An examination of the pharmacology of HER2 inhibitor responses in cellular models of breast cancer

So-called “targeted therapeutics”, agents with tumour-selective action, promise to revolutionise treatment of specific malignancies; however, realisation of the therapeutic promise of such drugs requires new methods of rapidly distinguishing patients who will derive treatment benefit. Tyrosine Kinase Inhibitors (TKIs), a group of small molecule therapeutics, inhibit specific aspects of the phosphorylation-mediated intracellular signalling pathways commonly altered in cancer. Overexpression of one such pathway, initiated by the HER2 growth factor receptor, occurs commonly in breast cancer. Lapatinib, a HER2 TKI, has been used in combinations with other cancer drugs for treating HER2 overexpressing breast cancer. The aim of this study was to evaluate gene expression changes in response to these targeted therapies to examine their ability to predict treatment response. In this thesis, microarray data from lapatinib-treated drug sensitive breast cancer cell lines was interrogated using an emerging bioinformatic technique, Co-inertia analysis (CIA). Using this technique, 512 genes were found to be altered in a specific response to lapatinib treatment in the cell lines. 27 gene targets were chosen for more detailed analysis using Taqman RT-PCR, of which five showed predictive response in a broader panel of breast cancer cell lines treated with lapatinib. Expression of the five genes was further examined in response to other HER2 targeted therapies and the analysis indicated that the gene expression changes remained consistent with these other treatments, demonstrating a more broadly representative anti-HER2 response pattern. An in vivo study sought to evaluate these gene expression responses in a more in vivo-relevant scenario and found that they were also conserved in this model. Our research indicates that there are commonalities among the gene expression response to HER2-targeting therapeutics in responsive cells which may extrapolate to HER2-amplified patient tumours and more broadly suggests that characterisation of gene changes shortly after treatment may provide a valuable rapid predictor of inhibitor response, potentially guiding a more specific use of such agents by identifying patients that will benefit from these therapies

An affordable smart sensor network for water level management in a catchment

Accurately monitoring water levels at high special and temporal scale is the key element in every catchment or flood risk management system. Building, evaluating and testing hydrological models typically require years of high frequency datasets. Current water level monitoring systems are expensive and usually deployed sparsely throughout a catchment. This may not provide sufficient information to simulate the hydrological variations of a catchment. In this paper, we evaluate the Kingspan Sonic SignalMan ultra-sonic sensor that is designed for monitoring liquid, such as diesel, AdBlue, lubricants additives etc., level autonomously over years. The cost of this sensor is relatively low, which enables the deploying of a water level monitoring system at a much larger spatial scale at an affordable cost. A smart sensor network for catchment management is proposed based on the use of the Kingspan sensor

Generating national projections of dementia cases for Ireland using a calibrated macro-simulation model.

INTRODUCTION: Epidemiological data on dementia is not available in many European countries and regions due to the high cost and complexity of conducting large scale dementia screening studies. The available epidemiological studies identify potentially substantial variation in the prevalence of dementia over time and across Europe. METHODS: In this paper we generate simulations of the number of dementia cases in Ireland from 1991 to 2036 using a three-state Markov illness-death model. Parameters values are selected for each simulation from a range using a random parameter search pattern. We employ a novel calibration method which exploits the strong relationship between dementia, ageing and mortality. Simulation weights are generated based on differences between observed and modelled cohorts of older people and the reported number of deaths from dementia. Irish Census data from 1991 to 2016 and the number of recorded deaths due to dementia in 2018 are used as calibration points. A weighted average projection of the number of dementia cases is generated. RESULTS: We estimate a weighted average number of cases of dementia in 2016 of 54 877 increasing to 98 946 in 2036; this estimate is substantially lower than the estimates generated using extrapolation methods. We show the wide range of possible outcomes given the range in the available parameter estimates and show that irrespective of whether the incidence rate of dementia is declining the number of cases of dementia is rapidly increasing due to population ageing. CONCLUSION: Previous studies have used parameter estimates from meta-analyses of the literature or from individual studies. In this paper we supplement these with a calibration approach using observed cause of death and population age structure data. These additional sources of data can be used to generate estimates of dementia prevalence in any country or region which has census data and data on deaths due to dementia

The aromatase inhibitor letrozole enhances the effect of doxorubicin and docetaxel in an MCF7 cell line model

Introduction: Post-menopausal women with estrogen receptor (ER) positive breast cancer receive adjuvant chemotherapy and endocrine therapy sequentially since tamoxifen may antagonise the cytotoxicity of chemotherapy drugs. With increased use of aromatase inhibitors (AIs) in place of tamoxifen, the potential use of concomitant chemo-endocrine treatments with the AI letrozole, before clinical trials are undertaken, requires evaluation. Methods: MCF7-aro cells expressing the aromatase gene were treated with letrozole, doxorubicin and docetaxel. The effects of different drug concentrations, drug combinations and scheduling on cytotoxicity and aromatase activity were investigated. Key receptor, cell cycle regulation and apoptosis proteins were examined by immunoblotting. Results: Administration of letrozole with either doxorubicin or docetaxel resulted in increased levels of cytotoxicity under all treatment schedules (add in, sequential or simultaneous drug administration) with the greatest anti-proliferative effect observed using concomitant treatment (letrozole first with chemotherapy added in). The inhibitory effect of letrozole on aromatase activity was unchanged by the addition of doxorubicin or docetaxel. Letrozole treatment resulted in decreased HER2 expression and addition of doxorubicin and docetaxel to letrozole led to elevated ER-ß levels. Conclusions: In vitro, letrozole, unlike tamoxifen, enhances the cytotoxicity of both doxorubicin and docetaxel. This supports the prospect of trials using letrozole with chemotherapy in postmenopausal women with ER positive breast cancer

The experience of mortgage distress in Western Sydney

Mortgage distress is affecting a growing number of Australian households. Distress ranges from arrears in mortgage payments to defaults, foreclosures and repossessions. The impacts of mortgage distress are complex and include issues relating to the ongoing financial viability of the affected households, wider neighbourhood effects, and a range of psychological and social impacts. In recent years, mortgage stress has had a consistently higher prevalence in certain parts of Western Sydney than in any other region across Australia.This study is an attempt to uncover the experiences of mortgage distress in Western Sydney and of mortgage holders’ coping strategies. While not claiming to be a representative sample of mortgagors in distress, the report reveals much about the circumstances contributing to mortgage distress and its considerable impacts on the lives of those affected

Intensive home care supports, informal care and private provision for people with dementia in Ireland.

BACKGROUND: This study analysed the cost of intensive home care packages for people with dementia living on the boundary of home care and residential care facilities in Ireland. The cost of community-based services and supports, including informal care and private out-of-pocket expenditure, was compared to the cost of public and private residential care. METHODS: The study recruited 42 people with dementia and/or their caregivers, who were living on the boundary of home care and residential care, to an in-depth study on the cost of care. The Resource Utilization in Dementia scale was used to collect data on the utilization of standard formal care and informal care by people with dementia in receipt of an intensive home care package. Information on private out-of-pocket expenditure on care was also collected. Unit costs were assigned and community-based care was compared with public and private residential care alternatives. RESULTS: The average weekly cost of home care, including the intensive home care package, standard formal community care provision, medications, consumption and housing, was estimated at €1127. This is lower than the average weekly cost of public long-stay care facilities (€1526) and around the same as for private nursing home fees in the Dublin region (€1149). When the opportunity cost valuation of informal care is included, the cost of home care is higher than all types of residential care. Adding private care expenditure further inflates the cost of home care. CONCLUSION: Keeping highly dependent people with dementia living at home is not cheap and raises questions about optimal resource allocation on the boundary of home care and residential care. Even with significant public spending on intensive home care packages, family care costs remain high. So too does private out-of-pocket expenditure on care for some people with dementia

Rapid prototyped biomimetic antifouling surfaces for marine applications

Fouling-release coatings typically rely on a mechanical shear force (usually generated by movement in the marine environment) to remove bio-matter. This is problematic in situations where the surface of interest will remain in a static state (e.g. marine sensors). Here we investigate the antifouling properties of textured surfaces of regular patterns in poly(methyl methacrylate) (PMMA) in a static marine environment. Nine PMMA samples were prepared and the effect of hole-size and spacing on marine diatom adhesion was studied. Self-replenishing silicone oil was tested in each textured surface, and impact of oil transfer on diatom settlement was also investigated

The place probe: exploring a sense of place in real and virtual environments.

This paper describes the design, application, and refinement of a qualitative tool designed to study sense of place. The Place Probe incorporates a range of stimuli and techniques aimed at articulating a person's sense of place. It has been developed, used, and undergone three revisions. The paper describes the background to the choice of measures that were included in the Place Probe and describes its application in both a physical place and a virtual representation of that place. This enables a comparison of the experiences. An analysis of the results reveals a similarity of reported experience, however the extremes experienced in the physical place were less pronounced in the virtual representation. The Place Probe has been refined in light of the results of the empirical work and now incorporates both qualitative and quantitative data on the experience of place

The association between frailty, care receipt and unmet need for care with the risk of hospital admissions

Background: Frailty is characterised by a decline in physical, cognitive, energy, and health reserves and is linked to greater functional dependency and higher social care utilisation. However, the relationship between receiving care, or receiving insufficient care among older people with different frailty status and the risk of unplanned admission to hospital for any cause, or the risk of falls and fractures remains unclear. Methods and findings: This study used information from 7,656 adults aged 60 and older participating in the English Longitudinal Study of Ageing (ELSA) waves 6-8. Care status was assessed through received care and self-reported unmet care needs, while frailty was measured using a frailty index. Competing-risk regression analysis was used (with death as a potential competing risk), adjusted for demographic and socioeconomic confounders. Around a quarter of the participants received care, of which approximately 60% received low levels of care, while the rest had high levels of care. Older people who received low and high levels of care had a higher risk of unplanned admission independent of frailty status. Unmet need for care was not significantly associated with an increased risk of unplanned admission compared to those receiving no care. Older people in receipt of care had an increased risk of hospitalisation due to falls but not fractures, compared to those who received no care after adjustment for covariates, including frailty status. Conclusions: Care receipt increases the risk of hospitalisation substantially, suggesting this is a group worthy of prevention intervention focus

“Lupus means sacrifices” – the perspectives of adolescents and young adults with systemic lupus erythematosus.

Background: Disease activity, organ damage and treatment burden are often substantial in children and adolescents with systemic lupus erythematous (SLE), and the complex interplay among the developing child, their parents, and their peers makes effective management difficult. We aimed to describe the experiences and perspectives of adolescents and young adults diagnosed with juvenile-onset SLE to inform strategies for improving treatment and health outcomes. Methods: Focus groups and face-to-face semi-structured interviews were conducted with 26 patients aged 14 to 26 years, from five Australian hospitals in 2013-2014. Focus groups and interview transcripts were thematically analyzed. Results: Five themes were identified: marring identity (misrepresented self, heightened self-consciousness, sense of isolation); restricting major life decisions (narrowed career options, threat to parenthood); multifaceted confusion and uncertainty (frustration of delayed or misdiagnosis, needing age and culturally appropriate information, ambiguity about cause of symptoms, prognostic uncertainty, confronting transition to adult care); resentment of long-term treatment (restricting ambition, animosity towards medication use); gaining resilience (desire for independence, developing self-reliance, recalibrating perceived disease severity, depending on family, trusting physicians). Conclusions: Young patients with SLE perceive they have substantially limited physical and social capacities and restricted personal and career goals. Psychosocial and educational interventions targeted at improving confidence, self-efficacy, disease-related knowledge, social support, and resolving insecurities regarding patients’ capacity for self-management may alleviate psychosocial distress, improve adherence, and thus optimize health outcomes of adolescents and young adults with SLE.DJT is funded by a postgraduate scholarship from the Sydney Medical School, The University of Sydney. All authors have no relevant financial affiliations that would cause a conflict of interes