Chemotherapeutic compounds targeting the DNA double-strand break repair pathways : the good, the bad, and the promising

The repair of DNA double-strand breaks (DSBs) is a critical cellular mechanism that exists to ensure genomic stability. DNA DSBs are the most deleterious type of insult to a cell’s genetic material and can lead to genomic instability, apoptosis, or senescence. Incorrectly repaired DNA DSBs have the potential to produce chromosomal translocations and genomic instability, potentially leading to cancer. The prevalence of DNA DSBs in cancer due to unregulated growth and errors in repair opens up a potential therapeutic window in the treatment of cancers. The cellular response to DNA DSBs is comprised of two pathways to ensure DNA breaks are repaired: homologous recombination and non-homologous end joining. Identifying chemotherapeutic compounds targeting proteins involved in these DNA repair pathways has shown promise as a cancer therapy for patients, either as a monotherapy or in combination with genotoxic drugs. From the beginning, there have been a number of chemotherapeutic compounds that have yielded successful responses in the clinic, a number that have failed (CGK-733 and iniparib), and a number of promising targets for future studies identified. This review looks in detail at how the cell responds to these DNA DSBs and investigates the chemotherapeutic avenues that have been and are currently being explored to target this repair process.

Offspring of mothers fed a high fat diet display hepatic cell cycle inhibition and associated changes in gene expression and DNA methylation

The association between an adverse early life environment and increased susceptibility to later-life metabolic disorders such as obesity, type 2 diabetes and cardiovascular disease is described by the developmental origins of health and disease hypothesis. Employing a rat model of maternal high fat (MHF) nutrition, we recently reported that offspring born to MHF mothers are small at birth and develop a postnatal phenotype that closely resembles that of the human metabolic syndrome. Livers of offspring born to MHF mothers also display a fatty phenotype reflecting hepatic steatosis and characteristics of non-alcoholic fatty liver disease. In the present study we hypothesised that a MHF diet leads to altered regulation of liver development in offspring; a derangement that may be detectable during early postnatal life. Livers were collected at postnatal days 2 (P2) and 27 (P27) from male offspring of control and MHF mothers (n = 8 per group). Cell cycle dynamics, measured by flow cytometry, revealed significant G0/G1 arrest in the livers of P2 offspring born to MHF mothers, associated with an increased expression of the hepatic cell cycle inhibitor Cdkn1a. In P2 livers, Cdkn1a was hypomethylated at specific CpG dinucleotides and first exon in offspring of MHF mothers and was shown to correlate with a demonstrable increase in mRNA expression levels. These modifications at P2 preceded observable reductions in liver weight and liver:brain weight ratio at P27, but there were no persistent changes in cell cycle dynamics or DNA methylation in MHF offspring at this time. Since Cdkn1a up-regulation has been associated with hepatocyte growth in pathologic states, our data may be suggestive of early hepatic dysfunction in neonates born to high fat fed mothers. It is likely that these offspring are predisposed to long-term hepatic dysfunction.

Building the youth sector from the bottom up : case studies from the Queensland CPLAN Initiative 2012-2013

As part of YANQ's decentralisation across the state, YANQ have set up 10 Networks across Queensland, with Facilitators based in each of the regions. We encourage you to get in contact with your local Facilitator if you would like to have input on Workforce Development or youth policy issues. CPLANs aim to create an ongoing and sustainable structure across ten regions in Queensland to support a consistent focus on: ⋅ Policy issues relevant to young people; and ⋅ Workforce development strategies for the youth sector from a local, regional and state perspective. The ten CPLANs fall under the existing structure of YANQ and utlise and lever off the comprehensive network of youth inter-­‐agencies and networks across the state. The ten CPLANs are made up of representatives from the youth sector in each region who have an interest in contributing to policy development and workforce issues.

It’s Not Just a Game: Contemporary Challenges for Games Research and the Internet

In this final chapter we will raise a number of issues that we have encountered as we have put this collection of papers together. In doing this, we also reflect upon the seven challenges for video game theory that Bernard Perron and Mark Wolf(2009)put forward in the introduction to the second video game theory reader given it is probably one of the most recent assessments in the area at the time of writing. These challenges are concerned with Terminology and Accuracy, History, Methodology, Technology, Interactivity, Play and the Integration of Interdisciplinary Approaches. These issues will be brought up throughout this chapter, but not necessarily in mutually exclusive fashion...

Mark Webb Survey Exhibition

The exhibiton brought together a diverse group of works using an array of presentational strategies, which critically facilitate a dialogue across the material and conceptual aspects of my practice over 25 years. It focussed on my ongoing explorations into art as a model for research, as a site for intermediary exchange between different discursive forms and as a space to engage the politics of the everyday.

Three sides to every story; Ernesto Love + Eve Roleston + Ernest Olove = 3SUM/3DUM

This was another in the project of using my three pseudonyms to investigate the strategic potential of the fictocritical as an approach to making visual art. It was large scale single artwork that took place over 21 days and combined 2D, 3D, Time-based elements and performance in an attempt to construct a Gesamtkunstwerk. Over the course of the exhibition I critically and creatively engaged with political, social, economic and cultural issues thorugh opening up a range of rhetorical modes such as the lyrical, the elegiac, the rhapsodic, the humorous, the parodic and the satirical.

Save Your Life Tonight : Heads Up

Save Your Life Tonight is a factual entertainment series produced by WildBear Entertainment for the Australian Broadcasting Corporation (ABC) and was filmed in front of a live studio audience at Royal Brisbane and Women's Hospital (RBWH). Save Your Life Tonight is a unique studio based medical series that explores Australia’s top 10 health issues in an exciting and entertaining way. Driven by charismatic host Andrew Daddo, along with resident GP Dr Liz Marles and a panel of leading experts, each episode is a fast-paced, dynamic exploration of the causes, symptoms, treatments and, most importantly, prevention of these leading health issues. But Save Your Life Tonight doesn't just talk about the issues, it shows the issues! Save Your Life Tonight features real patients, real doctors, real tests, real diagnoses, and real surgical procedures – live on stage! For the "Heads Up" episode, the program explores the issues of mental health. Only half of the Australians suffering from severe mental heath issues are receiving treatment. Featuring Ian Hickie on the panel, we also see a young mum face her crippling bird phobia with the help of a Wedge Tailed Eagle.

Organizations as distinction generating and processing systems : Niklas Luhmann's contribution to organization studies

Niklas Luhmann's theory of social systems has been widely influential in the German-speaking countries in the past few decades. However, despite its significance, particularly for organization studies, it is only very recently that Luhmann's work has attracted attention on the international stage as well. This Special Issue is in response to that. In this introductory paper, we provide a systematic overview of Luhmann's theory. Reading his work as a theory about distinction generating and processing systems, we especially highlight the following aspects: (i) Organizations are processes that come into being by permanently constructing and reconstructing themselves by means of using distinctions, which mark what is part of their realm and what not. (ii) Such an organizational process belongs to a social sphere sui generis possessing its own logic, which cannot be traced back to human actors or subjects. (iii) Organizations are a specific kind of social process characterized by a specific kind of distinction: decision, which makes up what is specifically organizational about organizations as social phenomena. We conclude by introducing the papers in this Special Issue. Copyright © 2006 SAGE.

The kite string tangle : blissed-out beats at the Brisbane Festival

Danny Harley has had a pretty big year with his one-man band project The Kite String Tangle. There have been festival appearances, both at home and abroad, a song in the top 20 of Triple J’s iconic Hottest 100 annual music poll and a sold-out tour to mark the release of his debut EP, which wrapped up this week with two shows in the Spiegeltent at the Brisbane Festival...

Queensland farmers rise up to take on the miners

Queensland’s Surat Basin has the third largest energy resource in the world — with vast coal seam gas and coal reserves — but farm groups are warning that mining areas, which are prime farm land, risk catastrophic environmental damage to food-producing areas. Mining development is moving very quickly with 36,000 wells due to be sunk in the next few years. A Senate inquiry into the impacts of mining in the Murray-Darling Basin heard evidence from farm and mining industry representatives in Oakey on the Darling Downs yesterday.

Literary Studies : The Author Cat - Clemens's Life in Fiction

A review of The Author Cat: Clemens's Life in Fiction by Forrest G. Robinson (Fordham UP, 2007). Even at its most basic, guilt forms a counterweight to the hesitancy and unpleasantness of authorship, forcing writers back to the desk when they have come to despise their work. Guilt as task-master is familiar to most, even those to whom more elevated feelings, such as inspiration, make occasional visits. It seems that guilt is effective because writing is so seldom an organic or natural activity - rather, good writing emerges out of unhappy pressures that eventually overwhelm the writer's evasive strategies, from visits to the fridge door to the most sophisticated forms they take, such as when the author creates a narrative persona that claims to have owned up...

The serum resistome of a globally disseminated multidrug resistant uropathogenic Escherichia coli Clone

Escherichia coli ST131 is a globally disseminated, multidrug resistant clone responsible for a high proportion of urinary tract and bloodstream infections. The rapid emergence and successful spread of E. coli ST131 is strongly associated with antibiotic resistance; however, this phenotype alone is unlikely to explain its dominance amongst multidrug resistant uropathogens circulating worldwide in hospitals and the community. Thus, a greater understanding of the molecular mechanisms that underpin the fitness of E. coli ST131 is required. In this study, we employed hyper-saturated transposon mutagenesis in combination with multiplexed transposon directed insertion-site sequencing to define the essential genes required for in vitro growth and the serum resistome (i.e. genes required for resistance to human serum) of E. coli EC958, a representative of the predominant E. coli ST131 clonal lineage. We identified 315 essential genes in E. coli EC958, 231 (73%) of which were also essential in E. coli K-12. The serum resistome comprised 56 genes, the majority of which encode membrane proteins or factors involved in lipopolysaccharide (LPS) biosynthesis. Targeted mutagenesis confirmed a role in serum resistance for 46 (82%) of these genes. The murein lipoprotein Lpp, along with two lipid A-core biosynthesis enzymes WaaP and WaaG, were most strongly associated with serum resistance. While LPS was the main resistance mechanism defined for E. coli EC958 in serum, the enterobacterial common antigen and colanic acid also impacted on this phenotype. Our analysis also identified a novel function for two genes, hyxA and hyxR, as minor regulators of O-antigen chain length. This study offers novel insight into the genetic make-up of E. coli ST131, and provides a framework for future research on E. coli and other Gram-negative pathogens to define their essential gene repertoire and to dissect the molecular mechanisms that enable them to survive in the bloodstream and cause disease.

Characterisation of a cell wall-anchored protein of Staphylococcus saprophyticus associated with linoleic acid resistance

The Gram-positive bacterium Staphylococcus saprophyticus is the second most frequent causative agent of community-acquired urinary tract infections (UTI), accounting for up to 20% of cases. A common feature of staphylococci is colonisation of the human skin. This involves survival against innate immune defenses including antibacterial unsaturated free fatty acids such as linoleic acid which act by disrupting bacterial cell membranes. Indeed, S. saprophyticus UTI is usually preceded by perineal skin colonisation.