Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: Results from two phase I studies

Purpose: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies. Patients and Methods: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points. Results: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P = .01 for oral dose; P = .0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P = .004%; and 51%, P = .006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status. Conclusion: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitiors, such as PTK/ZK, for further clinical development. © 2003 by American Society of Clinical Oncology.

Stop whining and make the best of it: a cross-national comparison of response to regional disadvantage in the wine industry

Our cross-national field study of wine entrepreneurship in the “wrong” places provides some redress to the focus of the “regional advantage” literature on places that have already won and on the firms that benefit from “clusters” and other centers of industry advantage. Regional “disadvantage” is at best a shadowy afterthought to this literature. By poking around in these shadows, we help to synthesize and extend the incipient yet burgeoning literature on entrepreneurial “resourcefulness” and we contribute to the developing body of insights and theory pertinent to the numerous but often ignored firms and startups that mostly need to worry about how they will compete at all now if they are ever to have of chance of “winning” in the future. The core of our findings suggests that understandable – though contested – processes of ingenuity underlie entrepreneurial responses to regional disadvantage. Because we study entrepreneurship that from many angles simply does not make sense, we are also able to proffer a novel perspective on entrepreneurial sensemaking.

Franchisor failure : an assessment of the adequacy of regulatory response

Franchisor failure is one of the most problematic areas of the franchise relationship. It impacts negatively on landlords and other suppliers, but the contracting parties that are currently without legal rights to respond when a franchisor fails, and thus without consumer protection, are its franchisees. In this thesis I explore the current contractual, regulatory and commercial environment that franchisees inhabit, within the context of franchisor failure. I conclude that ex ante there are opportunities to level the playing field through consumer protection legislation. I also conclude that the task is not one solely for the consumer protection legislation; the problem should also be addressed ex post through the Corporations Act.

Impacts and adaptation response of infrastructure and communities to heatwaves : the southern Australian experience of 2009

From 27 January to 8 February during the summer of 2009, southern Australia experienced one of the nation‘s most severe heatwaves. Governments, councils, utilities, hospitals and emergency response organisations and the community were largely underprepared for an extreme event of this magnitude. This case study targets the experience and challenges faced by decision makers and policy makers and focuses on the major metropolitan areas affected by the heatwave — Melbourne and Adelaide. The study examines the 2009 heatwave‘s characteristics; its impacts (on human health, infrastructure and human services); the degree of adaptive capacity (vulnerability and resilience) of various sectors, communities and individuals; and the reactive responses of government and emergency and associated services and their effectiveness. Barriers and challenges to adaptation and increasing resilience are also identified and further areas for research are suggested. This study does not include details of the heatwave‘s effects beyond Victoria and South Australia, or its economic impacts, or of Victoria‘s 'Black Saturday‘ bushfires.

Demand side response to mitigate electrical peak demand in Eastern and Southern Australia

The aim of this work is to develop a Demand-Side-Response (DSR) model, which assists electricity end-users to be engaged in mitigating peak demands on the electricity network in Eastern and Southern Australia. The proposed innovative model will comprise a technical set-up of a programmable internet relay, a router, solid state switches in addition to the suitable software to control electricity demand at user's premises. The software on appropriate multimedia tool (CD Rom) will be curtailing/shifting electric loads to the most appropriate time of the day following the implemented economic model, which is designed to be maximizing financial benefits to electricity consumers. Additionally the model is targeting a national electrical load be spread-out evenly throughout the year in order to satisfy best economic performance for electricity generation, transmission and distribution. The model is applicable in region managed by the Australian Energy Management Operator (AEMO) covering states of Eastern-, Southern-Australia and Tasmania.

Genotype x culture media interaction effects on regeneration response of three indica rice cultivars

Interactive effects of genotypes with callus induction and regeneration media combinations on green plantlet regeneration response were studied for three indica rice (Oryza sativa L.) cultivars, IR-72, IR-54 and Karnal Local. Isolated mature-embryoswere used to derive scutellar callus and fifteen media combinations involvingMS, N6, R2, SK1 and some modifications were tested. Regeneration percentage as well as the shoot-bud induction frequency were influenced by genotype, callus induction medium, regeneration medium, interaction between genotype and the two media (callus induction and regeneration) as well the interaction between the callus induction medium and regeneration medium. Basal media combination of SK1m (callusing) and MS (regeneration) was found to be the best for cv. Karnal Local in which regeneration frequency of 88% and shoot-bud induction of 233% was observed. In IR-72, the highest regeneration frequency of 47.5% and shoot-bud induction frequency of 77% was obtained on MS-MS combination. In IR-54, highest regeneration frequency (25%) was recorded on MMS(N)-MMS(N) combination, whereas, highest frequency of shoot-bud induction (50%) was observed on MMS(S)-MS combination. Although genotype and the composition of the callus induction basal medium were the major determinants of regeneration response, an overall analysis of variation also revealed a significant interaction between the media used for de-differentiation (callusing) and re-differentiation (plantlet regeneration)

Smart grid-demand side response model for optimization air conditioning

The growing demand of air-conditioning is one of the largest contributors to Australia’s overall electricity consumption. This has started to create peak load supply problems for some electricity utilities particularly in Queensland. This research aimed to develop consumer demand side response model to assist electricity consumers to mitigate peak demand on the electrical network. The model developed demand side response model to allow consumers to manage and control air conditioning for every period, it is called intelligent control. This research investigates optimal response of end-user toward electricity price for several cases in the near future, such as: no spike, spike and probability spike price cases. The results indicate the potential of the scheme to achieve energy savings, reducing electricity bills (costs) to the consumer and targeting best economic performance for electrical generation distribution and transmission.

Fluid Infrastructure : A response to a natural flood disaster in Brisbane

Fluid Infrastructure: Landscape Architecture Exhibition: This exhibition showcases the work of 4th Year undergraduate landscape architecture students in response to the 2011 Queensland floods through five installations: Systima Fluid Flux Flex Fluid Connectivity The Floods Verge Fluid Evolution The focus of these installations is the post-flood conditions of Brisbane’s riverside public infrastructure, within a scenario of flood as a normalised event. It recognises that within this scenario, parts of this city cannot be described as definitively ‘land’ or ‘water,’ but are best described as ‘fluid terrains’(Mathur, A. and Da Cunha, D. 2006). The landscape design propositions within the five installations include public transport diversification (RiverRats) schemes, greenspace elevations, ephemeral gardens and evolving landscapes, creative interpretation and warning devices and systems. These propositions do not resist fluid conditions, but work with them to propose a more resilient urban river landscape than Brisbane currently has. This QUT exhibition was developed as part of the 2011 Flood of Ideas Project (http://www.floodofideas.org.au) in partnership with Healthy Waterways (Water by Design), State Library of Queensland (The Edge), Brisbane City Council, Australian Institute of Architects, University of Queensland, Green Cross Australia, Stormwater Industry Association.

The development of an effective vaccine against Chlamydia : utilisation of a non-toxic mucosal adjuvant to generate a protective mucosal response

Chlamydia is responsible for a wide range of diseases with enormous global economic and health burden. As the majority of chlamydial infections are asymptomatic, a vaccine has greatest potential to reduce infection and disease prevalence. Protective immunity against Chlamydia requires the induction of a mucosal immune response, ideally, at the multiple sites in the body where an infection can be established. Mucosal immunity is most effectively stimulated by targeting vaccination to the epithelium, which is best accomplished by direct vaccine application to mucosal surfaces rather than by injection. The efficacy of needle-free vaccines however is reliant on a powerful adjuvant to overcome mucosal tolerance. As very few adjuvants have proven able to elicit mucosal immunity without harmful side effects, there is a need to develop non-toxic adjuvants or safer ways to administered pre-existing toxic adjuvants. In the present study we investigated the novel non-toxic mucosal adjuvant CTA1-DD. The immunogenicity of CTA1-DD was compared to our "gold-standard" mucosal adjuvant combination of cholera toxin (CT) and cytosine-phosphate-guanosine oligodeoxynucleotide (CpG-ODN). We also utilised different needle-free immunisation routes, intranasal (IN), sublingual (SL) and transcutaneous (TC), to stimulate the induction of immunity at multiple mucosal surfaces in the body where Chlamydia are known to infect. Moreover, administering each adjuvant by different routes may also limit the toxicity of the CT/CpG adjuvant, currently restricted from use in humans. Mice were immunised with either adjuvant together with the chlamydial major outer membrane protein (MOMP) to evaluate vaccine safety and quantify the induction of antigen-specific mucosal immune responses. The level of protection against infection and disease was also assessed in vaccinated animals following a live genital or respiratory tract infectious challenge. The non-toxic CTA1-DD was found to be safe and immunogenic when delivered via the IN route in mice, inducing a comparable mucosal response and level of protective immunity against chlamydial challenge to its toxic CT/CpG counterpart administered by the same route. The utilisation of different routes of immunisation strongly influenced the distribution of antigen-specific responses to distant mucosal surfaces and also abrogated the toxicity of CT/CpG. The CT/CpG-adjuvanted vaccine was safe when administered by the SL and TC routes and conferred partial immunity against infection and pathology in both challenge models. This protection was attributed to the induction of antigen-specific pro-inflammatory cellular responses in the lymph nodes regional to the site of infection and rather than in the spleen. Development of non-toxic adjuvants and effective ways to reduce the side effects of toxic adjuvants has profound implications for vaccine development, particularly against mucosal pathogens like Chlamydia. Interestingly, we also identified two contrasting vaccines in both infection models capable of preventing infection or pathology exclusively. This indicated that the development of pathology following an infection of vaccinated animals was independent of bacterial load and was instead the result of immunopathology, potentially driven by the adaptive immune response generated following immunisation. While both vaccines expressed high levels of interleukin (IL)-17 cytokines, the pathology protected group displayed significantly reduced expression of corresponding IL-17 receptors and hence an inhibition of signalling. This indicated that the balance of IL-17-mediated responses defines the degree of protection against infection and tissue damage generated following vaccination. This study has enabled us to better understand the immune basis of pathology and protection, necessary to design more effective vaccines.

Providing 'best practice' placements begins with mentoring skills : overview of the Program of Experience in the Palliative Approach (PEPA) quality improvement initiatives for mentors

Objectives PEPA is funded by the Department of Health and Ageing and aims to further improve the skill and confidence of the generalist workforce to work with people with palliative care needs. Recent quality improvement initiatives to promote transfer of learning into practice include appointment of a clinical educator, implementation of an online module for mentors and delivery of a mentoring workshop (collaborating with NSAP and PCC4U). This paper presents an overview of outcomes from these quality improvement initiatives. Methods PEPA host sites are selected based on their specialist palliative care level. Host site managers are surveyed six-monthly and participants are surveyed pre and three months post-placement to collect open and fixed response data on their experience of the program. Participants in the mentoring workshop (n=39) were asked to respond to a survey regarding the workshop outcomes. Results The percentage of placement participants who strongly agreed they ‘have the ability to implement the interventions required for people who have a life-limiting illness’ increased from 35% in 2011 (n=34) to 51% in 2012 (n=91) post-placement. Responses from mentor workshop participants indicated that 76% of respondents (n=25) agreed that they were able to identify principles for mentoring in the context of palliative care. In 2012, 61% of host site managers (n=54) strongly agreed that PEPA supports clinician working with people with a life-limiting illness. Conclusion Strategies to build the capabilities of palliative care professionals to mentor and support the learning experience of PEPA participants are critical to ongoing improvements of the program.

Demand-side response model to avoid spike of electricity price

The aim of this work is to develop a demand-side-response model, which assists electricity consumers exposed to the market price to independently and proactively manage air-conditioning peak electricity demand. The main contribution of this research is to show how consumers can optimize the energy cost caused by the air conditioning load considering to several cases e.g. normal price, spike price, and the probability of a price spike case. This model also investigated how air-conditioning applies a pre-cooling method when there is a substantial risk of a price spike. The results indicate the potential of the scheme to achieve financial benefits for consumers and target the best economic performance for electrical generation distribution and transmission. The model was tested with Queensland electricity market data from the Australian Energy Market Operator and Brisbane temperature data from the Bureau of Statistics regarding hot days from 2011 to 2012.

A transcriptomic analysis of striped catfish (Pangasianodon hypophthalmus) in response to salinity adaptation: De novo assembly, gene annotation and marker discovery

The striped catfish (Pangasianodon hypophthalmus) culture industry in the Mekong Delta in Vietnam has developed rapidly over the past decade. The culture industry now however, faces some significant challenges, especially related to climate change impacts notably from predicted extensive saltwater intrusion into many low topographical coastal provinces across the Mekong Delta. This problem highlights a need for development of culture stocks that can tolerate more saline culture environments as a response to expansion of saline water-intruded land. While a traditional artificial selection program can potentially address this need, understanding the genomic basis of salinity tolerance can assist development of more productive culture lines. The current study applied a transcriptomic approach using Ion PGM technology to generate expressed sequence tag (EST) resources from the intestine and swim bladder from striped catfish reared at a salinity level of 9 ppt which showed best growth performance. Total sequence data generated was 467.8 Mbp, consisting of 4,116,424 reads with an average length of 112 bp. De novo assembly was employed that generated 51,188 contigs, and allowed identification of 16,116 putative genes based on the GenBank non-redundant database. GO annotation, KEGG pathway mapping, and functional annotation of the EST sequences recovered with a wide diversity of biological functions and processes. In addition, more than 11,600 simple sequence repeats were also detected. This is the first comprehensive analysis of a striped catfish transcriptome, and provides a valuable genomic resource for future selective breeding programs and functional or evolutionary studies of genes that influence salinity tolerance in this important culture species.

BIM support for disaster response

The introduction of Building Information Modelling (BIM) to the design, construction and operation of buildings is changing the way that the building construction industry works. BIM involves the development of a full 3D virtual model of a building which not only contains the 3D information necessary to show the building as it will appear, but also contains significant additional data about each component in the building. BIM represents both physical and virtual objects in a building. This includes the rooms and spaces within and around the building. The additional data stored on each part of the building can support building maintenance opera- tions and, more importantly from the perspective of this paper, support the generation and running of simula- tions of the operation of the building and behaviour of people within it under both normal and emergency scenarios. The initial discussion is around the use of BIM to support the design of resilient buildings which references the various codes and standards that define current best practice. The remainder of the discussion uses various recent events as the basis for discussion on how BIM could have been used to support rapid recovery and re- building.

A biphasic response to adenosine in the coronary vasculature of the K+-arrested perfused rat heart

Biphasic vasodilatory responses to adenosine and 5'-N-ethylcarboxamidoadenosine (NECA) were observed in the coronary vasculature of K(+)-arrested perfused rat hearts. Dose-response data for both agonists were best represented by two-site models. For adenosine, two sites with negative log ED50 (pED50) values of 8.1 +/- 0.1 (mean +/- S.E.M) and 5.2 +/- 0.1 were obtained, mediating 31 +/- 2% and 69 +/- 2% of the total response. In the presence of 8-phenyltheophylline, the vasodilatory response to adenosine remained best fitted to a two-site model with pED50 values of 7.0 +/- 0.2 and 5.4 +/- 0.2. The relative contribution of each site to the total response remained unchanged. For NECA, pED50 values of 9.6 +/- 0.1 and 6.8 +/- 0.2 were obtained, representing 48 +/- 3% and 52 +/- 3% of the sites, respectively. In contrast, ATP produced a monophasic response with a pED50 value of 8.8 +/- 0.1. These results provide evidence of adenosine receptor and response heterogeneity in the in situ coronary vasculature.

A method to evaluate the response of the coronary circulation of perfused rat heart to adenosine

Exogenous adenosine causes a monophasic dilation of the coronary vessels in paced, perfused rat heart preparations. Because levels of endogenous adenosine in paced hearts may mask the presence of high potency adenosine receptors, we have developed a method to measure coronary vascular responses in a potassium-arrested heart. Hearts from adult male, Wistar rats were perfused at a constant flow rate of 10 mL/min in the nonrecirculating, Langendorff mode, using Krebs-Henseleit buffer. After 30 min, coronary perfusion pressure was 44 +/- 1 mmHg (mean +/- SEM). Hearts were then perfused with a modified Krebs-Henseleit buffer containing 35 mM potassium. Coronary perfusion pressure increased by 84 +/- 3 mmHg. Adenosine-induced reductions in coronary perfusion pressure were expressed as a percentage of the maximal increase in pressure produced by modified Krebs-Henseleit buffer from the equilibration level. A concentration-response curve for adenosine (n = 6) was biphasic and best described by the presence of two adenosine receptors, with negative log EC50 values of 8.8 +/- 0.3 and 4.3 +/- 0.1, representing 29 +/- 3 and 71 +/- 3%, respectively, of the observed response. Interstitial adenosine sampled by microdialysis during potassium arrest was 25% of the concentration found in paced hearts. Endogenous adenosine in nonarrested hearts may obscure the biphasic response of the coronary vessels to adenosine.