Crosstalk between developmental and tumour-specific signalling pathways : kallikrein-related serine peptidases and nodal in prostrate cancer

Prostate cancer is an important male health issue. The strategies used to diagnose and treat prostate cancer underscore the cell and molecular interactions that promote disease progression. Prostate cancer is histologically defined by increasingly undifferentiated tumour cells and therapeutically targeted by androgen ablation. Even as the normal glandular architecture of the adult prostate is lost, prostate cancer cells remain dependent on the androgen receptor (AR) for growth and survival. This project focused on androgen-regulated gene expression, altered cellular differentiation, and the nexus between these two concepts. The AR controls prostate development, homeostasis and cancer progression by regulating the expression of downstream genes. Kallikrein-related serine peptidases are prominent transcriptional targets of AR in the adult prostate. Kallikrein 3 (KLK3), which is commonly referred to as prostate-specific antigen, is the current serum biomarker for prostate cancer. Other kallikreins are potential adjunct biomarkers. As secreted proteases, kallikreins act through enzyme cascades that may modulate the prostate cancer microenvironment. Both as a panel of biomarkers and cascade of proteases, the roles of kallikreins are interconnected. Yet the expression and regulation of different kallikreins in prostate cancer has not been compared. In this study, a spectrum of prostate cell lines was used to evaluate the expression profile of all 15 members of the kallikrein family. A cluster of genes was co-ordinately expressed in androgenresponsive cell lines. This group of kallikreins included KLK2, 3, 4 and 15, which are located adjacent to one another at the centromeric end of the kallikrein locus. KLK14 was also of interest, because it was ubiquitously expressed among the prostate cell lines. Immunohistochemistry showed that these 5 kallikreins are co-expressed in benign and malignant prostate tissue. The androgen-regulated expression of KLK2 and KLK3 is well-characterised, but has not been compared with other kallikreins. Therefore, KLK2, 3, 4, 14 and 15 expression were all measured in time course and dose response experiments with androgens, AR-antagonist treatments, hormone deprivation experiments and cells transfected with AR siRNA. Collectively, these experiments demonstrated that prostatic kallikreins are specifically and directly regulated by the AR. The data also revealed that kallikrein genes are differentially regulated by androgens; KLK2 and KLK3 were strongly up-regulated, KLK4 and KLK15 were modestly up-regulated, and KLK14 was repressed. Notably, KLK14 is located at the telomeric end of the kallikrein locus, far away from the centromeric cluster of kallikreins that are stimulated by androgens. These results show that the expression of KLK2, 3, 4, 14 and 15 is maintained in prostate cancer, but that these genes exhibit different responses to androgens. This makes the kallikrein locus an ideal model to investigate AR signalling. The increasingly dedifferentiated phenotype of aggressive prostate cancer cells is accompanied by the re-expression of signalling molecules that are usually expressed during embryogenesis and foetal tissue development. The Wnt pathway is one developmental cascade that is reactivated in prostate cancer. The canonical Wnt cascade regulates the intracellular levels of β-catenin, a potent transcriptional co-activator of T-cell factor (TCF) transcription factors. Notably, β-catenin can also bind to the AR and synergistically stimulate androgen-mediated gene expression. This is at the expense of typical Wnt/TCF target genes, because the AR:β-catenin and TCF:β-catenin interactions are mutually exclusive. The effect of β-catenin on kallikrein expression was examined to further investigate the role of β-catenin in prostate cancer. Stable knockdown of β-catenin in LNCaP prostate cancer cells attenuated the androgen-regulated expression of KLK2, 3, 4 and 15, but not KLK14. To test whether KLK14 is instead a TCF:β-catenin target gene, the endogenous levels of β-catenin were increased by inhibiting its degradation. Although KLK14 expression was up-regulated by these treatments, siRNA knockdown of β-catenin demonstrated that this effect was independent of β-catenin. These results show that β-catenin is required for maximal expression of KLK2, 3, 4 and 15, but not KLK14. Developmental cells and tumour cells express a similar repertoire of signalling molecules, which means that these different cell types are responsive to one another. Previous reports have shown that stem cells and foetal tissues can reprogram aggressive cancer cells to less aggressive phenotypes by restoring the balance to developmental signalling pathways that are highly dysregulated in cancer. To investigate this phenomenon in prostate cancer, DU145 and PC-3 prostate cancer cells were cultured on matrices pre-conditioned with human embryonic stem cells (hESCs). Soft agar assays showed that prostate cancer cells exposed to hESC conditioned matrices had reduced clonogenicity compared with cells harvested from control matrices. A recent study demonstrated that this effect was partially due to hESC-derived Lefty, an antagonist of Nodal. A member of the transforming growth factor β (TGFβ) superfamily, Nodal regulates embryogenesis and is re-expressed in cancer. The role of Nodal in prostate cancer has not previously been reported. Therefore, the expression and function of the Nodal signalling pathway in prostate cancer was investigated. Western blots confirmed that Nodal is expressed in DU145 and PC-3 cells. Immunohistochemistry revealed greater expression of Nodal in malignant versus benign glands. Notably, the Nodal inhibitor, Lefty, was not expressed at the mRNA level in any prostate cell lines tested. The Nodal signalling pathway is functionally active in prostate cancer cells. Recombinant Nodal treatments triggered downstream phosphorylation of Smad2 in DU145 and LNCaP cells, and stably-transfected Nodal increased the clonogencity of LNCaP cells. Nodal was also found to modulate AR signalling. Nodal reduced the activity of an androgen-regulated KLK3 promoter construct in luciferase assays and attenuated the endogenous expression of AR target genes including prostatic kallikreins. These results demonstrate that Nodal is a novel example of a developmental signalling molecule that is reexpressed in prostate cancer and may have a functional role in prostate cancer progression. In summary, this project clarifies the role of androgens and changing cellular differentiation in prostate cancer by characterising the expression and function of the downstream genes encoding kallikrein-related serine proteases and Nodal. Furthermore, this study emphasises the similarities between prostate cancer and early development, and the crosstalk between developmental signalling pathways and the AR axis. The outcomes of this project also affirm the utility of the kallikrein locus as a model system to monitor tumour progression and the phenotype of prostate cancer cells.

TCSC control design for transient stability improvement of a multi-machine power system using trajectory sensitivity

This paper discusses the effects of thyristor controlled series compensator (TCSC), a series FACTS controller, on the transient stability of a power system. Trajectory sensitivity analysis (TSA) has been used to measure the transient stability condition of the system. The TCSC is modeled by a variable capacitor, the value of which changes with the firing angle. It is shown that TSA can be used in the design of the controller. The optimal locations of the TCSC-controller for different fault conditions can also be identified with the help of TSA. The paper depicts the advantage of the use of TCSC with a suitable controller over fixed capacitor operation.

Socioeconomic inequality profiles in physical and developmental health from 0-7 years : Australian National Study

Background: Early and persistent exposure to socioeconomic disadvantage impairs children’s health and wellbeing. However, it is unclear at what age health inequalities emerge or whether these relationships vary across ages and outcomes. We address these issues using cross-sectional Australian population data on the physical and developmental health of children at ages 0-1, 2-3, 4-5 and 6-7 years. Methods: 10 physical and developmental health outcomes were assessed in 2004 and 2006 for two cohorts each comprising around 5000 children. Socioeconomic position was measured as a composite of parental education, occupation and household income. Results: Lower socioeconomic position was associated with increased odds for poor outcomes. For physical health outcomes and socio-emotional competence, associations were similar across age groups and were consistent with either threshold effects (for poor general health, special healthcare needs and socio-emotional competence) or gradient effects (for illness with wheeze, sleep problems and injury). For socio-emotional difficulties, communication, vocabulary and emergent literacy, stronger socioeconomic associations were observed. The patterns were linear or accelerated and varied across ages. Conclusions: From very early childhood, social disadvantage was associated with poorer outcomes across most measures of physical and developmental health and showed no evidence of either strengthening or attenuating at older compared to younger ages. Findings confirm the importance of early childhood as a key focus for health promotion and prevention efforts.

Bubble rise velocity and trajectory in xanthan gum crystal suspension

An experimental set-up was used to visually observe the characteristics of bubbles as they moved up a column holding xanthan gum crystal suspensions. The bubble rise characteristics in xanthan gum solutions with crystal suspension are presented in this paper. The suspensions were made by using different concentrations of xanthan gum solutions with 0.23 mm mean diameter polystyrene crystal particles. The influence of the dimensionless quantities; namely the Reynolds number, Re, the Weber number, We, and the drag co-efficient, cd, are identified for the determination of the bubble rise velocity. The effect of these dimensionless groups together with the Eötvös number, Eo, the Froude number, Fr, and the bubble deformation parameter, D, on the bubble rise velocity and bubble trajectory are analysed. The experimental results show that the average bubble velocity increases with the increase in bubble volume for xanthan gum crystal suspensions. At high We, Eo and Re, bubbles are spherical-capped and their velocities are found to be very high. At low We and Eo, the surface tension force is significant compared to the inertia force. The viscous forces were shown to have no substantial effect on the bubble rise velocity for 45 < Re < 299. The results show that the drag co-efficient decreases with the increase in bubble velocity and Re. The trajectory analysis showed that small bubbles followed a zigzag motion while larger bubbles followed a spiral motion. The smaller bubbles experienced less horizontal motion in crystal suspended xanthan gum solutions while larger bubbles exhibited a greater degree of spiral motion than those seen in the previous studies on the bubble rise in xanthan gum solutions without crystal.

Autonomous underwater vehicle trajectory design coupled with predictive ocean models : a case study

Data collection using Autonomous Underwater Vehicles (AUVs) is increasing in importance within the oceano- graphic research community. Contrary to traditional moored or static platforms, mobile sensors require intelligent planning strategies to manoeuvre through the ocean. However, the ability to navigate to high-value locations and collect data with specific scientific merit is worth the planning efforts. In this study, we examine the use of ocean model predictions to determine the locations to be visited by an AUV, and aid in planning the trajectory that the vehicle executes during the sampling mission. The objectives are: a) to provide near-real time, in situ measurements to a large-scale ocean model to increase the skill of future predictions, and b) to utilize ocean model predictions as a component in an end-to-end autonomous prediction and tasking system for aquatic, mobile sensor networks. We present an algorithm designed to generate paths for AUVs to track a dynamically evolving ocean feature utilizing ocean model predictions. This builds on previous work in this area by incorporating the predicted current velocities into the path planning to assist in solving the 3-D motion planning problem of steering an AUV between two selected locations. We present simulation results for tracking a fresh water plume by use of our algorithm. Additionally, we present experimental results from field trials that test the skill of the model used as well as the incorporation of the model predictions into an AUV trajectory planner. These results indicate a modest, but measurable, improvement in surfacing error when the model predictions are incorporated into the planner.

A geometric approach to trajectory design for an autonomous underwater vehicle : surveying the bulbous bow of a ship

In this paper, we present a control strategy design technique for an autonomous underwater vehicle based on solutions to the motion planning problem derived from differential geometric methods. The motion planning problem is motivated by the practical application of surveying the hull of a ship for implications of harbor and port security. In recent years, engineers and researchers have been collaborating on automating ship hull inspections by employing autonomous vehicles. Despite the progresses made, human intervention is still necessary at this stage. To increase the functionality of these autonomous systems, we focus on developing model-based control strategies for the survey missions around challenging regions, such as the bulbous bow region of a ship. Recent advances in differential geometry have given rise to the field of geometric control theory. This has proven to be an effective framework for control strategy design for mechanical systems, and has recently been extended to applications for underwater vehicles. Advantages of geometric control theory include the exploitation of symmetries and nonlinearities inherent to the system. Here, we examine the posed inspection problem from a path planning viewpoint, applying recently developed techniques from the field of differential geometric control theory to design the control strategies that steer the vehicle along the prescribed path. Three potential scenarios for surveying a ship?s bulbous bow region are motivated for path planning applications. For each scenario, we compute the control strategy and implement it onto a test-bed vehicle. Experimental results are analyzed and compared with theoretical predictions.

A geometrical analysis of trajectory design for underwater vehicles

Designing trajectories for a submerged rigid body motivates this paper. Two approaches are addressed: the time optimal approach and the motion planning ap- proach using concatenation of kinematic motions. We focus on the structure of singular extremals and their relation to the existence of rank-one kinematic reduc- tions; thereby linking the optimization problem to the inherent geometric frame- work. Using these kinematic reductions, we provide a solution to the motion plan- ning problem in the under-actuated scenario, or equivalently, in the case of actuator failures. We finish the paper comparing a time optimal trajectory to one formed by concatenation of pure motions.

Trajectory design for autonomous underwater vehicles based on ocean model predictions for feature tracking

Trajectory design for Autonomous Underwater Vehicles (AUVs) is of great importance to the oceanographic research community. Intelligent planning is required to maneuver a vehicle to high-valued locations for data collection. We consider the use of ocean model predictions to determine the locations to be visited by an AUV, which then provides near-real time, in situ measurements back to the model to increase the skill of future predictions. The motion planning problem of steering the vehicle between the computed waypoints is not considered here. Our focus is on the algorithm to determine relevant points of interest for a chosen oceanographic feature. This represents a first approach to an end to end autonomous prediction and tasking system for aquatic, mobile sensor networks. We design a sampling plan and present experimental results with AUV retasking in the Southern California Bight (SCB) off the coast of Los Angeles.

Trajectory design and implementation for multiple autonomous underwater vehicles based on ocean model predictions

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Decoupled trajectory planning for a submerged rigid body subject to dissipative and potential forces

This paper studies the practical but challenging problem of motion planning for a deeply submerged rigid body. Here, we formulate the dynamic equations of motion of a submerged rigid body under the architecture of differential geometric mechanics and include external dissipative and potential forces. The mechanical system is represented as a forced affine-connection control system on the configuration space SE(3). Solutions to the motion planning problem are computed by concatenating and reparameterizing the integral curves of decoupling vector fields. We provide an extension to this inverse kinematic method to compensate for external potential forces caused by buoyancy and gravity. We present a mission scenario and implement the theoretically computed control strategy onto a test-bed autonomous underwater vehicle. This scenario emphasizes the use of this motion planning technique in the under-actuated situation; the vehicle loses direct control on one or more degrees of freedom. We include experimental results to illustrate our technique and validate our method.

Continuous appearance-based trajectory SLAM

This paper describes a novel probabilistic approach to incorporating odometric information into appearance-based SLAM systems, without performing metric map construction or calculating relative feature geometry. The proposed system, dubbed Continuous Appearance-based Trajectory SLAM (CAT-SLAM), represents location as a probability distribution along a trajectory, and represents appearance continuously over the trajectory rather than at discrete locations. The distribution is evaluated using a Rao-Blackwellised particle filter, which weights particles based on local appearance and odometric similarity and explicitly models both the likelihood of revisiting previous locations and visiting new locations. A modified resampling scheme counters particle deprivation and allows loop closure updates to be performed in constant time regardless of map size. We compare the performance of CAT-SLAM to FAB-MAP (an appearance-only SLAM algorithm) in an outdoor environment, demonstrating a threefold increase in the number of correct loop closures detected by CAT-SLAM.

Using developmental theories to inform the design of technology for children

Electronic Blocks are a new programming environment, designed specifically for children aged between three and eight years. As such, the design of the Electronic Block environment is firmly based on principles of developmentally appropriate practices in early childhood education. The Electronic Blocks are physical, stackable blocks that include sensor blocks, action blocks and logic blocks. Evaluation of the Electronic Blocks with both preschool and primary school children shows that the blocks' ease of use and power of engagement have created a compelling tool for the introduction of meaningful technology education in an early childhood setting. The key to the effectiveness of the Electronic Blocks lies in an adherence to theories of development and learning throughout the Electronic Blocks design process.

Motivational Interviewing changes the treatment trajectory of group Cognitive-Behavioural Therapy for anxiety

Anxiety disorders have been viewed as manifestations of broad underlying predisposing personality constructs such as neuroticism combined with more specific individual differences of unhelpful information processing styles. Given the high prevalence of anxiety and the significant impairment that it causes, there is an important need to continue to explore successful treatments for this disorder. Research indicates that there is still room for significantly improving attrition rates and treatment adherence. Traditionally Motivational Interviewing (MI) has been used to facilitate health behaviour change. Recently MI has been applied to psychotherapy and has been shown to improve the outcome of CBT. However, these studies have been limited to only considering pre- and post-treatment measures and neglected to consider when changes occur along the course of therapy. This leaves the unanswered question of what is the impact of pre-treatment MI on the treatment trajectory of therapy. This study provides preliminary research into answering this question by tracking changes on a weekly basis along the course of group CBT. Prior to group CBT, 40 individuals with a principal anxiety disorder diagnosis were randomly assigned to receive either 3 individual sessions of MI or placed on a waitlist control group. All participants then received the same dosage of 10 weekly 2 hour sessions of group CBT. Tracking treatment outcome trajectory over the course of CBT, the pre-treatment MI group, compared to the control group, experienced a greater improvement early on in the course of therapy in their symptom distress, interpersonal relationships and quality of life. This early advantage over the control group was then maintained throughout therapy. These results not only demonstrate the value of adding MI to CBT, but also highlight the immediacy of MI effects. Further research is needed to determine the robustness of these effects to inform clinical implications of how to best apply MI to improve treatment adherence to CBT for anxiety disorders.