Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status

BACKGROUND: Melanoma is the most lethal form of skin cancer, but recent advances in molecularly targeted agents against the Ras/Raf/MAPK pathway demonstrate promise as effective therapies. Despite these advances, resistance remains an issue, as illustrated recently by the clinical experience with vemurafenib. Such acquired resistance appears to be the result of parallel pathway activation, such as PI3K, to overcome single-agent inhibition. In this report, we describe the cytotoxicity and anti-tumour activity of the novel MEK inhibitor, E6201, in a broad panel of melanoma cell lines (n = 31) of known mutational profile in vitro and in vivo. We further test the effectiveness of combining E6201 with an inhibitor of PI3K (LY294002) in overcoming resistance in these cell lines. RESULTS: The majority of melanoma cell lines were either sensitive (IC50 < 500 nM, 24/31) or hypersensitive (IC50 < 100 nM, 18/31) to E6201. This sensitivity correlated with wildtype PTEN and mutant BRAF status, whereas mutant RAS and PI3K pathway activation were associated with resistance. Although MEK inhibitors predominantly exert a cytostatic effect, E6201 elicited a potent cytocidal effect on most of the sensitive lines studied, as evidenced by Annexin positivity and cell death ELISA. Conversely, E6201 did not induce cell death in the two resistant melanoma cell lines tested. E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees, but a more pronounced anti-tumour effect was observed for cell lines that previously demonstrated a cytocidal response in vitro. In vitro combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested, as defined by a mean combination index < 1. CONCLUSIONS: Our data demonstrate that E6201 elicits a predominantly cytocidal effect in vitro and in vivo in melanoma cells of diverse mutational background. Resistance to E6201 was associated with disruption of PTEN and activation of downstream PI3K signalling. In keeping with these data we demonstrate that co-inhibition of MAPK and PI3K is effective in overcoming resistance inherent in melanoma.

Toddlers’ food preferences : the impact of novel food exposure, maternal preferences and food neophobia

Food preferences have been identified as a key determinant of children’s food acceptance and consumption. The aim of this study was to identify factors that influence children’s liking for fruits, vegetables and non-core foods. Participants were Australian mothers (median age at delivery=31 years, 18-46 years) and their two-year-old children (M=25 months, SD=1 month; 52% female) allocated to the control group (N=230) of the NOURISH RCT. The effects of repeated exposure to new foods, maternal food preferences and child food neophobia on toddlers’ liking of vegetables, fruits and non-core foods and the proportion never tried were examined via hierarchical regression models; adjusting for key maternal (age, BMI, education) and child covariates (birth weight Z-score, gender), duration of breastfeeding and age of introduction to solids. Maternal preferences corresponded with child preferences. Food neophobia among toddlers was associated with liking fewer vegetables and fruits, and trying fewer vegetables. Number of repeated exposures to new food was not significantly associated with food liking at this age. Results highlight the need to: (i) encourage parents to offer a wide range of foods, regardless of their own food preferences, and (ii) provide parents with guidance on managing food neophobia.

Mediating identity narratives : a case study in queer digital storytelling as everyday activism

Digital Stories are short autobiographical documentaries, often illustrated with personal photographs and narrated in the first person, and typically produced in group workshops. As a media form they offer ‘ordinary people’ the opportunity to represent themselves to audiences of their choosing; and this amplification of hitherto unheard voices has significant repercussions for their social participation. Many of the storytellers involved in the ‘Rainbow Family Tree’ case study that is the subject of this paper can be characterised as ‘everyday’ activists for their common desire to use their personal stories to increase social acceptance of marginalised identity categories. However, in conflict with their willingness to share their personal stories, many fear the risks and ramifications of distributing them in public spaces (especially online) to audiences both intimate and unknown. Additionally, while technologies for production and distribution of rich media products have become more accessible and user-friendly, many obstacles remain. For many people there are difficulties with technological access and aptitude, personal agency, cultural capital, and social isolation, not to mention availability of the time and energy requisite to Digital Storytelling. Additionally, workshop context, facilitation and distribution processes all influence the content of stories. This paper explores the many factors that make ‘authentic’ self-representation far from straight forward. I use qualitative data drawn from interviews, Digital Story texts and ethnographic observation of GLBTQIS participants in a Digital Storytelling initiative that combined face-to-face and online modes of participation. I consider mediating influences in practice and theory and draw on strategies put forth in cultural anthropology and narrative therapy to propose some practical tools for nuanced and sensitive facilitation of Digital Storytelling workshops and webspaces. Finally, I consider the implications of these facilitation strategies for voice, identity and social participation.

Adaptive radiotherapy for virally mediated head and neck cancer : predicting which patients may benefit most

Background: Recent clinical studies have demonstrated an emerging subgroup of head and neck cancers that are virally mediated. This disease appears to be a distinct clinical entity with patients presenting younger and with more advanced nodal disease, having lower tobacco and alcohol exposure and highly radiosensitive tumours. This means they are living longer, often with the debilitating functional side effects of treatment. The primary objective of this study was to determine how virally mediated nasopharyngeal and oropharyngeal cancers respond to radiation therapy treatment. The aim was to determine risk categories and corresponding adaptive treatment management strategies to proactively manage these patients. Method/Results: 121 patients with virally mediated, node positive nasopharyngeal or oropharyngeal cancer who received radiotherapy treatment with curative intent between 2005 and 2010 were studied. Relevant patient demographics including age, gender, diagnosis, TNM stage, pre-treatment nodal size and dose delivered was recorded. Each patient’s treatment plan was reviewed to determine if another computed tomography (re-CT) scan was performed and at what time point (dose/fraction) this occurred. The justification for this re-CT was determined using four categories: tumour and/or nodal regression, weight loss, both or other. Patients who underwent a re-CT were further investigated to determine whether a new plan was calculated. If a re-plan was performed, the dosimetric effect was quantified by comparing dose volume histograms of planning target volumes and critical structures from the actual treatment delivered and the original treatment plan. Preliminary results demonstrated that 25/121 (20.7%) patients required a re-CT and that these re-CTs were performed between fractions 20 to 25 of treatment. The justification for these re-CTs consisted of a combination of tumour and/or nodal regression and weight loss. 16/25 (13.2%) patients had a replan calculated. 9 (7.4%) of these replans were implemented clinically due to the resultant dosimetric effect calculated. The data collected from this assessment was statistically analysed to identify the major determining factors for patients to undergo a re-CT and/or replan. Specific factors identified included nodal size and timing of the required intervention (i.e. how when a plan is to be adapted). This data was used to generate specific risk profiles that will form the basis of a biologically guided adaptive treatment management strategy for virally mediated head and neck cancer. Conclusion: Preliminary data indicates that virally mediated head and neck cancers respond significantly during radiation treatment (tumour and/or nodal regression and weight loss). Implications of this response are the potential underdosing or overdosing of tumour and/or surrounding critical structures. This could lead to sub-optimal patient outcomes and compromised quality of life. Consequently, the development of adaptive treatment strategies that improve organ sparing for this patient group is important to ensure delivery of the prescribed dose to the tumour volume whilst minimizing the dose received to surrounding critical structures. This could reduce side effects and improve overall patient quality of life. The risk profiles and associated adaptive treatment approaches developed in this study will be tested prospectively in the clinical setting in Phase 2 of this investigation.

Adaptive radiotherapy for virally mediated head and neck cancer

Purpose: Virally mediated head and neck cancers (VMHNC) often present with nodal involvement, and are generally considered radioresponsive, resulting in the need for plan adaptation during radiotherapy in a subset of patients. We sought to identify a high-risk group based on pre-treatment nodal size to be evaluated in a future prospective adaptive radiotherapy trial. Methodology: Between 2005-2010, 121 patients with virally-mediated, node positive nasopharyngeal or oropharyngeal cancers, receiving definitive radiotherapy were reviewed. Patients were analysed based on maximum size of the dominant node at diagnosis with a view to grouping them in varying risk categories for the need of re-planning. The frequency and timing of the re-planning scans were also evaluated. Results: Sixteen nasopharyngeal and 105 oropharyngeal tumours were reviewed. Twenty-five (21%) patients underwent a re-planning CT at a median of 22 (range, 0-29) fractions with 1 patient requiring re-planning prior to the commencement of treatment. Based on the analysis, patients were subsequently placed into 3 groups defined by pre-treatment nodal size; ≤ 35mm (Group 1), 36-45mm (Group 2), ≥ 46mm (Group 3). Applying these groups to the patient cohort, re-planning CT’s were performed in Group 1- 8/68 (11.8%), Group 2- 4/28 (14.3%), Group 3- 13/25 (52%). Conclusion: In this series, patients with VMHNC and nodal size > 46mm appear to be a high-risk group for the need of plan adaptation during a course of definitive radiotherapy. This finding will now be tested in a prospective adaptive radiotherapy study.

The effectiveness of energy feedback for conservation and peak demand : a literature review

This paper reviews electricity consumption feedback literature to explore the potential of electricity feedback to affect residential consumers’ electricity usage patterns. The review highlights a substantial amount of literature covering the debate over the effectiveness of different feedback criteria to residential customer acceptance and overall conservation and peak demand reduction. Researchers studying the effects of feedback on everyday energy use have observed substantial variation in effect size, both within and between studies. Although researchers still continue to question the types of feedback that are most effective in encouraging conservation and peak load reduction, some trends have emerged. These include that feedback be received as quickly as possible to the time of consumption; be related to a standard; be clear and meaningful and where possible both direct and indirect feedback be customised to the customer. In general, the literature finds that feedback can reduce electricity consumption in homes by 5 to 20 per cent, but that significant gaps remain in our knowledge of the effectiveness and cost benefit of feedback.

Standardising radiation therapy undergraduate competency levels

QUT Bachelor of Radiation Therapy students progress from first visiting a radiation therapy department to graduation and progression into the NPDP over a span of three years. Although there are clear guidelines as to expected competency level post-NPDP, there is still a variety of perceived levels prior to this. Staff and students feedback both suggest that different centres and within centres different staff have differing opinions of these levels. Indeed, many staff members object to the use of the word “competency” for a pre-NPODP undergraduate, preferring the term “achievement”. While it is acknowledged that students progress at different rates, it is vitally important for equity that staff expectations of students at different academic levels are identical. Provision of guidelines for different stages of progression are essential for equitable assessment and most assessments, including the NRTAT are complemented by statements to enable level to be determined. For the University-specific competency assessments some level of consensus between clinical staff is required, especially where students are placed at a large number of different placement sites. Aims The main aim of this initial study is to gauge staff opinions of levels of student progression in order to judge cross-centres consistency. A secondary objective is to evaluate the degree of correlation between staff seniority and perception of student levels. Informal feedback suggests that staff at or just post NPDP level have a different perception of student competency expectations than more senior staff. If these perceptions change with level it will make agreement of guidelines statements more challenging. Study Methods A standard evaluation questionnaire was provided to RT staff participating in ongoing updates to clinical assessment. As part of curriculum development staff were asked to provide anonymous and optional answers to further questions in order to audit current practice. This involved assigning level of student progression to different statements relating to tasks or competencies. After data collation, scores were assigned to level and totals used to rank statements according to perceived student level. Descriptive statistical analysis was used to identify which statements were easier to assign to student level and which were more ambiguous. Further sub-analysis was performed for each category of staff seniority to judge differences in perception. Strength of correlation between seniority and expectation was calculated to confirm or contradict the informal feedback. Results By collating different staff perceptions of competencies for different student levels commonly agreed statements can be used to define achievement level. This presentation outlines the results of the audit including statements that most staff perceived as relevant to a specific student group and statements that staff found to be harder to attribute. Strength of correlation between staff perception and seniority will be outlined where statistically significant.

Endocrine and immune responses to resistance training in prostate cancer patients

This study examined the effect of 20 weeks resistance training on a range of serum hormones and inflammatory markers at rest, and following acute bouts of exercise in prostate cancer patients undergoing androgen deprivation. Ten patients exercised twice weekly at high intensity for several upper and lower-body muscle groups. Neither testosterone nor prostate-specific antigen changed at rest or following an acute bout of exercise. However, serum growth hormone (GH), dehydroepiandrosterone (DHEA), interleukin-6, tumor necrosis factor-alpha and differential blood leukocyte counts increased (P < 0.05) following acute exercise. Resistance exercise does not appear to compromise testosterone suppression, and acute elevations in serum GH and DHEA may partly underlie improvements observed in physical function.

A retrospective cohort investigation of active range of motion within one week of open reduction and internal fixation of distal radius fractures

Distal radius fractures stabilized by open reduction internal fixation (ORIF) have become increasingly common. There is currently no consensus on the optimal time to commence range of motion (ROM) exercises post-ORIF. A retrospective cohort review was conducted over a five-year period to compare wrist and forearm range of motion outcomes and number of therapy sessions between patients who commenced active ROM exercises within the first seven days and from day eight onward following ORIF of distal radius fractures. One hundred and twenty-one patient cases were identified. Clinical data, active ROM at initial and discharge therapy assessments, fracture type, surgical approaches, and number of therapy sessions attended were recorded. One hundred and seven (88.4%) cases had complete datasets. The early active ROM group (n = 37) commenced ROM a mean (SD) of 4.27 (1.8) days post-ORIF. The comparator group (n = 70) commenced ROM exercises 24.3 (13.6) days post-ORIF. No significant differences were identified between groups in ROM at initial or discharge assessments, or therapy sessions attended. The results from this study indicate that patients who commenced active ROM exercises an average of 24 days after surgery achieved comparable ROM outcomes with similar number of therapy sessions to those who commenced ROM exercises within the first week.

Consumer acceptance of m-wellbeing services : a social marketing perspective

Purpose This study aims to employ the Model of Goal-Directed Behaviour (MGB) to examine the consumer acceptance of technology-based self-service (TBSS) for a credence service instrumental to a social goal. Credence services are increasingly delivered via self-service technology and in social marketing, the achievement of social goals can be contingent on consumer acceptance of these services. However, little is known about the determinants of acceptance and extant marketing literature fails to account for emotional and goal influences which are likely to be important. Design/methodology/approach The authors interviewed 30 young adults with self-reported stress, anxiety or depression as potential users of a self-help mental health service delivered via mobile phone. The data were analysed deductively and inductively with the assistance of NVivo. Findings The findings generally support using the MGB to enhance understanding of consumers' acceptance of TBSS. The paper also found evidence of the importance of maintenance self-efficacy, the self-evaluation of the ability to continue using the service, and a previously ignored element of consumer level competition that arises between alternatives that achieve the same goal. Originality/value This study is the first to examine factors that influence consumers' acceptance of TBSS for credence services aimed at achieving a social goal. It builds on understanding of consumer decision making in social marketing, particularly the influence of self-efficacy and competition. It also contributes to attitudinal research by providing initial evidence for deepening and broadening the MGB in the context of TBSSs.

Heritage language for Chinese Australians : negotiating 'Chineseness' and, capitalising on resources in the lived world

The ethnic identity and commitment of Heritage Language Learners play salient roles in Heritage Language learning process. The mutually constitutive effect amongst Heritage Language Learner's ethnic identity, commitment, and Heritage Language proficiency has been well documented in social psychological and poststructuralist literatures. Both social psychological and poststructural schools offer meaningful insights into particular contexts but receive critiques from other contexts. In addition, the two schools largely oppose each other. This study uses Bourdieu's sociological triad of habitus, capital, and field to reconcile the two schools through the examination of Chinese Heritage Language Learners in Australia, an idiosyncratic social, cultural, and historical context for these learners. Specifically, this study investigates how young Chinese Australian adults (18-35 in age) negotiate their 'Chineseness' and capitalise on resources through Chinese Heritage Language learning in the lived world. The study adopts an explanatory mixed methods design to combine the quantitative approach with the qualitative approach. The initial quantitative phase addresses the first research question: Is Chinese Heritage Language proficiency of young Chinese Australian adults influenced by their investment of capital, the strength of their habitus of 'Chineseness', or both? The subsequent qualitative phase addresses the second research question: How do young Chinese Australian adults understand their Chinese Heritage Language learning in relation to (potential) profits produced by this linguistic capital in given fields? The initial quantitative phase applies Structural Equation Modelling to analyse the data from an online survey with 230 respondents. Findings indicate the statistically significant positive contribution made by the habitus of 'Chineseness' and by investment of capital to Chinese Heritage Language proficiency (r = .71 and r = .86 respectively). Subsequent multiple regression analysis demonstrates that 62% of the variance of Chinese Heritage Language proficiency can be accounted for by the joint contribution of 'Chineseness' and 'capital'. The qualitative phase of the study uses multiple interviews with five participants. It reveals that Chinese Heritage Language offers meaningful benefits for participants in the forms of capital production and habitus capture or recapture. Findings from the two phases talk to each other in terms of the inherent entanglement amongst habitus of 'Chineseness', investment of capital, and Chinese Heritage Language proficiency. The study offers important contributions. Theoretically, by virtue of Bourdieu's signature concepts of habitus, capital, and field, the study provides answers to questions that both social psychological and poststructuralist theories have long been struggling to answer. Methodologically, the position of 'pluralism' talks back to Bourdieu's theory and forwards to the mixed methods design. Particularly, the study makes a methodological breakthrough: A set of instruments was developed and validated to quantify Bourdieu's key concepts of capital and habitus within certain social fields. Practically, understanding Chinese Australians' heterogeneity and the potential drivers behind Chinese Heritage Language learning contributes to the growing interest in Chinese Australians' contemporary life experiences and helps to better accommodate linguistically diverse Chinese Heritage Language Learners in Chinese language courses. In addition, this study is very timely. It resonates with the recently released Australia in the Asian Century White Paper: Chinese Australians, with sound knowledge of Chinese culture and language obtained through negotiating their 'Chineseness' and capitalising on diverse resources for learning, will help to serve Australia's economic, social, and political needs in unique ways.

The health outcomes and costs of people attending an interdisciplinary chronic disease service in regional Australia : protocol for a longitudinal cohort investigation

Background Rates of chronic disease are escalating around the world. To date health service evaluations have focused on interventions for single chronic diseases. However, evaluations of the effectiveness of new intervention strategies that target single chronic diseases as well as multimorbidity are required, particularly in areas outside major metropolitan centres where access to services, such as specialist care, is difficult and where the retention and recruitment of health professionals affects service provision. Methods This study is a longitudinal investigation with a baseline and three follow-up assessments comparing the health and health costs of people with chronic disease before and after intervention at a chronic disease clinic, in regional Australia. The clinic is led by students under the supervision of health professionals. The study will provide preliminary evidence regarding the effectiveness of the intervention, and evaluate the influence of a range of factors on the health outcomes and costs of the patients attending the clinic. Patients will be evaluated at baseline (intake to the service), and at 3-, 6-, and 12-months after intake to the service. Health will be measured using the SF-36 and health costs will be measured using government and medical record sources. The intervention involves students and health professionals from multiple professions working together to treat patients with programs that include education and exercise therapy programs for back pain, and Healthy Lifestyle programs; as well as individual consultations involving single professions. Discussion Understanding the effect of a range of factors on the health state and health costs of people attending an interdisciplinary clinic will inform health service provision for this clinical group and will determine which factors need to be controlled for in future observational studies. Preliminary evidence regarding changes in health and health costs associated with the intervention will be a platform for future clinical trials of intervention effectiveness. The results will be of interest to teams investigating new chronic disease programs particularly for people with multimorbidity, and in areas outside major metropolitan centres.

Exploring the experiences of embedding Indigenous knowledge and perspectives on teaching practicum through interpretive phenomenology

In this paper, we discuss interpretive/hermeneutic phenomenology as a theoretical approach to explore the experiences of three stakeholder groups in embedding Indigenous knowledge and perspectives on teaching practicum, a project sponsored by ALTC. We begin by asking the phenomenological question ‘what is your experience of practice teaching?’ An open, explorative, phenomenological framework seeks the meanings of experiences, not truths, from the participants’ words themselves. Interpretive phenomenology is particularly suitable to explore educational experiences (Grumet, 1992; M. van Manen, 1990), as it provides rich ground for listening to the stakeholders’ lived experience and documenting it for interpretation. In an interpretive process, perspectives on lifeworlds, worldview and lenses get highlighted (Cunningham & Stanley, 2003). We establish how through various project stages, interpretive phenomenology gets to the essence of practice teaching experience creating a pedagogical ‘understanding’ of the essential nature of shared experience as lived by the participants (M van Manen, 2002). Thereby, it foregrounds voices of agency, dissent, acceptance and resistance. We consider how our research study focuses on the pedagogic voice of Indigenous pre-service teachers and the recognition of complex pedagogic fields in Indigenous education. We explain how this study seeks insights into their evaluation of pedagogic relations with two other education stakeholders – their practicum supervising teachers at schools and university staff involved practicum experience. As such, our study aims to support and develop long term, future-oriented opportunities for Indigenous pre-service teachers to embed Indigenous knowledge in the curricula. We conclude with some projections into the discourse on how Indigenous knowledge (IK) and perspectives might be diversely exemplified in pre-service teachers’ professional works (particularly E-portfolios). We speculate how this change could in turn maximise opportunities for Indigenous pre-service teachers, their supervising teachers and university staff to demonstrate leadership in their field through the creation of future tangible products such as units of work, resources, assessment and reflection tools. The processes contextualising the cultural interface of competing knowledge systems (Nakata, 2007) provide important analytical tools for understanding issues affecting student-teacher-mentor relationships occurring on practicum.