Development of novel vaccine strategies to prevent genital tract chlamydial infections

Chlamydia trachomatis is the most prevalent bacterial sexually transmitted infection in the developed world and the leading cause of preventable blindness worldwide. As reported by the World Health Organization in 2001, there are approximately 92 million new infections detected annually, costing health systems billions of dollars to treat not only the acute infection, but also to treat infection-associated sequelae. The majority of genital infections are asymptomatic, with 50-70% going undetected. Genital tract infections can be easily treated with antibiotics when detected. Lack of treatment can lead to the development of pelvic inflammatory disease, ectopic pregnancies and tubal factor infertility in women and epididymitis and prostatitis in men. With infection rates on the continual rise and the large number of infections going undetected, there is a need to develop an efficacious vaccine which prevents not only infection, but also the development of infection-associated pathology. Before a vaccine can be developed and administered, the pathogenesis of chlamydial infections needs to be fully understood. This includes the kinetics of ascending infection and the effects of inoculating dose on ascension and development of pathology. The first aim in this study was to examine these factors in a murine model. Female BALB/c mice were infected intravaginally with varying doses of C. muridarum, the mouse variant of human C. trachomatis, and the ascension of infection along the reproductive tract and the time-course of infection-associated pathology development, including inflammatory cell infiltration, pyosalpinx and hydrosalpinx, were determined. It was found that while the inoculating dose did affect the rate and degree of infection, it did not affect any of the pathological parameters examined. This highlighted that the sexual transmission dose may have minimal effect on the development of reproductive sequelae. The results of the first section enabled further studies presented here to use an optimal inoculating dose that would ascend the reproductive tract and cause pathology development, so that vaccine efficacy could be determined. There has been a large amount of research into the development of an efficacious vaccine against genital tract chlamydial infections, with little success. However, there have been no studies examining the effects of the timing of vaccination, including the effects of vaccination during an active genital infection, or after clearance of a previous infection. These are important factors that need to be examined, as it is not yet known whether immunization will enhance not only the individual's immune response, but also pathology development. It is also unknown whether any enhancement of the immune responses will cause the Chlamydia to enter a dormant, persistent state, and possibly further enhance any pathology development. The second section of this study aimed to determine if vaccination during an active genital tract infection, or after clearance of a primary infection, enhanced the murine immune responses and whether any enhanced or reduced pathology occurred. Naïve, actively infected, or previously infected animals were immunized intranasally or transcutaneously with the adjuvants cholera toxin and CpG-ODN in combination with either the major outer membrane protein (MOMP) of C. muridarum, or MOMP and ribonucleotide reductase small chain protein (NrdB) of C. muridarum. It was found that the systemic immune responses in actively or previously infected mice were altered in comparison to animals immunized naïve with the same combinations, however mucosal antibodies were not enhanced. It was also found that there was no difference in pathology development between any of the groups. This suggests that immunization of individuals who may have an asymptomatic infection, or may have been previously exposed to a genital infection, may not benefit from vaccination in terms of enhanced immune responses against re-exposure. The final section of this study aimed to determine if the vaccination regimes mentioned above caused in vivo persistence of C. muridarum in the upper reproductive tracts of mice. As there has been no characterization of C. muridarum persistence in vitro, either ultrastructurally or via transcriptome analysis, this was the first aim of this section. Once it had been shown that C. muridarum could be induced into a persistent state, the gene transcriptional profiles of the selected persistent marker genes were used to determine if persistent infections were indeed present in the upper reproductive tracts of the mice. We found that intranasal immunization during an active infection induced persistent infections in the oviducts, but not the uterine horns, and that intranasal immunization after clearance of infection, caused persistent infections in both the uterine horns and the oviducts of the mice. This is a significant finding, not only because it is the first time that C. muridarum persistence has been characterized in vitro, but also due to the fact that there is minimal characterization of in vivo persistence of any chlamydial species. It is possible that the induction of persistent infections in the reproductive tract might enhance the development of pathology and thereby enhance the risk of infertility, factors that need to be prevented by vaccination, not enhanced. Overall, this study has shown that the inoculating dose does not affect pathology development in the female reproductive tract of infected mice, but does alter the degree and rate of ascending infection. It has also been shown that intranasal immunization during an active genital infection, or after clearance of one, induces persistent infections in the uterine horns and oviducts of mice. This suggests that potential vaccine candidates will need to have these factors closely examined before progressing to clinical trials. This is significant, because if the same situation occurs in humans, a vaccine administered to an asymptomatic, or previously exposed individual may not afford any extra protection and may in fact enhance the risk of development of infection-associated sequelae. This suggests that a vaccine may serve the community better if administered before the commencement of sexual activity.

Physical effect in patent law

This thesis addresses one of the fundamental issues that remains unresolved in patent law today. It is a question that strikes at the heart of what a patent is and what it is supposed to protect. That question is whether an invention must produce a physical effect or cause a physical transformation of matter to be patentable, or whether it is sufficient that an invention involves a specific practical application of an idea or principle to achieve a useful result. In short, the question is whether patent law contains a physicality requirement. Resolving this issue will determine whether only traditional mechanical, industrial and manufacturing processes are patent eligible, or whether patent eligibility extends to include purely intangible, or non-physical, products and processes. To this end, this thesis seeks to identify where the dividing line lies between patentable subject matter and the recognised categories of excluded matter, namely, fundamental principles of nature, physical phenomena, and abstract ideas. It involves determining which technological advances are worth the inconvenience monopoly protection causes the public at large, and which should remain free for all to use without restriction. This is an issue that has important ramifications for innovation in the ‘knowledge economy’ of the Information Age. Determining whether patent law contains a physicality requirement is integral to deciding whether much of the valuable innovation we are likely to witness, in what are likely to be the emerging areas of technology in the near future, will receive the same encouragement as industrial and manufacturing advances of previous times.

Editorial : advancing innovation in accounting research

We live in uncertain times. The sub-prime crisis that commenced in the U.S. in 2007, the global economic crisis that followed, and the recent sovereign debt crisis in various European countries have led to ongoing instability in global financial markets that continues to receive daily media attention. These uncertain times create enormous opportunities for researchers across many disciplines to research capital markets and business practices. From an accounting perspective, accounting regulators have been active in developing new standards to address risk management issues arising from the crises and have continued to develop and refine financial reporting standards. With the adoption of, or transition to international financial reporting standards (IFRS) in many countries, the globalisation of financial reporting standards is close to becoming a reality. However, doubts still remain about whether the IFRS will lead to any real long-term improvement in financial reporting and transparency (see Sunder, 2011)...

The nature of juristic paradigms : exploring the theoretical and conceptual relationship between adversarialism and therapeutic jurisprudence

Problem solving courts appear to achieve outcomes which are not common in mainstream courts. There are increasing calls for the adoption of more “therapeutic” and “problem solving” practices by mainstream judges in civil and criminal courts in a number of jurisdictions, most notably in the United States and Australia. Currently, a judge who sets out to exercise a significant therapeutic function is quite likely to be doing so in a specialist court or jurisdiction, outside the mainstream court system, and, arguably, from outside the adversarial paradigm itself. To some extent, his work is tolerated but marginalized. But do therapeutic and problem solving functions have the potential to define, rather than complement, the role of judicial officers? The basic question addressed in this paper is, therefore, whether the judicial role could evolve to be not just less adversarial, but fundamentally non-adversarial. In other words, could we see--or are we seeing--a paradigm shift not just in the colloquial, casual sense of the word, but in the strong, worldview changing sense meant by Thomas Kuhn?

The Impact of Parental Attachment on Adolescent Perception of the School Environment and School Connectedness

The extent to which students feel accepted, valued, respected and included in the school has recently surfaced as one of the most important predictors of adolescent mental health (particularly depressive symptoms). The school environment is an established predictor of school connectedness, but we set out to examine whether parental attachment predicts both adolescents' perception of the school environment and school connectedness. A study of 171 high school students from years 8 to 12 showed that parent attachment strongly predicted both. We also confirmed that the relationship between parent attachment and school connectedness is not a direct one but that parent attachment influences individual differences in the way adolescents perceive the school environment, which in turn influences school connectedness. This finding shows how multiple systems might be interlinked in influencing wellbeing in adolescents, and confirms the importance of intervening at the double level of both the family and the school system.

The legal framework for Australia's carbon pricing mechanism : a critique

As part of the Australian Government’s Clean Energy Plan, the Government has attempted to harness the legal innovation of the tradeable emissions unit, within a capped carbon trading system, to reduce greenhouse gas emissions. Such an approach promises to send a price signal to the market which will influence emitting behaviours and reduce our emissions in a cost-effective manner. However, if the carbon trading scheme is to successfully achieve cost-effective emissions reductions then the carbon market must be supported by an appropriate legal framework. This paper will consider the key features of the Australian Carbon Pricing Mechanism, including the Carbon Farming Initiative, and critique whether it has all the hallmarks of an effective legal framework to reduce Australia’s net greenhouse gas emissions. The likely future of the trading scheme, following the 2013 elections, will also be addressed.

Action research as foresight methodology

To the action researcher, who laboriously spends his or her hours working within the local contexts of communities or organisations to co-generate meaningful research, and who’s theories are hardened on the anvil of creating meaningful social change; futures studies might seem the discipline the most peripheral to its interests, and the most ill equipped to deal with the local and intimate domain of community existence. To the futurist, who laboriously spends his or her hours understanding the nuances of history and social change, who through persistent work, begins to make sense of the weak signals and the subtle shifts, action research would seem as simply an auxiliary field, inappropriate for understanding the greater scheme. I invite the reader, however, whether they belong to one camp or the other, to let go of their respective disciplinary perspectives, and see both belonging to each other. [Introduction] .

Conformance checking of service behavior

A service-oriented system is composed of independent software units, namely services, that interact with one another exclusively through message exchanges. The proper functioning of such system depends on whether or not each individual service behaves as the other services expect it to behave. Since services may be developed and operated independently, it is unrealistic to assume that this is always the case. This article addresses the problem of checking and quantifying how much the actual behavior of a service, as recorded in message logs, conforms to the expected behavior as specified in a process model.We consider the case where the expected behavior is defined using the BPEL industry standard (Business Process Execution Language for Web Services). BPEL process definitions are translated into Petri nets and Petri net-based conformance checking techniques are applied to derive two complementary indicators of conformance: fitness and appropriateness. The approach has been implemented in a toolset for business process analysis and mining, namely ProM, and has been tested in an environment comprising multiple Oracle BPEL servers.

A comparison of the psychological, social, and legal factors contributing to speeding and drink driving behaviour

Within Australia, motor vehicle injury is the leading cause of hospital admissions and fatalities. Road crash data reveals that among the factors contributing to crashes in Queensland, speed and alcohol continue to be overrepresented. While alcohol is the number one contributing factor to fatal crashes, speeding also contributes to a high proportion of crashes. Research indicates that risky driving is an important contributor to road crashes. However, it has been debated whether all risky driving behaviours are similar enough to be explained by the same combination of factors. Further, road safety authorities have traditionally relied upon deterrence based countermeasures to reduce the incidence of illegal driving behaviours such as speeding and drink driving. However, more recent research has focussed on social factors to explain illegal driving behaviours. The purpose of this research was to examine and compare the psychological, legal, and social factors contributing to two illegal driving behaviours: exceeding the posted speed limit and driving when over the legal blood alcohol concentration (BAC) for the drivers licence type. Complementary theoretical perspectives were chosen to comprehensively examine these two behaviours including Akers’ social learning theory, Stafford and Warr’s expanded deterrence theory, and personality perspectives encompassing alcohol misuse, sensation seeking, and Type-A behaviour pattern. The program of research consisted of two phases: a preliminary pilot study, and the main quantitative phase. The preliminary pilot study was undertaken to inform the development of the quantitative study and to ensure the clarity of the theoretical constructs operationalised in this research. Semi-structured interviews were conducted with 11 Queensland drivers recruited from Queensland Transport Licensing Centres and Queensland University of Technology (QUT). These interviews demonstrated that the majority of participants had engaged in at least one of the behaviours, or knew of someone who had. It was also found among these drivers that the social environment in which both behaviours operated, including family and friends, and the social rewards and punishments associated with the behaviours, are important in their decision making. The main quantitative phase of the research involved a cross-sectional survey of 547 Queensland licensed drivers. The aim of this study was to determine the relationship between speeding and drink driving and whether there were any similarities or differences in the factors that contribute to a driver’s decision to engage in one or the other. A comparison of the participants self-reported speeding and self-reported drink driving behaviour demonstrated that there was a weak positive association between these two behaviours. Further, participants reported engaging in more frequent speeding at both low (i.e., up to 10 kilometres per hour) and high (i.e., 10 kilometres per hour or more) levels, than engaging in drink driving behaviour. It was noted that those who indicated they drove when they may be over the legal limit for their licence type, more frequently exceeded the posted speed limit by 10 kilometres per hour or more than those who complied with the regulatory limits for drink driving. A series of regression analyses were conducted to investigate the factors that predict self-reported speeding, self-reported drink driving, and the preparedness to engage in both behaviours. In relation to self-reported speeding (n = 465), it was found that among the sociodemographic and person-related factors, younger drivers and those who score high on measures of sensation seeking were more likely to report exceeding the posted speed limit. In addition, among the legal and psychosocial factors it was observed that direct exposure to punishment (i.e., being detected by police), direct punishment avoidance (i.e., engaging in an illegal driving behaviour and not being detected by police), personal definitions (i.e., personal orientation or attitudes toward the behaviour), both the normative and behavioural dimensions of differential association (i.e., refers to both the orientation or attitude of their friends and family, as well as the behaviour of these individuals), and anticipated punishments were significant predictors of self-reported speeding. It was interesting to note that associating with significant others who held unfavourable definitions towards speeding (the normative dimension of differential association) and anticipating punishments from others were both significant predictors of a reduction in self-reported speeding. In relation to self-reported drink driving (n = 462), a logistic regression analysis indicated that there were a number of significant predictors which increased the likelihood of whether participants had driven in the last six months when they thought they may have been over the legal alcohol limit. These included: experiences of direct punishment avoidance; having a family member convicted of drink driving; higher levels of Type-A behaviour pattern; greater alcohol misuse (as measured by the AUDIT); and the normative dimension of differential association (i.e., associating with others who held favourable attitudes to drink driving). A final logistic regression analysis examined the predictors of whether the participants reported engaging in both drink driving and speeding versus those who reported engaging in only speeding (the more common of the two behaviours) (n = 465). It was found that experiences of punishment avoidance for speeding decreased the likelihood of engaging in both speeding and drink driving; whereas in the case of drink driving, direct punishment avoidance increased the likelihood of engaging in both behaviours. It was also noted that holding favourable personal definitions toward speeding and drink driving, as well as higher levels of on Type-A behaviour pattern, and greater alcohol misuse significantly increased the likelihood of engaging in both speeding and drink driving. This research has demonstrated that the compliance with the regulatory limits was much higher for drink driving than it was for speeding. It is acknowledged that while speed limits are a fundamental component of speed management practices in Australia, the countermeasures applied to both speeding and drink driving do not appear to elicit the same level of compliance across the driving population. Further, the findings suggest that while the principles underpinning the current regime of deterrence based countermeasures are sound, current enforcement practices are insufficient to force compliance among the driving population, particularly in the case of speeding. Future research should further examine the degree of overlap between speeding and drink driving behaviour and whether punishment avoidance experiences for a specific illegal driving behaviour serve to undermine the deterrent effect of countermeasures aimed at reducing the incidence of another illegal driving behaviour. Furthermore, future work should seek to understand the factors which predict engaging in speeding and drink driving behaviours at the same time. Speeding has shown itself to be a pervasive and persistent behaviour, hence it would be useful to examine why road safety authorities have been successful in convincing the majority of drivers of the dangers of drink driving, but not those associated with speeding. In conclusion, the challenge for road safety practitioners will be to convince drivers that speeding and drink driving are equally risky behaviours, with the ultimate goal to reduce the prevalence of both behaviours.

Red cap

The field of research is contemporary theatre practice with a community focus. In 2007, La Boite Theatre Company partnered with the Queensland Music Festival to produce an operatic representation of the 1964 Mt Isa industrial dispute, focussed on the charismatic figure of Pat Mackie. “Community theatre” is often criticised on grounds that the work aims only to satisfy community outcomes. This work explored whether a story from a specific location, which is very much an embedded story in the culture of the Mt Isa community, could be told in such a way as to appeal to, resonate with, and have relevance for, broader national and international audiences. To address this question required rigorous interrogation of both content and form. The play was researched through interviews with members of the Mt Isa community, political leadership at the time of the dispute, and participants of the dispute, including Pat Mackie himself. The production was then framed as an oratorio. Uniquely, the play had two back-to-back seasons; the first in Mount Isa (3 shows: 1500 people including a significant number of school children) and a 4-week season at the Roundhouse Theatre, Brisbane (over 5,000 attendances). In each location, a chorale was formed of community participants who, alongside the professional cast, performed the work. The production and its complementary exhibition had a significant local and national profile. The project was featured in The Australian newspaper’s Queensland Music Festival wrap-up as an exemplar of successful community engagement and creative adventure. Playlab Press has since published the script.

Vibrational spectroscopy and solubility study of the mineral stringhamite CaCuSiO4•H2O

Stringhamite CaCuSiO4·H2O is a hydrated calcium copper silicate and is commonly known as a significant ‘healing’ mineral and is potentially a semi-precious jewel. Stringhamite is a neosilicate with Cu2+ in square planar coordination. Vibrational spectroscopy has been used to characterise the molecular structure of stringhamite. The intense sharp Raman band at 956 cm−1 is assigned to the ν1 (A1g) symmetric stretching vibration. Raman bands at 980, 997, 1061 cm−1 are assigned to the ν3 (A2u, B1g) antisymmetric stretching vibrations. Splitting of the ν3 vibrational mode supports the concept that the stringhamite SiO4 tetrahedron is strongly distorted. The intense bands at 505 and 519 cm−1 and at 570 cm−1 are assigned to the ν2 and ν4 vibrational modes. The question arises as to whether the mineral stringhamite can actually function as a healing mineral. An estimation of the solubility product at pH < 5 shows that the cupric ion can be released. The copper ion is a very powerful antibiological agent and thus the mineral stringhamite may well function as a healing mineral.

Patterns of correlation between vehicle occupant seat pressure and anthropometry

Seat pressure is known as a major factor of seat comfort in vehicles. In passenger vehicles, there is lacking research into the seat comfort of rear seat occupants. As accurate seat pressure measurement requires significant effort, simulation of seat pressure is evolving as a preferred method. However, analytic methods are based on complex finite element modeling and therefore are time consuming and involve high investment. Based on accurate anthropometric measurements of 64 male subjects and outboard rear seat pressure measurements in three different passenger vehicles, this study investigates if a set of parameters derived from seat pressure mapping are sensitive enough to differentiate between different seats and whether they correlate with anthropometry in linear models. In addition to the pressure map analysis, H-Points were measured with a coordinate measurement system based on palpated body landmarks and the range of H-Point locations in the three seats is provided. It was found that for the cushion, cushion contact area and cushion front area/force could be modeled by subject anthropometry,while only seatback contact area could be modeled based on anthropometry for all three vehicles. Major differences were found between the vehicles for other parameters.

A radiological method to determine the accuracy of motion capture marker placement on palpable anatomical landmarks through a shoe

The accuracy of marker placement on palpable surface anatomical landmarks is an important consideration in biomechanics. Although marker placement reliability has been studied in some depth, it remains unclear whether or not the markers are accurately positioned over the intended landmark in order to define the static position and orientation of the segment. A novel method using commonly available X-ray imaging was developed to identify the accuracy of markers placed on the shoe surface by palpating landmarks through the shoe. An anterior–posterior and lateral–medial X-ray was taken on 24 participants with a newly developed marker set applied to both the skin and shoe. The vector magnitude of both skin- and shoe-mounted markers from the anatomical landmark was calculated, as well as the mean marker offset between skin- and shoe-mounted markers. The accuracy of placing markers on the shoe relative to the skin-mounted markers, accounting for shoe thickness, was less than 5mm for all markers studied. Further, when using the developed guidelines provided in this study, the method was deemed reliable (Intra-rater ICCs¼0.50–0.92). In conclusion, the method proposed here can reliably assess marker placement accuracy on the shoe surface relative to chosen anatomical landmarks beneath the skin.

Improving posture and decreasing pain with novel shoe insoles

A single subject longevity study is presented as a case study for the Medical Device Partnering Program (MDPP). The MDPP supports the development of cutting-edge medical devices and assistive technologies, through unique collaborations between researchers, industry, clinical end-users and government. The study aimed to identify what effect the innersole has on specific muscles that may influence stability and whether the innersole had any influence on gait. Three tests were conducted; a standard gait test, dynamic balance test and a standing balance test. Results from the kinematic analysis showed reduced variability in post testing results when compared to pre testing results. Reductions in muscle activation levels were also found across all tests. Further testing with a larger sample size is required to determine if these effects are due to the innersole.

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.