Prognostic significance of IGF and ECM induced signalling proteins in breast cancer patients

Breast cancer is a leading contributor to the burden of disease in Australia. Fortunately, the recent introduction of diverse therapeutic strategies have improved the survival outcome for many women. Despite this, the clinical management of breast cancer remains problematic as not all approaches are sufficiently sophisticated to take into account the heterogeneity of this disease and are unable to predict disease progression, in particular, metastasis. As such, women with good prognostic outcomes are exposed to the side effects of therapies without added benefit. Furthermore, women with aggressive disease for whom these advanced treatments would deliver benefit cannot be distinguished and opportunities for more intensive or novel treatment are lost. This study is designed to identify novel factors associated with disease progression, and the potential to inform disease prognosis. Frequently overlooked, yet common mediators of disease are the interactions that take place between the insulin-like growth factor (IGF) system and the extracellular matrix (ECM). Our laboratory has previously demonstrated that multiprotein insulin-like growth factor-I (IGF-I): insulin-like growth factor binding protein (IGFBP): vitronectin (VN) complexes stimulate migration of breast cancer cells in vitro, via the cooperative involvement of the insulin-like growth factor type I receptor (IGF-IR) and VN-binding integrins. However, the effects of IGF and ECM protein interactions on the dissemination and progression of breast cancer in vivo are unknown. It was hypothesised that interactions between proteins required for IGF induced signalling events and those within the ECM contribute to breast cancer metastasis and are prognostic and predictive indicators of patient outcome. To address this hypothesis, semiquantitative immunohistochemistry (IHC) analyses were performed to compare the extracellular and subcellular distribution of IGF and ECM induced signalling proteins between matched normal, primary cancer, and metastatic cancer among archival formalin-fixed paraffin-embedded (FFPE) breast tissue samples collected from women attending the Princess Alexandra Hospital, Brisbane. Multivariate Cox proportional hazards (PH) regression survival models in conjunction with a modified „purposeful selection of covariates. method were applied to determine the prognostic potential of these proteins. This study provides the first in-depth, compartmentalised analysis of the distribution of IGF and ECM induced signalling proteins. As protein function and protein localisation are closely correlated, these findings provide novel insights into IGF signalling and ECM protein function during breast cancer development and progression. Distinct IGF signalling and ECM protein immunoreactivity was observed in the stroma and/or in subcellular locations in normal breast, primary cancer and metastatic cancer tissues. Analysis of the presence and location of stratifin (SFN) suggested a causal relationship in ECM remodelling events during breast cancer development and progression. The results of this study have also suggested that fibronectin (FN) and ¥â1 integrin are important for the formation of invadopodia and epithelial-to-mesenchymal transition (EMT) events. Our data also highlighted the importance of the temporal and spatial distribution of IGF induced signalling proteins in breast cancer metastasis; in particular, SFN, enhancer-of-split and hairy-related protein 2 (SHARP-2), total-akt/protein kinase B 1 (Total-AKT1), phosphorylated-akt/protein kinase B (P-AKT), extracellular signal-related kinase-1 and extracellular signal-related kinase-2 (ERK1/2) and phosphorylated-extracellular signal-related kinase-1 and extracellular signal-related kinase-2 (P-ERK1/2). Multivariate survival models were created from the immunohistochemical data. These models were found to fit well with these data with very high statistical confidence. Numerous prognostic confounding effects and effect modifications were identified among elements of the ECM and IGF signalling cascade and corroborate the survival models. This finding provides further evidence for the prognostic potential of IGF and ECM induced signalling proteins. In addition, the adjusted measures of associations obtained in this study have strengthened the validity and utility of the resulting models. The findings from this study provide insights into the biological interactions that occur during the development of breast tissue and contribute to disease progression. Importantly, these multivariate survival models could provide important prognostic and predictive indicators that assist the clinical management of breast disease, namely in the early identification of cancers with a propensity to metastasise, and/or recur following adjuvant therapy. The outcomes of this study further inform the development of new therapeutics to aid patient recovery. The findings from this study have widespread clinical application in the diagnosis of disease and prognosis of disease progression, and inform the most appropriate clinical management of individuals with breast cancer

Reimbursement for the cost of compression therapy for the management of venous leg ulcers in Australia

Australia’s health system is world-class, however wound management in Australia is extremely complex and diverse, and the prevention and treatment of venous leg ulcers (VLUs), is an area where Australia particularly lags behind. Evidence-based Australian guidelines recommend compression therapy as the primary treatment for VLUs, however despite significant evidence of the health and economic benefits of compression therapy, it is not widely used in practice. Compression therapy is not subsidised through the Medicare Benefits Schedule (MBS) or Pharmaceutical Benefits Scheme (PBS) which list medicines subsidised by the Australian Government. Therefore patients must also pay high out-of-pocket costs for VLU treatments, including for products such as compression bandages. A large health economics collaboration culminated in a strong body of evidence showing that adequate reimbursement for guideline-based services and products would not only result in cost savings for patients and the health system but also improve health outcomes and quality of life for patients with VLUs in Australia. There is an urgent need to change current practice in Australia to allow the costs of compression therapy to be adequately reimbursed to both patients and health care providers by listing compression therapy in PBS for all affected individuals or creating wound-specific MBS items

Variation and Likeness in Ambient Artistic Portraiture

An artist-led exploration of portrait accuracy and likeness involved 12 Artists producing 12 portraits referencing a life-size 3D print of the same Sitter. The works were assessed during a public exhibition, and the resulting likeness assessments were compared to portrait accuracy as measured using geometric morphometrics (statistical shape analysis). Our results are that, independently of the assessors\u27 prior familiarity with the Sitter\u27s face, the likeness judgements tended to be higher for less morphologically accurate portraits. The two highest rated were the portrait that most exaggerated the Sitter\u27s distinctive features, and a portrait that was a more accurate (but not the most accurate) depiction. In keeping with research showing photograph likeness assessments involve recognition, we found familiar assessors rated the two highest ranked portraits even higher than those with some or no familiarity. In contrast, those lacking prior familiarity with the Sitter\u27s face showed greater favour for the portrait with the highest morphological accuracy, and therefore most likely engaged in face-matching with the exhibited 3D print. Furthermore, our research indicates that abstraction in portraiture may not enhance likeness, and we found that when our 12 highly diverse portraits were statistically averaged, this resulted in a portrait that is more morphologically accurate than any of the individual artworks comprising the average

Supplemental material for Variation and Likeness in Ambient Artistic Portraiture

<p>Supplemental material for Variation and Likeness in Ambient Artistic Portraiture by Susan Hayes, Nick Rheinberger, Meagan Powley, Tricia Rawnsley, Linda Brown, Malcolm Brown, Karen Butler, Ann Clarke, Stephen Crichton, Maggie Henderson, Helen McCosker, Ann Musgrave, Joyce Wilcock, Darren Williams, Karin Yeaman, T. S. Zaracostas, Adam C. Taylor and Gordon Wallace in Perception</p