Analysis of the CDKN2A, CDKN2B and CDK4 genes in 48 Australian melanoma kindreds

Germline mutations within the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene and one of its targets, the cyclin dependent kinase 4 (CDK4) gene, have been identified in a proportion of melanoma kindreds. In the case of CDK4, only one specific mutation, resulting in the substitution of a cysteine for an arginine at codon 24 (R24C), has been found to be associated with melanoma. We have previously reported the identification of germline CDKN2A mutations in 7/18 Australian melanoma kindreds and the absence of the R24C CDK4 mutation in 21 families lacking evidence of a CDKN2A mutation. The current study represents an expansion of these efforts and includes a total of 48 melanoma families from Australia. All of these families have now been screened for mutations within CDKN2A and CDK4, as well as for mutations within the CDKN2A homolog and 9p21 neighbor, the CDKN2B gene, and the alternative exon 1 (E1beta) of CDKN2A. Families lacking CDKN2A mutations, but positive for a polymorphism(s) within this gene, were further evaluated to determine if their disease was associated with transcriptional silencing of one CDKN2A allele. Overall, CDKN2A mutations were detected in 3/30 (10%) of the new kindreds. Two of these mutations have been observed previously: a 24 bp duplication at the 5' end of the gene and a G to C transversion in exon 2 resulting in an M531 substitution. A novel G to A transition in exon 2, resulting in a D108N substitution was also detected. Combined with our previous findings, we have now detected germline CDKN2A mutations in 10/48 (21%) of our melanoma kindreds. In none of the 'CDKN2A-negative' families was melanoma found to segregate with either an untranscribed CDKN2A allele, an R24C CDK4 mutation, a CDKN2B mutation, or an E1beta mutation. The last three observations suggest that these other cell cycle control genes (or alternative gene products) are either not involved at all, or to any great extent, in melanoma predisposition.

p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas

Once melanoma metastasizes, no effective treatment modalities prolong survival in most patients. This notorious refractoriness to therapy challenges investigators to identify agents that overcome melanoma resistance to apoptosis. Whereas many survival pathways contribute to the death-defying phenotype in melanoma, a defect in apoptotic machinery previously highlighted inactivation of Apaf-1, an apoptosome component engaged after mitochondrial damage. During studies involving Notch signaling in melanoma, we observed a gamma-secretase tripeptide inhibitor (GSI; z-Leu-Leu-Nle-CHO), selected from a group of compounds originally used in Alzheimer's disease, induced apoptosis in nine of nine melanoma lines. GSI only induced G2-M growth arrest (but not killing) in five of five normal melanocyte cultures tested. Effective killing of melanoma cells by GSI involved new protein synthesis and a mitochondrial-based pathway mediated by up-regulation of BH3-only members (Bim and NOXA). p53 activation was not necessary for up-regulation of NOXA in melanoma cells. Blocking GSI-induced NOXA using an antisense (but not control) oligonucleotide significantly reduced the apoptotic response. GSI also killed melanoma cell lines with low Apaf-1 levels. We conclude that GSI is highly effective in killing melanoma cells while sparing normal melanocytes. Direct enhancement of BH3-only proteins executes an apoptotic program overcoming resistance of this lethal tumor. Identification of a p53-independent apoptotic pathway in melanoma cells, including cells with low Apaf-1, bypasses an impediment to current cytotoxic therapy and provides new targets for future therapeutic trials involving chemoresistant tumors.

The Drinking Expectancy Questionnaire for Men who have Sex with Men (DEQ-MSM): A measure of substance-related beliefs

Introduction and Aims. Alcohol expectancies are associated with drinking behaviour and post-drinking use thoughts, feelings and behaviours. The expectancies held by specific cultural or sub-cultural groups have rarely been investigated. This research maps expectancies specific to gay and other men who have sex with men (MSM) and their relationship with substance use. This study describes the specific development of a measure of such beliefs for alcohol, the Drinking Expectancy Questionnaire for Men who have Sex with Men (DEQ-MSM). Design and Methods. Items selected through a focus group and interviews were piloted on 220 self-identified gay or other MSM via an online questionnaire. Results. Factor analysis revealed three distinct substance reinforcement domains ('Cognitive impairment', 'Sexual activity' and 'Social and emotional facilitation'). These factors were associated with consumption patterns of alcohol, and in a crucial test of discriminant validity were not associated with the consumption of cannabis or stimulants. Similarities and differences with existing measures will also be discussed. Discussion and Conclusions. The DEQ-MSM represents a reliable and valid measure of outcome expectancies, related to alcohol use among MSM, and represents an important advance as no known existing alcohol expectancy measure, to date, has been developed and/or normed for use among this group. Future applications of the DEQ-MSM in health promotion, clinical settings and research may contribute to reducing harm associated with alcohol use among MSM, including the development of alcohol use among young gay men.

Interactions between pedestrians and cyclists in the city centre

The city centre represents a complex environment for cycling with large volumes of pedestrians and motorised vehicles and frequent signalised intersections. Much of the previous literature has focused on cyclist-motor vehicle interactions because of the safety implications for cyclists, but there is increasing concern from pedestrians about the threats they perceive from cyclists. In the absence of objective data, this has the potential to lead to restrictions on cyclist access and behaviour. This presentation reports the development of a method to study the extent of cycling in the city centre and the frequency and nature of interactions between cyclists and pedestrians. Queensland is one of the few Australian jurisdictions that permits adults to cycle on the footpath and this was also of interest. 1992 cyclists were observed at six locations in the Brisbane city centre, during 7-9am, 9-11am, 2-4pm and 4-6pm on four weekdays in October 2010. The majority (85.5%) of cyclists were male, and 21.8% rode on the footpath. Females were more likely to travel on the footpath than males. One or more pedestrians were within 1m for 18.1% of observed cyclists, and one or more pedestrians were within 5m for 39.1% of observed cyclists. There were few conflicts, defined as an occasion where if no one took evasive action a collision would occur, between cyclists and pedestrians or vehicles (1.1% and 0.6% respectively) but they were more common for adolescents and riders not wearing (or not fastening) helmets.

Why do people ride on the footpath?

Recent increases in cycling have led to concerns about interactions between cyclists and pedestrians on footpaths and off-road paths. Much of the cycling research suggests that riding on the footpath is more dangerous than on the road. In most Australian jurisdictions, adults are only permitted to cycle on footpaths when accompanying a child. However, this rule does not apply in Queensland. This paper examines the predictors of footpath riding by adults in Queensland

Characteristics of new Queensland cyclists

Various state and local government initiatives have been implemented to encourage Australians to ride bicycles. Decreasing the number of trips taken by motor vehicle has benefits for the both the individual and the community, including health, congestion and environmental benefits. This research examined who the new cyclists are, how much and where they ride.

The relative importance of factors influencing bicycling crash risk

Government promotion of active transport has renewed interest in cycling safety. Research has shown that bicyclists are up to 20 times more likely to be involved in serious injury crashes than drivers. On-road cycling injuries are under-reported in police data, and many non-serious injuries are not recorded in any official database. This study aims to explore the relationships between rider characteristics and environmental factors that influence per kilometre risk of bicycle-related crash and non-crash injuries.

Sky high and back again : the evolution of simulation-based design from aerospace to construction

Emerging from the challenge to reduce energy consumption in buildings is a need for research and development into the more effective use of simulation as a decision-support tool. Despite significant research, persistent limitations in process and software inhibit the integration of energy simulation in early architectural design. This paper presents a green star case study to highlight the obstacles commonly encountered with current integration strategies. It then examines simulation-based design in the aerospace industry, which has overcome similar limitations. Finally, it proposes a design system based on this contrasting approach, coupling parametric modelling and energy simulation software for rapid and iterative performance assessment of early design options.

The relationship between parents’ self-efficacy beliefs, outcome expectations, child behaviour, and management of atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin condition, characterized by intense pruritis, with a complex aetiology comprising multiple genetic and environmental factors. It is a common chronic health problem among children, and along with other allergic conditions, is increasing in prevalence within Australia and in many countries worldwide. Successful management of childhood AD poses a significant and ongoing challenge to parents of affected children. Episodic and unpredictable, AD can have profound effects on children’s physical and psychosocial wellbeing and quality of life, and that of their caregivers and families. Where concurrent child behavioural problems and parenting difficulties exist, parents may have particular difficulty achieving adequate and consistent performance of the routine management tasks that promote the child’s health and wellbeing. Despite frequent reports of behaviour problems in children with AD, past research has neglected the importance of child behaviour to parenting confidence and competence with treatment. Parents of children with AD are also at risk of experiencing depression, anxiety, parenting stress, and parenting difficulties. Although these factors have been associated with difficulty in managing other childhood chronic health conditions, the nature of these relationships in the context of child AD management has not been reported. This study therefore examined relationships between child, parent, and family variables, and parents’ management of child AD and difficult child behaviour, using social cognitive and self-efficacy theory as a guiding framework. The study was conducted in three phases. It employed a quantitative, cross-sectional study design, accessing a community sample of 120 parents of children with AD, and a sample of 64 child-parent dyads recruited from a metropolitan paediatric tertiary referral centre. In Phase One, instruments designed to measure parents’ self-reported performance of AD management tasks (Parents’ Eczema Management Scale – PEMS) and parents’ outcome expectations of task performance (Parents’ Outcome Expectations of Eczema Management Scale – POEEMS) were adapted from the Parental Self-Efficacy with Eczema Care Index (PASECI). In Phase Two, these instruments were used to examine relationships between child, parent, and family variables, and parents’ self-efficacy, outcome expectations, and self-reported performance of AD management tasks. Relationships between child, parent, and family variables, parents’ self-efficacy for managing problem behaviours, and reported parenting practices, were also examined. This latter focus was explored further in Phase Three, in which relationships between observed child and parent behaviour, and parent-reported self-efficacy for managing both child AD and problem behaviours, were explored. Phase One demonstrated the reliability of both PEMS and POEEMS, and confirmed that PASECI was reliable and valid with modification as detailed. Factor analyses revealed two-factor structures for PEMS and PASECI alike, with both scales containing factors related to performing routine management tasks, and managing the child’s symptoms and behaviour. Factor analysis was also applied to POEEMS resulting in a three-factor structure. Factors relating to independent management of AD by the parent, involving healthcare professionals in management, and involving the child in management of AD were found. Parents’ self-efficacy and outcome expectations had a significant influence on self-reported task performance. In Phase Two, relationships emerged between parents’ self-efficacy and self-reported performance of AD management tasks, and AD severity, child behaviour difficulties, parent depression and stress, conflict over parenting issues, and parents’ relationship satisfaction. Using multiple linear regressions, significant proportions of variation in parents’ self-efficacy and self-reported performance of AD management tasks were explained by child behaviour difficulties and parents’ formal education, and self-efficacy emerged as a likely mediator for the relationships between both child behaviour and parents’ education, and performance of AD management tasks. Relationships were also found between parents’ self-efficacy for managing difficult child behaviour and use of dysfunctional parenting strategies, and child behaviour difficulties, parents’ depression and stress, conflict over parenting issues, and relationship satisfaction. While significant proportions of variation in self-efficacy for managing child behaviour were explained by both child behaviour and family income, family income was the only variable to explain a significant proportion of variation in parent-reported use of dysfunctional parenting strategies. Greater use of dysfunctional parenting strategies (both lax and authoritarian parenting) was associated with more severe AD. Parents reporting lower self-efficacy for managing AD also reported lower self-efficacy for managing difficult child behaviour; likewise, less successful self-reported performance of AD management tasks was associated with greater use of dysfunctional parenting strategies. When child and parent behaviour was directly observed in Phase Three, more aversive child behaviour was associated with lower self-efficacy, less positive outcome expectations, and poorer self-reported performance of AD management tasks by parents. Importantly, there were strong positive relationships between these variables (self-efficacy, outcome expectations, and self-reported task performance) and parents’ observed competence when providing treatment to their child. Less competent performance was also associated with greater parent-reported child behaviour difficulties, parent depression and stress, parenting conflict, and relationship dissatisfaction. Overall, this study revealed the importance of child behaviour to parents’ confidence and practices in the contexts of child AD and child behaviour management. Parents of children with concurrent AD and behavioural problems are at particular risk of having low self-efficacy for managing their child’s AD and difficult behaviour. Children with more severe AD are also at higher risk of behaviour problems, and thus represent a high-risk group of children whose parents may struggle to manage the disease successfully. As one of the first studies to examine the role and correlates of parents’ self-efficacy in child AD management, this study identified a number of potentially modifiable factors that can be targeted to enhance parents’ self-efficacy, and improve parent management of child AD. In particular, interventions should focus on child behaviour and parenting issues to support parents caring for children with AD and improve child health outcomes. In future, findings from this research will assist healthcare teams to identify parents most in need of support and intervention, and inform the development and testing of targeted multidisciplinary strategies to support parents caring for children with AD.

Substance-related expectancies among men who have sex with men : development of psychometric tools to predict unprotected sexual activity

Significant research has demonstrated direct and indirect associations between substance use and sexual behaviour. Substance use is related to sexual risk-taking and HIV seroconversion among some substance-using MSM. It remains unclear what factors mediate or underlie this relationship, and which substances are associated with greater harm. Substance-related expectancies are hypothesised as potential mechanisms. A conceptual model based on social-cognitive theory was tested, which explores the role of demographic factors, substance use, substance-related expectancies and novelty-seeking personality characteristics in predicting unprotected anal intercourse (UAI) while under the influence, across four commonly used substance types. Phase 1, a qualitative study (N = 20), explored how MSM perceive the effects of substance use on their thoughts, feelings and behaviours, including sexual behaviours. Information was attained through discussion and interviews, resulting in the establishment of key themes. Results indicated MSM experience a wide range of reinforcing aspects associated with substance use. General and specific effects were evident across substance types, and were associated with sexual behaviour and sexual risk-taking. Phase 2 consisted of developing a comprehensive profile of substance-related expectancies for MSM (SEP-MSM) regarding alcohol, cannabis, amyl nitrite and stimulants that possessed sound psychometric properties and was appropriate for use among this group. A cross-sectional questionnaire with 249 participants recruited through gay community networks was used to validate these measures, and involved online data collection, participants rating expectancy items and subsequent factor analysis. Results indicated expectancies can be reliably assessed, and predicted substance use patterns. Phase 3 examined demographic factors, substance use, substance-related expectancies, and novelty-seeking traits among another community sample of MSM (N = 277) throughout Australia, in predicting UAI while under the influence. Using a cross-sectional design, participants were recruited through gay community networks and completed online questionnaires. The SEP-MSM, and associated substance use, predicted UAI. This research extends social-cognitive theory regarding sexual behaviour, and advances understanding of the role of expectancies associated with substance use and sexual risk-taking. Future applications of the SEP-MSM in health promotion, prevention, clinical interventions and research are likely to contribute to reducing harm associated with substance-using MSM (e.g., HIV transmission).

How do level of experience, purpose for riding, and preference for facilities affect location of riding?

Characteristics of the road infrastructure affect both the popularity of bicycling and its safety, but comparisons of the safety performance of infrastructure may be confounded by differences in the profiles of cyclists who use them. Data from a survey of 2,532 adult bicycle riders in Queensland, Australia, demonstrated that many riders rode reluctantly in particular locations and that preference for riding location was influenced by degree of experience and riding purpose. Most riders rode most often and furthest per week on urban roads, but approximately one-third of all riders (and more new riders) rode there reluctantly. Almost two-thirds of riders rode on bicycle paths, most by choice, not reluctantly. New riders rode proportionally more on bicycle paths, but continuing riders rode further in absolute terms. Utilitarian riders were more likely to ride on bicycle paths than social and fitness riders and almost all of this riding was by choice. Fitness riders were more reluctant in their use of bicycle paths, but still most of their use was by choice. One-third of the respondents reported riding on the sidewalk (legal in Queensland), with approximately two-thirds doing so reluctantly. The frequency and distance ridden on the sidewalk was less than for urban roads and bicycle paths. Sidewalks and bicycle paths were important facilities for both inexperienced and experienced riders and for utilitarian riding, especially when urban roads were considered a poor choice for cycling.

Music selection using a touch screen interface : effect of auditory and visual feedback on driving and usability

This study aimed to examine the effects on driving, usability and subjective workload of performing music selection tasks using a touch screen interface. Additionally, to explore whether the provision of visual and/or auditory feedback offers any performance and usability benefits. Thirty participants performed music selection tasks with a touch screen interface while driving. The interface provided four forms of feedback: no feedback, auditory feedback, visual feedback, and a combination of auditory and visual feedback. Performance on the music selection tasks significantly increased subjective workload and degraded performance on a range of driving measures including lane keeping variation and number of lane excursions. The provision of any form of feedback on the touch screen interface did not significantly affect driving performance, usability or subjective workload, but was preferred by users over no feedback. Overall, the results suggest that touch screens may not be a suitable input device for navigating scrollable lists.

On the relationships between self-reported bicycling injuries and perceived risk among cyclists in Queensland, Australia

The focus of governments on increasing active travel has motivated renewed interest in cycling safety. Bicyclists are up to 20 times more likely to be involved in serious injury crashes than drivers so understanding the relationship among factors in bicyclist crash risk is critically important for identifying effective policy tools, for informing bicycle infrastructure investments, and for identifying high risk bicycling contexts. This study aims to better understand the complex relationships between bicyclist self reported injuries resulting from crashes (e.g. hitting a car) and non-crashes (e.g. spraining an ankle) and perceived risk of cycling as a function of cyclist exposure, rider conspicuity, riding environment, rider risk aversion, and rider ability. Self reported data from 2,500 Queensland cyclists are used to estimate a series of seemingly unrelated regressions to examine the relationships among factors. The major findings suggest that perceived risk does not appear to influence injury rates, nor do injury rates influence perceived risks of cycling. Riders who perceive cycling as risky tend not to be commuters, do not engage in group riding, tend to always wear mandatory helmets and front lights, and lower their perception of risk by increasing days per week of riding and by increasing riding proportion on bicycle paths. Riders who always wear helmets have lower crash injury risk. Increasing the number of days per week riding tends to decrease both crash injury and non crash injury risk (e.g. a sprain). Further work is needed to replicate some of the findings in this study.

Bribie Island groundwater resources : challenges in development of conceptual and numerical models

Groundwater is a major resource on Bribie Island and its sustainable management is essential to maintain the natural and modified eco-systems, as well as the human population and the integrity of the island as a sand mass. An effective numerical model is essential to enable predictions, and to test various water use and rainfall/climate scenarios. Such a numerical model must, however, be based on a representative conceptual hydrogeological model to allow incorporation of realistic controls and processes. Here we discuss the various hydrogeological models and parameters, and hydrological properties of the materials forming the island. We discuss the hydrological processes and how they can be incorporated into these models, in an integrated manner. Processes include recharge, discharge to wetlands and along the coastline, abstraction, evapotranspiration and potential seawater intrusion. The types and distributions of groundwater bores and monitoring are considered, as are scenarios for groundwater supply abstraction. Different types of numerical models and their applicability are also considered

The role of insulin and IGF2 signalling on metabolic pathways in prostate cancer progression

Prostate cancer (CaP) is the most commonly diagnosed cancer in males in Australia, North America, and Europe. If found early and locally confined, CaP can be treated with radical prostatectomy or radiation therapy; however, 25-40% patients will relapse and go on to advanced disease. The most common therapy in these cases is androgen deprivation therapy (ADT), which suppresses androgen production from the testis. Lack of the testicular androgen supply causes cells of the prostate to undergo apoptosis. However, in some cases the regression initially seen with ADT eventually gives way to a growth of a population of cancerous cells that no longer require testicular androgens. This phenotype is essentially fatal and is termed castrate resistant prostate cancer (CRPC). In addition to eventual regression, there are many undesirable side effects which accompany ADT, including development of a metabolic syndrome, which is defined by the U.S. National Library of Medicine as “a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes.” This project will focus on the effect of ADT induced hyperinsulinemia, as mimicked by treating androgen receptor positive CaP cells with insulin in a serum (hormone) deprived environment. While this side effect is not widely explored, in this thesis it is demonstrated for the first time that insulin upregulates pathways important to CaP progression. Our group has previously shown that during CaP progression, the enzymes necessary for de novo steroidogenesis are upregulated in the LNCaP xenograft model, total steroid levels are increased in tumours compared to pre castrate levels, and de novo steroidogenesis from radio-labelled acetate has been demonstrated. Because of the CaP dependence on AR for survival, we and other groups believe that CaP cells carry out de novo steroidogenesis to survive in androgen deprived conditions. Because (a) men on ADT often develop metabolic syndrome, and (b) men with lifestyle-induced obesity and hyperinsulinemia have worse prognosis and faster disease progression, and because (c) insulin causes steroidogenesis in other cell lines, the hypothesis that insulin may contribute to CaP progression through upregulation of steroidogenesis was explored. Insulin upregulates steroidogenesis enzymes at the mRNA level in three AR positive cell lines, as well as upregulating these enzymes at the protein level in two cell lines. It has also been demonstrated that insulin increases mitochondrial (functional) levels of steroid acute regulatory protein (StAR). Furthermore, insulin causes increased levels of total steroids in and induction of de novo steroid synthesis by insulin has been demonstrated at levels induced sufficient to activate AR. The effect of insulin analogs on CaP steroidogenesis in LNCaP and VCaP cells has also been investigated because epidemiological studies suggest that some of the analogs developed may have more cancer stimulatory effects than normal insulin. In this project, despite the signalling differences between glargine, X10, and insulin, these analogs did not appear to induce steroidogenesis any more potently that normal insulin. The effect of insulin of MCF7breast cancer cells was also investigated with results suggesting that breast cancer cells may be capable of de novo steroidogenesis, and that increase in estradiol production may be exacerbated by insulin. Insulin has also been long known to stimulate lipogenesis in the liver and adipocytes, and has been demonstrated to increase lipogenesis in breast cancer cells; therefore, investigation of the effect of insulin on lipogenesis, which is a hallmark of aggressive cancers, was investigated. In CaP progression sterol regulatory element binding protein (SREBP) is dysregulated and upregulates fatty acid synthase (FASN), acetyl CoA-carboxylase, and other lipogenesis genes. SREBP is important for steroidogenesis and in this project has been shown to be upregulated by insulin in CaP cells. Fatty acid synthesis provides building blocks of membrane growth, provides substrates for acid oxidation, the main energy source for CaP cells, provides building blocks for anti-apoptotic and proinflammatory molecules, and provides molecules that stimulate steroidogenesis. In this project it has been shown that insulin upregulates FASN and ACC, which synthesize fatty acids, as well as upregulating hormone sensitive lipase (HSL), diazepam-binding inhibitor (DBI), and long-chain acyl-CoA synthetase 3 (ACSL3), which contribute to lipid activation of steroidogenesis. Insulin also upregulates total lipid levels and de novo lipogenesis, which can be suppressed by inhibition of the insulin receptor (INSR). The fatty acids synthesized after insulin treatment are those that have been associated with CaP; furthermore, microarray data suggests insulin may upregulate fatty acid biosynthesis, metabolism and arachidonic acid metabolism pathways, which have been implicated in CaP growth and survival. Pharmacological agents used to treat patients with hyperinsulinemia/ hyperlipidemia have gained much interest in regards to CaP risk and treatment; however, the scientific rationale behind these clinical applications has not been examined. This thesis explores whether the use of metformin or simvastatin would decrease either lipogenesis or steroidogenesis or both in CaP cells. Simvastatin is a 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) inhibitor, which blocks synthesis of cholesterol, the building block of steroids/ androgens. It has also been postulated to down regulate SREBP in other metabolic disorders. It has been shown in this thesis, in LNCaP cells, that simvastatin inhibited and decreased insulin induced steroidogenesis and lipogenesis, respectively, but increased these pathways in the absence of insulin. Conversely, metformin, which activates AMP-activated protein kinase (AMPK) to shut down lipogenesis, cholesterol synthesis, and protein synthesis, highly suppresses both steroidogenesis and lipogenesis in the presence and absence of insulin. Lastly, because it has been demonstrated to increase steroidogenesis in other cell lines, and because the elucidation of any factors affecting steroidogenesis is important to understanding CaP, the effect of IGF2 on steroidogenesis in CaP cells was investigated. In patient samples, as men progress to CRPC, IGF2 mRNA and the protein levels of the receptors it may signal through are upregulated. It has also been demonstrated that IGF2 upregulates steroidogenic enzymes at both the mRNA and protein levels in LNCaP cells, increases intracellular and secreted steroid/androgen levels in LNCaPs to levels sufficient to stimulate the AR, and upregulated de novo steroidogenesis in LNCaPs and VCaPs. As well, inhibition of INSR and insulin-like growth factor 1 receptor (IGF1R), which IGF2 signals through, suggests that induction of steroidogenesis may be occurring predominantly through IGF1R. In summary, this project has illuminated for the first time that insulin is likely to play a large role in cancer progression, through upregulation of the steroidogenesis and lipogenesis pathways at the mRNA and protein levels, and production levels, and demonstrates a novel role for IGF-II in CaP progression through stimulation of steroidogenesis. It has also been demonstrated that metformin and simvastatin drugs may be useful in suppressing the insulin induction of these pathways. This project affirms the pathways by which ADT- induced metabolic syndrome may exacerbate CaP progression and strongly suggests that the monitoring and modulation of the metabolic state of CaP patients could have a strong impact on their therapeutic outcomes.