Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells

Patients with metastatic melanoma or multiple myeloma have a dismal prognosis because these aggressive malignancies resist conventional treatment. A promising new oncologic approach uses molecularly targeted therapeutics that overcomes apoptotic resistance and, at the same time, achieves tumor selectivity. The unexpected selectivity of proteasome inhibition for inducing apoptosis in cancer cells, but not in normal cells, prompted us to define the mechanism of action for this class of drugs, including Food and Drug Administration-approved bortezomib. In this report, five melanoma cell lines and a myeloma cell line are treated with three different proteasome inhibitors (MG-132, lactacystin, and bortezomib), and the mechanism underlying the apoptotic pathway is defined. Following exposure to proteasome inhibitors, effective killing of human melanoma and myeloma cells, but not of normal proliferating melanocytes, was shown to involve p53-independent induction of the BH3-only protein NOXA. Induction of NOXA at the protein level was preceded by enhanced transcription of NOXA mRNA. Engagement of mitochondrial-based apoptotic pathway involved release of cytochrome c, second mitochondria-derived activator of caspases, and apoptosis-inducing factor, accompanied by a proteolytic cascade with processing of caspases 9, 3, and 8 and poly(ADP)-ribose polymerase. Blocking NOXA induction using an antisense (but not control) oligonucleotide reduced the apoptotic response by 30% to 50%, indicating a NOXA-dependent component in the overall killing of melanoma cells. These results provide a novel mechanism for overcoming the apoptotic resistance of tumor cells, and validate agents triggering NOXA induction as potential selective cancer therapeutics for life-threatening malignancies such as melanoma and multiple myeloma.

Empowerment as a framework for Indigenous workforce development and organisational change

Relative powerlessness resulting from colonial dispossession and associated passive welfare policies has long been recognised as a critical factor influencing the health and wellbeing of Indigenous Australians, yet it is hard to find well-evaluated health and social interventions that take an explicit empowerment approach. This paper presents the findings of a Family Wellbeing Empowerment programme pilot delivered to Cairns Region Department of Families Indigenous youth workers and family and community workers in 2003/2004. The aim of the pilot was to build the capacity of these workers to address personal and professional issues as a basis for providing better support for their clients. The pilot demonstrated the effectiveness of the programme as a tool for worker empowerment and, to a lesser degree, organisational change.

Factors influencing health promotion activities in midlife and older Australian women with a chronic disease

Background: Chronic diseases including type 2 diabetes are a leading cause of morbidity and mortality in midlife and older Australian women. There are a number of modifiable risk factors for type 2 diabetes and other chronic diseases including smoking, nutrition, physical activity and overweight and obesity. Little research has been conducted in the Australian context to explore the perceived barriers to health promotion activities in midlife and older Australian women with a chronic disease. Aims: The primary aim of this study was to explore women’s perceived barriers to health promotion activities to reduce modifiable risk factors, and the relationship of perceived barriers to smoking behaviour, fruit and vegetable intake, physical activity and body mass index. A secondary aim of this study was to investigate nurses’ perceptions of the barriers to action for women with a chronic disease, and to compare those perceptions with those of the women. Methods: The study was divided into two phases where Phase 1 was a cross sectional survey of women, aged over 45 years with type 2 diabetes who were attending Diabetes clinics in the Primary and Community Health Service of the Metro North Health Service District of Queensland Health (N = 22). The women were a subsample of women participating in a multi-model lifestyle intervention, the ‘Reducing Chronic Disease among Adult Australian Women’ project. Phase 2 of the study was a cross sectional online survey of nurses working in Primary and Community Health Service in the Metro North Health Service District of Queensland Health (N = 46). Pender’s health promotion model was used as the theoretical framework for this study. Results: Women in this study had an average total barriers score of 32.18 (SD = 9.52) which was similar to average scores reported in the literature for women with a range of physical disabilities and illnesses. The leading five barriers for this group of women were: concern about safety; too tired; not interested; lack of information about what to do; with lack of time and feeling I can’t do things correctly the equal fifth ranked barriers. In this study there was no statistically significant difference in average total barriers scores between women in the intervention group and those is the usual care group of the parent study. There was also no significant relationship between the women’s socio-demographic variables and lifestyle risk factors and their level of perceived barriers. Nurses in the study had an average total barriers score of 44.48 (SD = 6.24) which was higher than all other average scores reported in the literature. The leading five barriers that nurses perceived were an issue for women with a chronic disease were: lack of time and interferes with other responsibilities the leading barriers; embarrassment about appearance; lack of money; too tired and lack of support from family and friends. There was no significant relationship between the nurses’ sociodemographic and nursing variables and the level of perceived barriers. When comparing the results of women and nurses in the study there was a statistically significant difference in the median total barriers score between the groups (p < 0.001), where the nurses perceived the barriers to be higher (Md = 43) than the women (Md = 33). There was also a significant difference in the responses to the individual barriers items in fifteen of the eighteen items (p < 0.002). Conclusion: Although this study is limited by a small sample size, it contributes to understanding the perception of midlife and older women with a chronic disease and also the perception of nurses, about the barriers to healthy lifestyle activities that women face. The study provides some evidence that the perceptions of women and nurses may differ and argues that these differences may have significant implications for clinical practice. The study recommends a greater emphasis on assessing and managing perceived barriers to health promotion activities in health education and policy development and proposes a conceptual model for understanding perceived barriers to action.

Theorising a model for teaching and assessing reflective learning in higher education

The importance of reflection in higher education, and across disciplinary fields is widely recognised; it is generally included in university graduate attributes, professional standards and program objectives. Furthermore, reflection is commonly embedded into assessment requirements in higher education subjects, often without necessary scaffolding or clear expectations for students. Despite the rhetoric around the importance of reflection for ongoing learning, there is scant literature on any systematic, developmental approach to teaching reflective learning across higher education programs/courses. Given that professional or academic reflection is not intuitive, and requires specific pedagogic intervention to do well, a program/course-wide approach is essential. This paper draws on current literature to theorise a new, transferable and customisable model for teaching and assessing reflective learning across higher education, which foregrounds and explains the pedagogic field of higher education as a multi-dimensional space. We argue that explicit and strategic pedagogic intervention, supported by dynamic resources, is necessary for successful, broad-scale approaches to reflection in higher education.

Conceptualising and teaching discursive and performative reflection in higher education

The importance of reflection in higher education, and across disciplinary fields is widely recognised. It is generally embedded in university graduate attributes, professional standards and course objectives. Furthermore, reflection is commonly included in assessment requirements in higher education subjects, often without necessary scaffolding or clear expectations for students. It is essential that academic staff have substantive knowledge and clear expectations about the aims of reflective activities, the most effective mode of representation, and appropriate teaching strategies to support students in deep, critical reflection. The paper argues the case for reflection to be represented in different modes, using discursive (language) or performative (symbolic practice) forms of expression according to disciplinary context and individual communicative strengths. It introduces key discursive and expressive elements that constitute different modes of representation in reflective tasks. This functional analysis of textual elements provides explicit knowledge for teaching and assessing multiple modes of reflection in higher education.

Notch and NOXA-related pathways in melanoma cells

Notch receptor-mediated intracellular events represent an ancient cell signaling system, and alterations in Notch expression are associated with various malignancies in which Notch may function as an oncogene or less commonly as a tumor suppressor. Notch signaling regulates cell fate decisions in the epidermis, including influencing stem cell dynamics and growth/differentiation control of cells in skin. Because of increasing evidence that the Notch signaling network is deregulated in human malignancies, Notch receptors have become attractive targets for selective killing of malignant cells. Compared with proliferating normal human melanocytes, melanoma cell lines are characterized by markedly enhanced levels of activated Notch-1 receptor. By using a small molecule gamma-secretase inhibitor (GSI) consisting of a tripeptide aldehyde, N-benzyloxycarbonyl-Leu-Leu-Nle-CHO, which can block processing and activation of all four different Notch receptors, we identified a specific apoptotic vulnerability in melanoma cells. GSI triggers apoptosis in melanoma cells, but only G2/M growth arrest in melanocytes without subsequent cell death. Moreover, GSI treatment induced a pro-apoptotic BH3-only protein, NOXA, in melanoma cells but not in normal melanocytes. The use of GSI to induce NOXA induction overcomes the apoptotic resistance of melanoma cells, which commonly express numerous cell survival proteins such as Mcl-1, Bcl-2, and survivin. Taken together, these results highlight the concept of synthetic lethality in which exposure to GSI, in combination with melanoma cells overexpressing activated Notch receptors, has lethal consequences, producing selective killing of melanoma cells, while sparing normal melanocytes. By identifying signaling pathways that contribute to the transformation of melanoma cells (e.g. Notch signaling), and anti-cancer agents that achieve tumor selectivity (e.g., GSI-induced NOXA), this experimental approach provides a useful framework for future therapeutic strategies in cutaneous oncology.

Mapping the language of science and science teaching practices : a case study of early childhood school science

Concerns raised in educational reports about school science in terms of students. outcomes and attitudes, as well as science teaching practices prompted investigation into science learning and teaching practices at the foundational level of school science. Without science content and process knowledge, understanding issues of modern society and active participation in decision-making is difficult. This study contended that a focus on the development of the language of science could enable learners to engage more effectively in learning science and enhance their interest and attitudes towards science. Furthermore, it argued that explicit teaching practices where science language is modelled and scaffolded would facilitate the learning of science by young children at the beginning of their formal schooling. This study aimed to investigate science language development at the foundational level of school science learning in the preparatory-school with students aged five and six years. It focussed on the language of science and science teaching practices in early childhood. In particular, the study focussed on the capacity for young students to engage with and understand science language. Previous research suggests that students have difficulty with the language of science most likely because of the complexities and ambiguities of science language. Furthermore, literature indicates that tensions transpire between traditional science teaching practices and accepted early childhood teaching practices. This contention prompted investigation into means and models of pedagogy for learning foundational science language, knowledge and processes in early childhood. This study was positioned within qualitative assumptions of research and reported via descriptive case study. It was located in a preparatory-school classroom with the class teacher, teacher-aide, and nineteen students aged four and five years who participated with the researcher in the study. Basil Bernstein.s pedagogical theory coupled with Halliday.s Systemic Functional Linguistics (SFL) framed an examination of science pedagogical practices for early childhood science learning. Students. science learning outcomes were gauged by focussing a Hallydayan lens on their oral and reflective language during 12 science-focussed episodes of teaching. Data were collected throughout the 12 episodes. Data included video and audio-taped science activities, student artefacts, journal and anecdotal records, semi-structured interviews and photographs. Data were analysed according to Bernstein.s visible and invisible pedagogies and performance and competence models. Additionally, Halliday.s SFL provided the resource to examine teacher and student language to determine teacher/student interpersonal relationships as well as specialised science and everyday language used in teacher and student science talk. Their analysis established the socio-linguistic characteristics that promoted science competencies in young children. An analysis of the data identified those teaching practices that facilitate young children.s acquisition of science meanings. Positive indications for modelling science language and science text types to young children have emerged. Teaching within the studied setting diverged from perceived notions of common early childhood practices and the benefits of dynamic shifting pedagogies were validated. Significantly, young students demonstrated use of particular specialised components of school-science language in terms of science language features and vocabulary. As well, their use of language demonstrated the students. knowledge of science concepts, processes and text types. The young students made sense of science phenomena through their incorporation of a variety of science language and text-types in explanations during both teacher-directed and independent situations. The study informs early childhood science practices as well as practices for foundational school science teaching and learning. It has exposed implications for science education policy, curriculum and practices. It supports other findings in relation to the capabilities of young students. The study contributes to Systemic Functional Linguistic theory through the development of a specific resource to determine the technicality of teacher language used in teaching young students. Furthermore, the study contributes to methodology practices relating to Bernsteinian theoretical perspectives and has demonstrated new ways of depicting and reporting teaching practices. It provides an analytical tool which couples Bernsteinian and Hallidayan theoretical perspectives. Ultimately, it defines directions for further research in terms of foundation science language learning, ongoing learning of the language of science and learning science, science teaching and learning practices, specifically in foundational school science, and relationships between home and school science language experiences.