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.

IGF2 increases de novo steroidogenesis in prostate cancer cells

Androgen-dependent pathways regulate maintenance and growth of normal and malignant prostate tissues. Androgen deprivation therapy (ADT) exploits this dependence and is used to treat metastatic prostate cancer; however, regression initially seen with ADT gives way to development of incurable castration-resistant prostate cancer (CRPC). Although ADT generates a therapeutic response, it is also associated with a pattern of metabolic alterations consistent with metabolic syndrome including elevated circulating insulin. Because CRPC cells are capable of synthesizing androgens de novo, we hypothesized that insulin may also influence steroidogenesis in CRPC. In this study, we examined this hypothesis by evaluating the effect of insulin on steroid synthesis in prostate cancer cell lines. Treatment with 10 nmol/L insulin increased mRNA and protein expression of steroidogenesis enzymes and upregulated the insulin receptor substrate insulin receptor substrate 2 (IRS-2). Similarly, insulin treatment upregulated intracellular testosterone levels and secreted androgens, with the concentrations of steroids observed similar to the levels reported in prostate cancer patients. With similar potency to dihydrotestosterone, insulin treatment resulted in increased mRNA expression of prostate-specific antigen. CRPC progression also correlated with increased expression of IRS-2 and insulin receptor in vivo. Taken together, our findings support the hypothesis that the elevated insulin levels associated with therapeutic castration may exacerbate progression of prostate cancer to incurable CRPC in part by enhancing steroidogenesis.

Curriculum, assessment teaching and learning for all

This chapter explores how the culture of classrooms and schools can acknowledge diversity and meet all learning needs. Classroom and school culture can and should enhance the belonging and learning of all students. Understanding of learning, curriculum, pedagogy and assessment influences the ways teachers consider their expectations of student achievement and participation in school. We revisit the theory of social constructionism to emphasise the development of shared and valued curriculum, which meets all learner needs. Decisions about what to teach, how to teach and assess, and what supports student needs are important considerations discussed in this chapter. Key messages drawn from the Australian and New Zealand curriculum reinforce the need to ensure education responds to the diversity of students in classrooms. A range of models of pedagogy that have influenced education in Australia and New Zealand are presented, with a particular focus on meeting the needs of students who have disabilities. In addition, the issues related to student and teacher identity, the importance of respectful partnerships that acknowledge family knowledge, and respectful collaboration are discussed. Belonging to a community of learners is made possible through teachers forming authentic relationships with students and their families. In turn, these relationships support teachers to understand how the students in their classrooms learn, and to know their students’ strengths and interests.

Students’ approaches to learning a new mathematical model

In this article, we report on the findings of an exploratory study into the experience of undergraduate students as they learn new mathematical models. Qualitative and quanti- tative data based around the students’ approaches to learning new mathematical models were collected. The data revealed that students actively adopt three approaches to under- standing a new mathematical model: gathering information for the task of understanding the model, practising with and using the model, and finding interrelationships between elements of the model. We found that the students appreciate mathematical models that have a real world application and that this can be used to engage students in higher level learning approaches.

Solo life to Second Life : the design of physical and virtual learning spaces inspired by the drama classroom

This paper explores the design of virtual and physical learning spaces developed for students of drama and theatre studies. What can we learn from the traditional drama workshop that will inform the design of drama and theatre spaces created in technology-mediated learning environments? The authors examine four examples of spaces created for online, distance and on-campus students and discuss the relationship between the choice of technology, the learning and teaching methods, and the outcomes for student engagement. Combining insights from two previous action research projects, the discussion focuses on the physical space used for contemporary drama workshops, supplemented by Web 2.0 technologies; a modular online theatre studies course; the blogging space of students creating a group devised play; and the open and immersive world of Second Life, where students explore 3D simulations of historical theatre sites. The authors argue that the drama workshop can be used as inspiration for the design of successful online classrooms. This is achieved by focusing on students’ contributions to the learning as individuals and group members, the aesthetics and mise-en-scene of the learning space, and the role of mobile and networked technologies. Students in this environment increase their capacity to become co-creators of knowledge and to achieve creative outcomes. The drama workshop space in its physical and virtual forms is seen as a model for classrooms in other disciplines, where dynamic, creative and collaborative spaces are required.

Responding to national curriculum goals for English language learners : enhancing reading strategies in high school content areas

The official need for content teachers to teach the language features of their fields has never been greater in Australia than now. In 2012, the recently formed national curriculum board announced that all teachers are responsible for the English language development of students whose first language or dialect is not Standard Australian English (SAE). This formal endorsement is an important juncture regarding the way expertise might be developed, perceived and exchanged between content and language teachers through collaboration, in order for the goals of English language learners in content areas to be realised. To that end, we conducted an action research project to explore and extend the reading strategies pedagogy of one English language teacher who teaches English language learners in a parallel junior high school Geography program. Such pedagogy will be valuable for all teachers as they seek to contribute to English language development goals as outlined in national curricula.

Craving as a predictor of treatment outcomes in heavy drinkers with comorbid depressed mood

Alcohol and depression comorbidity is high and is associated with poorer outcomes following treatment. The ability to predict likely treatment response would be advantageous for treatment planning. Craving has been widely studied as a potential predictor, but has performed inconsistently. The effect of comorbid depression on craving's predictive performance however, has been largely neglected, despite demonstrated associations between negative affect and craving. The current study examined the performance of craving, measured pretreatment using the Obsessive subscale of the Obsessive Compulsive Drinking Scale, in predicting 18-week and 12-month post-treatment alcohol use outcomes in a sample of depressed drinkers. Data for the current study were collected during a randomized controlled trial (Baker, Kavanagh, Kay-Lambkin, Hunt, Lewin, Carr, & Connolly, 2010) comparing treatments for comorbid alcohol and depression. A subset of 260 participants from that trial with a Timeline Followback measure of alcohol consumption was analyzed. Pre-treatment craving was a significant predictor of average weekly alcohol consumption at 18 weeks and of frequency of alcohol binges at 18 weeks and 12months, but pre-treatment depressive mood was not predictive, and effects of Baseline craving were independent of depressive mood. Results suggest a greater ongoing risk from craving than from depressive mood at Baseline.

Curriculum design and higher order skills : challenging assumptions

This paper is based on an Australian Learning & Teaching Council (ALTC) funded evaluation in 13 universities across Australia and New Zealand of the use of Engineers Without Borders (EWB) projects in first-year engineering courses. All of the partner institutions have implemented this innovation differently and comparison of these implementations affords us the opportunity to assemble "a body of carefully gathered data that provides evidence of which approaches work for which students in which learning environments". This study used a mixed-methods data collection approach and a realist analysis. Data was collected by program logic analysis with course co-ordinators, observation of classes, focus groups with students, exit survey of students and interviews with staff as well as scrutiny of relevant course and curriculum documents. Course designers and co-ordinators gave us a range of reasons for using the projects, most of which alluded to their presumed capacity to deliver experience in and learning of higher order thinking skills in areas such as sustainability, ethics, teamwork and communication. For some students, however, the nature of the projects decreased their interest in issues such as ethical development, sustainability and how to work in teams. We also found that the projects provoked different responses from students depending on the nature of the courses in which they were embedded (general introduction, design, communication, or problem-solving courses) and their mode of delivery (lecture, workshop or online).

Flexing some muscle: strategy and outcomes in the Queensland health and fitness industry

In 1993, contrary to the trend towards enterprise bargaining, and despite an employment environment favouring strong managerial prerogative, a small group of employers in the Queensland commercial health and fitness industry sought industrial regulation through an industry-specific award. A range of factors, including increased competition and unscrupulous profiteers damaging the industry’s reputation, triggered the actions as a business strategy. The strategic choices of the employer group, to approach a union to initiate a consent award, are the inverse of behaviours expected under strategic choice theory. This article argues that organizational size, collective employer action, focus on industry rather than organizational outcomes and the traditional industrial relations system providing broader impacts explain their atypical behaviour.

The prevalence and perception of pain amongst hospital in-patients

The aim of this paper is to describe the prevalence and perceptions of pain and pain management amongst hospital in-patients. A cross-sectional descriptive survey of 205 patients was conducted. Presence and severity of pain was assessed using verbal descriptor and visual analogue scales, and perceptions of pain were assessed using multi-item scales. Although the severity of pain reported was consistent across age groups and clinical areas, women in the study sample were significantly more likely to report high levels of pain than men. Differences in how men and women communicate their pain were observed, with women indicating that they were less willing to ask for help with their pain. Results suggest that pain continues to be an important problem for a large number of men and women in hospital, and that the experience of pain impacts negatively upon their well-being. Gender differences in the experience of and response to pain remain important considerations for clinical nurses who have major responsibilities for the management of pain in hospitalized patients.

Relationship between emotional climate and the fluency of classroom interactions

This study examined emotional climate in relation to the teaching and learning of grade 7 science. A multi-method and multi-theoretic approach used sociocultural frameworks as a foundation for interpretive research, conversation analysis, prosody analysis, and studies of nonverbal conduct. Emotional climate varied continuously throughout a lesson. Dialogues occurred and afforded learning when interactions between the teacher and students were fluent and included humour and collective effervescence. Emotional climate was negatively valenced when the teacher and/or students endeavoured to establish and maintain power by restricting others’ participation to spectator roles. The teacher’s endeavours to maintain and establish control over students were potentially detrimental to teaching and learning, teachers and learners. This type of teaching gradually evolved into a form we referred to as cranky teaching, whereby the teacher and her students showed signs of frustration and the enacted teaching and learning roles lacked fluency. The methods we pioneered in the present study might be helpful for other teachers who wish to participate in research on their classes to ascertain what works and should be strengthened, and identify practices and rituals that are deleterious and in need of change.

Directors at work : a practical guide for directors

Directors at Work: A Practical Guide for Boards is designed to be a practical tool for directors and boards wishing to implement leading practice corporate governance in their organisations. The book discusses contemporary issues in corporate governance, ways in which boards, directors and their advisers can be effective, and ways to improve their governance processes and procedures. The book also discusses an area that was only touched on briefly in the previous book, but is at the heart of effective decision making by boards: board behavioural dynamics, which deals with the types of behaviours that either support or destroy good governance.

Growth of confined cancer spheroids : a combined experimental marker, critical modelling approach

A critical step in the dissemination of ovarian cancer is the formation of multicellular spheroids from cells shed from the primary tumour. The objectives of this study were to apply bioengineered three-dimensional (3D) microenvironments for culturing ovarian cancer spheroids in vitro and simultaneously to build on a mathematical model describing the growth of multicellular spheroids in these biomimetic matrices. Cancer cells derived from human epithelial ovarian carcinoma were embedded within biomimetic hydrogels of varying stiffness and grown for up to 4 weeks. Immunohistochemistry, imaging and growth analyses were used to quantify the dependence of cell proliferation and apoptosis on matrix stiffness, long-term culture and treatment with the anti-cancer drug paclitaxel. The mathematical model was formulated as a free boundary problem in which each spheroid was treated as an incompressible porous medium. The functional forms used to describe the rates of cell proliferation and apoptosis were motivated by the experimental work and predictions of the mathematical model compared with the experimental output. This work aimed to establish whether it is possible to simulate solid tumour growth on the basis of data on spheroid size, cell proliferation and cell death within these spheroids. The mathematical model predictions were in agreement with the experimental data set and simulated how the growth of cancer spheroids was influenced by mechanical and biochemical stimuli including matrix stiffness, culture duration and administration of a chemotherapeutic drug. Our computational model provides new perspectives on experimental results and has informed the design of new 3D studies of chemoresistance of multicellular cancer spheroids.

Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010 : a systematic analysis for the Global Burden of Disease Study 2010

Background Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs). Methods Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis. Findings Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350 000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient −0·37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa. Interpretation Rates of YLDs per 100 000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world. Funding Bill & Melinda Gates Foundation.