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.

Mechanisms of mono- and poly-ubiquitination : ubiquitination specificity depends on compatibility between the E2 catalytic core and amino acid residues proximal to the lysine

Ubiquitination involves the attachment of ubiquitin to lysine residues on substrate proteins or itself, which can result in protein monoubiquitination or polyubiquitination. Ubiquitin attachment to different lysine residues can generate diverse substrate-ubiquitin structures, targeting proteins to different fates. The mechanisms of lysine selection are not well understood. Ubiquitination by the largest group of E3 ligases, the RING-family E3 s, is catalyzed through co-operation between the non-catalytic ubiquitin-ligase (E3) and the ubiquitin-conjugating enzyme (E2), where the RING E3 binds the substrate and the E2 catalyzes ubiquitin transfer. Previous studies suggest that ubiquitination sites are selected by E3-mediated positioning of the lysine toward the E2 active site. Ultimately, at a catalytic level, ubiquitination of lysine residues within the substrate or ubiquitin occurs by nucleophilic attack of the lysine residue on the thioester bond linking the E2 catalytic cysteine to ubiquitin. One of the best studied RING E3/ E2 complexes is the Skp1/Cul1/F box protein complex, SCFCdc4, and its cognate E2, Cdc34, which target the CDK inhibitor Sic1 for K48-linked polyubiquitination, leading to its proteasomal degradation. Our recent studies of this model system demonstrated that residues surrounding Sic1 lysines or lysine 48 in ubiquitin are critical for ubiquitination. This sequence-dependence is linked to evolutionarily conserved key residues in the catalytic region of Cdc34 and can determine if Sic1 is mono- or poly-ubiquitinated. Our studies indicate that amino acid determinants in the Cdc34 catalytic region and their compatibility to those surrounding acceptor lysine residues play important roles in lysine selection. This may represent a general mechanism in directing the mode of ubiquitination in E2 s.

A runtime integrity monitoring framework for real-time relative positioning systems based on GPS and DSRC

This paper provides a three-layered framework to monitor the positioning performance requirements of Real-time Relative Positioning (RRP) systems of the Cooperative Intelligent Transport Systems (C-ITS) that support Cooperative Collision Warning (CCW) applications. These applications exploit state data of surrounding vehicles obtained solely from the Global Positioning System (GPS) and Dedicated Short-Range Communications (DSRC) units without using other sensors. To this end, the paper argues the need for the GPS/DSRC-based RRP systems to have an autonomous monitoring mechanism, since the operation of CCW applications is meant to augment safety on roads. The advantages of autonomous integrity monitoring are essential and integral to any safety-of-life system. The autonomous integrity monitoring framework proposed necessitates the RRP systems to detect/predict the unavailability of their sub-systems and of the integrity monitoring module itself, and, if available, to account for effects of data link delays and breakages of DSRC links, as well as of faulty measurement sources of GPS and/or integrated augmentation positioning systems, before the information used for safety warnings/alarms becomes unavailable, unreliable, inaccurate or misleading. Hence, a monitoring framework using a tight integration and correlation approach is proposed for instantaneous reliability assessment of the RRP systems. Ultimately, using the proposed framework, the RRP systems will provide timely alerts to users when the RRP solutions cannot be trusted or used for the intended operation.

Market segmentation : insights for changing children's physical activity behaviour

Market segmentation has received relatively limited attention in social marketing, particularly within the context of changing children’s physical activity behaviour. This is an important area of investigation given growing concern over childhood obesity globally. The present research aims to extend current understanding of the applicability of market segmentation within this context. The results of a two-step cluster analysis on data from 512 respondents of an online survey show three distinct segments of caregivers, each with unique beliefs about their primary school children walking to/from school. The results demonstrate the validity of employing the process of market segmentation within this social context and provide further insights for targeting the identified segments through tailored social marketing programs.

Analysis and improvement of a construction permit approval process: A teaching case for developing business process development capabilities, targeting developing nations

With the increasing competitiveness in global markets, many developing nations are striving to constantly improve their services in search for the next competitive edge. As a result, the demand and need for Business Process Management (BPM) in these regions is seeing a rapid rise. Yet there exists a lack of professional expertise and knowledge to cater to that need. Therefore, the development of well-structured BPM training/ education programs has become an urgent requirement for these industries. Furthermore, the lack of textbooks or other self-educating material, that go beyond the basics of BPM, further ratifies the need for case based teaching and related cases that enable the next generation of professionals in these countries. Teaching cases create an authentic learning environment where complexities and challenges of the ‘real world’ can be presented in a narrative, enabling students to evolve crucial skills such as problem analysis, problem solving, creativity within constraints as well as the application of appropriate tools (BPMN) and techniques (including best practices and benchmarking) within richer and real scenarios. The aim of this paper is to provide a comprehensive teaching case demonstrating the means to tackle any developing nation’s legacy government process undermined by inefficiency and ineffectiveness. The paper also includes thorough teaching notes The article is presented in three main parts: (i) Introduction - that provides a brief background setting the context of this paper, (ii) The Teaching Case, and (iii) Teaching notes.

Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development

Glutamine is conditionally essential in cancer cells, being utilized as a carbon and nitrogen source for macromolecule production, as well as for anaplerotic reactions fuelling the tricarboxylic acid (TCA) cycle. In this study, we demonstrated that the glutamine transporter ASCT2 (SLC1A5) is highly expressed in prostate cancer patient samples. Using LNCaP and PC-3 prostate cancer cell lines, we showed that chemical or shRNA-mediated inhibition of ASCT2 function in vitro decreases glutamine uptake, cell cycle progression through E2F transcription factors, mTORC1 pathway activation and cell growth. Chemical inhibition also reduces basal oxygen consumption and fatty acid synthesis, showing that downstream metabolic function is reliant on ASCT2-mediated glutamine uptake. Furthermore, shRNA knockdown of ASCT2 in PC-3 cell xenografts significantly inhibits tumour growth and metastasis in vivo, associated with the down-regulation of E2F cell cycle pathway proteins. In conclusion, ASCT2-mediated glutamine uptake is essential for multiple pathways regulating the cell cycle and cell growth, and is therefore a putative therapeutic target in prostate cancer.

Measuring impact: Positioning evaluation in the Australian arts and culture landscape

Arts culture organisations and funding authorities increasingly need to evaluate the impact of festivals, events and performances. Economic impacts are often privileged over 'soft data' about community experience and engagement. This new book offers a timely and scholarly demonstration of how cultural value and impact can be evaluated. It offers an innovative approach whereby the relationship developed between the researchers/evaluator and the commissioning arts and cultural producer provides an opportunity to rethink the traditional process of reporting back on value and impact through the singular entity of funds acquittal. Using three commissioned evaluations undertaken at an Australian university as an extended case study, the book investigates the two positions most often adopted by researchers/evaluators - embedded and collaborative, or external and distanced - and argues the merits and deficiencies of the two approaches. Offering an examination of how arts evaluation 'works' in theory and practice and more importantly, why it is needed now and in the future to demonstrate the reach and cultural gains from arts and cultural projects, this will be essential reading for students in arts management, professionals working in arts and cultural organisations, scholars working in association with creative industries and cultural development.

Targeting Antiapoptotic Genes Upregulated by Androgen Withdrawal Using Antisense Oligodeoxynucleotides to Enhance Androgen-and Chemo-Sensitivity in Prostate Cancer

Androgen withdrawal is the only effective form of systemic therapy for men with advanced disease, producing symptomatic and/or objective response in 80% of patients. Unfortunately, androgen independent (AI) progression and death occurs within a few years in the majority of these cases (6). Prostate cancer is highly chemoresistant, with objective response rates of 10% and no demonstrated survival benefit (28). Hormone refractory prostate cancer (HRPC) is therefore the main obstacle to improving the survival and quality of life in patients with advanced disease, and novel therapeutic strategies that target the molecular basis of androgen and chemoresistance are required.

The impact of global positioning systems and plotters on fishing power in the northern prawn fishery, Australia

The impact of global positioning systems (GPS) and plotter systems on the relative fishing power of the northern prawn fishery fleet on tiger prawns (Penaeus esculentus Haswell, 1879, and P. semisulcatus de Haan, 1850) was investigated from commercial catch data. A generalized linear model was used to account for differences in fishing power between boats and changes in prawn abundance. It was found that boats that used a GPS alone had 4% greater fishing power than boats without a CPS. The addition of a plotter raised the power by 7% over boats without the equipment. For each year between the first to third that a fisher has been working with plotters, there is an additional 2 or 3% increase. It appears that when all boats have a GPS and plotter for at least 3 years, the fishing power of the fleet will increase by 12%. Management controls have reduced the efficiency of each boat and lowered the number of days available to fish, but this may not have been sufficient to counteract the increases. Further limits will be needed to maintain the desired levels of mortality.

Truckies and workplace health promotion: Targeting a hard-to-reach group

- Introduction Research identifies truck drivers as being at high risk of chronic disease. For most truck drivers their workplace is their vehicle. Truck drivers’ health is impacted by the limitations of this unique working environment, including reduced opportunities for physical activity and the intake of healthy foods. Workplaces are widely recognised as effective platforms for health promotion. However, the effectiveness of traditional and contemporary health promotion interventions in truck drivers’ novel workplace is unknown. - Methods This project worked with six transport industry workplaces in Queensland, Australia over a two-year period. Researchers used Participatory Action Research (PAR) processes to engage truck drivers and workplace managers in the implementation and evaluation of six workplace health promotion interventions. These interventions were designed to support truck drivers to increase their physical activity and access to healthy foods at work. They included traditional health promotion interventions such as a free fruit initiative, a ten thousand steps challenge, personal health messages and workplace posters, and a contemporary social media intervention. Participants were engaged via focus groups, interviews and mixed-methods surveys. - Results The project achieved positive changes in truck drivers’ health knowledge and health behaviours, particularly related to nutrition. There were positive changes in truck drivers’ self-reported health rating, body mass index (BMI) and readiness to make health-related lifestyle changes. There were also positive changes in truck drivers reporting their workplace as a key source of health information. These changes were underpinned by a positive shift in the culture of participating workplaces. Truck drivers’ perceptions of their workplace valuing, encouraging, modelling and facilitating healthy nutrition and physical activity behaviours improved. PAR processes enabled researchers to develop relationships with workplace managers, contextualise interventions and deliver rigorous outcomes. Despite the novelty of truck drivers’ mobile workplace, traditional health promotion interventions were more effective than contemporary ones. - Conclusion In this workplace health promotion project targeting a ‘hard-to-reach’ group of truck drivers, a combination of well-designed traditional workplace interventions and the PAR process resulted in positive health outcomes.

A systematic literature review of alcohol education programmes in middle and high school settings (2000-2014)

Purpose Social marketing benchmark criteria were used to understand the extent to which single-substance alcohol education programmes targeting adolescents in middle and high school settings sought to change behaviour, utilised theory, included audience research and applied the market segmentation process. The paper aims to discuss these issues. Design/methodology/approach A systematic literature review retrieved a total of 1,495 identified articles; 565 duplicates were removed. The remaining 930 articles were then screened. Articles detailing formative research or programmes targeting multiple substances, parents, families and/or communities, as well as elementary schools and universities were excluded. A total of 31 articles, encompassing 16 qualifying programmes, were selected for detailed evaluation. Findings The majority of alcohol education programmes were developed on the basis of theory and achieved short- and medium-term behavioural effects. Importantly, most programmes were universal and did not apply the full market segmentation process. Limited audience research in the form of student involvement in programme design was identified. Research limitations/implications This systematic literature review focused on single-substance alcohol education programmes targeted at middle and high school student populations, retrieving studies back to the year 2000. Originality/value The results of this systematic literature review indicate that application of the social marketing benchmark criteria of market segmentation and audience research may represent an avenue for further extending alcohol education programme effectiveness in middle and high school settings.

Multi-GNSS precise point positioning with raw single-frequency and dual-frequency measurement models

The emergence of multiple satellite navigation systems, including BDS, Galileo, modernized GPS, and GLONASS, brings great opportunities and challenges for precise point positioning (PPP). We study the contributions of various GNSS combinations to PPP performance based on undifferenced or raw observations, in which the signal delays and ionospheric delays must be considered. A priori ionospheric knowledge, such as regional or global corrections, strengthens the estimation of ionospheric delay parameters. The undifferenced models are generally more suitable for single-, dual-, or multi-frequency data processing for single or combined GNSS constellations. Another advantage over ionospheric-free PPP models is that undifferenced models avoid noise amplification by linear combinations. Extensive performance evaluations are conducted with multi-GNSS data sets collected from 105 MGEX stations in July 2014. Dual-frequency PPP results from each single constellation show that the convergence time of undifferenced PPP solution is usually shorter than that of ionospheric-free PPP solutions, while the positioning accuracy of undifferenced PPP shows more improvement for the GLONASS system. In addition, the GLONASS undifferenced PPP results demonstrate performance advantages in high latitude areas, while this impact is less obvious in the GPS/GLONASS combined configuration. The results have also indicated that the BDS GEO satellites have negative impacts on the undifferenced PPP performance given the current “poor” orbit and clock knowledge of GEO satellites. More generally, the multi-GNSS undifferenced PPP results have shown improvements in the convergence time by more than 60 % in both the single- and dual-frequency PPP results, while the positioning accuracy after convergence indicates no significant improvements for the dual-frequency PPP solutions, but an improvement of about 25 % on average for the single-frequency PPP solutions.

Targeting neuropilin-1 to inhibit prostate cancer invasion and metastasis

Recent reports provide evidence that the epithelial-to-mesenchymal transition (EMT) plays a key role in prostate cancer (PCa) metastasis and therapy resistance. We have recently identified the cell surface receptor, Neuropilin-1 (NRP1) to be increased during epithelial-mesenchymal transition (EMT) and this study aims to determine whether the inhibition of NRP1 will be a feasible therapeutic strategy for blocking PCa metastasis and therapy resistance.