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Following decades of ecologic and economic impacts from a growing list of nonindigenous and invasive species, government and management entities are committing to systematic early- detection monitoring (EDM). This has reinvigorated investment in the science underpinning such monitoring, as well as the need to convey that science in practical terms to those tasked with EDM implementation. Using the context of nonindigenous species in the North American Great Lakes, this article summarizes the current scientific tools and knowledge - including limitations, research needs, and likely future developments - relevant to various aspects of planning and conducting comprehensive EDM. We begin with the scope of the effort, contrasting target-species with broad-spectrum monitoring, reviewing information to support prioritization based on species and locations, and exploring the challenge of moving beyond individual surveys towards a coordinated monitoring network. Next, we discuss survey design, including effort to expend and its allocation over space and time. A section on sample collection and analysis overviews the merits of collecting actual organisms versus shed DNA, reviews the capabilities and limitations of identification by morphology, DNA target markers, or DNA barcoding, and examines best practices for sample handling and data verification. We end with a section addressing the analysis of monitoring data, including methods to evaluate survey performance and characterize and communicate uncertainty. Although the body of science supporting EDM implementation is already substantial, research and information needs (many already actively being addressed) include: better data to support risk assessments that guide choice of taxa and locations to monitor; improved understanding of spatiotemporal scales for sample collection; further development of DNA target markers, reference barcodes, genomic workflows, and synergies between DNA-based and morphology-based taxonomy; and tools and information management systems for better evaluating and communicating survey outcomes and uncertainty.

HK2 has a prominent role in glycolysis, acting as the rate-limiting step in the pathway. HK2 is highly expressed in many cancers, with overexpression associated with drug resistant phenotypes. In parallel, its inhibition has improved the effectiveness of anticancer agents. Evidence indicates that HK2 is epigenetically silenced in normal tissue, and hypomethylation is the driving factor of increased expression in tumours, suggesting HK2 as a potential genetic modifier and therapeutic target. This study determines the role of methylation and its association with expression levels of HK2 in glioblastoma multiforme (GBM) fresh frozen biopsies and patient-derived GBM short-term cultures, by pyrosequencing and quantitative PCR. Anti-proliferative effects of HK2 inhibitors and their mechanism of action was investigated by cytotoxicity assays and FACS analysis. Hypomethylation was seen in all GBM biopsies(n=85) compared to normal brain tissue; average methylation of 4.6% compared to 26% respectively (p< 0.0001). Hypomethylation was also in all culture samples(n=9). An increase in HK2 expression was detected, ranging between 6 to >1000fold change in GBM biopsies(n=50) and 30 to >1000 in cultures(n=10), compared to normal brain tissue. There was a strong correlation between methylation and level of expression (p< 0.0001) as biopsies with HK2 expression greater than the mean fold change additionally displayed hypomethylation levels below mean fold change) was associated with greater sensitivity to BPA. Significantly higher levels of apoptosis were induced after treatment with BPA at ID50 in cultures expressing high HK2 (>mean fold change) (p< 0.0014). This study establishes a strong correlation between hypomethylation and increased expression of HK2. Furthermore, demonstrating the potential of HK2 inhibitors as a novel therapy in a significant subset of GBM.

The European Union’s Marine Strategy Framework Directive (MSFD) aims to adopt integrated ecosystem management approaches to achieve or maintain “Good Environmental Status” for marine waters, habitats and resources, including mitigation of the negative effects of non-indigenous species (NIS). The Directive further seeks to promote broadly standardized monitoring efforts and assessment of temporal trends in marine ecosystem condition, incorporating metrics describing the distribution and impacts of NIS. Accomplishing these goals will require application of advanced tools for NIS surveillance and risk assessment, particularly given known challenges associated with surveying and monitoring with traditional methods. In the past decade, a host of methods based on nucleic acids (DNA and RNA) analysis have been developed or advanced that promise to dramatically enhance capacity in assessing and managing NIS. However, ensuring that these rapidly evolving approaches remain accessible and responsive to the needs of resource managers remains a challenge. This paper provides recommendations for future development of these genetic tools for assessment and management of NIS in marine systems, within the context of the explicit requirements of the MSFD. Issues considered include technological innovation, methodological standardization, data sharing and collaboration, and the critical importance of shared foundational resources, particularly integrated taxonomic expertise. Though the recommendations offered here are not exhaustive, they provide a basis for future intentional (and international) collaborative development of a genetic toolkit for NIS research, capable of fulfilling the immediate and long term goals of marine ecosystem and resource conservation.

HK2 is highly expressed in several cancers including colon and breast and its role as the rate-limiting step of glycolysis may potentially contribute to tumour growth. Overexpression of HK2 has also been associated with drug resistant phenotypes. Inhibition of HK2 has increased the effectiveness of anticancer agents suggesting HK2 as both a potential genetic modifier and therapeutic target. There is evidence that HK2 is epigenetically silenced in normal tissue and that increased expression in tumours is due to hypomethylation. In this study, methylation status and expression levels of HK2 were determined in 36 glioblastoma multiforme (GBM) fresh frozen biopsies and 9 patient-derived GBM short-term cultures by methylation specific-PCR (MS-PCR) and RT-PCR respectively. More than 90% (n=33) of the GBM biopsies showed some hypomethylation of HK2, including 5 tumour samples that were completely hypomethylated. Total hypermethylation of HK2 was present in only 3 biopsy samples. There was good correlation between methylation status and level of expression; no mRNA transcripts were detected in tumours samples with complete HK2 methylation. There was also complete hypomethylation of HK2 in 4 (44%) of the short-term cultures and the remaining 5 cultures had only partial methlyation. Expression of HK2 was detected in all culture samples. This data demonstrates that hypomethylation of HK2 is a frequent event in GBM compared to normal brain. Furthermore, the high levels of HK2 expression detected in short-term cultures will enable future investigations of HK2 inhibitors as a therapeutic option in GBM.

Background: Triple-negative breast cancer (TNBC) has significantly worse prognosis. Acquired chemoresistance remains the major cause of therapeutic failure of TNBC. In clinic, the relapsed TNBC is commonly pan-resistant to various drugs with completely different resistant mechanisms. Investigation of the mechanisms and development of new drugs to target pan-chemoresistance will potentially improve the therapeutic outcomes of TNBC patients. Methods: In this study, 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), combination index (CI)–isobologram, western blot, ALDEFLUOR analysis, clonogenic assay and immunocytochemistry were used. Results: The chemoresistant MDA-MB-231PAC10 cells are highly cross-resistant to paclitaxel (PAC), cisplatin (CDDP), docetaxel and doxorubicin. The MDA-MB-231PAC10 cells are quiescent with significantly longer doubling time (64.9 vs 31.7 h). This may be caused by high expression of p21Waf1. The MDA-MB-231PAC10 cells express high aldehyde dehydrogenase (ALDH) activity and a panel of embryonic stem cell-related proteins, for example, Oct4, Sox2, Nanog and nuclealisation of HIF2α and NF-κBp65. We have previously reported that disulfiram (DS), an antialcoholism drug, targets cancer stem cells (CSCs) and enhances cytotoxicity of anticancer drugs. Disulfiram abolished CSC characters and completely reversed PAC and CDDP resistance in MDA-MB-231PAC10 cells. Conclusion: Cancer stem cells may be responsible for acquired pan-chemoresistance. As a drug used in clinic, DS may be repurposed as a CSC inhibitor to reverse the acquired pan-chemoresistance.

The purpose of this paper is to present a case study focusing on a new technology start-up firm, founded by two graduate students, an engineer and a business major, who met during their university studies. The case is timely, in that only ten percent of new product introductions result in a profitable business. The causes of failure are numerous and include the following: the market may create failure; inadequate funding and capitalization; and competition from established enterprises. Several research studies also point to rising indications of interfunctional conflict in high technology companies. One reason may be that, today, management teams in such companies are typically comprised of greater levels of diversity in age, gender, ethnicity, education, and life experiences, all of which exacerbate conflicts. New venture teams, especially in a technology start-up, may be united because of the product innovation, but they may easily become disconnected and unrealistic when it comes to the management of the enterprise. The presentation and analysis of a conflict management process herein indicates that the way a start-up team manages its conflicts may have a permanent affect on the success of its entrepreneurial venture. Conflict management does not imply terminating conflict, but involves understanding strategies to minimize dysfunction and enhancing constructive effectiveness as a result of conflict. This case exposed the problems that arise due to the differences in the founders’ education, background, experience and understanding of the necessary entrepreneurial mindset for success. By using a model of conflict management that encompasses four negotiation skill sets, including assessment, intervention, resolution and maintenance, their conflicts were resolved quickly and their partnership re-engineered, increasing the chance of their firm’s long-term success.

PurposeThe purpose of this paper is to explore the issue of crisis management within the Toyota Corporation's series of worldwide recalls for multiple malfunctions on a number of different Toyota brands of vehicles. The analysis relates to the difficulty now faced by Toyota, previously recognized as the world's leading manufacturer of automotive vehicles. The crisis became so great that Toyota corporate leaders even traveled from Japan to testify before a US Congressional Committee hearing.Design/methodology/approachA crisis, typically considered to be a negative issue, can be a positive event in the life of a business firm, such as Toyota, if the management involved seizes the opportunity to make appropriate changes in its operations to facilitate continuing positive growth and development. However, this opportunity was not initially addressed by Toyota in a meaningful way, and the crisis continued to evolve through subsequent stages, bringing a vast array of negative international criticism. The crisis management paradigm that is the focus for this case identifies four stages of a crisis – the preliminary (pre‐) crisis, acute crisis, chronic crisis, and crisis resolution. The present crisis deals with several different malfunctions that were identified, apparently by customers, in various Toyota brands, but publically ignored by Toyota's management. Therefore, the pre‐crisis stage was not appropriately dealt with by Toyota, and the firm was thrust into an acute crisis that has now evolved into a chronic crisis. A brief overview of the historical development of Toyota is presented, and an analysis of the present crisis situation in which the firm found itself is presented in some detail.FindingsIt was concluded that Toyota is now in a very difficult position in the chronic crisis stage due to the failure of its management to facilitate a timely response to the malfunctions of its vehicles.Originality/valueThe paper presents an excellent example of crisis mismanagement by a previously recognized world leader.

Recent technological advances have driven rapid development of DNA-based methods designed to facilitate detection and monitoring of invasive species in aquatic environments. These tools promise to improve on traditional monitoring approaches by enhancing detection sensitivity, reducing analytical turnaround times and monitoring costs, and increasing specificity of target identifications. However, despite the promise of DNA-based monitoring methods, the adoption of these tools in decision-making frameworks remains challenging. Here, rather than explore technical aspects of method development, we examine impediments to effective translation of those methods into management contexts. In addition to surveying current use of DNA-based tools for aquatic invasive species monitoring, we explore potential sources of uncertainty associated with molecular technologies and possibilities for limiting that uncertainty and effectively communicating its implications for decision-making. We pay particular attention to the recent adoption of DNA-based methods for detection of invasive Asian carp species in the United States Great Lakes region, as this example illustrates many of the challenges associated with applying molecular tools to achieve desired management outcomes. Our goal is to provide a useful assessment of the obstacles associated with integrating DNA-based methods into aquatic invasive species management, and to offer recommendations for future efforts aimed at overcoming those obstacles.

Purpose – The purpose of this paper is to address the importance of effective crisis management, and the commensurate lessons to be learned from the Toyota Corporation's denial of malfunctions on a number of different Toyota brands of vehicles during the period 2007‐2010. The case analysis identifies key opportunities the Toyota Corporation had to minimize the crisis by acknowledging the issues and being transparent in its decision making. The article addresses the difficulty now faced by Toyota, previously recognized as the world's leading manufacturer of automotive vehicles, to re‐establish the consumers' trust.Design/methodology/approach – A crisis, typically considered to be a negative issue, can be a positive event in the life of a corporate firm, such as Toyota, if the corporate leadership involved seizes the opportunity to make appropriate changes in its operations. The crisis management paradigm that is the focus for this case identifies four stages of a crisis – the preliminary (pre‐) crisis, acu...

Most of the gemcitabine (dFdC) resistant cell lines manifested high NFkappaB activity. The NFkappaB activity can be induced by dFdC and 5-FU exposure. The chemosensitizing effect of disulfiram (DS), an anti-alcoholism drug and NFkappaB inhibitor, and copper (Cu) on the chemoresistant cell lines was examined. The DS/Cu complex significantly enhanced the cytotoxicity of dFdC (resistant cells: 12.2-1085-fold) and completely reversed the dFdC resistance in the resitant cell lines. The dFdC-induced NFkappaB activity was markedly inhibited by DS/Cu complex. The data from this study indicated that DS may be used in clinic to improve the therapeutic effect of dFdC in breast and colon cancer patients.

In today's competitive environment strongly influenced by increasingly new issues and perspectives, entrepreneurial business firms must be focused on leadership team-building. The purpose of this treatise is to present a conceptual case-based analysis of this team-building process, focusing on the importance of leadership styles within an entrepreneurship. Team-building implies mentoring and enhancement whereby members of a leadership team aze nurtured and developed in important ways. A key element of this process is the paradigm of individual leadership styles represented in the team which, in turn, reflects the many different ways by which the individuals involved behave, communicate, adjust, and respond to each other. Two interactive dimensions at the heart of an individual's behavior assertiveness and responsiveness are foundations of that person's leadership style. The basic interactive dimensions of assertiveness and responsiveness thereby form the two axes of the framework of the leadershi...

Entrepreneurship is fundamentally a way of thinking that facilitates the achievement of goals through innovative products and/or operations. To accomplish the desired outcomes, entrepreneurs typically gather around them a team of associates to make success possible. In the leadership of this team of individuals, communication plays a significant role. A review of research has identified seven key communication priorities that are important factors in entrepreneurial leadership; the purpose of this article is to explicate briefly each of these priorities, and illustrate their application within major entrepreneurial-led organizations. The seven priorities are: (1) Paradoxical Thinking that nurtures understanding based upon use of both hemispheres of the brain; (2) Controlled Reflecting that fosters reactions based upon internal self-talk rather than external events; (3) Intentional Focusing that facilitates the ability to be centered on expected outcomes; (4) Instinctive Responding that cultivates...

PurposeThe contemporary business arena continues to hold great promise for dramatic innovational developments unheard of in previous eras. The purpose of this paper is to suggest ways to achieve organizational excellence through entrepreneurship in today's dynamic environment of opportunities.Design/methodology/approachThe authors' research has focused on the foundation of successful entrepreneurial management leadership in the achievement of organizational excellence. Data were collected primarily from well‐known entrepreneurs identified during the past ten years in various publications.FindingsResearch shows that the major reflections of operational excellence in organizational entrepreneurship revolve around the care of customers, constant innovation, committed people and managerial leadership.Research limitations/implicationsMany relatively creative ideas regarding entrepreneurial management and leadership have been put forward in this treatise, which clearly require further validation by future research.Practical implicationsSuccessful leadership has been found to be based upon four key strategies: attention through vision, meaning through communication, trust through positioning, and confidence through respect. Research further suggests that at the heart of successful leadership strategies rest a concern for people and the interpersonal values of joy, hope, charity and peace. These values provide a new paradigm of interactive cues and a foundational core for the successful fulfillment of those key strategies.Originality/valueThis research contributes by developing a model of keys to organizational excellence, and leadership strategies and values. Furthermore, this paper may benefit companies that are trying to reinvent themselves by fostering innovativeness within their organizations.

The future continues to hold the promise for dramatic innovational changes with opportunities for entrepreneurial leadership typically unheard of in previous eras. And in this environment of entrepreneurial opportunities, achievement of organizational excellence remains a primary focus. Research by the authors shows that the major reflections of operational excellence and success in entrepreneurial organizations revolve around the care of customers, constant innovation, committed people and managerial leadership. An analysis of the keys to achieving acceptable levels of excellence focuses on the four primary entrepreneurial leadership strategies of attention through vision, meaning through communication, trust through positioning, and confidence through respect. Research further suggests that at the heart of successful entrepreneurial leadership strategies is a concern for people and interpersonal values that provide a paradigm of interactive cues and the foundational core for the successful fulf...

The 2011–2014 European Community project VECTORS (‘‘Vectors of Change in Oceans and SeasMarine Life, Impact on Economic Sectors’’) was an integrated, multidisciplinary European project which aimed to improve our understanding of how environmental anthropogenic drivers are impacting European marine ecosystems now and in the future. VECTORS investigated how these changes may affect marine biodiversity and ecosystem functioning, the range of goods and services provided by the oceans, the resulting socio-economic impacts and some possible future scenarios for mitigation and adaptation. The VECTORS Work Package WP2.1 (Mechanisms of Change: Outbreaks and Invasives) was committed to identifying mechanisms of species outbreaks and invasions and introduction vectors as both symptoms and drivers of change in European marine ecosystems. VECTORS particularly focused on native outbreak-forming species (OFS) and invasive alien species (IAS) (Box 1) to deliver new information on (1) IAS and OFS distribution in European seas, (2) stochastic and deterministic drivers of invasions and ecophysiological features boosting regime shifts of marine communities, (3) sources and vectors of bioinvasions, and (4) consequences of bioinvasions, in terms of impact on ecosystem functioning and services. These studies provided a substantive contribution to the understanding of the ecological conditions in which outbreaks and alien invasions are more likely to occur, and the determination of critical thresholds/tipping points that mark alternative regime shifts in community structure and organization. The progressive reduction in the inherent costs of molecular data over the past 20 years, along with rapid recent technological and analytical developments, has resulted in molecular methods becoming an inescapable component of investigation on biological invasions, from simple biodiversity assessment to historical reconstruction of invasion histories. Within this context, 60 participants frwom 14 nations gathered in Lecce, Italy on 12–14th September 2012 for MOLTOOLS (Fig. 1), a dedicated workshop to discuss and promote the use of molecular tools for monitoring and understanding marine invasive species. The workshop was designed to address several key questions regarding mechanisms and management J. A. Darling National Exposure Research Laboratory, United States Environmental Protection Agency, Durham, NC 27713, USA

Purpose – To introduce the behavioral style paradigm as a tool for creating effective upward influence within academic organizations.Design/methodology/approach – Concepts of upward influence, behavioral style, communication orientation, back‐up style, and style flexibility are described and analyzed.Findings – Provides information on creating more effective institutions of higher education by using the behavioral style perspective in managing upward influence situations.Research limitations/implications – Suggests a number of questions and ideas that may be examined in future research efforts.Practical implications – Outlines the importance of understanding behavioral style techniques for improving administrator effectiveness and the effects of behavioral style techniques on various outcomes within and outside the academic institution.Originality/value – Fulfills a need as universities face increasingly complex environments and require more effective leadership and administration. Offers practical help t...

During the past decade, several studies have explored the characteristics of Born International and Born Global business firms, and the reasons for their increase in size and numbers. The objective of this study is to explore the influence of financing strategies and the commensurate finance management capabilities on the globalization of Finnish Born International and Born Global small and medium size enterprises (SMEs). The resulting knowledge from this study should prove valuable for academic researchers, political decision‐makers and business managers. Interestingly, the results of the study show that Born Globals had greater access to superior financial resources and stronger finance‐related managerial resources right from the start‐up phase than did Born Internationals. An interesting finding also focused on the fact that Born Globals were able to more quickly obtain global management‐related skills and industry‐specific business experience through the use of external business partners and venture capital representatives. These findings may partially explain the Born Globals' rapid expansion into world markets in comparison to Born Internationals, and also the failures of other types of enterprises in these same markets.

This article focuses on a paradigm of ten key steps for successful decision making in export marketing for the European business firm. These ten steps are: analyze market opportunity; assess product potential; establish market entry mode; make a firm commitment; allocate necessary resources; identify technical issues; develop strategic marketing plan; organize operational team; implement marketing strategy; and evaluate and control operations. Tables of basic what, who, and how questions help to guide the reader through the decision‐making process, leading to successful export marketing operations. The article provides a decision‐making paradigm that is useful to top‐level management personnel as well as export managers. This model has been developed by the authors based upon over 25 years of consulting work with European business firms.

For the past ten years the management literature has increasingly discussed the concept of learning organizations. Yet, more that a decade later, few organizations have figured out how to create the structures and processes necessary to assure continuous learning. This article purports that this problem can be attributed to the mental models of those leading contemporary organizations. Learning organizations quite simply cannot be created by those who either consciously or unconsciously operate under the traditional, mechanistic organizational paradigm. If leaders are to create authentic learning organizations, they must adapt a new way of viewing reality – a new paradigm or mental model. The authors suggest that the new science theories of chaos, complexity, and quantum mechanics provide the foundation for a new way of thinking about organizations. They demonstrate the relevance of these theories for those who wish to create learning organizations and present a new‐science‐based skill set that enables twenty‐first‐century leaders to move beyond organizational adaptation to proactive change and continuous learning.

The past two decades have been characterized as a time of merger mania. Unprecedented numbers of consolidations have occurred. Paradoxically these mergers have typically failed to achieve the targeted results. From a general point of view, the financial track record of recent mergers is, in fact, abysmal. It appears that the proposed efficiencies of scale often do not materialize. Yet, the merger frenzy continues. Globalization is a contributing factor. However, the cultural, political, psychological and geographical hurdles of cross‐cultural integration are enormous. This article explores the challenge of global integration by examining the much‐publicized DaimlerChrysler merger. The authors discuss innovative integration strategies and present a set of quantum skills that can be used to neutralize cross‐cultural barriers, thus enabling global leaders to create high performance organizations.

IDH1 encodes for isocitrate dehydrogenase which catalyzes the oxidative carboxylation of isocitrate to α-ketoglutarate. Mutations in IDH1 are heterozygous and affect only codon 132. IDH1 mutation results in global hypermethylation (G-CIMP phenotype) and is significantly associated with MGMT promoter methylation. Tumours exhibiting both TERT mutations and IDH1/2 mutations have been previously reported to be primarily of oligodendroglial histology. In this study, IDH1 mutation analysis was performed by direct sequencing using BigDye® Terminator v3.1 cycle sequencing kit and the ABI 3730 DNA analyser in a cohort of 135 lower grade glioma at first presentation, comprising 84 grade II and 51 grade III tumours of astrocytic, oligodendroglial and mixed histologies. The incidence of TERT mutation was also determined in 52 of these cases. MGMT methylation analysis was carried out using MS-PCR in 130 tumours. IDH1 and TERT mutation and MGMT methylation was correlated with overall survival for patients for whom data was available. The incidences of IDH1 R132H mutation, MGMT methylation and TERT mutation in the whole cohort were 57%, 55% and 36% respectively. IDH1 R132H mutations were significantly more common in grade II tumours compared to grade III tumours (67% vs 41%; p = 0.004). In contrast, there was no significant difference in the incidence of MGMT methylation or TERT mutation based on the histological grade (p = 0.855 and p = 0.559, respectively). In grade II tumours, IDH1 R132H mutations were present more frequently in oligodendroglioma (81%) and oligoastrocytoma (82%) compared to astrocytoma (51%) (p = 0.005). Similarly, MGMT was significantly methylated in grade II oligodendroglioma (69%) and oligoastrocytoma (75%) than astrocytoma (35%) (p = 0.001). There were no differences in the incidence of TERT mutation in histological subgroups. IDH1 R132H mutation was a positive prognostic indicator of overall survival independent of grade (p < 0.0001). However, presence of MGMT methylation was significantly associated with increased overall survival in grade III tumours only (p = 0.006).

The aim of this study was to examine the range of sensitivity of a panel of short-term cultures derived from different types of malignant childhood brain tumours including medulloblastoma, ependymoma and glioblastoma multiforme to three cytotoxic drugs, lomustine (CCNU), vincristine (VCR) and procarbazine (PCB). Sensitivity was assessed using a modification of the dimethylthiazolyl-2,5-diphenyl tetrazolium bromide (MTT) assay. Short-term cell lines derived from ependymomas were considerably more resistant to VCR than other types of childhood brain tumours, while cultures derived from supratentorial primitive neuroectodermal tumour (PNET) displayed marked sensitivity to both lomustine and VCR. Cultures from ependymomas, medulloblastoma and astrocytic gliomas had similar sensitivity to lomustine and PCB as cultures derived from adult malignant astrocytoma.

During the past decade, the environment for multinational corporations has been quite volatile, with numerous challenges for the firms operating in this arena. However, throughout this period there have emerged a number of executive leaders who have been recognized for their contributions to organizational excellence and leadership despite the environmental fluctuations. An analysis of the strategies followed by these executives reflects a limited number of distinct themes. The themes reflect a focus on the care of customers, product innovation, committed people and management leadership. The leadership strategies reflected by these corporate leaders focus on attention through vision, meaning through communication, trust through positioning and confidence through respect. This article focuses on the top multinational executives identified for each year during the decade of the 1990s, and the organizational excellence and leadership strategies that have been at the heart of the practices implemented and followed by these executives.

Focuses on two fundamental issues facing firms competing in the global arena, namely – how should executives responsible for success in international consumer markets allocate their scare marketing resources? And why, based on what methods, should they do this? Concentrating on global/pan‐European consumers in the northern European country of Finland, a quasi‐longitudinal “gap analysis” of US versus Japanese product and marketing efforts is undertaken. Using empirical evidence gathered every five years (from 1975 to 1995), this research examines which dimensions of marketing contribute most to specific consumers’ “purchase and use” preferences? And, where (which “gaps”) should organizations competing for global consumers concentrate their marketing efforts in order to be successful? It is argued that the method employed in this research can be utilized in any global marketing setting to identify the most promising areas for resource expenditures.

This article deals basically with the dynamic environment of today’s businesses. Despite all of the efforts a company puts forth to scan the environmental issues, crises can occur and have to be managed. We have first reviewed several crises in businesses during the recent times, to define and identify the nature of a crisis. Then the anatomy of a crisis is presented schematically. Finally, by recommending certain preventive measures and interventions, the article concludes that acknowledging a crisis and communicating with the stakeholders are as important as planning the prevention, diagnosis, and intervention to solve crisis situations.

Great numbers of small European and US firms are trying to penetrate foreign markets. Misunderstood requirements and poorly investigated information typically cause missed opportunities and failures. Without the ability to recognize and utilize competitive information in a timely manner, the small firm cannot succeed in the foreign market. Small firms that are preparing for and meeting international opportunities could benefit from the utilization of the foundation‐building strategies proposed in this paper. Small firms can use these strategies for information gathering and analysis in international and domestic business environments. The authors of this paper recommend 11 interrelated sets of processes or “foundation‐building strategies” which provide the necessary framework for readying the small firm for successful entry into the foreign marketplace. These sets of processes or “foundation‐building strategies” comprise the 11 most important planning steps for small business success in foreign markets. Small businesses must know the right questions to ask and must analyze the findings carefully in order to enter and operate successfully in foreign markets.

Management teambuilding within a multinational enterprise is greatly enhanced if the interactive style reflected by each person is considered. The blend of behavioral styles can affect the collective achievements of the entire management team, as well as the accomplishments of each member of the team. In this context, behavioral style is a pervasive and enduring set of interpersonal characteristics focussing on how one acts ‐ on what one says and does. As noted in this article, there are four behavioral styles ‐ Relater, Analyzer, Director, Socializer ‐ no one of which is necessarily better or worse than any other. Effective management leadership teams are made up of and value individuals who reflect each of the four styles. In fact, it can be stated that the most productive leadership team in the multinational firm will usually have a balance of individuals who reflect each behavioral style. The functional dynamics of the team are thereby affected by the styles of its members; and, of course, each of the styles has strengths as well as characteristic weaknesses. Each of the behavioral styles also has a typical back‐up style that is the mode of behavior shifted into at the time individuals experience high levels of stress. The concept of behavioral style and a consideration of its elements are useful in helping to understand oneself and the interpersonal behaviors of others. However, it is not enough just to understand one’s behavior or the behavior of others in the multinational management team; one should also seek to adapt the skills of style flex than can enable the parties to function in a comfort zone congruent with the situation. Style flex thereby provides a way of interacting and communicating within another person’s comfort zone without losing one’s integrity or naturalness of expression. In short, style flex is a key to interacting effectively in the multinational enterprise.

Proposes that customer service training processes should be studied as a multidimensional issue, recognizing an analytical dimension of tasks, technique, procedure, and system; a behavioral dimension concerned with attitudes, perceptions, and motivation; and an organizational learning dimension concerned with management styles, corporate culture, structure, and information flows. Explores in addition three elements necessary for effective customer service training implementation.

Presents a longitudinal study examining the attitudes of consumers towards the products and associated marketing practices of selected European countries versus the USA. Covers the period from 1975‐95, focusing on Germany, the UK and France. Concludes, in particular, that there is a significant difference in the attitudes of consumers with regard to the products and associate marketing practices of these European countries in comparison to the USA.

Major downsizing efforts are now taking place in multinational business firms in virtually every corner of the world, despite the economic recovery that seems to be occurring in many countries. Those multinational firms that have been turned around most effectively through downsizing activities have based their decision making on a foundation of creative excellence and strategic leadership. The keys to organizational excellence in the downsized workplace centres on four variables – care of customers, constant innovation, committed people, and management leadership. A research study conducted by the authors has focused on leadership strategies followed by managers directing successful downsizing efforts in multinational firms. These strategies are: attention through vision, meaning through communication; trust through positioning; and confidence through respect. Each of these downsizing leadership strategies is discussed with some depth of analysis.

This article focuses on the entry of Central and Eastern European republics into the mainstream of global markets, which are highly competitive. For the new republics of the former East Bloc to gain significant market shares in global markets, their products and the marketing of those products must achieve world class standards in every respect. Using empirical evidence gathered from Finnish consumers from 1975 to 1990, this research addresses several fundamental questions including: How are products and marketing practices from the former USSR (and by inference the new republics) perceived by Finnish consumers? How have such perceptions changed over time, and how do they compare to their perceptions of Western competitors? Which marketing dimensions contribute most to product preferences of Finnish consumers, with respect to international alternatives? And finally, where should the new republics concentrate their future marketing efforts in order to improve their competitiveness? Results indicate that Finnish preferences are influenced most by “central product attributes” and “marketing practices satisfiers.”

Defines a leader in total quality management as a person who inspires, by appropriate means, sufficient competence to influence a group of individuals to become willing followers in the achievement of organizational goals. Reports research identifying the keys of successful leadership in quality management: (1) attention through vision, (2) meaning through communication, (3) trust through positioning, and (4) confidence through respect. Describes characteristics of leaders in quality management: they have an agenda and an unparalleled concern with outcomes; a mastery of communication; they are predictable and make their positions known; they necessarily have a positive self‐regard, and a commitment to bring out the best in others.

Using a cell line derived from the VM spontaneous murine astrocytoma, a reliable in vitro-in vivo model of human malignant glioma has been developed. In this paper we examine the effects of cytotoxic drugs with known activity against other animal brain tumour models and human disease on the in vivo VM model. The drugs BCNU, CCNU and vincristine produced significant volume reduction in tumours growing at a subcutaneous location in syngeneic animals. Procarbazine was ineffective. Similarly, BCNU, CCNU and vincristine produced small but statistically significant increases in survival of VM mice bearing the intracerebral tumour, but procarbazine was again ineffective. The modest, but significant, response of the VM model to the nitrosoureas mimics the human situation more closely than previously described animal models.

INTRODUCTION: Current treatments for glioblastoma multiforme (GBM) do not yield large benefits to patients and hence the repurposing of existing medications is a potentially valuable treatment option. Metformin and phenformin have been used for >60 years for the treatment of type 2 diabetes and recent research indicates that metformin may be associated with reduced risk of developing cancer. Sorafenib is a multikinase inhibitor used in the treatment of kidney, liver and thyroid cancer. A synergistic effect of metformin and sorafenib has been identified in some tumour types. METHOD: The IC50 values for metformin and phenformin were evaluated using sulforhodamine B colorimetric assay for cytotoxicity in 13 GBM-derived short-term cell cultures and the established GBM cell line U251MG. The p53 mutation status had been determined in all cultures. In 4 cultures, the cytotoxic effects of sorafenib alone and in combination with metformin were determined using non-linear regression to fit a 4-parameter hill equation. Synergy was determined by calculating combination index (Chou-Talalay) method. RESULTS: For metformin the IC50 values ranged from 4.97(±1.36)mM to 72.23(± 3.16)mM compared to phenformin with an IC50 range of 0.41(±0.299951)mM to 7.32(±0.82)mM. For both drugs, response was associated with p53 mutation status (p = 0.0152, p = 0.0140). The IC50 range for Sorafenib was 5.5(±0.28)uM to 9.4(±0.69)uM. Combining metformin and sorafenib resulted in synergy in 3 cases and an additive effect in 1 culture. CONCLUSION: Metformin and phenformin have potential as treatment for GBM. The synergistic interaction between metformin and sorafenib indicates that these drugs in combination have a potential to be used for GBM therapy.

Background: Chemoresistance is the major obstacle for the success of cancer treatment. The advanced breast cancer (BC) is commonly pan-resistant to different anticancer drugs. BC contains a small population of cancer stem cells (CSCs). CSCs express stem cell markers (CD24low/CD44high, ALDH+, CD133+) and are resistant to a wide range of anticancer drugs. Therefore, CSCs may be responsible for the pan-chemoresistance in advanced BC. We have recently developed several acquired chemoresistant BC cell lines. In this study, we investigated CSC traits in these cell lines and examined the cross-resistance of these cell lines to a panel of anticancer drugs. Disulfiram (DS), an antialcoholism drug, shows high cytotoxicity in several different types of cancer cell lines in vitro. It also targets CSCs and reverses pan-chemoresistance. However, the clinical application of DS in cancer treatment is limited by its very short half-life in the bloodstream. In order to increase the bio-stability of DS in the bloodstream, we recently developed a pluronic micelle-encapsulated DS (PM-DS). In this study, we examined the cytotoxicity of a newly developed (PM-DS) in the resistant cell lines. The effect of PM-DS on CSC traits in the resistant BC cell lines was also examined. Cell lines and Methods: Cell lines: MDA-MB-231, MCF7 and T47D and acquired resistant BC cell lines [gemcitabine (MDA-MB-231GEM100), 5-fluouracil (MCF7FU10) and doxorubicin (T47DDOX100nM)]; Methodologies: MTT assay, Western blot, CSC markers detection (ALDH, CD24low/CD44high, CD133), embryonic stem cell markers detection (Nanog, Sox2, Oct 4). Results: The resistant cell lines are highly cross-resistant to 6 conventional anticancer drugs e.g doxorubicin, gemcitabine, docetaxel, cisplatin, 5-fluouracil and vincristine. In comparison with the parental cells, the resistant cell lines have significantly longer doubling time. Significantly higher population of resistant cells expresses high levels of CSC markers e.g. ALDH+, CD24low/CD44high, and CD133+ and embryonic stem cell markers (OCT4, Sox2 and Nanog). DS was successfully encapsulated in pluronic micelles with a high entrapment efficiency of about 90% and our in vitro release studies showed that DS was slowly released from the micelles. Our formulation PM-DS has a relatively small size of about 200nm with high drug loading content (90μgDS/1mgPM). PM-DS was highly toxic to chemoresistant cell lines. It also targeted CSC population and enhanced cytotoxicity of anticancer drugs in the resistant cell lines. Conclusions: The acquired resistant BC cell lines are highly cross-resistant to 6 different kinds of anticancer drugs. CSCs may be responsible for the cross-chemoresistance. PM-DS targets CSC population and reverses the acquired pan-chemoresistance in acquired resistant BC cell lines. Key words: Disulfiram, micelles, breast cancer, stem-like cells. Citation Format: EREBI P. TAWARI, Peng Liu, Zhipeng Wang, Vinodh Kannappan, Christopher Mcconville, Angel Armesilla, John Darling, Juan Irache, Krassimira Yoncheva, Weiguang Wang, Petar Petrov. Pluronic micelle-encapsulated Disulfiram targets cancer stem-like cells and reverses pan-resistance in acquired resistant breast cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4067. doi:10.1158/1538-7445.AM2015-4067

A cystic pleomorphic adenoma of the posterior mandibular alveolar ridge of a 73-year-old white man is reported. This tumor presented considerable diagnostic problems which may have consequences in treatment in similar cases.

INTRODUCTION: Brain metastases pose many challenges in terms of prognosis, complexity of tumour biology and tumour evolution. Here, we have analysed epigenetically deregulated candidate metastatic suppressor genes in metastatic brain tumours that evolved from primary breast tumours. Identified genes may be useful as prognostic markers that could be used to predict the risk of brain metastases from breast tumours or provide novel therapeutic targets. METHOD: We screened 80 genes that are epigenetically deregulated in cancer but not frequently methylated in primary breast tumours. These genes were identified by interrogating The Cancer Genome Atlas and a broad literature review. We analysed these genes for promoter methylation in metastatic brain tumours and their associated primary breast tumours. We carried out tumorigenicity assays to investigate the role of these genes in invasion and metastasis. RESULTS: We identified five genes (BNC1, CCDC8, L3MBTL1, GALNT9 and mir127), which are infrequently methylated in primary breast tumours and frequently methylated in brain metastases. In vitro migration and invasion assays indicate that these genes contribute to the metastatic potential of breast cancer cell lines. CONCLUSION: We have identified a number of genes that may contribute to breast to brain metastasis. Two of which (BNC1, GALNT9) are methylated and silenced specifically in the brain metastasis, indicating an event that has occurred after the tumour has disseminated. Another three genes (CCDC8, L3MBTL1 and mir127) are methylated in primary tumours that metastasised to the brain indicating a potential early role in metastasis. These findings may help develop prognostic and therapeutic tools.

The relative resistance of malignant glioma to chemotherapy makes the identification of new cytotoxic drugs critically important. The use of short-term cultures derived from these tumors to screen drugs at doses that can be attained within human intracranial tumors provides a model system that should be capable of identifying effective drugs suitable for clinical evaluation. The sensitivity of a panel of short-term cultures derived from 22 malignant astrocytoma and four malignant oligodendroglioma was assessed to aziridinylbenzoquinone (AZQ), etoposide and doxorubicin (DOX) using a [(35)S] methione uptake assay. The ID(50) of each culture was compared to the levels of drug which could be achieved in the tumor using standard doses. There was marked heterogeneity between cultures in response to each drug. Whilst there was no evidence that cultures derived from grade III astrocytoma were more sensitive to any of the drugs than cultures derived from grade IV astrocytoma, cultures derived from oligodendroglioma tended to be more sensitive to the alkylating agent AZQ, but not to either of the other drugs. The sensitivity of these short-term cultures at concentrations that can be achieved in situ corresponded well with the clinical efficacy of AZQ and etoposide. Although DOX appeared to be toxic to human gliomas cells in vitro, its limited penetration into the intact brain would seem to preclude its use i.v., but it is likely to be effective if local drug delivery techniques could be employed. The study suggests that short-term cultures derived from malignant glioma should be used to screen investigational agents for potential clinical efficacy.

s from Neuro-Oncology are provided here courtesy of Society for Neuro-Oncology and Duke University Press.

Background Although the existence of cancer stem cells (CSCs) is still debatable, it is widely accepted that the cancer cells expressing CSC markers are highly resistant to chemo-radiation therapy. Up to 60% of locally advanced solid tumours exhibit hypoxia. Accumulated evidence demonstrates that hypoxia induces epithelial-to-mesenchymal transition and CSCs phenotypes in cancer cells. The pathways between hypoxia and CSCs are still largely in the dark. NFκB is a transcription factor being involved in chemo-radiation resistance. Activation of NFκB by hypoxia in a wide range of cells in inflammatory conditions has been identified for more than a decade. Recently, emerging evidence demonstrates that NFκB is also a key factor maintaining the stemness in breast CSCs. Therefore NFκB may mediate and be involved in hypoxia-induced CSCs phenotypes. Our previous studies show that disulfiram (DS), an anti-alcoholism drug, reverses chemoresistance of a variety of anticancer drugs in several types of cancer. In this study, we used an in vitro model to investigate the relationship between hypoxia-NFκB pathway and CSC phenotypes in two breast cancer cell lines (T47D and MCF7). The effect of DS on hypoxia-NFκB pathway and the cytotoxicity of conventional anticancer drugs (paclitaxel, gemcitabine and doxorubicin) in CSCs were also observed. RESULTS A huge proportion of hypoxic cells were detected in mammospheres. NFκB activation (AKT phosphorylation, IκBα degradation, p65 nuclear translocation, phosphorylation and NFκB transactivation) was detected in the CSCs. The percentage of breast cancer cells with CSC markers (ALDH+, CD24low/CD44high) is significantly increased in the NFκB p65 transfected cell lines. The transfected cell lines are highly resistant to doxorubicin, paclitaxel and gemcitabine. In contrast, breast CSCs do not show any resistance to DS. The cytotoxicity of DS is copper-dependent and cancer specific with no cytotoxicity in normal cell lines. CI-isobologram analysis demonstrates that DS significantly enhances cytotoxicity of conventional anticancer drugs (doxorubicin: 8 - 11-fold; gemcitabine: 1.2 - 23.5-fold; paclitaxel: 4 - 10-fold). DS simultaneously activates ROS-JNK pathway and blocks p65 nuclear translocation. The effect of DS on stemness of breast cancer cell lines is confirmed by its elimination of ALDH+VE CD24Low/CD44High population in mammospheres. To prolong the half-life of DS in bloodstream, we recently developed a liposome encapsulated DS. The liposomal DS shows very strong anticancer activity in an animal cancer model. CONCLUSIONS Our results demonstrate that hypoxia-NFκB pathway is involved in maintaining the stemness and chemoresistance in breast CSCs. DS is highly cytotoxic to breast CSCs and enhances cytotoxicity of conventional anticancer drugs. This may be caused by simultaneous induction of ROS and inhibition of NFkB pathway. Citation Format: Peng Liu, Sarah Brown, Vinodh Kannappan, Angel L. Armesilla, John L. Darling, Weiguang Wang. Manipulation of hypoxia-NFκB pathway to target breast cancer stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 227. doi:10.1158/1538-7445.AM2013-227 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Summary Hypothyroidism and Sweet's syndrome occurring together were diagnosed in a 33 woman. This association is uncommon, but may be underdiagnosed and underreported.

Many anticancer drugs induce reactive oxygen species (ROS) in cancer cells. High ROS will activate JNK pathway and induce cancer cell apoptosis. Meanwhile, ROS also strongly induces NFκB activity which triggers expression of many antiapoptotic factors and inhibits ROS/JNK pathway therefore antagonises anticancer drug-induced programmed cell death. The fate of anticancer agent-treated cancer cells is highly determined by the cross-talk between NFκB and JNK pathways. In this study, we demonstrated that a clinically used anti-alcoholism drug, disulfiram (DS), simultaneously activated ROS-JNK pathway and inhibited NFκB. DS was cytotoxic to breast cancer cell lines in vitro. As a divalent metal ion chelator, the cytotoxic effect of DS on breast cancer cell lines was highly copper-dependent. In the medium containing physiological concentration of copper (Cu, 1µM) the IC50 concentrations of DS to breast cancer cell lines were 200 - 500nM. The chemosensitizing effect of DS on 3 anti-breast-cancer agents, gemecitabine (dFdC), doxorubicine (DOX) and paclitaxel (PAC), was determined in 3 breast cancer cell lines (MCF-7, MDA-MB-231 and T47D). In combination with DS/Cu, the cytotoxicity of dFdC, DOX and PAC was significantly enhanced (Table 1. DOX: 8 - 11-fold; dFdC: 1.2 - 4-fold; PAC: 4 - 10-fold). DS also reversed dFdC resistance in acquired dFdC resistant cell lines. CI-isobologram analysis demonstrated synergistic effect between DS and anticancer drugs. Flow cytometric analysis showed DS enhanced anticancer drug-induced apoptosis. DS enhanced anticancer drug-induced ROS activity. The phosphorylated c-Jun and JNK protein in breast cancer cell lines was significantly induced by exposure of cancer cells to DS/Cu complex. Transfection of NFκB p50 and p65 induced dFdC resistance in MCF7 cells. DS inhibited drug-induced IκBα degradation and NFκB activation. Our data suggested that DS may be developed as a chemosensitizer for BC chemotherapy. *Equal contributionTable 1.DS/Cu sensitised cytotoxicity of anticancer drugs to breast cancer cell linesTreatmentsDrug: DS/CuMCF7MDA-MB-231T47DDOX (nM) 440.5 (16.2)178.5 (11.9)160.0 (5.5)DOX + DS/Cu1:540.3 (9.3)22.0 (2.0)21.5 (3.1)dFdC (nM) 22.1 (3.4)12.3 (2.2)35.0 (4.3)dFdC + DS/Cu1:104.9 (0.5)11.3 (1.2)12.4 (0.7)PAC (nM) 4.3 (1.4)9.3 (0.7)2.6 (0.3)PAC + DS/Cu1:62.50.4 (0.1)0.6 (0.02)0.7 (0.1) Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5410.

Cell proliferation was assessed in brain tumours using the monoclonal antibody Ki67 which recognizes a nuclear antigen expressed by proliferating cells. Using a novel stereotactic biopsy procedure, serial 1 cm biopsies were taken along a trajectory through six malignant brain tumours. Specimens were also obtained from 10 other brain tumours during conventional surgery. The percentage of Ki67 positive cells was determined as a fraction of the total number of tumour cells present. The Ki67 index for anaplastic astrocytomas and glioblastomas was significantly higher (Ki67 index range 11-18%) than that for benign or low grade tumours. Significant variation in proliferation was measured along the biopsy track through individual tumours (e.g. 0-12.3%) which correlated well with histological appearance. The Ki67 indices of normal brain were very low. In general the Ki67 indices increased with increasing histological grade and also appear to be a useful indicator of the active tumour volume and margin. This method provides spatial information about tumour proliferation which may be used to decide between different treatments and relate to prognosis.

The issue of advertising among professional groups is currently drawing a great deal of attention, with several Supreme Court rulings gradually serving to loosen the controls traditionally placed on this activity. The present study focuses on the attitudes held by accountants, attorneys, dentists, and physicians regarding advertising. The data in this research study lead to the conclusion that there is a significant difference in the attitudes of these four professional groups with regard to the various issues surrounding the advertising of their fees and services. In general, the data seem to reflect a negative perception on the part of all four groups of respondents with regard to the issue of advertising. However, accountants and attorneys are more positive toward the potential role that advertising can play in their professions.