Gene transfer vectors targeted to human prostate cancer : do we need better preclinical testing systems?

Destruction of cancer cells by genetically modified viral and nonviral vectors has been the aim of many research programs. The ability to target cytotoxic gene therapies to the cells of interest is an essential prerequisite, and the treatment has always had the potential to provide better and more long-lasting therapy than existing chemotherapies. However, the potency of these infectious agents requires effective testing systems, in which hypotheses can be explored both in vitro and in vivo before the establishment of clinical trials in humans. The real prospect of off-target effects should be eliminated in the preclinical stage, if current prejudices against such therapies are to be overcome. In this review we have set out, using adenoviral vectors as a commonly used example, to discuss some of the key parameters required to develop more effective testing, and to critically assess the current cellular models for the development and testing of prostate cancer biotherapy. Only by developing models that more closely mirror human tissues will we be able to translate literature publications into clinical trials and hence into acceptable alternative treatments for the most commonly diagnosed cancer in humans.

The phylogeny of Ureaplasma urealyticum based on the mba gene fragment

Sequencing of mba gene fragments of reference strains of Ureaplasma urealyticum serovars 1, 3, 6, 14, in addition to 33 clinical U. urealyticum isolates is reported. A phylogenetic tree deduced from an alignment of these sequences clearly demonstrates two major clusters (confidence limit 100%), which equate to the parvo and T960 biovars, and five types which we have designated mba 1, 3, 6, 8 and X. These relationships are supported by bootstrap analysis. Polymorphisms within the mba fragment of types mba 1, 3, and 6 were used to define nine subtypes (mba 1a, 1b, 3a, 3b, 3c, 3d, 3e, 6a, and 6b) thus facilitating high resolution typing of U. urealyticum. Inclusion of the reference strains for serovars 1, 3, 6, and 8 in the mba typing scheme showed that the results of this analysis are broadly consistent with currently accepted serotyping. In addition a ure gene fragment from nine of the clinical isolates was amplified and sequenced. Comparisons of the sequences clearly distinguished the two biovars of U. urealyticum; however this fragment was invariant within the parvo biovar. This study has shown that the sequence of the mba can reveal the fine details of the relationships between U. urealyticum isolates and also supports the significant evolutionary gap between the two biovars.

Seed-based biclustering of gene expression data

Background Accumulated biological research outcomes show that biological functions do not depend on individual genes, but on complex gene networks. Microarray data are widely used to cluster genes according to their expression levels across experimental conditions. However, functionally related genes generally do not show coherent expression across all conditions since any given cellular process is active only under a subset of conditions. Biclustering finds gene clusters that have similar expression levels across a subset of conditions. This paper proposes a seed-based algorithm that identifies coherent genes in an exhaustive, but efficient manner. Methods In order to find the biclusters in a gene expression dataset, we exhaustively select combinations of genes and conditions as seeds to create candidate bicluster tables. The tables have two columns: (a) a gene set, and (b) the conditions on which the gene set have dissimilar expression levels to the seed. First, the genes with less than the maximum number of dissimilar conditions are identified and a table of these genes is created. Second, the rows that have the same dissimilar conditions are grouped together. Third, the table is sorted in ascending order based on the number of dissimilar conditions. Finally, beginning with the first row of the table, a test is run repeatedly to determine whether the cardinality of the gene set in the row is greater than the minimum threshold number of genes in a bicluster. If so, a bicluster is outputted and the corresponding row is removed from the table. Repeating this process, all biclusters in the table are systematically identified until the table becomes empty. Conclusions This paper presents a novel biclustering algorithm for the identification of additive biclusters. Since it involves exhaustively testing combinations of genes and conditions, the additive biclusters can be found more readily.

Bilingual asynchronous online discussion groups : design and delivery of an e-Learning distance study module for nurse academics in a developing country

The advent of eLearning has seen online discussion forums widely used in both undergraduate and postgraduate nursing education. This paper reports an Australian university experience of design, delivery and redevelopment of a distance education module developed for Vietnamese nurse academics. The teaching experience of Vietnamese nurse academics is mixed and frequently limited. It was decided that the distance module should attempt to utilise the experience of senior Vietnamese nurse academics - asynchronous online discussion groups were used to facilitate this. Online discussion occurred in both Vietnamese and English and was moderated by an Australian academic working alongside a Vietnamese translator. This paper will discuss the design of an online learning environment for foreign correspondents, the resources and translation required to maximise the success of asynchronous online discussion groups, as well as the rationale of delivering complex content in a foreign language. While specifically addressing the first iteration of the first distance module designed, this paper will also address subsequent changes made for the second iteration of the module and comment on their success. While a translator is clearly a key component of success, the elements of simplicity and clarity combined with supportive online moderation must not be overlooked.

Design and delivery of a distance education programme : educating Vietnamese nurse academics from Australia

In 2008 a move away from medical staff providing nursing education in Vietnam saw the employment of many new nurse academics. To assist in the instruction of these novice academics and provide them with sound teaching and learning practice as well as curriculum design and implementation skills, Queensland University of Technology (QUT) successfully tendered an international grant. One of QUT’s initiatives in educating the Vietnamese academics was a distance learning programme. Developed specifically for Vietnamese nurse academics, the programme was designed for Australian based delivery to academics in Vietnam. This paper will present an overview of why four separate modules were utilised for the delivery of content (modules were delivered at a rate of one per semester). It will address bilingual online discussion boards which were used in each of the modules and the process of moderating these given comments were posted in both Vietnamese and English. It will describe how content was scaffolded across four modules and how the modules themselves modelled new teaching delivery strategies. Lastly, it will discuss the considerations of programme delivery given the logistics of an Australian based delivery. Feedback from the Vietnamese nurse academics across their involvement in the programme (and at the conclusion of their fourth and final module) has been overwhelmingly positive. Feedback suggests the programme has altered teaching and assessment approaches used by some Vietnamese nurse academics. Additionally, Vietnamese nurse academics are reporting that they are engaging more with the application of their content indicating a cultural shift in the approach taken in Vietnamese nurse education.

The use of hypnosis in labor and delivery : a preliminary study

Self-hypnosis was taught to 87 obstetric patients (HYP) and was not taught to 56 other patients (CNTRL), all delivered by the same family physician, in order to determine whether the use of self-hypnosis by low-risk obstetric patients leads to fewer technologic interventions during their deliveries or greater satisfaction of parturients with their delivery experience or both. The outcomes of the deliveries of these two groups were compared, and the HYP group was compared to 352 low-risk patients delivered by other family physicians at the same hospital (WCH). Questionnaires were mailed postpartum to 156 patients, all delivered by the same family physician, to determine satisfaction with delivery using the Labor and Delivery Satisfaction Index (LADSI). The hypnosis group showed a significant reduction in the number of epidurals (11.4% less than CNTRL and 17.9% less than WCH, p < 0.05) and the use of intravenous lines (18.5% less for both, p < 0.05). The number of episiotomies was significantly less in the HYP group compared to WCH (15.9%, p < 0.05) and 11.5% less when compared to CNTRL. The tear rate was not statistically different. Combined use of the intervention triad (epidural–forceps–episiotomy) was less for HYP than for CNTRL (15.8% less) and WCH (10.2% less, p < 0.05). More deliveries were done in the labor room with HYP than CNTRL (21%, p < 0.05). The second stage was shortened by 10 min (HYP vs CNTRL). Overall satisfaction of HYP and CNTRL patients was similar and generally favorable.

Prediction of IBD based on population history for fine gene mapping

A novel multiple regression method (RM) is developed to predict identity-by-descent probabilities at a locus L (IBDL), among individuals without pedigree, given information on surrounding markers and population history. These IBDL probabilities are a function of the increase in linkage disequilibrium (LD) generated by drift in a homogeneous population over generations. Three parameters are sufficient to describe population history: effective population size (Ne), number of generations since foundation (T), and marker allele frequencies among founders (p). IBD L are used in a simulation study to map a quantitative trait locus (QTL) via variance component estimation. RM is compared to a coalescent method (CM) in terms of power and robustness of QTL detection. Differences between RM and CM are small but significant. For example, RM is more powerful than CM in dioecious populations, but not in monoecious populations. Moreover, RM is more robust than CM when marker phases are unknown or when there is complete LD among founders or Ne is wrong, and less robust when p is wrong. CM utilises all marker haplotype information, whereas RM utilises information contained in each individual marker and all possible marker pairs but not in higher order interactions. RM consists of a family of models encompassing four different population structures, and two ways of using marker information, which contrasts with the single model that must cater for all possible evolutionary scenarios in CM.

Candidate gene analysis for quantitative traits using the transmission disequilibrium test : the example of the melanocortin 4-receptor in pigs

Population-wide associations between loci due to linkage disequilibrium can be used to map quantitative trait loci (QTL) with high resolution. However, spurious associations between markers and QTL can also arise as a consequence of population stratification. Statistical methods that cannot differentiate between loci associations due to linkage disequilibria from those caused in other ways can render false-positive results. The transmission-disequilibrium test (TDT) is a robust test for detecting QTL. The TDT exploits within-family associations that are not affected by population stratification. However, some TDTs are formulated in a rigid-form, with reduced potential applications. In this study we generalize TDT using mixed linear models to allow greater statistical flexibility. Allelic effects are estimated with two independent parameters: one exploiting the robust within-family information and the other the potentially biased between-family information. A significant difference between these two parameters can be used as evidence for spurious association. This methodology was then used to test the effects of the fourth melanocortin receptor (MC4R) on production traits in the pig. The new analyses supported the previously reported results; i.e., the studied polymorphism is either causal of in very strong linkage disequilibrium with the causal mutation, and provided no evidence for spurious association.

Extending services delivery with lightweight composition

The tertiary sector is an important employer and its growth is well above average. The Texo project’s aim is to support this development by making services tradable. The composition of new or value-added services is a cornerstone of the proposed architecture. It is, however, intended to cater for build-time. Yet, at run-time unforseen exceptions may occur and user’s requirements may change. Varying circumstances require immediate sensemaking of the situation’s context and call for prompt extensions of existing services. Lightweight composition technology provided by the RoofTop project enables domain experts to create simple widget-like applications, also termed enterprise mashups, without extensive methodological skills. In this way RoofTop can assist and extend the idea of service delivery through the Texo platform and is a further step towards a next generation internet of services.

A comparative study of governmental one-stop portals for public service delivery

The continuing need for governments to radically improve the delivery of public services has led to a new, holistic government reform strategy labeled “Transformational Government” that strongly emphasizes customer-centricity. Attention has turned to online portals as a cost effective front-end to deliver services and engage customers as well as to the corresponding organizational approaches for the back-end to decouple the service interface from the departmental structures. The research presented in this paper makes three contributions: Firstly, a systematic literature review of approaches to the evaluation of online portal models in the public sector is presented. Secondly, the findings of a usability study comparing the online presences of the Queensland Government, the UK Government and the South Australian Government are reported and the relative strengths and weaknesses of the different approaches are discussed. And thirdly, the limitations of the usability study in the context of a broader “Transformational Government” approach are identified and service bundling is suggested as an innovative solution to further improve online service delivery.

Synthesis of an erodible biomimetic hydrogel for drug delivery using native chemical ligation

Hydrogels are hydrophilic, three dimensional polymers that imbibe large quantities of water while remaining insoluble in aqueous solutions due to chemical or physical cross-linking. The polymers swell in water or biological fluids, immobilizing the bioactive agent, leading to drug release in a well-defined specific manner. Thus the hydrogels’ elastic properties, swellability and biocompatibility make them excellent formulations for drug delivery. Currently, many drug potencies and therapeutic effects are limited or otherwise reduced because of the partial degradation that occurs before the administered drug reaches the desired site of action. On the other hand, sustained release medications release drugs continually, rather than providing relief of symptoms and protection solely when necessary. In fact, it would be much better if drugs could be administered in a manner that precisely matches physiological needs at desired times and at the desired site (site specific targeting). There is therefore an unmet need to develop controlled drug delivery systems especially for delivery of peptide and protein bound drugs. The purpose of this project is to produce hydrogels for structural drug delivery and time-dependent sustained release of drugs (bioactive agents). We use an innovative polymerisation strategy based on native chemical ligation (NCL) to covalently cross-link polymers to form hydrogels. When mixed in aqueous solution, four armed (polyethylene glycol) amine (PEG-4A) end functionalised with thioester and four branched Nterminal cysteine peptide dendrimers spontaneously conjugated to produce biomimetic hydrogels. These hydrogels showed superior resistance to shear stress compared to an equivalent PEG macromonomer system and were shown to be proteolytically degradable with concomitant release of a model payload molecule. This is the first report of a peptide dendrimers/PEG macromonomer approach to hydrogel production and opens up the prospect of facile hydrogel synthesis together with tailored payload release.

Modelling, collaboration and integration : a case study for the delivery of public buildings

An evolution in the use of digital modelling has occurred in the Queensland Department of Public Works Division of Project Services over the last 20 years from: the initial implementation of computer aided design and documentation (CADD); to experimentation with building information modelling (BIM); to embedding integrated practice (IP); to current steps towards integrated project delivery (IPD) including the active involvement of consultants and contractors in the design/delivery process. This case study is one of three undertaken through the Australian Sustainable Built Environment National Research Centre investigating past R&D investment. The intent of these cases is to inform the development of policy guidelines for future investment in the construction industry in Australia. This research is informing the activities of CIB Task Group 85 R&D Investment and Impact. The uptake of digital modelling by Project Services has been approached through an incremental learning approach. This has been driven by a strong and clear vision with a focus on developing more efficient delivery mechanisms through the use of new technology coupled with process change. Findings reveal an organisational focus on several areas including: (i) strategic decision making including the empowerment of innovation leaders and champions; (ii) the acquisition and exploitation of knowledge; (iii) product and process development (with a focus on efficiency and productivity); (iv) organisational learning; (v) maximising the use of technology; and (vi) supply chain integration. Key elements of this approach include pilot projects, researcher engagement, industry partnerships and leadership.