PARP inhibition induces BAX/BAK-independent synthetic lethality of BRCA1-deficient non-small cell lung cancer

Evasion of apoptosis contributes to both tumourigenesis and drug resistance in non-small cell lung carcinoma (NSCLC). The pro-apoptotic BCL-2 family proteins BAX and BAK are critical regulators of mitochondrial apoptosis. New strategies for targeting NSCLC in a mitochondria-independent manner should bypass this common mechanism of apoptosis block. BRCA1 mutation frequency in lung cancer is low; however, decreased BRCA1 mRNA and protein expression levels have been reported in a significant proportion of lung adenocarcinomas. BRCA1 mutation/deficiency confers a defect in homologous recombination DNA repair that has been exploited by synthetic lethality through inhibition of PARP (PARPi) in breast and ovarian cells; however, it is not known whether this same synthetic lethal mechanism exists in NSCLC cells. Additionally, it is unknown whether the mitochondrial apoptotic pathway is required for BRCA1/PARPi-mediated synthetic lethality. Here we demonstrate that silencing of BRCA1 expression by RNA interference sensitizes NSCLC cells to PARP inhibition. Importantly, this sensitivity was not attenuated in cells harbouring mitochondrial apoptosis block induced by co-depletion of BAX and BAK. Furthermore, we demonstrate that BRCA1 inhibition cannot override platinum resistance, which is often mediated by loss of mitochondrial apoptosis signalling, but can still sensitize to PARP inhibition. Finally we demonstrate the existence of a BRCA1-deficient subgroup (11–19%) of NSCLC patients by analysing BRCA1 protein levels using immunohistochemistry in two independent primary NSCLC cohorts. Taken together, the existence of BRCA1-immunodeficient NSCLC suggests that this molecular subgroup could be effectively targeted by PARP inhibitors in the clinic and that PARP inhibitors could be used for the treatment of BRCA1-immunodeficient, platinum-resistant tumours.

Hospital to home outreach for malnourished elders (HHOME) : a feasibility pilot

Objectives: Malnutrition is common in older hospitalised patients, and barriers to adequate intake in hospital limit the effectiveness of hospital-based nutrition interventions. This pilot study was undertaken to determine whether nutrition-focussed care at discharge and in the early post-hospital period is feasible and acceptable to patients and carers, and improves nutritional status. Design: Prospective cohort study Setting: Internal medicine wards of a tertiary teaching hospital in Brisbane, Australia Participants: Patients aged 65 and older admitted for at least 3 days, identified as malnourished or at risk of malnutrition using Mini Nutritional Assessment (MNA). Interventions: An interdisciplinary discharge team (specialist discharge planning nurse and accredited practicing dietitian) provided nutrition-focussed education, advice, service coordination and follow-up (home visits and telephone) for 6 weeks following hospitalisation Measurements: Nutritional intake, weight, functional status and MNA were recorded 6 and 12 weeks after discharge. Service intensity and changes to care were noted, and hospital readmissions recorded. Service feedback from patients and carers was sought using a brief questionnaire. Results: 12 participants were enrolled during the 6 week pilot (mean age 82 years, 50% male). All received 1-2 home visits, and 3-8 telephone calls. Four participants had new community services arranged, 4 were commenced on oral nutritional supplements, and 7 were referred to community dietetics services for follow-up. Two participants had a decline in MNA score of more than 10% at 12 week follow-up, while the remainder improved by at least 10%. Individualised care including community service coordination was valued by participants. Conclusion: The proposed model of care for older adults was feasible, acceptable to patients and carers, and associated with improved nutritional status at 12 weeks for most participants. The pilot data will be useful for design of intervention trials.

Client intentions and Bruno Taut’s Glashaus

An often overlooked aspect concerning the Glashaus is the significant influence exerted by the client in the design of the building. In an intentional endeavour to create an exhibition pavilion that best showcased their glazed products and construction technologies, the German Luxfer Prism Syndicate both commissioned and majority financed the Glashaus. It would therefore seem strange that the official histories of the Glashaus would rather record the utopian, romanticised and arguably imagined intentions of Bruno Taut as the architect, as opposed to the reality of the client’s intentions. This paper offers a reinterpretation of the Glashaus from the perspective of German Luxfer Prism Syndicate. This reinterpretation is achieved through an investigation that primarily concentrates on the glazed areas of the Glashaus where the German Luxfer Prism Syndicates products were most evident. Using the arguments initially presented by Dietrich Neumann as a foundation, this research is additionally interwoven with inquiry into diverse aspects such as patents filed by the Luxfer group of companies and a close examination of the original black and white photographs of the Glashaus. A dramatically different understanding emerges when the Glashaus is argued from the perspective of the client; an understanding that is cold, hard and commercial as opposed to utopian and romanticised. As a result, this research makes a contribution to the current debate concerning the Glashaus and the re-evaluation of the histories of the modern movement.

Malnutrition screening tools : comparison against two validated nutrition assessment methods in older medical inpatients

Objective Although several validated nutritional screening tools have been developed to “triage” inpatients for malnutrition diagnosis and intervention, there continues to be debate in the literature as to which tool/tools clinicians should use in practice. This study compared the accuracy of seven validated screening tools in older medical inpatients against two validated nutritional assessment methods. Methods This was a prospective cohort study of medical inpatients at least 65 y old. Malnutrition screening was conducted using seven tools recommended in evidence-based guidelines. Nutritional status was assessed by an accredited practicing dietitian using the Subjective Global Assessment (SGA) and the Mini-Nutritional Assessment (MNA). Energy intake was observed on a single day during first week of hospitalization. Results In this sample of 134 participants (80 ± 8 y old, 50% women), there was fair agreement between the SGA and MNA (κ = 0.53), with MNA identifying more “at-risk” patients and the SGA better identifying existing malnutrition. Most tools were accurate in identifying patients with malnutrition as determined by the SGA, in particular the Malnutrition Screening Tool and the Nutritional Risk Screening 2002. The MNA Short Form was most accurate at identifying nutritional risk according to the MNA. No tool accurately predicted patients with inadequate energy intake in the hospital. Conclusion Because all tools generally performed well, clinicians should consider choosing a screening tool that best aligns with their chosen nutritional assessment and is easiest to implement in practice. This study confirmed the importance of rescreening and monitoring food intake to allow the early identification and prevention of nutritional decline in patients with a poor intake during hospitalization.

Patient-practitioner relationships desired by overweight/obese adults

Objective: This study investigated the characteristics of the patient-practitioner relationship desired by overweight/obese individuals in weight management. The aim was to identify characteristics of the relationship which empower patients to make lifestyle changes. Methods: Grounded theory was used inductively to build a model of the patient-practitioner relationship based on the perspectives of 21 overweight/obese ¬adults. Results: Emerging from the match between patient and practitioner characteristics, collaboration was the key process explicitly occurring in the patient-practitioner relationship, and was characterised by two subcategories; perceived power dimensions and openness. Trust emerged implicitly from the collaborative process, being fostered by relational, informational, and credible aspects of the interaction. Patient trust in their practitioner consequently led to empowering outcomes including goal ownership and perceiving the utility of changes. Conclusion: An appropriate match between patient and practitioner characteristics facilitates collaboration which leads to trust, both of which appear to precede empowering outcomes for patients such as goal ownership and perceiving the utility of changes. Collaboration is an explicit process and precedes the patient trusting their practitioner. Practice implications: Practitioners should be sensitive to patient preferences for collaboration and the opportunity to develop trust with patients relationally, through information provision, and modelling a healthy lifestyle.

Creative industries after the first decade of debate

It has now been over a decade since the concept of creative industries was first put into the public domain by the Blair Labour government’s Creative Industries Mapping Documents in Britain. The concept has gained traction globally, but it has also been understood and developed in different ways in Europe, Asia, Australia, New Zealand, and North America, as well as through international bodies such as UNCTAD and UNESCO. A review of the policy literature reveals that although questions and issues remain around definitional coherence, there is some degree of consensus emerging about the size, scope, and significance of the sectors in question in both advanced and developing economies. At the same time, debate about the concept remains highly animated in media, communication, and cultural studies, with its critics dismissing the concept outright as a harbinger of neoliberal ideology in the cultural sphere. This article couches such critiques in light of recent debates surrounding the intellectual coherence of the concept of neoliberalism, arguing that this term itself possesses problems when taken outside of the Anglo-American context in which it originated. It is argued that issues surrounding the nature of participatory media culture, the relationship between cultural production and economic innovation, and the future role of public cultural institutions can be developed from within a creative industries framework and that writing off such arguments as a priori ideological and flawed does little to advance debates about twentieth-century information and media culture.

The creative cities discourse : production and/or consumption?

The already considerable debate about what constitutes a 'creative' city becomes ever more critical as the world urbanizes at a rapid pace. In this chapter the author argues that the key tensions in discussions over what makes cities more conducive to and supportive of creativity revolve around perspectives that are either production-centric or consumption-centric. Scholars are increasing prepared to claim priority for the city-region over the nation-state as an economic and cultural agent in the contemporary world, but are they ready to deal with major changes in the nature of cultural production and consumption themselves? A number of examples of new challenges for the creative cities 'discourse' rounds out the chapter.

Emergent innovation through the co-evolution of informal and formal media economies

Well-established distinctions between amateur and professional are blurring as the impact of social media, changes in cultural consumption, and crises in copyright industries’ business models are felt across society and economy. I call this the increasingly rapid co-evolution of the formal market and informal household sectors and analyse it through the concept of ‘social network markets’ – individual choices are made on the basis of other’s choices and such networked preferencing is enhanced by the growing ubiquity of social media platforms. This may allow us better to understand sources of disruption and innovation in audiovisual production and distribution in wealthy Western markets which are as significant as those posed by informal practices outside the West. I examine what is happening around the monetization and professionalization of online video (YouTube, for example) and the socialization of professional production strategies (transmedia, for example) as innovation from the margins.

Convergence and Australian content : the importance of access

In the light of new and complex challenges to media policy and regulation, the Austrlaian government commissioned the Convergence Review in late 2010 to assess the continuing applicability and utility of the principles and objectives that have shaped the policy framework to this point. It proposed a range of options for policy change and identified three enduring priorities for continued media regulation: media ownership and control; content standards; and Australian content production and distribution. The purpose of this article is to highlight an area where we feel there are opportunities for further discussion and research: the question of how the accessibility and visibility of Australian and local content may be assured in the future media policy framework via a combination of regulation and incentives to encourage innovation in content distribution.

Weight bias on psychological and physical health

It is a round table discussion article. "Weight bias refers to negative weight-related attitudes and beliefs, expressed in a range of forms towards individuals who are overweight or obese. Consequences of weight bias could be very significant to the individuals which may predispose them to additional weight gain. This brief literature review discusses the concept of weight bias and its impact on psychological and physical health on overweight and obese individuals..."

Polyandry and paternity skew in natural and experimental populations of Drosophila serrata

Many species engage in polyandry, resulting in the potential for sexual selection to continue post-copulation through sperm competition and/or cryptic female choice. The relative importance of pre- vs. post-copulatory processes remains unknown for most species despite this information being fundamental for understanding the evolutionary consequences of sexual selection. The Australian fruit fly Drosophila serrata has become a prominent model system for studying precopulatory sexual selection, such as mating preferences and their influence on the evolution of sexually selected traits. Here, we investigated polyandry and the potential for post-copulatory sexual selection in this species using indirect paternity analysis. We genotyped 21 wild-caught and 19 laboratory-reared mothers and their offspring (a total of 787 flies) at six microsatellite loci and found extensive polyandry, with all broods surveyed having at least two sires. Female remating rates were higher than in other Drosophila surveyed to date and no significant differences were found between laboratory and field populations. Additionally, we found evidence for biased sperm usage in several broods of D. serrata. Paternity skew occurred more frequently in broods from the field population than the laboratory one, suggesting differences between the two environments in the level of post-copulatory sexual selection. Our data suggest that D. serrata represents a promising system for studying the interaction between pre- and post-copulatory sexual selection in driving the evolution of sexually selected phenotypes.

Performance reporting : assessing the annual reports of Malaysian local authorities

There have been calls for Malaysian local authorities to be more transparent and accountable in the discharge of their functional responsibilities. This study empirically evaluates the extent and quality of current performance reporting by local authorities. The disclosure of relevant information for discharging accountability obligations, as defined by a broad range of stakeholders, falls short of best practice. Therefore, the performance of Malaysian local authorities lacks transparency. The findings could assist in the development of more comprehensive guidelines for local authority reporting and raise awareness of information stakeholders expect to be reported in the context of accountability