Haplotype analysis of two recurrent CDKN2A mutations in 10 melanoma families : evidence for common founders and independent mutations

Germ-line mutations in CDKN2A have been shown to predispose to cutaneous malignant melanoma. We have identified 2 new melanoma kindreds which carry a duplication of a 24bp repeat present in the 5' region of CDKN2A previously identified in melanoma families from Australia and the United States. This mutation has now been reported in 5 melanoma families from 3 continents: Europe, North America, and Australasia. The M53I mutation in exon 2 of CDKN2A has also been documented in 5 melanoma families from Australia and North America. The aim of this study was to determine whether the occurrence of the mutations in these families from geographically diverse populations represented mutation hotspots within CDKN2A or were due to common ancestors. Haplotypes of 11 microsatellite markers flanking CDKN2A were constructed in 5 families carrying the M53I mutation and 5 families carrying the 24bp duplication. There were some differences in the segregating haplotypes due primarily to recombinations and mutations within the short tandem-repeat markers; however, the data provide evidence to indicate that there were at least 3 independent 24bp duplication events and possibly only 1 original M53I mutation. This is the first study to date which indicates common founders in melanoma families from different continents.

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.

Scaling digital radiographs for templating in total hip arthroplasty using conventional acetate templates independent of calibration markers

We describe a scaling method for templating digital radiographs using conventional acetate templates independent of template magnification without the need for a calibration marker. The mean magnification factor for the radiology department was determined (119.8%, range117%-123.4%). This fixed magnification factor was used to scale the radiographs by the method described. 32 femoral heads on postoperative THR radiographs were then measured and compared to the actual size. The mean absolute accuracy was within 0.5% of actual head size (range 0 to 3%) with a mean absolute difference of 0.16mm (range 0-1mm, SD 0.26mm). Intraclass Correlation Coefficient (ICC) showed excellent reliability for both inter and intraobserver measurements with ICC scores of 0.993 (95% CI 0.988-0.996) for interobserver measurements and intraobserver measurements ranging between 0.990-0.993 (95% CI 0.980-0.997).

Competition and innovation : independent production in the Chinese TV industry

Independent television production is recognised for its capacity to generate new kinds of program content, as well as deliver innovation in formats. Globally, the television industry is entering into the post-broadcasting era where audiences are fragmented and content is distributed across multiple platforms. The effects of this convergence are now being felt in China, as it both challenges old statist models and presents new opportunities for content innovation. This thesis discusses the status of independent production in China, making relevant comparisons with independent production in other countries. Independent television production has become an important element in the reform of broadcasting in China in the past decade. The first independent TV production company was registered officially in 1994. While there are now over 4000 independent companies, the term „independent. does not necessarily constitute autonomy. The question the thesis addresses is: what is the status and nature of independence in China? Is it an appropriate term to use to describe the changing environment, or is it a misnomer? The thesis argues that Chinese independents operate alongside the mainstream state-owned system; they are „dependent. on the mainstream. Therefore independent television in China is a relative term. By looking at several companies in Beijing, mainly in entertainment, TV drama and animation, the thesis shows how the sector is injecting fresh ideas into the marketplace and how it plays an important role in improving innovation in many aspects of the television industry. The thesis shows how independent television companies in China are looking to protect their property rights. It demonstrates that far from being at the cutting edge, independents are reliant on a system that has many inbuilt structural problems. The thesis outlines many of the challenges facing 'independents'.

Developing and enhancing independent learning skills : using video tutorials as a means of helping students help themselves

Purpose – The purpose of this paper is to examine the use of short video tutorials in a post-graduate accounting subject, as a means of helping students develop and enhance independent learning skills. Design/methodology/approach – In total, five short (approximately five to 10 minutes) video tutorials were introduced in an effort to shift the reliance for learning from the lecturer to the student. Data on students’ usage of online video tutorials, and comments by students in university questionnaires were collated over three semesters from 2008 to 2009. Interviews with students were then conducted in late 2009 to more comprehensively evaluate the use and perceived benefits of video tutorials. Findings – Findings reveal preliminary but positive outcomes in terms of both more efficient and effective teaching and learning. Research limitations/implications – The shift towards more independent learning through the use of video tutorials has positive implications for educators, employers, and professional accounting bodies; each of whom has identified the need for this skill in accounting graduates. Practical implications – The use of video tutorials has the potential for more rewarding teaching and more effective learning. Originality/value – This study is one of the first to examine the use and benefits of video tutorials as a means of developing independent learning skills in accountancy students – addressing a key concern within the profession.

'Homes for Life' : a critical ecological study of an independent living project

In this paper, an ‘ecological’ lens is applied to an independent living project aiming to provide ‘homes for life’ for adult children with disabilities. The qualities of the project as ecological praxis are highlighted along with the implications for an open-ended enquiry into ecologies for and of the interior. In terms of the ecological concern for intimate modes of being, interior design is shown to be well placed through its association with environments in which people spend most of their life and through powerful concepts such as ‘interiority’ and ‘home’ which link to fundamental existential notions of ‘self ’ and ‘identity’. However, despite the interior being a significant generative force, this has not happened to the exclusion of other disciplines. Ignoring territorial urges to claim areas and concepts as one’s own, the paper describes how the project has actively encouraged design disciplines to trespass in each other’s territories. Ecologies for and of the interior, while recognising the need for discipline emphasis, also demand an integrated and collective approach through what is in effect transdisciplinary practice.

Three carrier ambiguity resolution : distance-independent performance demonstrated using semi-generated triple frequency GPS signals

In spite of significant research in the development of efficient algorithms for three carrier ambiguity resolution, full performance potential of the additional frequency signals cannot be demonstrated effectively without actual triple frequency data. In addition, all the proposed algorithms showed their difficulties in reliable resolution of the medium-lane and narrow-lane ambiguities in different long-range scenarios. In this contribution, we will investigate the effects of various distance-dependent biases, identifying the tropospheric delay to be the key limitation for long-range three carrier ambiguity resolution. In order to achieve reliable ambiguity resolution in regional networks with the inter-station distances of hundreds of kilometers, a new geometry-free and ionosphere-free model is proposed to fix the integer ambiguities of the medium-lane or narrow-lane observables over just several minutes without distance constraint. Finally, the semi-simulation method is introduced to generate the third frequency signals from dual-frequency GPS data and experimentally demonstrate the research findings of this paper.

Tinamous and moa flock together : mitochondrial genome sequence analysis reveals independent losses of flight among ratites

Ratites are large, flightless birds and include the ostrich, rheas, kiwi, emu, and cassowaries, along with extinct members, such as moa and elephant birds. Previous phylogenetic analyses of complete mitochondrial genome sequences have reinforced the traditional belief that ratites are monophyletic and tinamous are their sister group. However, in these studies ratite monophyly was enforced in the analyses that modeled rate heterogeneity among variable sites. Relaxing this topological constraint results in strong support for the tinamous (which fly) nesting within ratites. Furthermore, upon reducing base compositional bias and partitioning models of sequence evolution among protein codon positions and RNA structures, the tinamou–moa clade grouped with kiwi, emu, and cassowaries to the exclusion of the successively more divergent rheas and ostrich. These relationships are consistent with recent results from a large nuclear data set, whereas our strongly supported finding of a tinamou–moa grouping further resolves palaeognath phylogeny. We infer flight to have been lost among ratites multiple times in temporally close association with the Cretaceous–Tertiary extinction event. This circumvents requirements for transient microcontinents and island chains to explain discordance between ratite phylogeny and patterns of continental breakup. Ostriches may have dispersed to Africa from Eurasia, putting in question the status of ratites as an iconic Gondwanan relict taxon. [Base composition; flightless; Gondwana; mitochondrial genome; Palaeognathae; phylogeny; ratites.]

Deprivation is an independent predictor of 1-year mortality in outpatients with chronic obstructive pulmonary disease

Deprivation is linked to increased incidence in a number of chronic diseases but its relationship to chronic obstructive pulmonary disease (COPD) is uncertain despite suggestions that the socioeconomic gradient seen in COPD is as great, if not greater, than any other disease (Prescott and Vestbo).1 There is also a need to take into account the confounding effects of malnutrition which have been shown to be independently linked to increased mortality (Collins et al).2 The current study investigated the influence of social deprivation on 1-year survival rates in COPD outpatients, independently of malnutrition. 424 outpatients with COPD were routinely screened for malnutrition risk using the ‘Malnutrition Universal Screening Tool’; ‘MUST’ (Elia),3 between July and May 2009; 222 males and 202 females; mean age 73 (SD 9.9) years; body mass index 25.8 (SD 6.3) kg/m2. Each individual's deprivation was calculated using the index of multiple deprivation (IMD) which was established according to the geographical location of each patient's address (postcode). IMD includes a number of indicators covering economic, housing and social issues (eg, health, education and employment) into a single deprivation score (Nobel et al).4 The lower the IMD score, the lower an individual's deprivation. The IMD was assigned to each outpatient at the time of screening and related to1-year mortality from the date screened. Outpatients who died within 1-year of screening were significantly more likely to reside within a deprived postcode (IMD 19.7±SD 13.1 vs 15.4±SD 10.7; p=0.023, OR 1.03, 95% CI 1.00 to 1.06) than those that did not die. Deprivation remained a significant independent risk factor for 1-year mortality even when adjusted for malnutrition as well as age, gender and disease severity (binary logistic regression; p=0.008, OR 1.04, 95% CI 1.04 to 1.07). Deprivation was not associated with disease-severity (p=0.906) or body mass index, kg/m2 (p=0.921) using ANOVA. This is the first study to show that deprivation, assessed using IMD, is associated with increased 1-year mortality in outpatients with COPD independently of malnutrition, age and disease severity. Deprivation should be considered in the targeted management of these patients.

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.

Clines in cuticular hydrocarbons in two Drosophila species with independent population histories

We took a comparative approach utilizing clines to investigate the extent to which natural selection may have shaped population divergence in cuticular hydrocarbons (CHCs) that are also under sexual selection in Drosophila. We detected the presence of CHC clines along a latitudinal gradient on the east coast of Australia in two fly species with independent phylogenetic and population histories, suggesting adaptation to shared abiotic factors. For both species, significant associations were detected between clinal variation in CHCs and temperature variation along the gradient, suggesting temperature maxima as a candidate abiotic factor shaping CHC variation among populations. However, rainfall and humidity correlated with CHC variation to differing extents in the two species, suggesting that response to these abiotic factors may vary in a species-specific manner. Our results suggest that natural selection, in addition to sexual selection, plays a significant role in structuring among-population variation in sexually selected traits in Drosophila.