available. CONCLUSIONS: In navigating the sequential stages of the expansive learning cycle, the clinical team ultimately redefined the 'object' of their activity and crossed previously impervious boundaries between healthcare delivery and student supervision with benefits to all parties.

Best-practice care for people with advanced chronic obstructive pulmonary disease: the potential role of a chronic obstructive pulmonary disease care co-ordinator.

OBJECTIVE: To explore service availability and accessibility for people with advanced chronic obstructive pulmonary disease (COPD) and their carers and strategies for improvement, including the potential role of a COPD care co-ordinator in ensuring best-practice care in the Australian context. METHODS: This qualitative study used focus groups and interviews with health professionals, carers and consumers to explore gaps and restrictions in services, barriers to access and the functioning of services. Data were analysed deductively. RESULTS: Key themes arising from the data included difficulties around access to care, lack of continuity of care, poor care co-ordination, the need for active disease management as well as supportive care, and poor communication. A COPD care co-ordinator was suggested as an effective strategy for ensuring best-practice care. CONCLUSIONS: People with advanced COPD often have difficulty navigating the acute, primary and community care systems to deal with the multiple services that they may require. Lack of communication between health professionals and services is frequently a significant issue. A COPD care co-ordinator, encompassing advanced nursing skills, could ensure that care is centred on the needs of the person and their carer and that they receive continuing, appropriate and accessible care as they approach the end of their life.

Rilotumumab Resistance Acquired by Intracrine Hepatocyte Growth Factor Signaling.

Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for molecularly-targeted therapeutics that otherwise have shown unprecedented successes in disease control. The hepatocyte growth factor (HGF)/Met receptor pathway signaling is frequently involved in cancer and has been a subject of targeted drug development for nearly 30 years. To anticipate and study specific resistance mechanisms associated with targeting this pathway, we engineered resistance to the HGF-neutralizing antibody rilotumumab in glioblastoma cells harboring autocrine HGF/Met signaling, a frequent abnormality of this brain cancer in humans. We found that rilotumumab resistance was acquired through an unusual mechanism comprising dramatic HGF overproduction and misfolding, endoplasmic reticulum (ER) stress-response signaling and redirected vesicular trafficking that effectively sequestered rilotumumab and misfolded HGF from native HGF and activated Met. Amplification of MET and HGF genes, with evidence of rapidly acquired intron-less, reverse-transcribed copies in DNA, was also observed. These changes enabled persistent Met pathway activation and improved cell survival under stress conditions. Point mutations in the HGF pathway or other complementary or downstream growth regulatory cascades that are frequently associated with targeted drug resistance in other prevalent cancer types were not observed. Although resistant cells were significantly more malignant, they retained sensitivity to Met kinase inhibition and acquired sensitivity to inhibition of ER stress signaling and cholesterol biosynthesis. Defining this mechanism reveals details of a rapidly acquired yet highly-orchestrated multisystem route of resistance to a selective molecularly-targeted agent and suggests strategies for early detection and effective intervention.

Twelve tips for supporting student learning in multidisciplinary clinical placements.

Healthcare profession students participate in a range of clinical placements within multidisciplinary health care settings. Often these placements offer students opportunities to participate in activities with staff and/or students from other healthcare disciplines. Although health service staff generally recognise the importance of clinical placements for student learning, they sometimes feel overwhelmed by workload and resource constraints. As a consequence, the potential of the clinical team to contribute to student learning may not be fully realised. A key element of successful clinical placement programs across all healthcare disciplines is a coordinated approach to the development and management of complex university/health service partnerships. Explicit mechanisms to support clinical team members in their teaching roles can also contribute to develop and sustain staff capacity for student supervision, as appropriate recognition of clinical staff contributes to student learning. Twelve tips are offered for consideration by universities, health services and clinical staff when planning and implementing student clinical placements in multidisciplinary healthcare settings.

The experience of patients with advanced chronic obstructive pulmonary disease and advance care-planning: A South Australian perspective.

Advance care-planning conversations with people who have chronic obstructive pulmonary disease (COPD) are important because of the severity of the disease and the unpredictable timing of death. Advance care-planning is a process involving conversations about future wishes, including end-of-life care and the appointment of a substitute decision-maker. This qualitative research explored issues relating to end-of-life decisions with 15 individuals and their carers living in the community who had severe COPD. Findings indicated that, although patients and carers would welcome the opportunity to discuss end-of-life decisions, almost no conversation about care-planning had been initiated by health professionals with any of the participants. It also demonstrated that professional support is required to assist with advance care-planning and the completion of the legal advance directive documents.

Older Adults' Perspectives of Smart Technologies to Support Aging at Home: Insights from Five World Café Forums.

Globally, there is an urgent need for solutions that can support our aging populations to live well and reduce the associated economic, social and health burdens. Implementing smart technologies within homes and communities may assist people to live well and 'age in place'. To date, there has been little consultation with older Australians addressing either the perceived benefits, or the potential social and ethical challenges associated with smart technology use. To address this, we conducted five World Cafés in two Australian states, aiming to capture citizen knowledge about the possibilities and challenges of smart technologies. The participants (n = 84) were aged 55 years and over, English-speaking, and living independently. Grounding our analysis in values-based social science and biomedical ethical principles, we identified the themes reflecting the participants' understanding, resistance, and acceptance of smart technologies, and the ethical principles, including beneficence, non-maleficence, autonomy, privacy, confidentiality, and justice. Similar to other studies, many of the participants demonstrated cautious and conditional acceptance of smart technologies, while identifying concerns about social isolation, breaches of privacy and confidentiality, surveillance, and stigmatization. Attention to understanding and incorporating the values of older citizens will be important for the acceptance and effectiveness of smart technologies for supporting independent and full lives for older citizens.

Radiosensitization of glioma cells by modulation of Met signalling with the hepatocyte growth factor neutralizing antibody, AMG102.

The hepatocyte growth factor (HGF)/Met signalling pathway is up-regulated in many cancers, with downstream mediators playing a role in DNA double strand break repair. Previous studies have shown increased radiosensitization of tumours through modulation of Met signalling by genetic methods. We investigated the effects of the anti-HGF monoclonal antibody, AMG102, on the response to ionizing radiation in a model of glioblastoma multiforme in vitro and in vivo. Radiosensitivity was evaluated in vitro in the U-87 MG human glioma cell line. Met activation was measured by Western blot, and the effect on survival following radiation was evaluated by clonogenic assay. Mechanism of cell death was evaluated by apoptosis and mitotic catastrophe assays. DNA damage was quantitated by γH2AX foci and neutral comet assay. Growth kinetics of subcutaneous tumours was used to assess the effects of AMG102 on in vivo tumour radiosensitivity. AMG102 inhibited Met activation after irradiation. An enhancement of radiation cell killing was shown with no toxicity using drug alone. Retention of γH2AX foci at 6 and 24 hrs following the drug/radiation combination indicated an inhibition of DNA repair following radiation, and comet assay confirmed DNA damage persisting over the same duration. At 48 and 72 hrs following radiation, a significant increase of cells undergoing mitotic catastrophe was seen in the drug/radiation treated cells. Growth of subcutaneous tumours was slowed in combination treated mice, with an effect that was greater than additive for each modality individually. Modulation of Met signalling with AMG102 may prove a novel radiation sensitizing strategy. Our data indicate that DNA repair processes downstream of Met are impaired leading to increased cell death through mitotic catastrophe.

Molecular imaging of c-Met tyrosine kinase activity.

The receptor tyrosine kinase c-Met and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), modulate signaling cascades implicated in cellular proliferation, survival, migration, invasion, and angiogenesis. Therefore, dysregulation of HGF/c-Met signaling can compromise the cellular capacity to moderate these activities and can lead to tumorigenesis, metastasis, and therapeutic resistance in various human malignancies. To facilitate studies investigating HGF/c-Met receptor coupling or c-Met signaling events in real time and in living cells and animals, here we describe a genetically engineered reporter where bioluminescence can be used as a surrogate for c-Met tyrosine kinase activity. c-Met kinase activity in cultured cells and tumor xenografts was monitored quantitatively and dynamically in response to the activation or inhibition of the HGF/c-Met signaling pathway. Treatment of tumor-bearing animals with a c-Met inhibitor and the HGF neutralizing antibody stimulated the reporter's bioluminescence activity in a dose-dependent manner and led to a regression of U-87 MG tumor xenografts. Results obtained from these studies provide unique insights into the pharmacokinetics and pharmacodynamics of agents that modulate c-Met activity and validate c-Met as a target for human glioblastoma therapy.

A homogeneous SIRPα-CD47 cell-based, ligand-binding assay: Utility for small molecule drug development in immuno-oncology.

CD47 is an immune checkpoint protein that downregulates both the innate and adaptive anti-tumor immune response via its counter receptor SIRPα. Biologics, including humanized CD47 monoclonal antibodies and decoy SIRPα receptors, that block the SIRPα-CD47 interaction, are currently being developed as cancer immunotherapy agents. However, adverse side effects and limited penetration of tumor tissue associated with their structure and large size may impede their clinical application. We recently developed a quantitative high throughput screening assay platform to identify small molecules that disrupt the binding of SIRPα and CD47 as an alternative approach to these protein-based therapeutics. Here, we report on the development and optimization of a cell-based binding assay to validate active small molecules from our biochemical screening effort. This assay has a low volume, high capacity homogenous format that relies on laser scanning cytometry (LSC) and associated techniques to enhance signal to noise measurement of cell surface binding. The LSC assay is specific, concentration dependent, and validated for the two major human SIRPα variants (V1 and V2), with results that parallel those of our biochemical data as well as published studies. We also utilized the LSC assay to confirm published studies showing that the inhibition of amino-terminal pyroglutamate formation on CD47 using the glutaminyl cyclase inhibitor SEN177 disrupts SIRPα binding. The SIRPα-CD47 interaction could be quantitatively measured in live and fixed tumor cells. Use of fixed cells reduces the burden of cell maintenance and provides stable cell standards to control for inter- and intra-assay variations. We also demonstrate the utility of the assay to characterize the activity of the first reported small molecule antagonists of the SIRPα-CD47 interaction. This assay will support the screening of thousands of compounds to identify or validate active small molecules as hits, develop structure activity relationships and assist in the optimization of hits to leads by a typical iterative medicinal chemistry campaign.

Quantitative high-throughput screening assays for the discovery and development of SIRPα-CD47 interaction inhibitors.

CD47 is an immune checkpoint molecule that downregulates key aspects of both the innate and adaptive anti-tumor immune response via its counter receptor SIRPα, and it is expressed at high levels in a wide variety of tumor types. This has led to the development of biologics that inhibit SIRPα engagement including humanized CD47 antibodies and a soluble SIRPα decoy receptor that are currently undergoing clinical trials. Unfortunately, toxicological issues, including anemia related to on-target mechanisms, are barriers to their clinical advancement. Another potential issue with large biologics that bind CD47 is perturbation of CD47 signaling through its high-affinity interaction with the matricellular protein thrombospondin-1 (TSP1). One approach to avoid these shortcomings is to identify and develop small molecule molecular probes and pretherapeutic agents that would (1) selectively target SIRPα or TSP1 interactions with CD47, (2) provide a route to optimize pharmacokinetics, reduce on-target toxicity and maximize tissue penetration, and (3) allow more flexible routes of administration. As the first step toward this goal, we report the development of an automated quantitative high-throughput screening (qHTS) assay platform capable of screening large diverse drug-like chemical libraries to discover novel small molecules that inhibit CD47-SIRPα interaction. Using time-resolved Förster resonance energy transfer (TR-FRET) and bead-based luminescent oxygen channeling assay formats (AlphaScreen), we developed biochemical assays, optimized their performance, and individually tested them in small-molecule library screening. Based on performance and low false positive rate, the LANCE TR-FRET assay was employed in a ~90,000 compound library qHTS, while the AlphaScreen oxygen channeling assay served as a cross-validation orthogonal assay for follow-up characterization. With this multi-assay strategy, we successfully eliminated compounds that interfered with the assays and identified five compounds that inhibit the CD47-SIRPα interaction; these compounds will be further characterized and later disclosed. Importantly, our results validate the large library qHTS for antagonists of CD47-SIRPα interaction and suggest broad applicability of this approach to screen chemical libraries for other protein-protein interaction modulators.

AMG 102, a fully human anti-hepatocyte growth factor/scatter factor neutralizing antibody, enhances the efficacy of temozolomide or docetaxel in U-87 MG cells and xenografts.

PURPOSE: Hepatocyte growth factor (HGF/SF) and its receptor c-Met have previously been shown to be up-regulated in multiple human cancers, including glioblastoma multiforme. To better understand if AMG 102, a fully human, anti-HGF/SF-neutralizing antibody, could be incorporated into current clinical practice, AMG 102 was tested preclinically in combination with temozolomide or docetaxel to determine if enhanced efficacy was observed compared with AMG 102 alone. EXPERIMENTAL DESIGN: The effects of AMG 102 were tested for antiproliferative activity in combination with temozolomide or docetaxel on U-87 MG cells in vitro and for antitumor activity in a U-87 MG xenograft model in vivo. Apoptotic activity was also measured for AMG 102 and docetaxel combined in vitro. RESULTS: Treatment with temozolomide combined with AMG 102 resulted in increased inhibition of cell growth in vitro compared with treatment with either single agent alone. In U-87 MG xenografts in vivo, AMG 102 combined with temozolomide or docetaxel significantly increased the inhibitory effect on tumor growth when compared with treatment with either agent alone (P < 0.0001 and P < 0.015, respectively). In vitro, docetaxel alone induced both caspase-3/7 activity as well as poly(ADP)ribose polymerase and caspase-7 cleavage in U-87 MG cells; these events were enhanced when used in combination with AMG 102. Importantly, there was no evidence of interference between AMG 102 and either temozolomide or docetaxel in vitro or in vivo. CONCLUSION: These studies support testing of AMG 102 in combination with temozolomide or docetaxel. Such combinations may represent promising, novel clinical therapeutic strategies for cancers that are dependent on the HGF/SF/SF:c-Met pathway in the oncology setting.

I don't think general practice should be the front line: Experiences of general practitioners working with refugees in South Australia.

INTRODUCTION: Many refugees arrive in Australia with complex health needs. In South Australia (SA), providing initial health care to refugees is the responsibility of General Practitioners (GPs) in private practice. Their capacity to perform this work effectively for current newly arrived refugees is uncertain. The aim of this study was to document the challenges faced by GPs in private practice in SA when providing initial care to refugees and to discuss the implications of this for policy relating to optimising health care services for refugees. METHODS: Semi-structured interviews with twelve GPs in private practice and three Medical Directors of Divisions of General Practice. Using a template analysis approach the interviews were coded and analysed thematically. RESULTS: Multiple challenges providing care to refugees were found including those related to: (1) refugee health issues; (2) the GP-refugee interaction; and (3) the structure of general practice. The Divisions also reported challenges assisting GPs to provide effective care related to a lack of funding and awareness of which GPs required support. Although respondents suggested a number of ways that GPs could be assisted to provide better initial care to refugees, strong support was voiced for the initial care of refugees to be provided via a specialist refugee health service. CONCLUSION: GPs in this study were under-resourced, at both an individual GP level as well as a structural level, to provide effective initial care for refugees. In SA, there are likely to be a number of challenges attempting to increase the capacity of GPs in private practice to provide initial care. An alternative model is for refugees with multiple and complex health care needs as well as those with significant resettlement challenges to receive initial health care via the existing specialist refugee health service in Adelaide.

Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors.

c-Met is a well-characterized receptor tyrosine kinase for hepatocyte growth factor (HGF). Compelling evidence from studies in human tumors and both cellular and animal tumor models indicates that signaling through the HGF/c-Met pathway mediates a plethora of normal cellular activities, including proliferation, survival, migration, and invasion, that are at the root of cancer cell dysregulation, tumorigenesis, and tumor metastasis. Inhibiting HGF-mediated signaling may provide a novel therapeutic approach for treating patients with a broad spectrum of human tumors. Toward this goal, we generated and characterized five different fully human monoclonal antibodies that bound to and neutralized human HGF. Antibodies with subnanomolar affinities for HGF blocked binding of human HGF to c-Met and inhibited HGF-mediated c-Met phosphorylation, cell proliferation, survival, and invasion. Using a series of human-mouse chimeric HGF proteins, we showed that the neutralizing antibodies bind to a unique epitope in the beta-chain of human HGF. Importantly, these antibodies inhibited HGF-dependent autocrine-driven tumor growth and caused significant regression of established U-87 MG tumor xenografts. Treatment with anti-HGF antibody rapidly inhibited tumor cell proliferation and significantly increased the proportion of apoptotic U-87 MG tumor cells in vivo. These results suggest that an antibody to an epitope in the beta-chain of HGF has potential as a novel therapeutic agent for treating patients with HGF-dependent tumors.