Genetically Engineered Oncolytic Adenoviruses for the Treatment of Kidney and Breast Cancer

Metastatic kidney and breast cancer are devastating diseases currently lacking efficient treatment options. One promising developmental approach in cancer treatment are oncolytic adenoviruses, which have demonstrated excellent safety in many clinical trials. However, antitumor efficacy needs to be improved in order to make oncolytic viruses a viable treatment alternative. To be able to follow oncolytic virus replication in vivo, we set up a non-invasive imaging system based on coinjection of a replication deficient luciferase expressing virus and a replication competent virus. The system was validated in vitro and in vivo and used in other projects of the thesis. In another study we showed that capsid modifications on adenoviruses result in enhanced gene transfer and increased oncolytic effect on renal cancer cells in vitro. Moreover, capsid modified oncolytic adenoviruses demonstrated significantly improved antitumor efficacy in murine kidney cancer models. To transcriptionally target kidney cancer tissue we evaluated two hypoxia response elements for their usability as tissue specific promoters using a novel dual luciferase imaging system. Based on the results of the promoter evaluation and the studies on capsid modifications, we constructed a transcriptionally and transductionally targeted oncolytic adenovirus armed with an antiangiogenic transgene for enhanced renal cell cancer specificity and improved antitumor efficacy. This virus exhibited kidney cancer specific replication and significantly improved antitumor effect in a murine model of intraperitoneal disseminated renal cell cancer. Cancer stem cells are thought to be resistant to conventional cancer drugs and might play an important role in breast cancer relapse and the formation of metastasis. Therefore, we examined if capsid modified oncolytic adenoviruses are able to kill these cells proposed to be breast cancer initiating. Efficient oncolytic effect and significant antitumor efficacy on tumors established with breast cancer initiating cells was observed, suggesting that oncolytic adenoviruses might be able to prevent breast cancer relapse and could be used in the treatment of metastatic disease. In conclusion, the results presented in this thesis suggest that genetically engineered oncolytic adenoviruses have great potential in the treatment of metastatic kidney and breast cancer.

Design and Performance Evaluation of EXMAN: An EXtended MANchester Data Flow Computer

Data flow computers are high-speed machines in which an instruction is executed as soon as all its operands are available. This paper describes the EXtended MANchester (EXMAN) data flow computer which incorporates three major extensions to the basic Manchester machine. As extensions we provide a multiple matching units scheme, an efficient, implementation of array data structure, and a facility to concurrently execute reentrant routines. A simulator for the EXMAN computer has been coded in the discrete event simulation language, SIMULA 67, on the DEC 1090 system. Performance analysis studies have been conducted on the simulated EXMAN computer to study the effectiveness of the proposed extensions. The performance experiments have been carried out using three sample problems: matrix multiplication, Bresenham's line drawing algorithm, and the polygon scan-conversion algorithm.

Design and testing of stand-specific bucking instructions for use on modern cut-to-length harvesters

This study addresses three important issues in tree bucking optimization in the context of cut-to-length harvesting. (1) Would the fit between the log demand and log output distributions be better if the price and/or demand matrices controlling the bucking decisions on modern cut-to-length harvesters were adjusted to the unique conditions of each individual stand? (2) In what ways can we generate stand and product specific price and demand matrices? (3) What alternatives do we have to measure the fit between the log demand and log output distributions, and what would be an ideal goodness-of-fit measure? Three iterative search systems were developed for seeking stand-specific price and demand matrix sets: (1) A fuzzy logic control system for calibrating the price matrix of one log product for one stand at a time (the stand-level one-product approach); (2) a genetic algorithm system for adjusting the price matrices of one log product in parallel for several stands (the forest-level one-product approach); and (3) a genetic algorithm system for dividing the overall demand matrix of each of the several log products into stand-specific sub-demands simultaneously for several stands and products (the forest-level multi-product approach). The stem material used for testing the performance of the stand-specific price and demand matrices against that of the reference matrices was comprised of 9 155 Norway spruce (Picea abies (L.) Karst.) sawlog stems gathered by harvesters from 15 mature spruce-dominated stands in southern Finland. The reference price and demand matrices were either direct copies or slightly modified versions of those used by two Finnish sawmilling companies. Two types of stand-specific bucking matrices were compiled for each log product. One was from the harvester-collected stem profiles and the other was from the pre-harvest inventory data. Four goodness-of-fit measures were analyzed for their appropriateness in determining the similarity between the log demand and log output distributions: (1) the apportionment degree (index), (2) the chi-square statistic, (3) Laspeyres quantity index, and (4) the price-weighted apportionment degree. The study confirmed that any improvement in the fit between the log demand and log output distributions can only be realized at the expense of log volumes produced. Stand-level pre-control of price matrices was found to be advantageous, provided the control is done with perfect stem data. Forest-level pre-control of price matrices resulted in no improvement in the cumulative apportionment degree. Cutting stands under the control of stand-specific demand matrices yielded a better total fit between the demand and output matrices at the forest level than was obtained by cutting each stand with non-stand-specific reference matrices. The theoretical and experimental analyses suggest that none of the three alternative goodness-of-fit measures clearly outperforms the traditional apportionment degree measure. Keywords: harvesting, tree bucking optimization, simulation, fuzzy control, genetic algorithms, goodness-of-fit

Male traits and herd reproductive capability in tropical beef cattle. 1. Experimental design and animal measures

Research into the genetics of whole herd profitability has been a focus of the Beef Cooperative Research Centre for Beef Genetic Technologies over the past decade and it has been identified that measures of male reproduction may offer a potential indirect means of selecting for improved female reproduction. This paper describes the experimental design and provides a descriptive analysis of an array of male traits in Brahman and Tropical Composite genotypes managed under the medium to high stress, semi-extensive to extensive production systems of northern Australia. A total of 1639 Brahman and 2424 Tropical Composite bulls with known pedigrees, bred and raised in northern Australia, were evaluated for a comprehensive range of productive and reproductive traits. These included blood hormonal traits (luteinising hormone, inhibin and insulin-like growth factor-I); growth and carcass traits (liveweight, body condition score, ultrasound scanned 12-13th rib fat, rump P8 fat, eye muscle area and hip height); adaptation traits (flight time and rectal temperature); and a bull breeding soundness evaluation (leg and hoof conformation, sheath score, length of everted prepuce, penile anatomy, scrotal circumference, semen mass activity, sperm motility and sperm morphology). Large phenotypic variation was evident for most traits, with complete overlap between genotypes, indicating that there is likely to be a significant opportunity to improve bull fertility traits through management and bull selection.

Design and assessment of weirs for fish passage under drowned conditions

In aquatic systems, in-stream structures such as dams, weirs and road crossings can act as barriers to fish movement along waterways. There is a growing array of technological fish-pass solutions for the movement of fish across large structures such as weirs and dams. However, most existing weir structures lack dedicated fishways, and fish often have to rely on drowned conditions to move upstream. In order to assess the adequacy of a given or proposed weir for upstream fish passage under drowned conditions, it is necessary to determine, firstly, the hydraulic properties of the drowned weir with respect to the requirements of the fish community and, secondly, the duration and timing of drowning flows with respect to the hydrograph for the site and the likely timing of fish movements. This paper primarily addresses the first issue. A computer program has been developed and incorporated in a simple-to-operate spreadsheet for the determination of the hydraulic characteristics of a drowned weir which are important to fish movement. The program is based on a theoretical analysis of drowned weirs and subsequent extensive verification in laboratory experiments. Inputs to the program include site information comprising channel cross-section data, channel slope, and channel roughness, and weir information comprising weir height and the required minimum drowned depth over the weir for migrating fish passage. The program then calculates the flow rate at which the required level of drowning occurs, the velocity characteristics above the weir (including transverse distributions), and flow depths and velocities upstream and downstream of the weir. The paper discusses (briefly) the theoretical background of the program and its experimental verification. A case study is then presented that illustrates the use of the program in the field to assess fish passage opportunities at an existing weir and to develop a case for retrofitting a fishway. Some discussion is also provided on the contribution of a modelled drownout volume to the assessment of how significant a barrier a weir is to fish passage. It is shown that the program is an important new additional tool in the assessment of the adequacy of weir structures in providing for fish movement and informing associated fish passage solutions. (C) 2011 Elsevier B.V. All rights reserved.

Design and flight testing of a bio-inspired plume tracking algorithm for unmanned serial vehicles

There is an increased interest on the use of UAVs for environmental research such as tracking bush fires, volcanic eruptions, chemical accidents or pollution sources. The aim of this paper is to describe the theory and results of a bio-inspired plume tracking algorithm. A method for generating sparse plumes in a virtual environment was also developed. Results indicated the ability of the algorithms to track plumes in 2D and 3D. The system has been tested with hardware in the loop (HIL) simulations and in flight using a CO2 gas sensor mounted to a multi-rotor UAV. The UAV is controlled by the plume tracking algorithm running on the ground control station (GCS).

Exploring the relationships between design and public libraries through the lens of service design

Design is ubiquitous to the life of contemporary societies and key to their progress, but for some, it is an elitist concept. This thesis investigates the role of public libraries contribution to the general public's understanding of "Design". This study compared participants views in the context of State Libraries in two cities: Brisbane and Curitiba. Findings revealed that exploring four new aspects in the Development and Deliver Stages of a service design framework for public libraries can be an effective tool to enhance people"s access and experiences of Design, and ultimately, it can contribute to the democratisation of design.

An algebraic algorithm for the design and analysis of linear dynamical systems

In an earlier paper [1], it has been shown that velocity ratio, defined with reference to the analogous circuit, is a basic parameter in the complete analysis of a linear one-dimensional dynamical system. In this paper it is shown that the terms constituting velocity ratio can be readily determined by means of an algebraic algorithm developed from a heuristic study of the process of transfer matrix multiplication. The algorithm permits the set of most significant terms at a particular frequency of interest to be identified from a knowledge of the relative magnitudes of the impedances of the constituent elements of a proposed configuration. This feature makes the algorithm a potential tool in a first approach to a rational design of a complex dynamical filter. This algorithm is particularly suited for the desk analysis of a medium size system with lumped as well as distributed elements.

Modeling multi-stakeholder multi-objective decisions during public participation in major infrastructure and construction projects: A decision rule approach

Major infrastructure and construction (MIC) projects are those with significant traffic or environmental impact, of strategic and regional significance and high sensitivity. The decision making process of schemes of this type is becoming ever more complicated, especially with the increasing number of stakeholders involved and their growing tendency to defend their own varied interests. Failing to address and meet the concerns and expectations of stakeholders may result in project failures. To avoid this necessitates a systematic participatory approach to facilitate decision-making. Though numerous decision models have been established in previous studies (e.g. ELECTRE methods, the analytic hierarchy process and analytic network process) their applicability in the decision process during stakeholder participation in contemporary MIC projects is still uncertain. To resolve this, the decision rule approach is employed for modeling multi-stakeholder multi-objective project decisions. Through this, the result is obtained naturally according to the “rules” accepted by any stakeholder involved. In this sense, consensus is more likely to be achieved since the process is more convincing and the result is easier to be accepted by all concerned. Appropriate “rules”, comprehensive enough to address multiple objectives while straightforward enough to be understood by multiple stakeholders, are set for resolving conflict and facilitating consensus during the project decision process. The West Kowloon Cultural District (WKCD) project is used as a demonstration case and a focus group meeting is conducted in order to confirm the validity of the model established. The results indicate that the model is objective, reliable and practical enough to cope with real world problems. Finally, a suggested future research agenda is provided.

Auditing design and innovation programmes within a multinational insurance provider

The financial services industry is key to the success of the Australian economy, however even established businesses need to continually push to innovate. At present, design is becoming widely accepted as means to innovate and many companies currently have design and innovation programmes. The goal of these programmes is to foster a design capability amongst staff members. However, little is known as to the impact of the innovation capabilities such design programmes claim to instil. Therefore, this paper seeks to investigate how a financial services firm is currently attempting to build a design capability amongst staff members. Using a case study approach the research team audited four design capability programmes currently being deployed by the case firm. The study highlights the strengths and weaknesses of current efforts by the firm and current barriers to achieving design capability. The implications of this paper include key insights for both academics and industry.

Design and synthesis of novel 3-hydroxy-cyclobut-3-ene-1,2-dione derivatives as thyroid hormone receptor β (TR-β) selective ligands

Design and synthesis of a novel 3-hydroxy-cyclobut-3-ene-1,2-dione derivatives are reported and their in vitro thyroid hormone receptor selectivity has been evaluated in the thyroid luciferase receptor assay. The 3-[3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)-phenylamino]-4-hydroxy-cyclobut-3-ene-1,2-dione 21 has shown selectivity towards thyroid hormone receptor β.

Design and characterization of in-plane MEMS yaw rate sensor

In this paper, we present the design and characterization of a vibratory yaw rate MEMS sensor that uses in-plane motion for both actuation and sensing. The design criterion for the rate sensor is based on a high sensitivity and low bandwidth. The required sensitivity of the yawrate sensor is attained by using the inplane motion in which the dominant damping mechanism is the fluid loss due to slide film damping i.e. two-three orders of magnitude less than the squeeze-film damping in other rate sensors with out-of-plane motion. The low bandwidth is achieved by matching the drive and the sense mode frequencies. Based on these factors, the yaw rate sensor is designed and finally realized using surface micromachining. The inplane motion of the sensor is experimentally characterized to determine the sense and the drive mode frequencies, and corresponding damping ratios. It is found that the experimental results match well with the numerical and the analytical models with less than 5% error in frequencies measurements. The measured quality factor of the sensor is approximately 467, which is two orders of magnitude higher than that for a similar rate sensor with out-of-plane sense direction.

New perspectives on design and delivery: The context of service desk

This research has identified the trends apparent in service desk design and delivery literature. By doing archival analysis, this investigation has led to the development of a generic framework which has identified three themes in service desk design – User groups, Support models, and Technology types – and two themes in service desk delivery – Direction of delivery, and Executive support level. This research also aims to provide an understanding of service desk functions and the challenges faced by organisations in delivering those functions.

A shallow water AUV for benthic and water column observations

Autonomous underwater vehicles (AUVs) are becoming commonplace in the study of inshore coastal marine habitats. Combined with shipboard systems, scientists are able to make in-situ measurements of water column and benthic properties. In CSIRO, autonomous gliders are used to collect water column data, while surface vessels are used to collect bathymetry information through the use of swath mapping, bottom grabs, and towed video systems. Although these methods have provided good data coverage for coastal and deep waters beyond 50m, there has been an increasing need for autonomous in-situ sampling in waters less than 50m deep. In addition, the collection of benthic and water column data has been conducted separately, requiring extensive post-processing to combine data streams. As such, a new AUV was developed for in-situ observations of both benthic habitat and water column properties in shallow waters. This paper provides an overview of the Starbug X AUV system, its operational characteristics including vision-based navigation and oceanographic sensor integration.