In vivo knockdown of the androgen receptor results in growth inhibition and regression of well-established, castration-resistant prostate tumours

Purpose: Progression to the castration-resistant state is the incurable and lethal end stage of prostate cancer, and there is strong evidence that androgen receptor (AR) still plays a central role in this process. We hypothesize that knocking down AR will have a major effect on inhibiting growth of castration-resistant tumors. Experimental Design: Castration-resistant C4-2 human prostate cancer cells stably expressing a tetracycline-inducible AR-targeted short hairpin RNA (shRNA) were generated to directly test the effects of AR knockdown in C4-2 human prostate cancer cells and tumors. Results:In vitro expression of AR shRNA resulted in decreased levels of AR mRNA and protein, decreased expression of prostate-specific antigen (PSA), reduced activation of the PSA-luciferase reporter, and growth inhibition of C4-2 cells. Gene microarray analyses revealed that AR knockdown under hormone-deprived conditions resulted in activation of genes involved in apoptosis, cell cycle regulation, protein synthesis, and tumorigenesis. To ensure that tumors were truly castration-resistant in vivo, inducible AR shRNA expressing C4-2 tumors were grown in castrated mice to an average volume of 450 mm3. In all of the animals, serum PSA decreased, and in 50% of them, there was complete tumor regression and disappearance of serum PSA. Conclusions: Whereas castration is ineffective in castration-resistant prostate tumors, knockdown of AR can decrease serum PSA, inhibit tumor growth, and frequently cause tumor regression. This study is the first direct evidence that knockdown of AR is a viable therapeutic strategy for treatment of prostate tumors that have already progressed to the castration-resistant state.

Natural and engineered kallikrein inhibitors: an emerging pharmacopoeia

The kallikreins and kallikrein-related peptidases are serine proteases that control a plethora of developmental and homeostatic phenomena, ranging from semen liquefaction to skin desquamation and blood pressure. The diversity of roles played by kallikreins has stimulated considerable interest in these enzymes from the perspective of diagnostics and drug design. Kallikreins already have well-established credentials as targets for therapeutic intervention and there is increasing appreciation of their potential both as biomarkers and as targets for inhibitor design. Here, we explore the current status of naturally occurring kallikrein protease-inhibitor complexes and illustrate how this knowledge can interface with strategies for rational re-engineering of bioscaffolds and design of small-molecule inhibitors.

A longitudinal study of the impact of chronic psychological stress on health-related quality of life and clinical biomarkers : protocol for the Australian Healthy Aging of Women Study

BACKGROUND: Despite advancements in our understanding of the importance of stress reduction in achieving good health, we still only have limited insight into the impact of stress on cellular function. Recent studies have suggested that exposure to prolonged psychological stress may alter an individual's physiological responses, and contribute to morbidity and mortality. This paper presents an overview of the study protocol we are using to examine the impact of life stressors on lifestyle factors, health-related quality of life and novel and established biomarkers of stress in midlife and older Australian women.The primary aim of this study is to explore the links between chronic psychological stress on both subjective and objective health markers in midlife and older Australian women. The study examines the extent to which exposure frightening, upsetting or stressful events such as natural disasters, illness or death of a relative, miscarriage and relationship conflict is correlated with a variety of objective and subjective health markers.Methods/design: This study is embedded within the longitudinal Healthy Aging of Women's study which has collected data from midlife and older Australian women at 5 yearly intervals since 2001, and uses the Allostastic model of women's health by Groer and colleagues in 2010. The current study expands the focus of the HOW study and will assess the impact of life stressors on quality of life and clinical biomarkers in midlife and older Australian women to explain the impact of chronic psychological stress in women. DISCUSSION: The proposed study hypothesizes that women are at increased risk of exposure to multiple or repeated stressors, some being unique to women, and the frequency and chronicity of stressors increases women's risk of adverse health outcomes. This study aims to further our understanding of the relationships between stressful life experiences, perceived quality of life, stress biomarkers, chronic illness, and health status in women.

Time pressure and coworker support mediate the curvilinear relationship between age and occupational well-being

As the proportion of older employees in the workforce is growing, researchers have become increasingly interested in the association between age and occupational well-being. The curvilinear nature of relationships between age and job satisfaction and between age and emotional exhaustion is well-established in the literature, with employees in their late 20s to early 40s generally reporting lower levels of occupational well-being than younger and older employees. However, the mechanisms underlying these curvilinear relationships are so far not well understood due to a lack of studies testing mediation effects. Based on an integration of role theory and research from the adult development and career literatures, this study examined time pressure, work–home conflict, and coworker support as mediators of the relationships between age and job satisfaction and between age and emotional exhaustion. Data came from 771 employees between 17 and 74 years of age in the construction industry. Results showed that employees in their late 20s to early 40s had lower job satisfaction and higher emotional exhaustion than younger and older employees. Time pressure and coworker support fully mediated both the U-shaped relationship between age and job satisfaction and the inversely U-shaped relationship between age and emotional exhaustion. These findings suggest that organizational interventions may help increase the relatively low levels of occupational well-being in certain age groups.

Heathcote’s practice-led teaching: Pioneering research as well as pioneering pedagogy

It is widely recognized that Dorothy Heathcote was a dynamic and radical teacher who transformed and continually reinvented drama teaching. She did this by allowing her emerging thinking and understandings to flow from, and be tested by, regular and intensive ‘practicing’ in the classroom. In this way theoretical claims were grounded and evidenced in authentic classroom practice. And yet, for all her impact, it is rare to hear the claim that Heathcote’s pedagogic breakthroughs resulted from a legitimate research methodology. Clever and charismatic teaching yes; research no. One of the world’s best teachers certainly, but not a researcher; even though every lesson was experimental and every classroom was a site for discovery. This paper investigates that conundrum firstly by acknowledging that Heathcote’s practice-led teaching approach to discovery did not map comfortably on to the established educational research traditions of the day. It argues that traditional research methodologies, with their well-established protocols and methods, could not understand or embrace a research process which does its work by creating ‘fictional realities’ of openness, allegory and uncertainty. In recent years however it can be seen that Heathcote’s practice led-teaching, so essential for advancing the field, closely aligns with what many contemporary researchers are now calling practice-led research or practice as research or, in many Nordic countries, artistic research. A form of performative research, practice-led research has not emerged from the field of education but rather from the creative arts. Seeking to develop ways of researching creative practice which is deeply sympathetic and respectful of that practice, artist-researchers have developed practice-led research “which is initiated in practice, where questions, problems, challenges are identified and formed by the needs of practice and practitioners” (Grey, 1996). This sits comfortably with Heathcote’s classroom priority of “discovering by trial, error and testing; using available materials with respect for their nature, and being guided by this appreciation of their potential” (Heathcote, 1967). The paper will conclude by testing the dynamics of Heathcote’s practice-led teaching against the six conditions of practice-led research (Haseman&Mafe, 2011), a testing which will allow for a re-interpretation and re-housing of Dorothy Heathcote’s classroom-based teaching methodology as a form of performative research in its own right.

The kallikrein-related peptidase family: Dysregulation and functions during cancer progression

Cancer is the second leading cause of death with 14 million new cases and 8.2 million cancer-related deaths worldwide in 2012. Despite the progress made in cancer therapies, neoplastic diseases are still a major therapeutic challenge notably because of intra- and inter-malignant tumour heterogeneity and adaptation/escape of malignant cells to/from treatment. New targeted therapies need to be developed to improve our medical arsenal and counter-act cancer progression. Human kallikrein-related peptidases (KLKs) are secreted serine peptidases which are aberrantly expressed in many cancers and have great potential in developing targeted therapies. The potential of KLKs as cancer biomarkers is well established since the demonstration of the association between KLK3/PSA (prostate specific antigen) levels and prostate cancer progression. In addition, a constantly increasing number of in vitro and in vivo studies demonstrate the functional involvement of KLKs in cancer-related processes. These peptidases are now considered key players in the regulation of cancer cell growth, migration, invasion, chemo-resistance, and importantly, in mediating interactions between cancer cells and other cell populations found in the tumour microenvironment to facilitate cancer progression. These functional roles of KLKs in a cancer context further highlight their potential in designing new anti-cancer approaches. In this review, we comprehensively review the biochemical features of KLKs, their functional roles in carcinogenesis, followed by the latest developments and the successful utility of KLK-based therapeutics in counteracting cancer progression.

A model for assessing and correcting construction project health

Abstract Maintaining the health of a construction project can help to achieve the desired outcomes of the project. An analogy is drawn to the medical process of a human health check where it is possible to broadly diagnose health in terms of a number of key areas such as blood pressure or cholesterol level. Similarly it appears possible to diagnose the current health of a construction project in terms of a number of Critical Success Factors (CSFs) and key performance indicators (KPIs). The medical analogy continues into the detailed investigation phase where a number of contributing factors are evaluated to identify possible causes of ill health and through the identification of potential remedies to return the project to the desired level of health. This paper presents the development of a model that diagnoses the immediate health of a construction project, investigates the factors which appear to be causing the ill health and proposes a remedy to return the project to good health. The proposed model uses the well-established continuous improvement management model (Deming, 1986) to adapt the process of human physical health checking to construction project health.

Business and software service lifecycle management

Although the service-oriented paradigm has been well established in the technical domain for quite some time now, service governance is still considered a research gap. To ensure adequate governance, there is a necessity to manage services as first-class assets throughout the lifecycle. Now that the concept of ser-vice-orientation is also increasingly applied on the business level to structure an organisation’s capabili-ties, the problem has become an even bigger chal-lenge. This paper presents a generic business and software service lifecycle and aligns it with the com-mon management layers in organisations. Using ser-vice analysis as an example, it moreover illustrates how activities in the service lifecycle may vary on lower levels of granularity depending on the focus on business or software services.

Open Specification for BIM : Sydney Opera House Case Study

Executive Summary The objective of this report was to use the Sydney Opera House as a case study of the application of Building Information Modelling (BIM). The Sydney opera House is a complex, large building with very irregular building configuration, that makes it a challenging test. A number of key concerns are evident at SOH: • the building structure is complex, and building service systems - already the major cost of ongoing maintenance - are undergoing technology change, with new computer based services becoming increasingly important. • the current “documentation” of the facility is comprised of several independent systems, some overlapping and is inadequate to service current and future services required • the building has reached a milestone age in terms of the condition and maintainability of key public areas and service systems, functionality of spaces and longer term strategic management. • many business functions such as space or event management require up-to-date information of the facility that are currently inadequately delivered, expensive and time consuming to update and deliver to customers. • major building upgrades are being planned that will put considerable strain on existing Facilities Portfolio services, and their capacity to manage them effectively While some of these concerns are unique to the House, many will be common to larger commercial and institutional portfolios. The work described here supported a complementary task which sought to identify if a building information model – an integrated building database – could be created, that would support asset & facility management functions (see Sydney Opera House – FM Exemplar Project, Report Number: 2005-001-C-4 Building Information Modelling for FM at Sydney Opera House), a business strategy that has been well demonstrated. The development of the BIMSS - Open Specification for BIM has been surprisingly straightforward. The lack of technical difficulties in converting the House’s existing conventions and standards to the new model based environment can be related to three key factors: • SOH Facilities Portfolio – the internal group responsible for asset and facility management - have already well established building and documentation policies in place. The setting and adherence to well thought out operational standards has been based on the need to create an environment that is understood by all users and that addresses the major business needs of the House. • The second factor is the nature of the IFC Model Specification used to define the BIM protocol. The IFC standard is based on building practice and nomenclature, widely used in the construction industries across the globe. For example the nomenclature of building parts – eg ifcWall, corresponds to our normal terminology, but extends the traditional drawing environment currently used for design and documentation. This demonstrates that the international IFC model accurately represents local practice for building data representation and management. • a BIM environment sets up opportunities for innovative processes that can exploit the rich data in the model and improve services and functions for the House: for example several high-level processes have been identified that could benefit from standardized Building Information Models such as maintenance processes using engineering data, business processes using scheduling, venue access, security data and benchmarking processes using building performance data. The new technology matches business needs for current and new services. The adoption of IFC compliant applications opens the way forward for shared building model collaboration and new processes, a significant new focus of the BIM standards. In summary, SOH current building standards have been successfully drafted for a BIM environment and are confidently expected to be fully developed when BIM is adopted operationally by SOH. These BIM standards and their application to the Opera House are intended as a template for other organisations to adopt for the own procurement and facility management activities. Appendices provide an overview of the IFC Integrated Object Model and an understanding IFC Model Data.

A model for assessing and correcting project Health

Maintaining the health of a construction project can help to achieve the desired outcomes of the project. An analogy is drawn to the medical process of a human health check where it is possible to broadly diagnose health in terms of a number of key areas such as blood pressure or cholesterol level. Similarly it appears possible to diagnose the current health of a construction project in terms of a number of Critical Success Factors (CSFs) and key performance indicators (KPIs). The medical analogy continues into the detailed investigation phase where a number of contributing factors are evaluated to identify possible causes of ill health and through the identification of potential remedies to return the project to the desired level of health. This paper presents the development of a model that diagnoses the immediate health of a construction project, investigates the factors which appear to be causing the ill health and proposes a remedy to return the project to good health. The proposed model uses the well-established continuous improvement management model (Deming, 1986) to adapt the process of human physical health checking to construction project health.

Knowing a donor and identifying as one : determinants of people's willingness for related and anonymous living donation in Australia

While LRD (living donation to a genetically/emotionally related recipient) is well established in Australia, LAD (living anonymous donation to a stranger) is rare. Given the increasing use of LAD overseas, Australia may likely follow suit. Understanding the determinants of people’s willingness for LAD is essential but infrequently studied in Australia. Consequently, we compared the determinants of people’s LRD and LAD willingness, and assessed whether these determinants differed according to type of living donation. We surveyed 487 health students about their LRD and LAD willingness, attitudes, identity, prior experience with blood and organ donation, deceased donation preference, and demographics. We used Structural Equation Modelling (SEM) to identify the determinants of willingness for LRD and LAD and paired sample t-tests to examine differences in LRD and LAD attitudes, identity, and willingness. Mean differences in willingness (LRD 5.93, LAD 3.92), attitudes (LRD 6.43, LAD 5.53), and identity (LRD 5.69, LAD 3.58) were statistically significant. Revised SEM models provided a good fit to the data (LRD: x2 (41) = 67.67, p = 0.005, CFI = 0.96, RMSEA = 0.04; LAD: x2 (40) = 79.64, p < 0.001, CFI = 0.95, RMSEA = 0.05) and explained 45% and 54% of the variation in LRD and LAD willingness, respectively. Four common determinants of LRD and LAD willingness emerged: identity, attitude, past blood donation, and knowing a deceased donor. Religious affiliation and deceased donation preference predicted LAD willingness also. Identifying similarities and differences in these determinants can inform future efforts aimed at understanding people’s LRD and LAD willingness and the evaluation of potential living donor motives. Notably, this study highlights the importance of people’s identification as a living donor as a motive underlying their willingness to donate their organs while living.

Establishment of a preclinical ovine model for tibial segmental bone defect repair by applying bone tissue engineering strategies

Currently, well-established clinical therapeutic approaches for bone reconstruction are restricted to the transplantation of autografts and allografts, and the implantation of metal devices or ceramic-based implants to assist bone regeneration. Bone grafts possess osteoconductive and osteoinductive properties, however they are limited in access and availability and associated with donor site morbidity, haemorrhage, risk of infection, insufficient transplant integration, graft devitalisation, and subsequent resorption resulting in decreased mechanical stability. As a result, recent research focuses on the development of alternative therapeutic concepts. The field of tissue engineering has emerged as an important approach to bone regeneration. However, bench to bedside translations are still infrequent as the process towards approval by regulatory bodies is protracted and costly, requiring both comprehensive in vitro and in vivo studies. The subsequent gap between research and clinical translation, hence commercialization, is referred to as the ‘Valley of Death’ and describes a large number of projects and/or ventures that are ceased due to a lack of funding during the transition from product/technology development to regulatory approval and subsequently commercialization. One of the greatest difficulties in bridging the Valley of Death is to develop good manufacturing processes (GMP) and scalable designs and to apply these in pre-clinical studies. In this article, we describe part of the rationale and road map of how our multidisciplinary research team has approached the first steps to translate orthopaedic bone engineering from bench to bedside byestablishing a pre-clinical ovine critical-sized tibial segmental bone defect model and discuss our preliminary data relating to this decisive step.

The genetic basis of human height : the role of estrogen

Height is a complex physical trait that displays strong heritability. Adult height is related to length of the long bones, which is determined by growth at the epiphyseal growth plate. Longitudinal bone growth occurs via the process of endochondral ossification, where bone forms over the differentiating cartilage template at the growth plate. Estrogen plays a major role in regulating longitudinal bone growth and is responsible for inducing the pubertal growth spurt and fusion of the epiphyseal growth plate. However, the mechanism by which estrogen promotes epiphyseal fusion is poorly understood. It has been hypothesised that estrogen functions to regulate growth plate fusion by stimulating chondrocyte apoptosis, angiogenesis and bone cell invasion in the growth plate. Another theory has suggested that estrogen exposure exhausts the proliferative capacity of growth plate chondrocytes, which accelerates the process of chondrocyte senescence, leading to growth plate fusion. The overall objective of this study was to gain a greater understanding of the molecular mechanisms behind estrogen-mediated growth and height attainment by examining gene regulation in chondrocytes and the role of some of these genes in normal height inheritance. With the heritability of height so well established, the initial hypothesis was that genetic variation in candidate genes associated with longitudinal bone growth would be involved in normal adult height variation. The height-related genes FGFR3, CBFA1, ER and CBFA1 were screened for novel polymorphisms using denaturing HPLC and RFLP analysis. In total, 24 polymorphisms were identified. Two SNPs in ER (rs3757323 C>T and rs1801132 G>C) were strongly associated with adult male height and displayed an 8 cm and 9 cm height difference between homozygous genotypes, respectively. The TC haplotype of these SNPs was associated with a 6 cm decrease in height and remarkably, no homozygous carriers of the TC haplotype were identified in tall subjects. No significant associations with height were found for polymorphisms in the FGFR3, CBFA1 or VDR genes. In the epiphyseal growth plate, chondrocyte proliferation, matrix synthesis and chondrocyte hypertrophy are all major contributors to long bone growth. As estrogen plays such a significant role in both growth and final height attainment, another hypothesis of this study was that estrogen exerted its effects in the growth plate by influencing chondrocyte proliferation and mediating the expression of chondrocyte marker genes. The examination of genes regulated by estrogen in chondrocyte-like cells aimed to identify potential regulators of growth plate fusion, which may further elucidate mechanisms involved in the cessation of linear growth. While estrogen did not dramatically alter the proliferation of the SW1353 cell line, gene expression experiments identified several estrogen regulated genes. Sixteen chondrocyte marker genes were examined in response to estrogen concentrations ranging from 10-12 M to 10-8 M over varying time points. Of the genes analysed, IHH, FGFR3, collagen II and collagen X were not readily detectable and PTHrP, GHR, ER, BMP6, SOX9 and TGF1 mRNAs showed no significant response to estrogen treatments. However, the expression of MMP13, CBFA1, BCL-2 and BAX genes were significantly decreased. Interestingly, the majority of estrogen regulated genes in SW1353 cells are expressed in the hypertrophic zone of the growth plate. Estrogen is also known to regulate systemic GH secretion and local GH action. At the molecular level, estrogen functions to inhibit GH action by negatively regulating GH signalling. GH treated SW1353 cells displayed increases in MMP9 mRNA expression (4.4-fold) and MMP13 mRNA expression (64-fold) in SW1353 cells. Increases were also detected in their respective proteins. Treatment with AG490, an established JAK2 inhibitor, blocked the GH mediated stimulation of both MMP9 and MMP13 mRNA expression. The application of estrogen and GH to SW1353 cells attenuated GH-stimulated MMP13 levels, but did not affect MMP9 levels. Investigation of GH signalling revealed that SW1353 cells have high levels of activated JAK2 and exposure to GH, estrogen, AG490 and other signalling inhibitors did not affect JAK2 phosphorylation. Interestingly, AG490 treatment dramatically decreased ERK2 signalling, although GH did stimulate ERK2 phosphorylation above control levels. AG490 also decreased CBFA1 expression, a transcription factor known to activate MMP9 and MMP13. Finally, GH and estrogen treatment increased expression of SOCS3 mRNA, suggesting that SOCS3 may regulate JAK/STAT signalling in SW1353 cells. The modulation of GH-mediated MMP expression by estrogen in SW1353 cells represents a potentially novel mechanism by which estrogen may regulate longitudinal bone growth. However, further investigation is required in order to elucidate the precise mechanisms behind estrogen and GH regulation of MMP13 expression in SW1353 cells. This study has provided additional evidence that estrogen and the ER gene are major factors in the regulation of growth and the determination of adult height. Newly identified polymorphisms in the ER gene not only contribute to our understanding of the genetic basis of human height, but may also be useful in association studies examining other complex traits. This study also identified several estrogen regulated genes and indicated that estrogen modifies the expression of genes which are primarily expressed in the hypertrophic region of the epiphyseal growth plate. Furthermore, synergistic studies incorporating GH and estrogen have revealed the ability of estrogen to attenuate the effects of GH on MMP13 expression, revealing potential pathways by which estrogen may modulate growth plate fusion, longitudinal bone growth and even arthritis.

Developing a best practice framework for implementing public private partnerships (PPP) in Hong Kong

Public Private Partnership (PPP) is a well established methodology for procuring public works projects. By incorporating the private sector’s expertise, efficiency, innovation, business sense, risk sharing, financing etc. into public works projects, the quality of public services and facilities can be uplifted. Like many jurisdictions, Hong Kong is also keen to take aboard this methodology which is so familiar but yet so distant. Although they have been one of the first jurisdictions to utilise the private sector in public works projects, their comfortable financial reserves has meant that there has been no urge to push the movement until recently. PPP has become increasingly popular amongst governments. The Hong Kong Special Administrative Region (HKSAR) government is no exception. Some of the more active works departments have commissioned studies to investigate the best ways to deliver these projects, others have even trialed the method themselves. The efficiency Unit of the HKSAR government has also become an active arm in conducting research in this area. Although so, the information that is currently available is still very broad. Building from their works there is a need to develop a best practice framework for implementing PPP projects in Hong Kong by incorporating international experiences. To develop a best practice framework will require thorough investigation into the benefits, difficulties and critical success factor of PPP. PPP should also be compared with other procurement methods. In order to do so it is important to clearly understand the local situation by an analysis of projects conducted to date. Lessons learnt can further be derived from other countries and incorporated to those derived locally. Finally the best conditions in terms of project nature, complexity, types, and scales for adopting PPP should be derived. The aim and objectives of this study were achieved via a comprehensive literature review, in-depth case analyses, interview survey with experts from both Hong Kong and overseas, and finally a large scale data collection was conducted via a questionnaire survey with PPP practitioners. These findings were further triangulated before they were used as the basis to form the best practice framework presented in this thesis. The framework was then further validated by PPP experts to ensure it is comprehensive, objective, reliable and practical. This study has presented a methodology that can be adopted for future studies. It has also updated our knowledge on the development trends of PPP as well as opened up the experiences of other jurisdictions. The findings have shown that the local industry is familiar with “what” should be done in PPP projects but they are unsure of “how” these goals can be achieved. This framework has allowed this further knowledge to be delivered to PPP practitioners. As a result, the development of this framework can help to resolve the current economic crisis by encouraging more developments and business opportunities for the private sector. In addition, the correct projects can be delivered by PPP, the advantages of PPP can be maximised, and the general public can benefit from the private sector’s participation.

Waterfront Development for Residential Property in Malaysia

Rivers and water are valuable natural resources for human life, environment and national development. Recognition of water resources as national heritage will contribute towards more long term sustainable property development. Waterfront development is already a well-established phenomenon internationally. In Malaysia, as the economy began to change in 1980s, so did the land uses along many of the river and waterfront locations. The pressures of new technology coupled with an urban population growth and urbanization began to force a transition from water dependent industry to a variety of non-water dependent developments such as apartments, offices, and retail shopping areas. Residential waterfront development has taken advantage of available land and water amenities and incorporated as a feature or “selling point” of the development. It has been found that wide views of water add an average of 59% to the value of waterfront property, as well as providing attractive landscaping and better property neighborhoods respectively. Development of waterfront lands in Malaysia occurred with limited federal, state, or municipal planning guidance; resulting in cost aspects like flooding and pollution. Although some waterfront development projects continue to remain profitable with a maintained successful public access component, many have not. This paper provides a brief introduction to the research project to address this issue, which is currently on-going.