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.

Benefits and challenges of using restorative justice approaches for victims of crime committed by adults: An exploration of theory and evidence

Book Abstract: Current experimentations with approaches to restorative justice for adult offenders represents a compelling new direction in the criminal justice system. This book examines the values and challenges of restorative justice for adult offenders, victims and communities. The discussion is situated within current debate, available research, and the international literature. In canvassing the structure, content, and delivery of key Australian and New Zealand restorative justice programs for adult offenders, the distinguished authors offer critical analysis of the emergence and impact of program developements for practitioners and professionals. This collection brings together stimulating and informed articles by experienced practitioners, leading academics and new researchers in the field. It also offers valuable insights into emerging restorative justice practice for adult offenders and provides a real alternative to the adversarial justice system.

Paramedic empathy levels : results from seven Australian universities

Purpose Evidence suggests that improved empathy behaviours among healthcare professionals directly impacts on healthcare outcomes. However, the ‘nebulous’ properties of empathic behaviour often means that healthcare profession educators fail to incorporate the explicit teaching and assessment of empathy within the curriculum. This represents a potential mismatch between what is taught by universities and what is actually needed in the healthcare industry. The objective of this study was to assess the extent of empathy in paramedic students across seven Australian universities. Methods A cross-sectional study using a paper-based questionnaire employing a convenience sample of first, second, and third year undergraduate paramedic students. Student empathy levels were measured using a standardised self-reporting instrument: Jefferson Scale of Physician Empathy – Health Profession Students (JSPE-HPS). Findings A total of 783 students participated in the study of which 57% were females. The overall JSPE-HPS mean score was 106.74 (SD=14.8). Females had greater mean empathy scores than males 108.69 v 103.58 (p=0.042). First year undergraduate paramedic mean empathy levels were the lowest, 106.29 (SD=15.40) with second years the highest at 107.17 (SD=14.90). Value The overall findings provide a framework for educators to begin constructing guidelines focusing on the need to incorporate, promote and instil empathy into paramedic students in order to better prepare them for future out-of-hospital healthcare practice.

Quantitative studies of lower motor neuron degeneration in amyotrophic lateral sclerosis : Evidence for exponential decay of motor unit numbers and greatest rate of loss at the site of onset

Objective: To use our Bayesian method of motor unit number estimation (MUNE) to evaluate lower motor neuron degeneration in ALS. Methods: In subjects with ALS we performed serial MUNE studies. We examined the repeatability of the test and then determined whether the loss of MUs was fitted by an exponential or Weibull distribution. Results: The decline in motor unit (MU) numbers was well-fitted by an exponential decay curve. We calculated the half life of MUs in the abductor digiti minimi (ADM), abductor pollicis brevis (APB) and/or extensor digitorum brevis (EDB) muscles. The mean half life of the MUs of ADM muscle was greater than those of the APB or EDB muscles. The half-life of MUs was less in the ADM muscle of subjects with upper limb than in those with lower limb onset. Conclusions: The rate of loss of lower motor neurons in ALS is exponential, the motor units of the APB decay more quickly than those of the ADM muscle and the rate of loss of motor units is greater at the site of onset of disease. Significance: This shows that the Bayesian MUNE method is useful in following the course and exploring the clinical features of ALS. 2012 International Federation of Clinical Neurophysiology.

An Assessment of Undergraduate Paramedic Students’ Empathy Levels

Abstract: Objectives Evidence suggests that improved empathy behaviours among healthcare professionals directly impacts on healthcare outcomes. However, the ‘nebulous’ properties of empathic behaviour often means that healthcare profession educators fail to incorporate the explicit teaching and assessment of empathy within the curriculum. The objective of this study was to assess the extent of empathy in paramedic students across seven Australian universities. Methods A cross-sectional study using a paper-based questionnaire employing a convenience sample of first, second, and third year undergraduate paramedic students. Student empathy levels were measured using the Medical Condition Regard Scale (MCRS). Results A total of 783 students participated in the study of which 57% were females. The medical conditions: intellectual disability, attempted suicide, and acute mental illness all produced mean scores above 50 suggesting good empathetic regard, while patients presenting with substance abuse produced the lowest mean score M= 41.57 (SD=12.29). There was a statistically significant difference between males (M= 49.79) and females (M=51.61) p=0.006, for patients with intellectual disability. Conclusions The findings from this study found that student reported poor empathetic regard for patients with substance abuse, while female students report higher levels of empathy than their male colleagues across each medical condition. The overall findings provide a framework for educators to begin constructing guidelines focusing on the need to incorporate, promote and instil empathy into paramedic students in order to better prepare them for future out-of-hospital healthcare practice.

An update and extension of the Canadian evidence on gender wage differentials

The paper utilizes the 1989 Labour Market Activity Survey to examine the gender wage differential in Canada. The aim is to update previous studies and extend earlier analysis in two significant ways. First, occupation is treated as endogenously determined. Secondly,the Zabalza and Arrufat(1985) imputation method is utilized to estimate the level of female labour market experience. The results suggest that the level of estimated gender discrimination is sensitive to the measure of labour market experience. The paper also concludes that intra-occupation wage effects explain most of gender wage gap.

The moderating role of learning on competitive advantage : longitudinal evidence from young firms

The question of how young firms reconcile the absence of well-established learning routines arising from the “liabilities of newness” with the “learning advantages of newness” has received scant attention in entrepreneurship. While older firms follow established learning routines and sometimes face problems in overcoming inertia, young firms with lower levels of inertia are better poised to explore, search and test unique avenues for their products and services. The process of learning and capability development as well as establishing uniqueness in their product offerings is an important part not only in the early stages of firm growth, but also in firm survival. Given their inexperience, for young firms, these learning processes are iterative and include contrasting learning loops that sometimes progress and at other times digress from initially perceived unique ideas. Such processes are embedded within capabilities that the firm develops and nurtures. Based on this premise and adopting a capabilities-based view, we examine how strategic networks and environmental knowledge affects uniqueness- mediated performance in young firms. We identify firms with digressive learning strategies based on their self-assessment of learning and compare them with other firms to demonstrate a differential effect on performance.

Polyandry and paternity skew in natural and experimental populations of Drosophila serrata

Many species engage in polyandry, resulting in the potential for sexual selection to continue post-copulation through sperm competition and/or cryptic female choice. The relative importance of pre- vs. post-copulatory processes remains unknown for most species despite this information being fundamental for understanding the evolutionary consequences of sexual selection. The Australian fruit fly Drosophila serrata has become a prominent model system for studying precopulatory sexual selection, such as mating preferences and their influence on the evolution of sexually selected traits. Here, we investigated polyandry and the potential for post-copulatory sexual selection in this species using indirect paternity analysis. We genotyped 21 wild-caught and 19 laboratory-reared mothers and their offspring (a total of 787 flies) at six microsatellite loci and found extensive polyandry, with all broods surveyed having at least two sires. Female remating rates were higher than in other Drosophila surveyed to date and no significant differences were found between laboratory and field populations. Additionally, we found evidence for biased sperm usage in several broods of D. serrata. Paternity skew occurred more frequently in broods from the field population than the laboratory one, suggesting differences between the two environments in the level of post-copulatory sexual selection. Our data suggest that D. serrata represents a promising system for studying the interaction between pre- and post-copulatory sexual selection in driving the evolution of sexually selected phenotypes.

Driver sleepiness self-regulation : physiological and subjective evidence

Introduction: Sleepiness contributes to a substantial proportion of fatal and severe road crashes. Efforts to reduce the incidence of sleep-related crashes have largely focussed on driver education to promote self-regulation of driving behaviour. However, effective self-regulation requires accurate self-perception of sleepiness. The aim of this study was to assess capacity to accurately identify sleepiness, and self-regulate driving cessation, during a validated driving simulator task. Methods: Participants comprised 26 young adult drivers (20-28 years) who had open licenses. No other exclusion criteria where used. Participants were partially sleep deprived (05:00 wake up) and completed a laboratory-based hazard perception driving simulation, counterbalanced to either at mid-morning or mid-afternoon. Established physiological measures (i.e., EEG, EOG) and subjective measures (Karolinska Sleepiness Scale), previously found sensitive to changes in sleepiness levels, were utilised. Participants were instructed to ‘drive’ on the simulator until they believed that sleepiness had impaired their ability to drive safely. They were then offered a nap opportunity. Results: The mean duration of the drive before cessation was 36.1 minutes (±17.7 minutes). Subjective sleepiness increased significantly from the beginning (KSS=6.6±0.7) to the end (KSS=8.2±0.5) of the driving period. No significant differences were found for EEG spectral power measures of sleepiness (i.e., theta or alpha spectral power) from the start of the driving task to the point of cessation of driving. During the nap opportunity, 88% of the participants (23/26) were able to reach sleep onset with an average latency of 9.9 minutes (±7.5 minutes). The average nap duration was 15.1 minutes (±8.1 minutes). Sleep architecture during the nap was predominately comprised of Stages I and II (combined 92%). Discussion: Participants reported high levels of sleepiness during daytime driving after very moderate sleep restriction. They were able to report increasing sleepiness during the test period despite no observed change in standard physiological indices of sleepiness. This increased subjective sleepiness had behavioural validity as the participants had high ‘napability’ at the point of driving cessation, with most achieving some degree of subsequent sleep. This study suggests that the nature of a safety instruction (i.e. how to view sleepiness) can be a determinant of driver behaviour.

National Institute for Clinical Studies Report for Phase 1, Evidence Uptake Network : Best Practice Community Care for Clients with Chronic Venous Leg Ulcers

Chronic leg ulcers cause significant pain, cost, decreased quality of life and morbidity for a considerable segment of the older population (Graham et al., 2003a). At any given time the prevalence of patients with open leg ulcers receiving treatment is between 0.11% - 0.18% (Briggs & Closs 2003). Chronic leg ulcers occur in approximately 1 - 2% of the over 60 population in the US, UK, Europe and Australia (Baker & Stacey 1994; Johnson 1995; Lees & Lambert 1992; Margolis et al. 2002). Considerable research has been undertaken to determine the best treatment practices that will aid in the management and the healing of these ulcers, and practical and effective strategies and techniques for healing venous leg ulcers have been trialled to demonstrate their beneficial effects (Nelson et al. 2004; Cullum et al. 2001)...

Sustainable urban infrastructure development in South East Asia : evidence from Hong Kong, Kuala Lumpur and Singapore

Many South East Asian cities have experienced substantial physical, economic and social transformations during the past several decades. The rapid pace of globalization and economic restructuring has resulted in these cities receiving the full impact of urbanization pressures. In an attempt to ease these pressures, cities such as Singapore, Hong Kong and Kuala Lumpur have advocated growth management approaches focusing especially on urban infrastructure sustainability. These approaches aim to achieve triple bottom line sustainability by balancing economic and social development, and environmental protection. This chapter evaluates three Asia-Pacific city cases, Singapore, Hong Kong and Kuala Lumpur, and assesses their experiences in managing their urban forms and infrastructure whilst promoting sustainable patterns of urban development.

Aromatherapy for treatment of postoperative nausea and vomiting

Background: Postoperative nausea and vomiting is a common and unpleasant phenomenon and current therapies are not always effective for all patients. Aromatherapy has been suggested as a possible addition to the available treatment strategies. Objectives: This review sought to establish what effect the use of aromatherapy has on the severity and duration of established postoperative nausea and vomiting and whether aromatherapy can be used with safety and clinical effectiveness comparable to standard pharmacological treatments. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3); MEDLINE; EMBASE; CINAHL; CAM on PubMed; Meditext; LILACS database; and ISI Web of Science as well as grey literature sources and the reference lists of retrieved articles. We conducted database searches up to August 2011. Selection criteria: We included all randomized controlled trials (RCTs) and controlled clinical trials (CCTs) where aromatherapy was used to treat postoperative nausea and vomiting. Interventions were all types of aromatherapy. Aromatherapy was defined as the inhalation of the vapours of any substance for the purposes of a therapeutic benefit. Primary outcomes were the severity and duration of postoperative nausea and vomiting. Secondary outcomes were adverse reactions, use of rescue anti-emetics and patient satisfaction with treatment. Data collection and analysis: Two review authors assessed risk of bias in the included studies and extracted data. As all outcomes analysed were dichotomous, we used a fixed-effects model and calculated relative risk (RR) with associated 95% confidence interval (95% CI). Results: The nine included studies comprised six RCTs and three CCTs with a total of 402 participants. The mean age and range data for all participants were not reported for all studies. The method of randomization in four of the six included RCTs was explicitly stated and adequate. Incomplete reporting of data affected the completeness of the analysis. Compared with placebo, isopropyl alcohol vapour inhalation was effective in reducing the proportion of participants requiring rescue anti-emetics (RR 0.30, 95%CI 0.09 to 1.00, P = 0.05). However, compared with standard anti-emetic treatment, isopropyl alcohol was not effective in reducing the proportion of participants requiring rescue anti-emetics (RR 0.66 95%CI 0.39 to 1.13, P = 0.13) except when the data from a possibly confounded study were included (RR 0.66, 95% CI 0.45 to 0.98, P = 0.04). Where studies reported data on patient satisfaction with aromatherapy, there were no statistically significant differences between the groups (RR 1.12, 95%CI 0.62 to 2.03, P = 0.71). Authors' conclusions: Isopropyl alcohol was more effective than saline placebo for reducing postoperative nausea and vomiting but less effective than standard anti-emetic drugs. There is currently no reliable evidence for the use of peppermint oil.

Revision total hip replacement using the cement-in-cement technique for the acetabular component : technique and results for 60 hips

The technique of femoral cement-in-cement revision is well established, but there are no previous series reporting its use on the acetabular side at the time of revision total hip arthroplasty. We describe the surgical technique and report the outcome of 60 consecutive cement-in-cement revisions of the acetabular component at a mean follow-up of 8.5 years (range 5-12 years). All had a radiologically and clinically well fixed acetabular cement mantle at the time of revision. 29 patients died. No case was lost to follow-up. The 2 most common indications for acetabular revision were recurrent dislocation (77%) and to compliment a femoral revision (20%). There were 2 cases of aseptic cup loosening (3.3%) requiring re-revision. No other hip was clinically or radiologically loose (96.7%) at latest follow-up. One case was re-revised for infection, 4 for recurrent dislocation and 1 for disarticulation of a constrained component. At 5 years, the Kaplan-Meier survival rate was 100% for aseptic loosening and 92.2% (95% CI; 84.8-99.6%) with revision for all causes as the endpoint. These results support the use of the cement-in-cement revision technique in appropriate cases on the acetabular side. Theoretical advantages include preservation of bone stock, reduced operating time, reduced risk of complications and durable fixation.

Evidence for a dual function of EphB4 as tumor promoter and suppressor regulated by the absence or presence of the ephrin-B2 ligand

Overexpression of the receptor tyrosine kinase EphB4 is common in epithelial cancers and linked to tumor progression by promoting angiogenesis, increasing survival and facilitating invasion and migration. However, other studies have reported loss of EphB4 suggesting a tumor suppressor function in some cancers. These opposing roles may be regulated by (i) the presence of the primary ligand ephrin-B2 that regulates pathways involved in tumor suppression or (ii) the absence of ephrin-B2 that allows EphB4 signaling via ligand-independent pathways that contribute to tumor promotion. To explore this theory, EphB4 was overexpressed in the prostate cancer cell line 22Rv1 and the mammary epithelial cell line MCF-10A. Overexpressed EphB4 localized to lipid-rich regions of the plasma membrane and confirmed to be ligand-responsive as demonstrated by increased phosphorylation of ERK1/2 and internalization. EphB4 overexpressing cells demonstrated enhanced anchorage-independent growth, migration and invasion, all characteristics associated with an aggressive phenotype, and therefore supporting the hypothesis that overexpressed EphB4 facilitates tumor promotion. Importantly, these effects were reversed in the presence of ephrin-B2 which led to a reduction in EphB4 protein levels, demonstrating that ligand-dependent signaling is tumor suppressive. Furthermore, extended ligand stimulation caused a significant decrease in proliferation that correlated with a rise in caspase-3/7 and -8 activities. Together, these results demonstrate that overexpression of EphB4 confers a transformed phenotype in the case of MCF-10A cells and an increased metastatic phenotype in the case of 22Rv1 cancer cells and that both phenotypes can be restrained by stimulation with ephrin-B2, in part by reducing EphB4 levels.