p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas

Once melanoma metastasizes, no effective treatment modalities prolong survival in most patients. This notorious refractoriness to therapy challenges investigators to identify agents that overcome melanoma resistance to apoptosis. Whereas many survival pathways contribute to the death-defying phenotype in melanoma, a defect in apoptotic machinery previously highlighted inactivation of Apaf-1, an apoptosome component engaged after mitochondrial damage. During studies involving Notch signaling in melanoma, we observed a gamma-secretase tripeptide inhibitor (GSI; z-Leu-Leu-Nle-CHO), selected from a group of compounds originally used in Alzheimer's disease, induced apoptosis in nine of nine melanoma lines. GSI only induced G2-M growth arrest (but not killing) in five of five normal melanocyte cultures tested. Effective killing of melanoma cells by GSI involved new protein synthesis and a mitochondrial-based pathway mediated by up-regulation of BH3-only members (Bim and NOXA). p53 activation was not necessary for up-regulation of NOXA in melanoma cells. Blocking GSI-induced NOXA using an antisense (but not control) oligonucleotide significantly reduced the apoptotic response. GSI also killed melanoma cell lines with low Apaf-1 levels. We conclude that GSI is highly effective in killing melanoma cells while sparing normal melanocytes. Direct enhancement of BH3-only proteins executes an apoptotic program overcoming resistance of this lethal tumor. Identification of a p53-independent apoptotic pathway in melanoma cells, including cells with low Apaf-1, bypasses an impediment to current cytotoxic therapy and provides new targets for future therapeutic trials involving chemoresistant tumors.

Notch and NOXA-related pathways in melanoma cells

Notch receptor-mediated intracellular events represent an ancient cell signaling system, and alterations in Notch expression are associated with various malignancies in which Notch may function as an oncogene or less commonly as a tumor suppressor. Notch signaling regulates cell fate decisions in the epidermis, including influencing stem cell dynamics and growth/differentiation control of cells in skin. Because of increasing evidence that the Notch signaling network is deregulated in human malignancies, Notch receptors have become attractive targets for selective killing of malignant cells. Compared with proliferating normal human melanocytes, melanoma cell lines are characterized by markedly enhanced levels of activated Notch-1 receptor. By using a small molecule gamma-secretase inhibitor (GSI) consisting of a tripeptide aldehyde, N-benzyloxycarbonyl-Leu-Leu-Nle-CHO, which can block processing and activation of all four different Notch receptors, we identified a specific apoptotic vulnerability in melanoma cells. GSI triggers apoptosis in melanoma cells, but only G2/M growth arrest in melanocytes without subsequent cell death. Moreover, GSI treatment induced a pro-apoptotic BH3-only protein, NOXA, in melanoma cells but not in normal melanocytes. The use of GSI to induce NOXA induction overcomes the apoptotic resistance of melanoma cells, which commonly express numerous cell survival proteins such as Mcl-1, Bcl-2, and survivin. Taken together, these results highlight the concept of synthetic lethality in which exposure to GSI, in combination with melanoma cells overexpressing activated Notch receptors, has lethal consequences, producing selective killing of melanoma cells, while sparing normal melanocytes. By identifying signaling pathways that contribute to the transformation of melanoma cells (e.g. Notch signaling), and anti-cancer agents that achieve tumor selectivity (e.g., GSI-induced NOXA), this experimental approach provides a useful framework for future therapeutic strategies in cutaneous oncology.

Moral and social development : teachers’ knowledge of learning and teaching strategies in the early years

The intention of the analysis in this paper was to determine, from interviews with eleven early years’ teachers, what knowledge guided their teaching of moral behaviour. Six of the teachers defined moral behaviour in terms of social conventions only. Children’s learning was attributed by five of the teachers to incidental/contextual issues. Nine of the teachers used discussion of issues, in various contexts, as a way of teaching about social and moral issues. The majority of the teachers (n=7) gave the source of their knowledge of pedagogy as practical as opposed to theoretically informed. There was no clear relationship between their definitions, understanding of children’s learning, pedagogy or source of knowledge. Most of the teachers were using discussion, negotiation and reflection to develop the children’s moral and social behaviour. This is probably effective; however, it suggests a strong need for teaching of moral development to be given more prominence and addressed directly in in-service courses so that teachers are clear about their intentions and the most effective ways of achieving them.

Effective attacking strategies in rugby union

Evasive change-of-direction manoeuvres (agility skills) are a fundamental ability in rugby union. In this study, we explored the attributes of agility skill execution as they relate to effective attacking strategies in rugby union. Seven Super 14 games were coded using variables that assessed team patterns and individual movement characteristics during attacking ball carries. The results indicated that tackle-breaks are a key determinant of try-scoring ability and team success in rugby union. The ability of the attacking ball carrier to receive the ball at high speed with at least two body lengths from the defence line against an isolated defender promoted tackle-breaks. Furthermore, the execution of a side-step evasive manoeuvre at a change of direction angle of 20–60° and a distance of one to two body lengths from the defence, and then straightening the running line following the initial direction change at an angle of 20–60°, was associated with tackle-breaks. This study provides critical insight regarding the attributes of agility skill execution that are associated with effective ball carries in rugby union.

Coupling hybrid-game strategies with particle swarm optimisation for multi-objective high lift systems design optimisation

This paper investigates the High Lift System (HLS) application of complex aerodynamic design problem using Particle Swarm Optimisation (PSO) coupled to Game strategies. Two types of optimization methods are used; the first method is a standard PSO based on Pareto dominance and the second method hybridises PSO with a well-known Nash Game strategies named Hybrid-PSO. These optimization techniques are coupled to a pre/post processor GiD providing unstructured meshes during the optimisation procedure and a transonic analysis software PUMI. The computational efficiency and quality design obtained by PSO and Hybrid-PSO are compared. The numerical results for the multi-objective HLS design optimisation clearly shows the benefits of hybridising a PSO with the Nash game and makes promising the above methodology for solving other more complex multi-physics optimisation problems in Aeronautics.

Children’s strategies for making friends when starting school

Starting school is a critical and potentially stressful time for many young children, and having supportive relationships with parents, teachers and peers and friends offer better outcomes for school adjustment and social relationships. This paper explores matters of friendship when young children are starting school, and how they initiate friendships. In audio-recorded conversations with a researcher and their peers, the children proposed a number of strategies, including making requests, initiating clubs and teams, and peer intervention to support a friend. Their accounts drew on social knowledge and relational understandings, and showed that having someone, a friend, to play with was important for starting school. Children gave serious attention to developing strategies to initiate friendships.

What the hare can teach the tortoise about make-buy strategies for radical innovations

Purpose of this paper – The purpose of this investigation is to help establish: whether or not strong relationships between suppliers and customers improve performance; and if prescriptive frameworks on outsourcing radical innovations are dependent on industry clockspeed. Design/methodology/approach – A survey of UK-based manufacturers, followed by a statistical analysis. Findings – Long-term supplier links seem not to play a role in the development of radical innovations. Moreover, industry clockspeed has no significant bearing on the success or failure of any outsourcing strategy for radically new technologies. Research limitations/implications – Literature about outsourcing in the face of radical innovation can be more confidently applied to industries of all clockspeeds. Practical implications – Prescriptions for fast clockspeed industries should be applied more broadly: all industries should maintain a high degree of vertical integration in the early days of a radical innovation. Originality/value – Prior papers had explored whether or not a company should outsource radical innovations, but none had determined if this is equally true for slow industries and fast ones. Therein lies the original contribution of this paper.

Outsourcing strategies for radical innovations: does industry clockspeed make a difference?

Purpose – To determine whether or not clockspeed is an important variable in outsourcing strategies throughout the development of radical innovations. Design/methodology/approach – An internet-based survey of manufacturing firms from all over the world. Findings – An industry's clockspeed does not play a significant role in the success or failure of a particular outsourcing strategy for a radical innovation. Research limitations/implications – Conclusions from earlier research in this area are not necessarily industry-specific. Practical implications – Lessons learned via previous investigations about the computer industry need not be confined to that sector. Vertical integration may be a more robust outsourcing strategy when developing a radical innovation in industries of all clockspeeds. Originality/value – Previous research efforts in this field focused on a single technology jump, but this approach may have overlooked a potentially important variable: industry clockspeed. Thus, this investigation explores whether clockspeed is an important factor.

Efficient hybrid-game strategies coupled to evolutionary algorithms for robust multidisciplinary design optimization in aerospace engineering

A number of game strategies have been developed in past decades and used in the fields of economics, engineering, computer science, and biology due to their efficiency in solving design optimization problems. In addition, research in multiobjective and multidisciplinary design optimization has focused on developing a robust and efficient optimization method so it can produce a set of high quality solutions with less computational time. In this paper, two optimization techniques are considered; the first optimization method uses multifidelity hierarchical Pareto-optimality. The second optimization method uses the combination of game strategies Nash-equilibrium and Pareto-optimality. This paper shows how game strategies can be coupled to multiobjective evolutionary algorithms and robust design techniques to produce a set of high quality solutions. Numerical results obtained from both optimization methods are compared in terms of computational expense and model quality. The benefits of using Hybrid and non-Hybrid-Game strategies are demonstrated.

Hunters & gatherers : strategies for curriculum mapping and data collection for assurance of learning

Assurance of learning is a predominant feature in both quality enhancement and assurance in higher education. Assurance of learning is a process that articulates explicit program outcomes and standards, and systematically gathers evidence to determine the extent to which performance matches expectations. Benefits accrue to the institution through the systematic assessment of whole of program goals. Data may be used for continuous improvement, program development, and to inform external accreditation and evaluation bodies. Recent developments, including the introduction of the Tertiary Education and Quality Standards Agency (TEQSA) will require universities to review the methods they use to assure learning outcomes. This project investigates two critical elements of assurance of learning: 1. the mapping of graduate attributes throughout a program; and 2. the collection of assurance of learning data. An audit was conducted with 25 of the 39 Business Schools in Australian universities to identify current methods of mapping graduate attributes and for collecting assurance of learning data across degree programs, as well as a review of the key challenges faced in these areas. Our findings indicate that external drivers like professional body accreditation (for example: Association to Advance Collegiate Schools of Business (AACSB)) and TEQSA are important motivators for assuring learning, and those who were undertaking AACSB accreditation had more robust assurance of learning systems in place. It was reassuring to see that the majority of institutions (96%) had adopted an embedding approach to assuring learning rather than opting for independent standardised testing. The main challenges that were evident were the development of sustainable processes that were not considered a burden to academic staff, and obtainment of academic buy in to the benefits of assuring learning per se rather than assurance of learning being seen as a tick box exercise. This cultural change is the real challenge in assurance of learning practice.

Understanding the coping strategies of international students : a qualitative approach

International students encounter a range of additional challenges as a part of their tertiary study experience. A qualitative approach was used to understand the challenges faced by international students, coping strategies that promoted their personal resilience and advice they have for future international students. Twenty-two international students from an Australian university participated in four focus groups. The challenges identified by students included adjustment, social isolation, English language skills, academic difficulties, unmet expectations, employment, culture shock and psychological distress. Participants shared their own personal experiences and strategies used by them to cope and identified strategies that future students could use prior to leaving their home country and whilst in Australia to improve their adjustment. Uses of international student stories in prevention interventions are discussed.

Apoptosis-related genes confer resistance to Fusarium wilt in transgenic ‘Lady Finger’ bananas

Fusarium wilt, caused by Fusarium oxysporum f. sp. cubense (Foc), is one of the most devastating diseases of banana (Musa spp.). Apart from resistant cultivars, there are no effective control measures for the disease. We investigated whether the transgenic expression of apoptosis-inhibition related genes in banana could be used to confer disease resistance. Embryogenic cell suspensions of the banana cultivar, ‘Lady Finger’, were stably transformed with animal genes that negatively regulate apoptosis, namely Bcl-xL, Ced-9 and Bcl-2 3’ UTR, and independently transformed plant lines were regenerated for testing. Following a 12 week exposure to Foc race 1 in small-plant glasshouse bioassays, seven transgenic lines (2 x Bcl-xL, 3 x Ced-9 and 2 x Bcl-2 3’ UTR) showed significantly less internal and external disease symptoms than the wild-type susceptible ‘Lady Finger’ banana plants used as positive controls. Of these, one Bcl-2 3’ UTR line showed resistance that was equivalent to that of wild-type Cavendish bananas that were included as resistant negative controls. Further, the resistance of this line continued for 23 weeks post-inoculation at which time the experiment was terminated. Using TUNEL assays, Foc race 1 was shown to induce apoptosis-like features in the roots of wild-type ‘Lady Finger’ plants consistent with a necrotrophic phase in the lifecycle of this pathogen. This was further supported by the observed reduction of these effects in the roots of the resistant Bcl-2 3’ UTR transgenic line. This is the first report on the generation of transgenic banana plants with resistance to Fusarium wilt.

SNP diversity of Enterococcus faecalis and Enterococcus faecium in a South East Queensland waterway, Australia, and associated antibiotic resistance gene profiles

BACKGROUND: Enterococcus faecalis and Enterococcus faecium are associated with faecal pollution of water, linked to swimmer-associated gastroenteritis and demonstrate a wide range of antibiotic resistance. The Coomera River is a main water source for the Pimpama-Coomera watershed and is located in South East Queensland, Australia, which is used intensively for agriculture and recreational purposes. This study investigated the diversity of E. faecalis and E. faecium using Single Nucleotide Polymorphisms (SNPs) and associated antibiotic resistance profiles. RESULTS: Total enterococcal counts (cfu/ml) for three/six sampling sites were above the United States Environmental Protection Agency (USEPA) recommended level during rainfall periods and fall into categories B and C of the Australian National Health and Medical Research Council (NHMRC) guidelines (with a 1-10% gastrointestinal illness risk). E. faecalis and E. faecium isolates were grouped into 29 and 23 SNP profiles (validated by MLST analysis) respectively. This study showed the high diversity of E. faecalis and E. faecium over a period of two years and both human-related and human-specific SNP profiles were identified. 81.8% of E. faecalis and 70.21% of E. faecium SNP profiles were associated with genotypic and phenotypic antibiotic resistance. Gentamicin resistance was higher in E. faecalis (47% resistant) and harboured the aac(6')-aph(2') gene. Ciprofloxacin resistance was more common in E. faecium (12.7% resistant) and gyrA gene mutations were detected in these isolates. Tetracycline resistance was less common in both species while tet(L) and tet(M) genes were more prevalent. Ampicillin resistance was only found in E. faecium isolates with mutations in the pbp5 gene. Vancomycin resistance was not detected in any of the isolates. We found that antibiotic resistance profiles further sub-divided the SNP profiles of both E. faecalis and E. faecium. CONCLUSIONS: The distribution of E. faecalis and E. faecium genotypes is highly diverse in the Coomera River. The SNP genotyping method is rapid and robust and can be applied to study the diversity of E. faecalis and E. faecium in waterways. It can also be used to test for human-related and human-specific enterococci in water. The resolving power can be increased by including antibiotic-resistant profiles which can be used as a possible source tracking tool. This warrants further investigation.

Comparing the cost-effectiveness of MRSA control strategies between ICU and non-ICU settings

Introduction / objectives Many strategies are used to control MRSA in hospitals. Only a few have been assessed in clinical trials and it is not obvious how findings should be generalised between settings. Uncertainty remains about which strategies represent the most appropriate use of scarce resources. We assess the cost-effectiveness of alternative MRSA screening and infection control strategies in England and Wales and discuss international relevance. Methods Models of MRSA transmission in ICUs and general medical (GM) wards were developed and used to evaluate different screening methods combined with decolonisation or isolation. Strategies were compared in terms of costs and health benefits (quality adjusted life years, QALYs). Different prevalences, proportions of high risk patients and ward sizes were investigated, and probabilistic sensitivity analyses (PSA) conducted. Results Decolonisation strategies were cost-saving in ICUs at a 5% admission prevalence, with admission and weekly PCR screening the most cost-effective (£3,929/QALY). In ICUs, screening and isolation reduced infection rates by ~10%. With admission prevalence ≤5%, targeting screening and isolation to high risk patients was optimal. In GM wards decolonisation and isolation strategies, though able to reduce MRSA infection rates up to ~50%, were not cost-effective. Conclusion The largest reductions in MRSA infection were achieved by screening and decolonisation strategies, and were cost-effective in ICU settings. In comparison, there is limited potential for screening and control strategies to be cost-effective in GM wards due to lower infection and mortality rates.