In vitro experiments towards a mathematical model of solid tumour treatment by thermosensitive liposomes

Thermosensitive Liposomes (TSLs) are at a crossroads as a delivery platform. Recent attempts at clinical translation have had mixed outcomes. The HEAT and OPTIMA trials, using TSL doxorubicin and radiofrequency ablation (RFA) as a heating modality did not demonstrate improved outcomes compared to RFA alone. In contrast, the TARDOX trial demonstrated for the first time that the delivery of TSL doxorubicin with localised ultrasound-mediated mild hyperthermia of a deep-seated tumour was safe and feasible, as well as finding elevated levels of intratumoural doxorubicin after heating. Most notably, despite the fact many of the patients had diagnoses which would not ordinarily be expected to respond to doxorubicin therapy, a majority of patients had a localised radiological response following only a single cycle of treatment. Several key parameters in the TARDOX trial (such as infusion duration, TSL dose, and heating duration) were chosen based on limited prior experimentation and practical considerations associated with an early stage trial. In this thesis, in vitro experiments and computational modelling are used to explore the effect of changing these variables on the likely treatment outcome, with a view to optimising the clinical translation of TSLs. Three scales associated with the delivery of drug to tumours are identified: the clearance scale, which describes the concentration of drug in the systemic plasma; the delivery scale, which describes the extravasation of drug from the tumour vasculature and its transport through the extracellular space; and the pharmacodynamic scale, describing the cellular uptake and cytotoxic effect of the drug. In the first chapter, a compartment model is used to demonstrate that literature data (from the delivery and pharmacodynamic scales) can be used to accurately resolve treatment of tumours with TSLs in man, comparing the model outputs to the clinical measurements obtained in the TARDOX trial. An initial optimisation is performed considering only the clearance and pharmacodynamic scales, and a sensitivity analysis shows that the predicted optimal treatment parameters are robust to fluctuations in parameters, however the predicted intratumoural concentrations do fluctuate more substantially with changing cellular uptake parameters. The second research chapter therefore focuses on the pharmacodynamic scale, using experiments to quantify the beneficial effects of mild hyperthermia on cellular uptake and cytotoxicity of doxorubicin in CT26 cells, and provide improved parameters for the computational treatment model. It is found that the addition of mild hyperthermia results in significant increases in both uptake and cytotoxicity, with the cells exhibiting increased sensitivity to intracellular doxorubicin (compared to cells treated at normothermic conditions). Finally, in the third research chapter, the aforementioned experimental data is used in a model which includes spatial heterogeneity (i.e., the delivery scale). It is demonstrated that spatial heterogeneity is not a substantial issue for doxorubicin TSLs, however in treatment with drugs that exhibit more rapid cellular uptake, this may be more limiting. Overall, the work in this thesis demonstrates that TSLs should be able to bring a clinical benefit to patients, as increased delivery of drug is predicted with TSLs (compared to non-liposomal forms)

Case Study: Visitor Perceptions of Captive Wildlife Tourism in a Western Australian Natural Setting

Wildlife tourism involves a broad sweep of experiences that includes all of the aspects of the tourism genre with the distinguishing feature of animals as the primary attraction. The uniqueness of Australian wildlife in combination with factors such as remoteness and rarity appear to have provided the ideal context for successful wildlife tourism operations. Barna Mia, located in a large remnant woodland in the central southern wheatbelt of Western Australia, is approximately 165 km southeast of the state's capital, Perth. Dryandra Woodland, the location of Barna Mia, consists of a closely grouped and connected cluster of native remnant vegetation blocks. The enclosure is surrounded by electrified, vermin proof fencing to keep feral predators out and the captive fauna in. The results of the visitor survey at Barna Mia suggested the experience provided a great sense of satisfaction amongst respondents. This was both in terms of the overall satisfaction as well as satisfaction with specific parts of the experience. The feeling of being "in the wild" may have been enhanced by the lack of barriers between visitors and the animals and the absence of constraints on animal movement through the enclosure. Improving the operation of Barna Mia as an attraction in itself and as part of the Dryandra Woodland product may serve to improve its success as an attraction. However, an innately attractive tourism experience cannot work without appropriate integration within the specific wildlife tourism product of Dryandra Woodland, while coordination with tourism on a regional scale is also important

Comparative Analysis Of Employee Job Satisfaction In The Accounting Profession

Evaluating job satisfaction among accounting professionals is an increasingly important area of concern for employers, which strive to recruit and retain quality employees and to improve their competitive positions. This study examines the results of surveys of accounting graduates from two AACSB International accredited universities from 1980 to 2003. Respondents were asked a variety of questions on job satisfaction as it relates to many factors including profession, firm size, certification, age, sex, race, advanced degrees and parent education. The findings of this study on job satisfaction provide benchmarks upon which accounting firms can use to evaluate job satisfaction levels among their own employees

Differences in Health-related Behaviors and Attitudes between Urban, Rural, and Isolated Households in Western West Virginia

This study uses data from a 2013 survey of 275 randomly sampled households across nine counties in western West Virginia to examine the significant differences between the health behaviors and attitudes of rural and isolated populations. The results show that age, education, and income are significant factors in explaining differences in health-related behaviors and attitudes for all urban, rural and isolated respondents. However, after controlling for socio-demographic differences, isolation is found to have only a few significant effects, and some of the effects run counter to stereotypes of isolated populations. Rural respondents are significantly more likely than isolated respondents to be obese and to have ever been diagnosed with hypertension. Rural respondents are significantly less likely than isolated respondents to have annual dental or medical checkups, to engage in physical activity during the spring months, and to raise their own chickens and cattle for food

Association of Self-Efficacy and Self-Regulation with Nutrition and Exercise Behaviors in a Community Sample of Adults

This study examined the association of self-efficacy and self-regulation with nutrition and exercise behaviors. The study used a cross-sectional design and included 108 participants (54 men, 54 women). Nutrition behaviors (fruit/vegetable consumption, dinner cooking, and restaurant eating) and exercise were measured using total days in last week a behavior was reported. Instruments measuring self-efficacy and self-regulation demonstrated excellent Cronbach’s alphas (.93–.95). Path analysis indicated only fruit/vegetable consumption and exercise were associated with self-efficacy and self-regulation. Self-regulation showed direct association with fruit/vegetable consumption and exercise, but self-efficacy had direct association only with exercise. Self-efficacy and self-regulation should be strategically used to promote health behaviors

The Release of Vaccinia Virus from Infected Cells Requires RhoA-mDia Modulation of Cortical Actin

SummaryPrior to being released from the infected cell, intracellular enveloped vaccinia virus particles are transported from their perinuclear assembly site to the plasma membrane along microtubules by the motor kinesin-1. After fusion with the plasma membrane, stimulation of actin tails beneath extracellular virus particles acts to enhance cell-to-cell virus spread. However, we lack molecular understanding of events that occur at the cell periphery just before and during the liberation of virus particles. Using live cell imaging, we show that virus particles move in the cell cortex, independently of actin tail formation. These cortical movements and the subsequent release of virus particles, which are both actin dependent, require F11L-mediated inhibition of RhoA-mDia signaling. We suggest that the exit of vaccinia virus from infected cells has strong parallels to exocytosis, as it is dependent on the assembly and organization of actin in the cell cortex

503 Phase I radioimmunotherapy (RIT) study of 90Y-CC49 monoclonal antibody (MAb) therapy in patients with advanced non-small cell lung cancer (NSCLC)

503 Phase I radioimmunotherapy (RIT) study of 90Y-CC49 monoclonal antibody (MAb) therapy in patients with advanced non-small cell lung cancer (NSCLC) × Close The Infona portal uses cookies, ie strings of text saved by a browser on the user\u27s device. The portal can access those files and use them to remember the user\u27s data, such as their chosen settings (screen view, interface language, etc.), or their login data. By using the Infona portal the user accepts automatic saving and using this information for portal operation purposes. More information on the subject can be found in the Privacy Policy and Terms of Service. By closing this window the user confirms that they have read the information on cookie usage, and they accept the privacy policy and the way cookies are used by the portal

An applied ecology of fear framework: linking theory to conservation practice

Research on the ecology of fear has highlighted the importance of perceived risk from predators and humans in shaping animal behavior and physiology, with potential demographic and ecosystem-wide consequences. Despite recent conceptual advances and potential management implications of the ecology of fear, theory and conservation practices have rarely been linked. Many challenges in animal conservation may be alleviated by actively harnessing or compensating for risk perception and risk avoidance behavior in wild animal populations. Integration of the ecology of fear into conservation and management practice can contribute to the recovery of threatened populations, human–wildlife conflict mitigation, invasive species management, maintenance of sustainable harvest and species reintroduction plans. Here, we present an applied framework that links conservation interventions to desired outcomes by manipulating ecology of fear dynamics. We discuss how to reduce or amplify fear in wild animals by manipulating habitat structure, sensory stimuli, animal experience (previous exposure to risk) and food safety trade-offs to achieve management objectives. Changing the optimal decision-making of individuals in managed populations can then further conservation goals by shaping the spatiotemporal distribution of animals, changing predation rates and altering risk effects that scale up to demographic consequences. We also outline future directions for applied research on fear ecology that will better inform conservation practices. Our framework can help scientists and practitioners anticipate and mitigate unintended consequences of management decisions, and highlight new levers for multi-species conservation strategies that promote human–wildlife coexistence

A Scoping Review of Dingo and Wild-Living Dog Ecology and Biology in Australia to Inform Parameterisation for Disease Spread Modelling

Background: Dingoes and wild-living dogs in Australia, which include feral domestic dogs and dingo-dog hybrids, play a role as reservoirs of disease. In the case of an exotic disease incursion—such as rabies—these reservoirs could be a threat to the health of humans, domestic animals and other wildlife in Australia. Disease spread models are needed to explore this impact and develop mitigation strategies for responding to an incursion. Our study aim was to describe relevant information from the literature, using a scoping review, on specific topics related to dingo and wild-living dog ecology and biology (topics of interest) in Australia to inform parameterisation of disease spread modelling and identify major research gaps.Methods: A broad electronic search was conducted in five bibliographic databases and grey literature. Two levels of screening and two levels of data extraction were each performed independently by two reviewers. Data extracted included topics of interest investigated, type of population sampled, the presence of lethal control, type of environment, years of collection and GPS coordinates of study sites.Results: From 1666 records captured, the screening process yielded 229 individual studies published between 1862 and 2016. The most frequently reported topics of interest in studies were index of abundance (n = 93) and diet (n = 68). Among the three key parameters in disease spread modelling (i.e., density, contacts and home range), data on density and contacts were identified as major research gaps in the literature due to the small number of recent studies on these topics and the scarcity of quantitative estimates. The research reviewed was mostly located around central Australia and the east coast, including a few studies on density, contacts and home range. Data from these regions could potentially be used to inform parameterisation for disease spread modelling of dingoes and wild-living dogs. However, the number of studies is limited in equatorial and tropical climate zones of northern Australia, which is a high-risk area for a rabies incursion.Conclusions: Research in northern regions of Australia, especially to generate data regarding density, contacts and home ranges, should be prioritised for future research on dingoes and wild-living dogs