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.

Interleukin-13 promotes susceptibility to chlamydial infection of the respiratory and genital tracts

Chlamydiae are intracellular bacteria that commonly cause infections of the respiratory and genital tracts, which are major clinical problems. Infections are also linked to the aetiology of diseases such as asthma, emphysema and heart disease. The clinical management of infection is problematic and antibiotic resistance is emerging. Increased understanding of immune processes that are involved in both clearance and immunopathology of chlamydial infection is critical for the development of improved treatment strategies. Here, we show that IL-13 was produced in the lungs of mice rapidly after Chlamydia muridarum (Cmu) infection and promoted susceptibility to infection. Wild-type (WT) mice had increased disease severity, bacterial load and associated inflammation compared to IL-13 deficient (−/−) mice as early as 3 days post infection (p.i.). Intratracheal instillation of IL-13 enhanced bacterial load in IL-13−/− mice. There were no differences in early IFN-g and IL-10 expression between WT and IL-13−/− mice and depletion of CD4+ T cells did not affect infection in IL-13−/− mice. Collectively, these data demonstrate a lack of CD4+ T cell involvement and a novel role for IL-13 in innate responses to infection. We also showed that IL-13 deficiency increased macrophage uptake of Cmu in vitro and in vivo. Moreover, the depletion of IL-13 during infection of lung epithelial cells in vitro decreased the percentage of infected cells and reduced bacterial growth. Our results suggest that enhanced IL-13 responses in the airways, such as that found in asthmatics, may promote susceptibility to chlamydial lung infection. Importantly the role of IL-13 in regulating infection was not limited to the lung as we showed that IL-13 also promoted susceptibility to Cmu genital tract infection. Collectively our findings demonstrate that innate IL-13 release promotes infection that results in enhanced inflammation and have broad implications for the treatment of chlamydial infections and IL-13-associated diseases.

The genesis of 'the new geography and the new imperialism : 1870-1918', or 'how I came to Jamaica and joined the UWI Geography Department

In this article, Brian Hudson relates how he came to write the paper published in the journal Antipode, for which he gained recognition as a radical geographer in the late 1970's. It is a tale of a journey in which the loves of his life, geography, history, travel and his wife of over 40 years, came together through living in a number of different places: the United Kingdom, Ghana, Hong Kong, and Jamaica. After leaving UWI, Brian and his family settled in Brisbane, Australia where he taught at Queensland University of Technology until his retirement.

…Where did I lose you? Accessing the literacy demands of assessment

In this study we sought to find out how teachers could make assessment fairer for Indigenous students in learning mathematics, given the context of the high stakes of the National Assessment Program Literacy and Numeracy (NAPLAN). Today, teachers are experiencing the full range of demands from their own students who require individual attention, through to system level expectations of improved performances for all students. Many staff experience reform fatigue with limited time for critical reflection and a reduction in support for the use and the analysis of the overwhelming amount of data that has become available in recent years. Over the past three years we worked with teachers in seven schools to gradually refine our research focus to centre on how we might best support teachers in this demanding context with the important outcome of improved teaching and learning of mathematics with particular consideration of how to respond to the cultural needs of Indigenous (Aboriginal and Torres Strait Islander) students.

Sampling environmental acoustic recordings to determine species richness : I

Acoustic sensors provide an effective means of monitoring biodiversity at large spatial and temporal scales. They can continuously and passively record large volumes of data over extended periods, however these data must be analysed to detect the presence of vocal species. Automated analysis of acoustic data for large numbers of species is complex and can be subject to high levels of false positive and false negative results. Manual analysis by experienced users can produce accurate results, however the time and effort required to process even small volumes of data can make manual analysis prohibitive. Our research examined the use of sampling methods to reduce the cost of analysing large volumes of acoustic sensor data, while retaining high levels of species detection accuracy. Utilising five days of manually analysed acoustic sensor data from four sites, we examined a range of sampling rates and methods including random, stratified and biologically informed. Our findings indicate that randomly selecting 120, one-minute samples from the three hours immediately following dawn provided the most effective sampling method. This method detected, on average 62% of total species after 120 one-minute samples were analysed, compared to 34% of total species from traditional point counts. Our results demonstrate that targeted sampling methods can provide an effective means for analysing large volumes of acoustic sensor data efficiently and accurately.

Effect of outdoor site location on calculated I/O ratios

Motor vehicle emissions have been identified as one of the major contributors of fine and ultrafine particles (UFP) in urban areas. Schools located near major roads could potentially be exposed to high levels of UPFs and school classroom is an important microenvironment where significant exposure to UFPs is likely to occur. Most of the research conducted to date has investigated the relationship between indoor and outdoor particle number concentration (PNC) in schools based on one outdoor location, which may introduce a level of error when calculating the variation of total UPFs, and can result in the underestimation or overestimation of indoor to outdoor (I/O) ratio values.

Influence of filtration on I/O particle concentration ratios at urban office buildings

Epidemiological research has consistently shown an association between fine and ultrafine particle concentrations, and increases in both respiratory and cardiovascular morbidity and mortality. These particles, often found in vehicle emissions outside buildings, can penetrate inside via their envelopes and mechanically ventilated systems. Indoor activities such as printing, cooking and cleaning, as well as the movement of building occupants are also an additional source of these particles. In this context, the filtration systems of mechanically ventilated buildings can reduce indoor particle concentrations. Several studies have quantified the efficiency of dry-media and electrostatic filters, but they mainly focused on the particle size range > 300 nm. Some others studied ultrafine particles but their investigations were conducted in laboratories. At this point, there is still only limited information on in situ filter efficiency and an incomplete understanding of filtration influence on I/O ratios of particle concentrations. To help address these gaps in knowledge and provide new information for the selection of appropriate filter types in office building HVAC systems, we aimed to: (1) measure particle concentrations at up and down stream flows of filter devices, as well as outdoor and indoor office buildings; (2) quantify efficiency of different filter types at different buildings; and (3) assess the impact of these filters on I/O ratios at different indoor and outdoor source operation scenarios.

I just want to design a sexy flying car! Teaching design-led innovation to designers

Many international management programs have capitalised on the value design can have upon potential business solutions and strategies (Martin, 2009 & Brown, 2008) as well as many international design programs introducing designers to business theory and curriculum (Manzini & Rizzo, 2011). This paper presents the findings from structured interviews with undergraduate design students and design industry professionals. Current literature surrounding design led innovation and the role designers’ play within it is also discussed and the challenges facing designers in this emerging design era are presented. The findings from this study indicate that most designers enter an undergraduate program not wanting to become the business leaders of tomorrow. Instead, they enter in the hope they can humbly help people and to make a difference in the world. There are contentions with this perspective, felt by industry, academia and students around why designers need to be taught business theory content. This paper provides the first step to overcoming this challenge by providing insight into the attitudes, perceptions and challenges designers are facing with this new design era.

Serine protease inhibition and mitochondrial dysfunction associated with cisplatin resistance in human tumor cell lines : targets for therapy

Indicators of mitochondrial function were studied in two different cell culture models of cis-diamminedichloroplatinum-II (CDDP) resistance: the intrinsically resistant human ovarian cancer cell line CI-80-13S, and resistant clones (HeLa-S1a and HeLa-S1b) generated by stable expression of the serine protease inhibitor—plasminogen activator inhibitor type-2 (PAI-2), in the human cervical cancer cell line HeLa. In both models, CDDP resistance was associated with sensitivity to killing by adriamycin, etoposide, auranofin, bis[1,2-bis(diphenylphosphino)ethane]gold(I) chloride {[Au(DPPE)2]Cl}, CdCl2 and the mitochondrial inhibitors rhodamine-123 (Rhl23), dequalinium chloride (DeCH), tetraphenylphosphonium (TPP), and ethidium bromide (EtBr) and with lower constitutive levels of ATP. Unlike the HeLa clones, CI-80-13S cells were additionally sensitive to chloramphenicol, 1-methyl-4-phenylpyridinium ion (MPP+), rotenone, thenoyltrifluoroacetone (TTFA), and antimycin A, and showed poor reduction of 1-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), suggesting a deficiency in NADH dehydrogenase and/or succinate dehydrogenase activities. Total platinum uptake and DNA-bound platinum were slightly lower in CI-80-13S than in sensitive cells. The HeLa-S1a and HeLa-S1b clones, on the other hand, showed poor reduction of triphenyltetrazolium chloride (TTC), indicative of low cytochrome c oxidase activity. Total platinum uptake by HeLa-S1a was similar to HeLa, but DNA-bound platinum was much lower than for the parent cell line. The mitochondria of CI-80-13S and HeLa-S1a showed altered morphology and were fewer in number than those of JAM and HeLa. In both models, CDDP resistance was associated with less platinum accumulation and with mitochondrial and membrane defects, brought about one case with expression of a protease inhibitor which is implicated in tumor progression. Such markers may identify tumors suitable for treatment with gold phosphine complexes or other mitochondrial inhibitors.

‘I always look under the bed for a man’. Needs and barriers to the expression of sexuality in residential aged care: the views of residents with and without dementia

Objectives: This qualitative study canvassed residents' perceptions of the needs and barriers to the expression of sexuality in long-term care. Methods: Sixteen residents, including five with dementia, from six aged care facilities in two Australian states were interviewed. Data were analysed using a constant comparative method. Results: Four categories describe residents' views about sexuality, their needs and barriers to its expression: ‘It still matters’; ‘Reminiscence and resignation’, ‘It's personal’, and ‘It's an unconducive environment’. Discussion: Residents, including those with dementia, saw themselves as sexual beings and with a continuing need and desire to express their sexuality. The manner in which it was expressed varied. Many barriers to sexual expression were noted, including negative attitudes of staff, lack of privacy and limited opportunities for the establishment of new relationships or the continuation of old ones. Interviewees agreed that how a resident expressed their sexuality was their business and no one else's.

Lysosomal secretion of Flightless I upon injury has the potential to alter inflammation

Intracellular Flightless I (Flii), a gelsolin family member, has been found to have roles modulating actin regulation, transcriptional regulation and inflammation. In vivo Flii can regulate wound healing responses. We have recently shown that a pool of Flii is secreted by fibroblasts and macrophages, cells typically found in wounds, and its secretion can be upregulated upon wounding. We show that secreted Flii can bind to the bacterial cell wall component lipopolysaccharide and has the potential to regulate inflammation. We now show that secreted Flii is present in both acute and chronic wound fluid.