In vitro primary cell culture as a physiologically relevant method for preclinical testing of human oncolytic adenovirus

Ad[I/PPT-E1A] is an oncolytic adenovirus that specifically kills prostate cells via restricted replication by a prostate-specific regulatory element. Off-target replication of oncolytic adenoviruses would have serious clinical consequences. As a proposed ex vivo test, we describe the assessment of the specificity of Ad[I/PPT-E1A] viral cytotoxicity and replication in human nonprostate primary cells. Four primary nonprostate cell types were selected to mimic the effects of potential in vivo exposure to Ad[I/PPT-E1A] virus: bronchial epithelial cells, urothelial cells, vascular endothelial cells, and hepatocytes. Primary cells were analyzed for Ad[I/PPT-E1A] viral cytotoxicity in MTS assays, and viral replication was determined by hexon titer immunostaining assays to quantify viral hexon protein. The results revealed that at an extreme multiplicity of infection of 500, unlikely to be achieved in vivo, Ad[I/PPT-E1A] virus showed no significant cytotoxic effects in the nonprostate primary cell types apart from the hepatocytes. Transmission electron microscopy studies revealed high levels of Ad[I/PPT-E1A] sequestered in the cytoplasm of these cells. Adenoviral green fluorescent protein reporter studies showed no evidence for nuclear localization, suggesting that the cytotoxic effects of Ad[I/PPT-E1A] in human primary hepatocytes are related to viral sequestration. Also, hepatocytes had increased amounts of coxsackie adenovirus receptor surface protein. Active viral replication was only observed in the permissive primary prostate cells and LNCaP prostate cell line, and was not evident in any of the other nonprostate cells types tested, confirming the specificity of Ad[I/PPT-E1A]. Thus, using a relevant panel of primary human cells provides a convenient and alternative preclinical assay for examining the specificity of conditionally replicating oncolytic adenoviruses in vivo.

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.

BRCA1 is an essential mediator of vinorelbine-induced apoptosis in mesothelioma

The rapeutic options for malignant pleural mesothelioma (MPM) are limited despite the increasing incidence globally. The vinca alkaloid vinorelbine exhibits clinical activity; however, to date, treatment optimization has not been achieved using biomarkers. BRCA1 regulates sensitivity to microtubule poisons; however, its role in regulating vinorelbine-induced apoptosis in mesothelioma is unknown. Here we demonstrate that BRCA1 plays an essential role in mediating vinorelbine-induced apoptosis, as evidenced by (1) the strong correlation between vinorelbine sensitivity and BRCA1 expression level; (2) induction of resistance to vinorelbine by BRCA1 using siRNA oligonucleotides; (3) dramatic down-regulation of BRCA1 following selection for vinorelbine resistance; and (4) the re-activation of vinorelbine-induced apoptosis following re-expression of BRCA1 in resistant cells. To determine whether loss of BRCA1 expression in mesothelioma was potentially relevant in vivo, BRCA1 immunohistochemistry was subsequently performed on 144 primary mesothelioma specimens. Loss of BRCA1 protein expression was identified in 38.9% of samples. Together, these data suggest that BRCA1 plays a critical role in mediating apoptosis by vinorelbine in mesothelioma, warranting its clinical evaluation as a predictive biomarker. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Extending the explanatory utility of the EPPM beyond fear-based persuasion

In the 20 years since its inception, the EPPM has attracted much empirical support. Currently, and unsurprisingly given that is a model of fear-based persuasion, the EPPM’s explanatory utility has been based only upon fear-based messages. However, an argument is put forth herein, which draws upon existing evidence, that the EPPM may be an efficacious framework for explaining the persuasive process and outcomes of emotion-based messages more broadly when such messages are addressing serious health topics. For the current study, four different types of emotional appeals were purposefully devised and included a fear, an annoyance/agitation, a pride, and a humour-based message. All messages addressed the serious health issue of road safety, and in particular the risky behaviour of speeding. Participants (N = 551) were exposed to only one of the four messages and subsequently provided responses within a survey. A series of 2 (threat: low, high) x 2 (efficacy: low, high) analysis of variance was conducted for each of the appeals based on the EPPM’s message outcomes of acceptance and rejection. Support was found for the EPPM with a number of main effects of threat and efficacy emerging, reflecting that, irrespective of emotional appeal type, high levels of threat and efficacy enhanced message outcomes via maximising acceptance and minimising rejection. Theoretically, the findings provide support for the explanatory utility of the EPPM for emotion-based health messages more broadly. In an applied sense, the findings highlight the value of adopting the EPPM as a framework when devising and evaluating emotion-based health messages for serious health topics.

Factors influencing funding decisions by elected politicians at the state/provincial level : a case study of public libraries in Canada

The purpose of this study was to determine factors (internal and external) that influenced Canadian provincial (state) politicians when making funding decisions about public libraries. Using the case study methodology, Canadian provincial/state level funding for public libraries in the 2009-10 fiscal year was examined. After reviewing funding levels across the country, three jurisdictions were chosen for the case: British Columbia's budget revealed dramatically decreased funding, Alberta's budget showed dramatically increased funding, and Ontario's budget was unchanged from the previous year. The primary source of data for the case was a series of semi-structured interviews with elected officials and senior bureaucrats from the three jurisdictions. An examination of primary and secondary documents was also undertaken to help set the political and economic context as well as to provide triangulation for the case interviews. The data were analysed to determine whether Cialdini's theory of influence (2001) and specifically any of the six tactics of influence (i.e, commitment and consistency, authority, liking, social proof, scarcity and reciprocity) were instrumental in these budget processes. Findings show the principles of "authority", "consistency and commitment" and "liking" were relevant, and that "liking" were especially important to these decisions. When these decision makers were considering funding for public libraries, they most often used three distinct lenses: the consistency lens (what are my values? what would my party do?), the authority lens (is someone with hierarchical power telling me to do this? are the requests legitimate?), and most importantly, the liking lens (how much do I like and know about the requester?). These findings are consistent with Cialdini's theory, which suggests the quality of some relationships is one of six factors that can most influence a decision maker. The small number of prior research studies exploring the reasons for increases or decreases in public library funding allocation decisions have given little insight into the factors that motivate those politicians involved in the process and the variables that contribute to these decisions. No prior studies have examined the construct of influence in decision making about funding for Canadian public libraries at any level of government. Additionally, no prior studies have examined the construct of influence in decision making within the context of Canadian provincial politics. While many public libraries are facing difficult decisions in the face of uncertain funding futures, the ability of the sector to obtain favourable responses to requests for increases may require a less simplistic approach than previously thought. The ability to create meaningful connections with individuals in many communities and across all levels of government should be emphasised as a key factor in influencing funding decisions.

Numerical solution of an optimal control model of dendritic cell treatment of a growing tumour

A new optimal control model of the interactions between a growing tumour and the host immune system along with an immunotherapy treatment strategy is presented. The model is based on an ordinary differential equation model of interactions between the growing tu- mour and the natural killer, cytotoxic T lymphocyte and dendritic cells of the host immune system, extended through the addition of a control function representing the application of a dendritic cell treat- ment to the system. The numerical solution of this model, obtained from a multi species Runge–Kutta forward-backward sweep scheme, is described. We investigate the effects of varying the maximum al- lowed amount of dendritic cell vaccine administered to the system and find that control of the tumour cell population is best effected via a high initial vaccine level, followed by reduced treatment and finally cessation of treatment. We also found that increasing the strength of the dendritic cell vaccine causes an increase in the number of natural killer cells and lymphocytes, which in turn reduces the growth of the tumour.

A transcription factor map as revealed by a genome-wide gene expression analysis of whole-blood mRNA transcriptome in multiple sclerosis

Background Several lines of evidence suggests that transcription factors are involved in the pathogenesis of Multiple Sclerosis (MS) but a complete mapping the whole network has been elusive. One of the reasons is that there are several clinical subtypes of MS and transcription factors which may be involved in one subtype may not be in others. We investigated the possibility that this network could be mapped using microarray technologies and modern bioinformatics methods on a dataset from whole blood in 99 untreated MS patients (36 Relapse Remitting MS, 43 Primary Progressive MS, and 20 Secondary Progressive MS) and 45 age-matched healthy controls, Methodology/Principal Findings We have used two different analytical methodologies: a differential expression analysis and a differential co-expression analysis, which have converged on a significant number of regulatory motifs that seem to be statistically overrepresented in genes which are either differentially expressed (or differentially co-expressed) in cases and controls (e.g. V$KROX_Q6, p-value < 3.31E-6; V$CREBP1_Q2, p-value < 9.93E-6, V$YY1_02, p-value < 1.65E-5). Conclusions/significance: Our analysis uncovered a network of transcription factors that potentially dysregulate several genes in MS or one or more of its disease subtypes. Analysing the published literature we have found that these transcription factors are involved in the early T-lymphocyte specification and commitment as well as in oligodendrocytes dedifferentiation and development. The most significant transcription factors motifs were for the Early Growth response EGR/KROX family, ATF2, YY1 (Yin and Yang 1), E2F-1/DP-1 and E2F-4/DP-2 heterodimers, SOX5, and CREB and ATF families.

Exploiting Web 2.0 technologies to forge live connectedness in class

The economics of supporting learning has seen institutional encouragement of a wide range of blended learning initiatives in face to face and online teaching and learning. This has become one of the key drivers for the adoption of technology in teaching, in a manner occassionally guilty of putting the cart before the horse. Learning spaces are increasingly equipped with a dizzying array of technological options testifying to institutional and governmental investment and commitment in supporting face to face blended learning (QUT, 2011, C/4.2). Yet innovation within traditional learning and teaching models faces a number of challenges both at an institutional level and at the teaching coal face. Web 2.0 technologies present a vast array of opportunities to harness and capture the attention of students in engaging learning opportunitites. This presentation will explore technologies supportive of active learning pedagogies.

Improved rural health through a collaborative model of care – qualitative findings

INTRODUCTION Health disparity between urban and rural regions in Australia is well-documented. In the Wheatbelt catchments of Western Australia there is higher incidence and rate of avoidable hospitalisation for chronic diseases. Structured care approach to chronic illnesses is not new but the focus has been on single disease state. A recent ARC Discovery Project on general practice nurse-led chronic disease management of diabetes, hypertension and stable ischaemic heart disease reported improved communication and better medical administration.[1] In our study we investigated the sustainability of such a multi-morbidities general practice –led collaborative model of care in rural Australia. METHODS A QUAN(qual) design was utilised. Eight pairs of rural general practices were matched. Inclusion criteria used were >18 years and capable of giving informed consent, at least one identified risk factor or diagnosed with chronic conditions. Patients were excluded if deemed medically unsuitable. A comprehensive care plan was formulated by the respective general practice nurse in consultation with the treating General Practitioner (GP) and patient based on the individual’s readiness to change, and was informed by available local resource. A case management approach was utilised. Shediaz-Rizkallah and Lee’s conceptual framework on sustainability informed our evaluation.[2] Our primary outcome on measures of sustainability was reduction in avoidable hospitalisation. Secondary outcomes were patients and practitioners acceptance and satisfaction, and changes to pre-determined interim clinical and process outcomes. RESULTS The qualitative interviews highlighted the community preference for a ‘sustainable’ local hospital in addition to general practice. Costs, ease of access, low prioritisation of self chronic care, workforce turnover and perception of losing another local resource if underutilised influenced the respondents’ decision to present at local hospital for avoidable chronic diseases regardless. CONCLUSIONS Despite the pragmatic nature of rural general practice in Australia, the sustainability of chronic multi-morbidities management in general practice require efficient integration of primary-secondary health care and consideration of other social determinants of health. What this study adds: What is already known on this subject: Structured approach to chronic disease management is not new and has been shown to be effective for reducing hospitalisation. However, the focus has been on single disease state. What does this study add: Sustainability of collaborative model of multi-morbidities care require better primary-secondary integration and consideration of social determinants of health.

Lumbar epidural steroids are not cost effective in sciatica

Background Lumbar Epidural Steroids Injections (ESI’s) have previously been shown to provide some degree of pain relief in sciatica. Number Needed To Treat (NNT) to achieve 50% pain relief has been estimated at 7 from the results of randomised controlled trials. Pain relief is temporary. They remain one of the most commonly provided procedures in the UK. It is unknown whether this pain relief represents good value for money. Methods 228 patients were randomised into a multi-centre Double Blind Randomised Controlled Trial. Subjects received up to 3 ESI’s or intra-spinous saline depending on response and fall off with the first injection. All other treatments were permitted. All received a review of analgesia, education and physical therapy. Quality of life was assessed using the SF36 at 6 points and compared using independent sample t-tests. Follow up was up to 1 yr. Missing data was imputed using last observation carried forward (LOCF). QALY’s (Quality of Life Years) were derived from preference based heath values (summary health utility score). SF-6D health state classification was derived from SF-36 raw score data. Standard gambles (SG) were calculated using Model 10. SG scores were calculated on trial results. LOCF was not used for this. Instead average SG were derived for a subset of patients with observations for all visits up to week 12. Incremental QALY’s were derived as the difference in the area between the SG curve for the active group and placebo group. Results SF36 domains showed a significant improvement in pain at week 3 but this was not sustained (mean 54 Active vs 61 Placebo P<0.05). Other domains did not show any significant gains compared with placebo. For derivation of SG the number in the sample in each period differed. In week 12, average SG scores for active and placebo converged. In other words, the health gain for the active group as measured by SG was achieved by the placebo group by week 12. The incremental QALY gained for a patient under the trial protocol compared with the standard care package was 0.0059350. This is equivalent to an additional 2.2 days of full health. The cost per QALY gained to the provider from a patient management strategy administering one epidural as suggested by results was £25 745.68. This result was derived assuming that the gain in QALY data calculated for patients under the trial protocol would approximate that under a patient management strategy based on the trial results (one ESI). This is above the threshold suggested by some as a cost effective treatment. Conclusions The transient benefit in pain relief afforded by ESI’s does not appear to be cost-effective. Further work is needed to develop more cost-effective conservative treatments for sciatica.

'Music eScape': mHealth application

Research Background Young people’s avid use of mobile technologies in daily life has led to an increase in the design and research on mHealth (mobile health) interventions targeting young people. ‘Music eScape’ is a mobile based mood regulation app that uses an innovative approach to promoting young people’s wellbeing using music. Research Question The design, research, development and evaluation of ‘Music eScape’ addressed a number of research questions from across the fields of Psychology and Interactive and Visual Design. The specific design research question addressed was: How can interaction and visual design be utilized to promote and enable young people to effectively regulate their mood using music and how can the new design further promote their experience of empowerment, control and agency over actively directing their mood journey? Research Contribution Innovation and New Knowledge Through its unique visual interface design and interactivity, the application presents a novel approach to promoting young people’s wellbeing using music and a specific function that allows users to ‘draw’ their mood journey in order to generate a playlist. The mobile app is the first to contain a function that enables users to plan their mood journey and exercise a sense of agency, intentional choice and control over the mood shift and by extension, their wellbeing. The feature ‘drawing’ interface was designed by Oksana Zelenko using participatory design research and Russell’s circumplex model of affect (1980) to inform the key visual design concept and underpinning interaction design. Research Significance The significance of the design research component within the larger interdisciplinary practices that have informed ‘Music eScape’ (e.g. field of psychology, reported through journal articles and other related outcomes), is the unique visual and interactive presentation of participant data and music therapy research within the app interface and interaction design which improves and increases young people’s engagement with the health messages it contains. The industry quality standard is further demonstrated by the launch on Apple iTunes. This demonstrates the application meets the high professional requirements for national release and meets international standards. The app also creates a new benchmark for the quality of health apps on the market as it marks the industry release of a trialled evidence-based mHealth intervention co-designed with young people.

The cost-effectiveness of total laparoscopic hysterectomy compared to total abdominal hysterectomy for the treatment of early stage endometrial cancer

Objective To summarise how costs and health benefits will change with the adoption of total laparoscopic hysterectomy compared to total abdominal hysterectomy for the treatment of early stage endometrial cancer. Design Cost-effectiveness modelling using the information from a randomised controlled trial. Participants Two hypothetical modelled cohorts of 1000 individuals undergoing total laparoscopic hysterectomy and total abdominal hysterectomy. Outcome measures Surgery costs; hospital bed days used; total healthcare costs; quality-adjusted life years; and net monetary benefits. Results For 1000 individuals receiving total laparoscopic hysterectomy surgery, the costs were $509 575 higher, 3548 hospital fewer bed days were used and total health services costs were reduced by $3 746 221. There were 39.13 more quality-adjusted life years for a 5 year period following surgery. Conclusions The adoption of total laparoscopic hysterectomy is almost certainly a good decision for health services policy makers. There is 100% probability that it will be cost saving to health services, a 86.8% probability that it will increase health benefits and a 99.5% chance that it returns net monetary benefits greater than zero.

Transforming the future of treatment for ovarian cancer

As for many other cancers, metastasis is the leading cause of death of patients with ovarian cancer. Vigorous basic and clinical research is being performed to initiate more efficacious treatment strategies to improve the poor outcome of women with this cancer. Current treatment for ovarian cancer includes advanced cyto-reductive surgery and traditional platinum and taxane combined chemotherapy. Clinical trials using novel cytotoxic reagents and tyrosine kinase inhibitors have also been progressing. In parallel, the application of robust unbiased high throughput research platforms using transcriptomic and proteomic approaches has identified that not only individual cell signalling pathways, but a network of molecular pathways, play an important role in the biology of ovarian cancer. Furthermore, intensive genomic and epigenetic analyses have also revealed single nucleotide polymorphisms associated with risk and/or aetiology of this cancer including patient response to treatment. Taken together, these approaches, that are advancing our understanding, will have an impact on the generation of new therapeutic approaches and strategies for improving the outcome and quality of life of patients with ovarian cancer in the near future.

Modeling of protein signaling networks in clinical proteomics

Molecular interactions that underlie pathophysiological states are being elucidated using techniques that profile proteomicend points in cellular systems. Within the field of cancer research, protein interaction networks play pivotal roles in the establishment and maintenance of the hallmarks of malignancy, including cell division, invasion, and migration. Multiple complementary tools enable a multifaceted view of how signal protein pathway alterations contribute to pathophysiological states.One pivotal technique is signal pathway profiling of patient tissue specimens. This microanalysis technology provides a proteomic snapshot at one point in time of cells directly procured from the native context of a tumor micro environment. To study the adaptive patterns of signal pathway events over time, before and after experimental therapy, it is necessary to obtain biopsies from patients before, during, and after therapy. A complementary approach is the profiling of cultured cell lines with and without treatment. Cultured cell models provide the opportunity to study short-term signal changes occurring over minutes to hours. Through this type of system, the effects of particular pharmacological agents may be used to test the effects of signal pathway inhibition or activation on multiple endpoints within a pathway. The complexity of the data generated has necessitated the development of mathematical models for optimal interpretation of interrelated signaling pathways. In combination,clinical proteomic biopsy profiling, tissue culture proteomic profiling, and mathematical modeling synergistically enable a deeper understanding of how protein associations lead to disease states and present new insights into the design of therapeutic regimens.

The role of interpersonal influence in budget decision making: The Canadian public library experience

This study determined factors which influenced Canadian provincial (state) politicians when making funding decisions for public libraries. Using the case study methodology, Canadian provincial/state-level funding for public libraries in the 2009-2010 fiscal year was examined. The data were analyzed to determine whether Cialdini’s theory of influence and specifically any of the six tactics of influence (i.e., commitment and consistency, authority, liking, social proof, scarcity, and reciprocity) were instrumental in these budgetary decision-making processes. Findings show the principles of “authority,” “consistency and commitment,” and “liking” were relevant, and that “liking” was especially important to these decisions.