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.

Is the unigram relevance model term independent? Classifying term dependencies in query expansion

This paper develops a framework for classifying term dependencies in query expansion with respect to the role terms play in structural linguistic associations. The framework is used to classify and compare the query expansion terms produced by the unigram and positional relevance models. As the unigram relevance model does not explicitly model term dependencies in its estimation process it is often thought to ignore dependencies that exist between words in natural language. The framework presented in this paper is underpinned by two types of linguistic association, namely syntagmatic and paradigmatic associations. It was found that syntagmatic associations were a more prevalent form of linguistic association used in query expansion. Paradoxically, it was the unigram model that exhibited this association more than the positional relevance model. This surprising finding has two potential implications for information retrieval models: (1) if linguistic associations underpin query expansion, then a probabilistic term dependence assumption based on position is inadequate for capturing them; (2) the unigram relevance model captures more term dependency information than its underlying theoretical model suggests, so its normative position as a baseline that ignores term dependencies should perhaps be reviewed.

Civil and Criminal Liability of Players

The liability of players in their particular sporting fields has increasingly become prevalent in the minds of government, sport administrators, the medical and legal professions and the parents and players themselves. This awareness has arisen for numerous reasons. Due to the enormous volume of sport to which the community is being exposed through the varied levels of the media together with our aspirations towards a healthier lifestyle and longevity, participation in sports has increased. Accordingly, sports injury litigation has increased. A number of other factors may be advanced to explain the increase. Sport has become big business all over the world. A talent for sport may bring the lucky player fame and fortune. It is not surprising therefore, where such ambitions are frustrated by deliberately or carelessly inflicted injury to the player, thought will be given to seeking compensation for that injury in the courts of law. Other factors are that litigation is on the increase as a means of dispute resolution and lawyers see sporting organisations better able to afford compensation to their players because they are more likely to carry insurance.

Piecing together an integrative taxonomic puzzle: microsatellite, wing shape and aedeagus length analyses of Bactrocera dorsalis s.l. (Diptera: Tephritidae) find no evidence of multiple lineages in a proposed contact zone along the Thai/Malay Peninsula

Bactrocera dorsalis (Hendel) and B. papayae Drew & Hancock represent a closely related sibling species pair for which the biological species limits are unclear; i.e., it is uncertain if they are truely two biological species, or one biological species which has been incorrectly taxonomically split. The geographic ranges of the two taxa are thought to abut or overlap on or around the Isthmus of Kra, a recognised biogeographic barrier located on the narrowest portion of the Thai Peninsula. We collected fresh material of B. dorsalis sensu lato (i.e., B. dorsalis sensu stricto + B. papayae) in a north-south transect down the Thai Peninsula, from areas regarded as being exclusively B. dorsalis s.s., across the Kra Isthmus, and into regions regarded as exclusively B. papayae. We carried out microsatellite analyses and took measurements of male genitalia and wing shape. Both the latter morphological tests have been used previously to separate these two taxa. No significant population structuring was found in the microsatellite analysis and results were consistent with an interpretation of one, predominantly panmictic population. Both morphological datasets showed consistent, clinal variation along the transect, with no evidence for disjunction. No evidence in any tests supported historical vicariance driven by the Isthmus of Kra, and none of the three datasets supported the current taxonomy of two species. Rather, within and across the area of range overlap or abutment between the two species, only continuous morphological and genetic variation was recorded. Recognition that morphological traits previously used to separate these taxa are continuous, and that there is no genetic evidence for population segregation in the region of suspected species overlap, is consistent with a growing body of literature that reports no evidence of biological differentiation between these taxa.

The roles of the preproghrelin-derived peptides - ghrelin, desacyl ghrelin and obestatin - in prostate cancer

Prostate cancer is the second most common cause of cancer related deaths in Western men. Despite the significant improvements in current treatment techniques, there is no cure for advanced metastatic, castrate-resistant disease. Early detection and prevention of progression to a castrate-resistant state may provide new strategies to improve survival. A number of growth factors have been shown to act in an autocrine/paracrine manner to modulate prostate cancer tumour growth. Our laboratory has previously shown that ghrelin and its receptors (the functional GHS-R1a and the non-functional GHS-R1b) are expressed in prostate cancer specimens and cell lines. We have shown that ghrelin increases cell proliferation in the PC3 and LNCaP prostate cancer cell lines through activation of ERK1/2, suggesting that ghrelin could regulate prostate cancer cell growth and play a role in the progression of the disease. Ghrelin is a 28 amino-acid peptide hormone, identified to be the natural ligand of the growth hormone secretagogue receptor (GHS-R1a). It is well characterised as a growth hormone releasing and as an orexigenic peptide that stimulates appetite and feeding and regulates energy expenditure and bodyweight. In addition to its orexigenic properties, ghrelin has been shown to play a regulatory role in a number of systems, including the reproductive, immune and cardiovascular systems and may play a role in a number of pathological conditions such as chronic heart failure, anorexia, cachexia, obesity, diabetes and cancer. In cancer, ghrelin and its receptor are expressed in a range of tumours and cancer cell lines and ghrelin has been demonstrated to modulate cell proliferation, apoptosis, migration and invasion in some cell types. The ghrelin gene (GHRL) encodes preproghrelin peptide, which is processed to produce three currently known functional peptides - ghrelin, desacyl ghrelin and obestatin. Prohormone convertases (PCs) have been shown to cleave the preproghrelin peptide into two primary products - the 28 amino acid peptide, ghrelin, and the remaining 117 amino acid C-terminal peptide, C-ghrelin. C-ghrelin can then be further processed to produce the 23 amino acid peptide, obestatin. Ghrelin circulates in two different forms - an octanoylated form (known as ghrelin) and a non-octanoylated form, desacyl ghrelin. The unique post-translational addition of octanoic acid to the serine 3 residue of the propeptide chain to form acylated ghrelin is catalysed by ghrelin O-acyltransferase (GOAT). This modification is necessary for binding of ghrelin to its only known functional receptor, the GHS-R1a. As desacyl ghrelin cannot bind and activate the GHS-R1a, it was initially thought to be an inactive peptide, despite the fact that it circulates at much higher levels than ghrelin. Further research has demonstrated that desacyl ghrelin is biologically active and shares some of the actions of ghrelin, as well as having some opposing and distinct roles. Interestingly, both ghrelin and desacyl ghrelin have been shown to modulate apoptosis, cell differentiation and proliferation in some cell types, and to stimulate cell proliferation through activation of ERK1/2 and PI3K/Akt pathways. The third known peptide product of the ghrelin preprohormone, obestatin, was initially thought to oppose the actions of ghrelin in appetite regulation and food intake and to mediate its effects through the G protein-coupled receptor 39 (GPR39). Subsequent research failed to reproduce the initial findings, however, and the possible anorexigenic effects of obestatin, as well as the identity of its receptor, remain unclear. Obestatin plays some important physiological roles, including roles in improving memory, the inhibition of thirst and anxiety, increased secretion of pancreatic juice, and regulation of cell proliferation, survival, apoptosis and differentiation. Preliminary studies have also shown that obestatin stimulates cell proliferation in some cell types through activation of ERK1/2, Akt and PKC pathways. Overall, however, at the commencement of this PhD project, relatively little was known regarding the functions and mechanisms of action of the preproghrelin-derived functional peptides in modulating prostate cancer cell proliferation. The roles of obestatin, and desacyl ghrelin as potential growth factors had not previously been investigated, and the potential expression and regulation of the preproghrelin processing enzymes, GOAT and prohormone convertases was unknown in prostate cancer cell lines. Therefore, the overall objectives of this study were to: 1. investigate the effects of obestatin on cell proliferation and signaling in prostate cancer cell lines 2. compare the effects of desacyl ghrelin and ghrelin on cell proliferation and signaling in prostate cancer cell lines 3. investigate whether prostate cancer cell lines possess the necessary enzymatic machinery to produce ghrelin and desacyl ghrelin and if these peptides can regulate GOAT expression Our laboratory has previously shown that ghrelin stimulates cell proliferation in the PC3 and LNCaP prostate cancer cell line through activation of the ERK1/2 pathway. In this study it has been demonstrated that treatments with either ghrelin, desacyl ghrelin or obestatin over 72 hours significantly increased cell proliferation in the PC3 prostate cancer cell line but had no significant effect in the RWPE-1 transformed normal prostate cell line. Ghrelin (1000nM) stimulated cell proliferation in the PC3 prostate cancer cell line by 31.66 6.68% (p<0.01) with the WST-1 method, and 13.55 5.68% (p<0.05) with the CyQUANT assay. Desacyl ghrelin (1000nM) increased cell proliferation in PC3 cells by 21.73 2.62% (p<0.01) (WST-1), and 15.46 7.05% (p<0.05) (CyQUANT) above untreated control. Obestatin (1000nM) induced a 28.37 7.47% (p<0.01) (WST-1) and 12.14 7.47% (p<0.05) (CyQUANT) significant increase in cell proliferation in the PC3 prostate cancer cell line. Ghrelin and desacyl ghrelin treatments stimulated Akt and ERK phosphorylation across a range of concentrations (p<0.01). Obestatin treatment significantly stimulated Akt, ERK and PKC phosphorylation (p<0.05). Through the use of specific inhibitors, the MAPK inhibitor U0126 and the Akt1/2 kinase inhibitor, it was demonstrated that ghrelin- and obestatin-induced cell proliferation in the PC3 prostate cancer cell line is mediated through activation of ERK1/2 and Akt pathways. Although desacyl ghrelin significantly stimulated Akt and ERK phosphorylation, U0126 failed to prevent desacyl ghrelin-induced cell proliferation suggesting ghrelin and desacyl ghrelin might act through different mechanisms to increase cell proliferation. Ghrelin and desacyl ghrelin have shown a proliferative effect in osteoblasts, pancreatic -cells and cardiomyocytes through activation of ERK1/2 and PI3K/Akt pathways. Here it has been shown that ghrelin and its non-acylated form exert the same function and stimulate cell proliferation in the PC3 prostate cancer cell line through activation of the Akt pathway. Ghrelin-induced proliferation was also mediated through activation of the ERK1/2 pathway, however, desacyl ghrelin seems to stimulate cell proliferation in an ERK1/2-independent manner. As desacyl ghrelin does not bind and activate GHSR1a, the only known functional ghrelin receptor, the finding that both ghrelin and desacyl ghrelin stimulate cell proliferation in the PC3 cell line suggests that these peptides could be acting through the yet unidentified alternative ghrelin receptor in this cell type. Obestatin treatment also stimulated PKC phosphorylation, however, a direct role for this pathway in stimulating cell proliferation could not be proven using available PKC pathway inhibitors, as they caused significant cell death over the extended timeframe of the cell proliferation assays. Obestatin has been shown to stimulate cell proliferation through activation of PKC isoforms in human retinal epithelial cells and in the human gastric cancer cell line KATO-III. We have demonstrated that all of the prostate-derived cell lines examined (PC3, LNCaP, DU145, 22Rv1, RWPE-1 and RWPE-2) expressed GOAT and at least one of the prohormone convertases, which are known to cleave the proghrelin peptide, PC1/3, PC2 and furin, at the mRNA level. These cells, therefore, are likely to possess the necessary machinery to cleave the preproghrelin protein and to produce the mature ghrelin and desacyl ghrelin peptides. In addition to prohormone convertases, the presence of octanoic acid is essential for acylated ghrelin production. In this study octanoic acid supplementation significantly increased cell proliferation in the PC3 prostate cancer cell line by over 20% compared to untreated controls (p<0.01), but surprisingly, not in the DU145, LNCaP or 22Rv1 prostate cancer cell lines or in the RWPE-1 and RWPE-2 prostate-derived cell lines. In addition, we demonstrated that exogenous ghrelin induced a statistically significant two-fold decrease in GOAT mRNA expression in the PC3 cell line (p<0.05), suggesting that ghrelin could pontentially downregulate its own acylation and, therefore, regulate the balance between ghrelin and desacyl ghrelin. This was not observed, however, in the DU145 and LNCaP prostate cancer cell lines. The GOAT-ghrelin system represents a direct link between ingested nutrients and regulation of ghrelin production and the ghrelin/desacyl ghrelin ratio. Regulation of ghrelin acylation is a potentially attractive and desirable tool for the development of better therapies for a number of pathological conditions where ghrelin has been shown to play a key role. The finding that desacyl ghrelin stimulates cell proliferation in the PC3 prostate cancer cell line, and responds to ghrelin in the same way, suggests that this cell line expresses an alternative ghrelin receptor. Although all the cell lines examined expressed both GHS-R1a and GHS-R1b mRNA, it remains uncertain whether these cell lines express the unidentified alternative ghrelin receptor. It is possible that the varied responses seen could be due to the expression of different ghrelin receptors in different cell lines. In addition to GOAT, prohormone convertases and octanoic acid availability may regulate the production of different peptides from the ghrelin preprohormone. The studies presented in this thesis provide significant new information regarding the roles and mechanisms of action of the preproghrelin-derived peptides, ghrelin, desacyl ghrelin and obestatin, in modulating prostate cancer cell line proliferation. A number of key questions remain to be resolved, however, including the identification of the alternative ghrelin/desacyl ghrelin receptor, the identification of the obestatin receptor, a clarification of the signaling mechanisms which mediate cell proliferation in response to obestatin treatment and a better understanding of the regulation at both the gene and post-translational levels of functional peptide generation. Further studies investigating the role of the ghrelin axis using in vivo prostate cancer models may be warranted. Until these issues are determined, the potential for the ghrelin axis, to be recognised as a novel useful target for therapy for cancer or other pathologies will be uncertain.

An empirical study of business method patent applications filed in Australia 2000-2009

This article sets out the results of an empirical research study into the uses to which the Australian patent system is being put in the early 21st century. The focus of the study is business method patents, which are of interest because they are a controversial class of patent that are thought to differ significantly from the mechanical, chemical and industrial inventions that have traditionally been the mainstay of the patent system. The purpose of the study is to understand what sort of business method patent applications have been lodged in Australia in the first decade of this century and how the patent office is responding to those applications.

Barriers and facilitators to public bicycle scheme use : a qualitative approach

The purpose of this study was to explore barriers and facilitators to using CityCycle, a public bicycle share scheme in Brisbane, Australia. Focus groups were conducted with participants belonging to one of three categories. Group one consisted of infrequent and noncyclists (no bicycle riding over the past month), group two were regular bicycle riders (ridden a bicycle at least once in the past month) and group three was composed of CityCycle members. A thematic analytic method was used to analyse the data. Three main themes were found: Accessibility/spontaneity, safety and weather/topography. The lengthy sign-up process was thought to stifle the spontaneity typically thought to attract people to public bike share. Mandatory helmet legislation was thought to reduce spontaneous use. Safety was a major concern for all groups and this included a perceived lack of suitable bicycle infrastructure, as well as regular riders describing a negative attitude of some car drivers. Interestingly, CityCycle riders unanimously perceived car driver attitudes to improve when on CityCycle bicycles relative to riding on personal bicycles. Conclusions: In order to increase the popularity of the CityCycle scheme, the results of this study suggest that a more accessible, spontaneous sign-up process is required, 24/7 opening hours, and greater incentives to sign up new members and casual users, as seeing people using CityCycle appears critical to further take up.

Can we teach advertising students to think? Strategies to engage student thinking

Understanding and effectively managing students’ engagement in education plays a significant role in enhancing learning processes and outcomes. Research has shown that students learn more when they are actively engaged in their learning. However, as many educators know, this is not as easy as one might expect. Using a range of teaching approaches, we attempt to impart knowledge and develop understanding and comprehension (Angelo 1993; Biggs and Telfer 1987; Patti 2003; Ranburuth and McCormick 2001). These vary from “information dump” or teacher-centric approaches, to those that stimulate more active involvement. From the literature, we know that experiential learning, such as those strategies that help students acquire practice skills, apply critical thought and active learning, are likely to have achieve higher levels of intellectual skill and ability (Benson and Blackman 2003; Hampton and Lawrence 1995; Hopkinson and Hogg 2004; Kolb 1984).

Languages of Communication : Indigenous language and/or English?

My interest in producing this paper on Indigenous languages was borne out of conversations with and learnings from community members in the Torres Straits and those connected to the ‘Dream Circle’. Nakata (2003, p. 12) laments the situation whereby ‘teachers are transitionary and take their hard-earned knowledge with them when they leave’. I am thus responding to the call to add to the conversation in a productive albeit culturally loaded way. To re-iterate, I am neither Indigenous nor am I experienced in teaching and learning in these contexts. As problematic as these two points are, I am in many ways typical of the raft of inexperienced white Australian teachers assigned to positions in school contexts where Indigenous students are enrolled or in mainstream contexts with substantial populations of Indigenous students. By penning this article, it is neither my intention to contribute to the silencing of Indigenous educators or Indigenous communities. My intention is to articulate my teacherly reflections as they apply to the topic under discussion. The remainder of this paper is presented in three sections. The next section provides a brief overview of the number of Indigenous people and Indigenous languages in Australia and the role of English as a language of communication. The section which follows draws on theorisations from second/additional language acquisition to overview three different schools of thought about the consequences of English in the lives of Indigenous Australians. The paper concludes by considering the tensions for inexperienced white Australian teachers caught up in the fray.

How research findings can inform legislation and school policy on cyberbullying.

Recent empirical research has found that the psychological consequences for young people involved in cyberbullying are more severe than in the case of traditional bullying (Campbell, Spears, Slee, Butler, & Kift, 2012; Perren, Dooley, Shaw, & Cross, 2010). Cybervictimisation has been found to be a significant predictor of depressive symptoms over and above that of being victimised by traditional bullying (Perren et al., 2010). Cybervictims also have reported higher anxiety scores and social difficulties than traditional victims, with those students who had been bullied by both forms showing similar anxiety and depression scores to cyberbullying victims (Campbell et al., 2012). This is supported by the subjective views of many young people, not involved in bullying, who believed that cyberbullying is far more harmful than traditional bullying (Cross et al., 2009). However, students who were traditionally bullied thought the consequences of traditional bullying were harsher than did those students who were cyberbullied (Campbell, et al., 2012). In Slonje and Smith’s study (2008), students reported that text messaging and email bullying had less of an impact than traditional bullying, but that bullying by pictures or video clips had more negative impact than traditional bullying.

Neuronal nicotinic acetylcholine receptors : neuroplastic changes underlying alcohol and nicotine addictions

Addictive drugs can activate systems involved in normal reward-related learning, creating long-lasting memories of the drug's reinforcing effects and the environmental cues surrounding the experience. These memories significantly contribute to the maintenance of compulsive drug use as well as cue-induced relapse which can occur even after long periods of abstinence. Synaptic plasticity is thought to be a prominent molecular mechanism underlying drug-induced learning and memories. Ethanol and nicotine are both widely abused drugs that share a common molecular target in the brain, the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are ligand-gated ion channels that are vastly distributed throughout the brain and play a key role in synaptic neurotransmission. In this review, we will delineate the role of nAChRs in the development of ethanol and nicotine addiction. We will characterize both ethanol and nicotine's effects on nAChR-mediated synaptic transmission and plasticity in several key brain areas that are important for addiction. Finally, we will discuss some of the behavioral outcomes of drug-induced synaptic plasticity in animal models. An understanding of the molecular and cellular changes that occur following administration of ethanol and nicotine will lead to better therapeutic strategies.

Child, Adolescent and Family Development [3rd ed.]

"This book explores the foundations of modern developmental thought, incorporating the latest in international research set within a cultural and historical context. Richly illustrated and enhanced by a range of practical teaching resources, this clear and engaging text is intended to reach students across a range of teaching, psychology, social science and health science disciplines. By employing a thematic approach within the chronologically ordered chapters, this text offers a systematic and intuitive structure for both learning and teaching. This new edition features a set of fully updated case studies that consider current trends and issues in developmental theory and practice, as well as end-of-chapter sections that address important stages in the family life cycle."--publisher website

What do current planning students and recent graduates think planners do?

A planner’s view of the purpose of their actions, the role they play, the focus of their work and in whose interest they operate greatly influence their approach to planning and the outcome of their work. However there is no common and established understanding within the profession on these themes. Contemporary planning theory, practice and education is characterised by the parallel existence of multiple, often contradictory schools of thought. What values and perspectives are held by the next generation of planning professionals as they emerge from contemporary planning programs? This preliminary investigation seeks to identify the views and perspectives of early career planners on the purpose and role of planning, the degree to which planning is oriented on the future and the nature of the public interest, using various schools of planning thought as a thematic framework. In the current phase of a larger project, extant students and recent graduates from planning courses at three Queensland universities were surveyed electronically to ascertain their views, with plans to undertake a broader study of similar populations across Australia. Within the current pilot, students and graduates did not identify strongly with a single school of planning thought, but favoured contrasting rational and collaborative definitions of the role and purpose of planning and the public interest and pragmatic concepts of partial knowledge of the future and the value of experience in managing present issues.