RanGTPase : a candidate for myc-mediated cancer progression

Background Ras-related nuclear protein (Ran) is required for cancer cell survival in vitro and human cancer progression, but the molecular mechanisms are largely unknown. Methods We investigated the effect of the v-myc myelocytomatosis viral oncogene homolog (Myc) on Ran expression by Western blot, chromatin immunoprecipitation, and luciferase reporter assays and the effects of Myc and Ran expression in cancer cells by soft-agar, cell adhesion, and invasion assays. The correlation between Myc and Ran and the association with patient survival were investigated in 14 independent patient cohorts (n = 2430) and analyzed with Spearman's rank correlation and Kaplan-Meier plots coupled with Wilcoxon-Gehan tests, respectively. All statistical tests were two-sided. Results Myc binds to the upstream sequence of Ran and transactivates Ran promoter activity. Overexpression of Myc upregulates Ran expression, whereas knockdown of Myc downregulates Ran expression. Myc or Ran overexpression in breast cancer cells is associated with cancer progression and metastasis. Knockdown of Ran reverses the effect induced by Myc overexpression in breast cancer cells. In clinical data, a positive association between Myc and Ran expression was revealed in 288 breast cancer and 102 lung cancer specimens. Moreover, Ran expression levels differentiate better or poorer survival in Myc overexpressing breast (χ2 = 24.1; relative risk [RR] = 9.1, 95% confidence interval [CI] = 3.3 to 24.7, P <. 001) and lung (χ2 = 6.04; RR = 2.8, 95% CI = 1.2 to 6.3; P =. 01) cancer cohorts. Conclusions Our results suggest that Ran is required for and is a potential therapeutic target of Myc-driven cancer progression in both breast and lung cancers. © 2013 The Author.

Targeting amino acid transport in metastatic castration-resistant prostate cancer : effects on cell cycle, cell growth, and tumor development

Background L-type amino acid transporters (LATs) uptake neutral amino acids including L-leucine into cells, stimulating mammalian target of rapamycin complex 1 signaling and protein synthesis. LAT1 and LAT3 are overexpressed at different stages of prostate cancer, and they are responsible for increasing nutrients and stimulating cell growth. Methods We examined LAT3 protein expression in human prostate cancer tissue microarrays. LAT function was inhibited using a leucine analog (BCH) in androgen-dependent and -independent environments, with gene expression analyzed by microarray. A PC-3 xenograft mouse model was used to study the effects of inhibiting LAT1 and LAT3 expression. Results were analyzed with the Mann-Whitney U or Fisher exact tests. All statistical tests were two-sided. Results LAT3 protein was expressed at all stages of prostate cancer, with a statistically significant decrease in expression after 4–7 months of neoadjuvant hormone therapy (4–7 month mean = 1.571; 95% confidence interval = 1.155 to 1.987 vs 0 month = 2.098; 95% confidence interval = 1.962 to 2.235; P = .0187). Inhibition of LAT function led to activating transcription factor 4–mediated upregulation of amino acid transporters including ASCT1, ASCT2, and 4F2hc, all of which were also regulated via the androgen receptor. LAT inhibition suppressed M-phase cell cycle genes regulated by E2F family transcription factors including critical castration-resistant prostate cancer regulatory genes UBE2C, CDC20, and CDK1. In silico analysis of BCH-downregulated genes showed that 90.9% are statistically significantly upregulated in metastatic castration-resistant prostate cancer. Finally, LAT1 or LAT3 knockdown in xenografts inhibited tumor growth, cell cycle progression, and spontaneous metastasis in vivo. Conclusion Inhibition of LAT transporters may provide a novel therapeutic target in metastatic castration-resistant prostate cancer, via suppression of mammalian target of rapamycin complex 1 activity and M-phase cell cycle genes.

Exact parametric confidence intervals for Bland-Altman limits of agreement

Purpose The previous literature on Bland-Altman analysis only describes approximate methods for calculating confidence intervals for 95% Limits of Agreement (LoAs). This paper describes exact methods for calculating such confidence intervals, based on the assumption that differences in measurement pairs are normally distributed. Methods Two basic situations are considered for calculating LoA confidence intervals: the first where LoAs are considered individually (i.e. using one-sided tolerance factors for a normal distribution); and the second, where LoAs are considered as a pair (i.e. using two-sided tolerance factors for a normal distribution). Equations underlying the calculation of exact confidence limits are briefly outlined. Results To assist in determining confidence intervals for LoAs (considered individually and as a pair) tables of coefficients have been included for degrees of freedom between 1 and 1000. Numerical examples, showing the use of the tables for calculating confidence limits for Bland-Altman LoAs, have been provided. Conclusions Exact confidence intervals for LoAs can differ considerably from Bland and Altman’s approximate method, especially for sample sizes that are not large. There are better, more precise methods for calculating confidence intervals for LoAs than Bland and Altman’s approximate method, although even an approximate calculation of confidence intervals for LoAs is likely to be better than none at all. Reporting confidence limits for LoAs considered as a pair is appropriate for most situations, however there may be circumstances where it is appropriate to report confidence limits for LoAs considered individually.

Dominant negative ATM mutations in breast cancer families

BACKGROUND: The ATM gene encoding a putative protein kinase is mutated in ataxia-telangiectasia (A-T), an autosomal recessive disorder with a predisposition for cancer. Studies of A-T families suggest that female heterozygotes have an increased risk of breast cancer compared with noncarriers. However, neither linkage analyses nor mutation studies have provided supporting evidence for a role of ATM in breast cancer predisposition. Nevertheless, two recurrent ATM mutations, T7271G and IVS10-6T-->G, reportedly increase the risk of breast cancer. We examined these two ATM mutations in a population-based, case-control series of breast cancer families and multiple-case breast cancer families. METHODS: Five hundred twenty-five or 262 case patients with breast cancer and 381 or 68 control subjects, respectively, were genotyped for the T7271G and IVS10-6T-->G ATM mutations, as were index patients from 76 non-BRCA1/2 multiple-case breast cancer families. Linkage and penetrance were analyzed. ATM protein expression and kinase activity were analyzed in lymphoblastoid cell lines from mutation carriers. All statistical tests were two-sided. RESULTS: In case and control subjects unselected for family history of breast cancer, one case patient had the T7271G mutation, and none had the IVS10-6T-->G mutation. In three multiple-case families, one of these two mutations segregated with breast cancer. The estimated average penetrance of the mutations was 60% (95% confidence interval [CI] = 32% to 90%) to age 70 years, equivalent to a 15.7-fold (95% CI = 6.4-fold to 38.0-fold) increased relative risk compared with that of the general population. Expression and activity analyses of ATM in heterozygous cell lines indicated that both mutations are dominant negative. CONCLUSION: At least two ATM mutations are associated with a sufficiently high risk of breast cancer to be found in multiple-case breast cancer families. Full mutation analysis of the ATM gene in such families could help clarify the role of ATM in breast cancer susceptibility.

Internetalisation : the Internet's influence on international market growth in the firm's outward internationalisation process

It has been suggested that the Internet is the most significant driver of international trade in recent years to the extent that the term =internetalisation‘ has been coined (Bell, Deans, Ibbotson & Sinkovics, 2001; Buttriss & Wilkinson, 2003). This term is used to describe the Internet‘s affect on the internationalisation process of the firm. Consequently, researchers have argued that the internationalisation process of the firm has altered due to the Internet, hence is in need of further investigation. However, as there is limited research and understanding, ambiguity remains in how the Internet has influenced international market growth. Thus, the purpose of this study was to explore how the Internet influences firms‘ internationalisation process, specifically, international market growth. To this end, Internet marketing and international market growth theories are used to illuminate this ambiguity in the body of knowledge. Thus, the research problem =How and why does the Internet influence international market growth of the firm’ is justified for investigation. To explore the research question a two-stage approach is used. Firstly, twelve case studies were used to evaluate key concepts, generate hypotheses and to develop a model of Internetalisation for testing. The participants held key positions within their firm, so that rich data could be drawn from international market growth decision makers. Secondly, a quantitative confirmation process analysed the identified themes or constructs, using two hundred and twenty four valid responses. Constructs were evaluated through an exploratory factor analysis, confirmatory factor analysis and structural equation modelling process. Structural equation modelling was used to test the model of =internetalisation‘ to examine the interrelationships between the internationalisation process components: information availability, information usage, interaction communication, international mindset, business relationship usage, psychic distance, the Internet intensity of the firm and international market growth. This study found that the Internet intensity of the firm mediates information availability, information usage, international mindset, and business relationships when firms grow in international markets. Therefore, these results provide empirical evidence that the Internet has a positive influence on international information, knowledge, entrepreneurship and networks and these in turn influence international market growth. The theoretical contributions are three fold. Firstly, the study identifies a holistic model of the impact the Internet has had on the outward internationalisation of the firm. This contribution extends the body of knowledge pertaining to Internet international marketing by mapping and confirming interrelationships between the Internet, internationalisation and growth concepts. Secondly, the study highlights the broad scope and accelerated rate of international market growth of firms. Evidence that the Internet influences the traditional and virtual networks for the pursuit of international market growth extends the current understanding. Thirdly, this study confirms that international information, knowledge, entrepreneurship and network concepts are valid in a single model. Thus, these three contributions identify constructs, measure constructs in a multi-item capacity, map interrelationships and confirm single holistic model of ‗internetalisation‘. The main practical contribution is that the findings identified information, knowledge and entrepreneurial opportunities for firms wishing to maximise international market growth. To capitalise on these opportunities suggestions are offered to assist firms to develop greater Internet intensity and internationalisation capabilities. From a policy perspective, educational institutions and government bodies need to promote more applied programs for Internet international marketing. The study provides future researchers with a platform of identified constructs and interrelationships related to internetalisation, with which to investigate. However, a single study has limitations of generalisability; thus, future research should replicate this study. Such replication or cross validation will assist in the verification of scales used in this research and enhance the validity of causal predications. Furthermore, this study was undertaken in the Australian outward-bound context. Research in other nations, as well as research into inbound internationalisation would be fruitful.

The role of the internet on international market growth of Australian firms : an exploratory study

The Internet has been shown to positively influence the internationalisation activities of firms through enhanced information, knowledge and network development. Although there has been evidence of a positive impact of the Internet on internationalisation process components, it is vague as to whether the Internet has an impact on firm international market growth. This paper examines the role of the Internet in the outward internationalisation of a cross-national sample of 224 firms from Australia. The results show evidence that a there is a link between Internet usage, Internet intensity and the international market growth of the firm. The findings indicate that firms are using Internet technologies beyond simple e-mail and websites in their international marketing. For example, Internet directories and Internet market spaces are assisting international market expansion of the firm. Firms are integrating the Internet into international marketing processes such as advertising, marketing, market research and international market management as well as in data transference between company and supplier and company and customer. Further, there is evidence in this study of the statistical relationships between the use of website, e-mail and online sales with the international market growth of the firm.

The role of the Internet on export market growth : an empirical study in Latin America

The Internet has been shown to positively influence the export activities of firms from developed countries. However, the literature is vague as to whether the Internet has an impact on the export market growth of firms form developing countries. This paper examines of a cross-national sample of 204 firms from a Latin American country (Chile). The results show that Internet marketing activities positively influence information availability and business relationships, which lead to an increase in export market growth. The findings indicate that the Internet influences not only information availability for export performance but also business relationships generally thought to be face to face interactions in nature.

Internet marketing and export market growth in Chile

Previous studies show that the Internet positively influences firms’ export activities from developed markets. However, the literature is vague as to whether the Internet has an impact on the export performance of firms from emerging markets. This study tests a conceptual model that includes the effect of Internet marketing capabilities on export market growth in an emerging market. Drawing on a cross-national sample of 204 export firms from a Latin American country (Chile), findings indicate that Internet marketing capabilities positively influence the availability of export information, which in turn impacts the development of business network relationships and export market growth.

Evaluation of Australian Performing Arts Market 2014-2018 REPORT TWO APAM inter-year report 2015 DECEMBER

The report follows up on data and trends tabled in August 2015 that collected data from two key sources – six identified case study productions that have been tracked for eighteen months, and an online survey delivered to all APAM 2014 delegates. The comparative report has been constructed through an analysis of data reported from the August 2015 and the most recent online survey to all 2104 PM delegates conducted in late November 2015. The report highlights six key trends emerging from the data: The majority of survey respondents will return to APAM 2016; The central reason for attending is the networking opportunities the Market affords; Respondents are confident that a range of new relationships forged at the Market will afford long-term interest and buying opportunities and that as a result of the 2014 event, real touring outcomes were realised for some respondents; Respondents would like to see greater attention to a greater number of networking activities within the program to enable touring outcomes; The multi-venue model is still of concern, and is a recurrent issue from earlier surveys; The level of expense incurred by producers to present work at APAM. Throughout the report, extracted data from the online survey responses will be tabled to develop a narrative in response to the key research aims outlined in the Brisbane Powerhouse Tender document (2011). A full version of the collated responses to the survey questions can be found in the appendices of the report.

Internet marketing capabilities and international market growth

The Internet has been shown to facilitate elements of internationalisation such as information accumulation and network opportunities. However, there is limited understanding of how the Internet combined with marketing capabilities drives international market growth. This study, based on a sample of 224 Australian firms, develops and tests, using structural equation modelling (SEM), a conceptual model of Internet marketing capabilities and international market growth. Results indicate that firms deploying Internet marketing capabilities will benefit due to the reduction of information uncertainty and increased capacity to develop international network capabilities. Moreover, Internet marketing capabilities indirectly lead to international market growth when the firm has a high level of international strategic orientation and international network capabilities. Overall, Internet marketing capabilities enhance the firm's ability to generate other internal capabilities within the firm, which in turn have a positive impact on the international market growth of the firm.

Deniable Authenticated Key Establishment for Internet Protocols

We propose two public-key schemes to achieve “deniable authentication” for the Internet Key Exchange (IKE). Our protocols can be implemented using different concrete mechanisms and we discuss different options; in particular we suggest solutions based on elliptic curve pairings. The protocol designs use the modular construction method of Canetti and Krawczyk which provides the basis for a proof of security. Our schemes can, in some situations, be more efficient than existing IKE protocols as well as having stronger deniability properties.

Two main challenges in service description : Web service tunnel vision and semantic myopia

Through media such as newspapers, letterbox flyers, corporate brochures and television we are regularly confronted with descriptions for conventional (bricks 'n' mortar style) services. These representations vary in the terminology utilised, the depth of the description, the aspects of the service that are characterised and their applicability to candidate service requestors. Existing service catalogues (such as the Yellow Pages) provide little relief for service requestors from the burdensome task of discovering, comparing and substituting services. Add to this environment the rapidly evolving area of web services with its associated surfeit of standards, and the result is a considerably fragmented approach to the description of services. It leaves the reality of the Semantic Web somewhat clouded. --------- Let's consider service description briefly, before discussing our concerns with existing approaches to description. The act of describing is performed prior to advertising. This simple fact provides an interesting paradox as services cannot be described exactly before advertisement. This doesn't mean they can't be described comprehensively. By "exactly", we are referring to the fact that context provided by a service requestor (and their service needs) will alter the description of the service that is presented to the discoverer. For example, a service provider who operates a cinema wants to describe the price of their service. Let's say the advertised price is $15. They also want to state that a pensioner discount and a student discount is available which provides a 50% discount. A customer (i.e. service requestor) uses the cinema web site to purchase tickets online. They find the movie of their choice at a time that suits. However, its not until some context is provided by the requestor that the exact price is determined. The requestor might state that they are a pensioner. The same is applicable for a service requestor who purchases multiple tickets perhaps on behalf of other people. The disconnect between when the service is described and when a requestor provides context introduces challenges to the description process. A service provider would be ill-advised to offer independent descriptions that represent all the permutations possible for a single service. The descriptive effort would be prohibitive.

The relationship between Internet use and perceived performance in retail and professional service firms

lnformation technology (IT) and, in particular, the Internet is dramatically impacting on the services sector. This paper specifically investigates the relative impact of several forms of internet use on perceived performance for two groups of service organisations - retail service firms and professlonal health service firms. Using a mailed out self-administered questionnaire, 625 completed questionnaires were obtained and 43 per cent of respondents reported that they used the lternet. Thus the final usable sample in the study comprised 262 respondents. Results showed that the Internet does significantly influence perceived performance in both types of service firms. However,there are differences in the forms of lntemet use between the two service groups and their relative effect on performance. For retail firms, use of transactional function, such as ordering, selling and payment was found to be positively related to increases in perceived performance. In contrast, for professional health service firms, the ability to search for information on products and/or services was found to be positively associated with perceived performance. Finally, theoretical and managerial implications of the findings of this study are discussed.