Circulating tumour cells, their role in metastasis and their clinical utility in lung cancer

Circulating tumour cells (CTCs) have attracted much recent interest in cancer research as a potential biomarker and as a means of studying the process of metastasis. It has long been understood that metastasis is a hallmark of malignancy, and conceptual theories on the basis of metastasis from the nineteenth century foretold the existence of a tumour "seed" which is capable of establishing discrete tumours in the "soil" of distant organs. This prescient "seed and soil" hypothesis accurately predicted the existence of CTCs; microscopic tumour fragments in the blood, at least some of which are capable of forming metastases. However, it is only in recent years that reliable, reproducible methods of CTC detection and analysis have been developed. To date, the majority of studies have employed the CellSearch™ system (Veridex LLC), which is an immunomagnetic purification method. Other promising techniques include microfluidic filters, isolation of tumour cells by size using microporous polycarbonate filters and flow cytometry-based approaches. While many challenges still exist, the detection of CTCs in blood is becoming increasingly feasible, giving rise to some tantalizing questions about the use of CTCs as a potential biomarker. CTC enumeration has been used to guide prognosis in patients with metastatic disease, and to act as a surrogate marker for disease response during therapy. Other possible uses for CTC detection include prognostication in early stage patients, identifying patients requiring adjuvant therapy, or in surveillance, for the detection of relapsing disease. Another exciting possible use for CTC detection assays is the molecular and genetic characterization of CTCs to act as a "liquid biopsy" representative of the primary tumour. Indeed it has already been demonstrated that it is possible to detect HER2, KRAS and EGFR mutation status in breast, colon and lung cancer CTCs respectively. In the course of this review, we shall discuss the biology of CTCs and their role in metastagenesis, the most commonly used techniques for their detection and the evidence to date of their clinical utility, with particular reference to lung cancer.

The cancer stem-cell hypothesis : its emerging role in lung cancer biology and its relevance for future therapy

The cancer stem-cell (CSC) hypothesis suggests that there is a small subset of cancer cells that are responsible for tumor initiation and growth, possessing properties such as indefinite self-renewal, slow replication, intrinsic resistance to chemotherapy and radiotherapy, and an ability to give rise to differentiated progeny. Through the use of xenotransplantation assays, putative CSCs have been identified in many cancers, often identified by markers usually expressed in normal stem cells. This is also the case in lung cancer, and the accumulated data on side population cells, CD133, CD166, CD44 and ALDH1 are beginning to clarify the true phenotype of the lung cancer stem cell. Furthermore, it is now clear that many of the pathways of normal stem cells, which guide cellular proliferation, differentiation, and apoptosis are also prominent in CSCs; the Hedgehog (Hh), Notch, and Wnt signaling pathways being notable examples. The CSC hypothesis suggests that there is a small reservoir of cells within the tumor, which are resistant to many standard therapies, and can give rise to new tumors in the form of metastases or relapses after apparent tumor regression. Therapeutic interventions that target CSC pathways are still in their infancy and clinical data of their efficacy remain limited. However Smoothened inhibitors, gamma-secretase inhibitors, anti-DLL4 antagonists, Wnt antagonists, and CBP/β-catenin inhibitors have all shown promising anticancer effects in early studies. The evidence to support the emerging picture of a lung cancer CSC phenotype and the development of novel therapeutic strategies to target CSCs are described in this review.

The role of mindfulness in an extended TPB framework to understand drivers’ speeding intentions in school zones.

Many researchers have demonstrated the applicability of the Theory of Planned Behaviour (TPB) in predicting both intention to speed and actual speeding behaviour. However, there remain shortcomings in the explanatory power of the TPB, with research suggesting that even when drivers had reported an intention to not speed approximately 25% of drivers report behaviour that does not align with their intentions (i.e., they engaged in speeding, Elliott & Armitage, 2006). This research explores the role of a novel and promising construct, mindfulness, in enhancing the explanatory utility of the TPB for the understanding of drivers’ speeding behaviour in school zones. Mindfulness is a concept which has been widely used in studies of consciousness, but has recently been applied to the understanding of behaviour in other areas, including clinical psychology, physical activity, education and business. It has been suggested that mindfulness can also be applied to road safety, though its application within this context currently remains limited. This study was based on an e-survey of the general driving public (N=240). Overall, the results identified mindfulness as a construct which may aid understanding of the relationship between drivers’ intentions and behaviour. Theoretically, the findings may have implications in terms of identifying mindfulness as an additional explanatory construct within a TPB framework. In road safety practice, the findings suggest that efficacious countermeasures around school zones may be those that function to heighten drivers’ mindfulness, such as flashing lights and physical speed reduction measures.

Chinese fashion designers in Shanghai : identifying a fresh perspective about their role in the world order of fashion

Shanghai possesses an apt legacy, once referred to as “Paris of the East”. Municipal aspirations for Shanghai to assume a position among the great fashion cities of the world have been integrated in the recent re-shaping of this modern city into a role model for Chinese creative enterprise yet China is still known primarily as centre of clothing production. Increasingly however, “Made in China” is being replaced by “Created in China” drawing attention to two distinct consumer markets for Chinese designers. Fashion designers who have entered the global fashion system for education or by showing their collections have generally adopted a design aesthetic that aligns with Western markets, allowing little competitive advantage. In contrast, Chinese designers who rest their attention on the domestic Chinese market find a disparate, highly competitive marketplace. The pillars of authenticity that for foreign fashion brands extend far into their cultural and creative histories, often for many decades in the case of Louis Vuitton, Hermes and Christian Dior do not yet exist in China in this era of rapid globalisation. Here, the cultural bedrock allows these same pillars to extend only thirty years or so into the past reaching the moments when Deng Xiaoping granted China’s creative entrepreneurs passage. To this end, interviews with fashion designers in Shanghai have been undertaken during the last twelve months for a PhD dissertation. Production of culture theory has been used to identify working methods, practices of production and the social and cultural milieu necessary for designers to achieve viability. Preliminary findings indicate that some fashion designers have adopted an as-yet unexplored strategy of business and brand development with a distinct Chinese aesthetic at its core, in contrast to the clichéd cultural iconography often viewed by Western viewers as representative of Chinese creativity.

Chinese fashion designers in Shanghai : a new perspective about their role in the construction of a fashion city

Shanghai possesses an apt legacy, once referred to as ‘Paris of the East’. Municipal aspirations for Shanghai to assume a position among the great fashion cities of the world have been integrated in the recent re-shaping of this modern city into a role model for Chinese creative enterprise yet China is still known primarily as centre of clothing production. Increasingly however, ‘Made in China’ is being replaced by ‘Created in China’ drawing attention to two distinct consumer markets for Chinese designers. Fashion designers who have entered the global fashion system for education or by showing their collections have generally adopted a design aesthetic that aligns with Western markets, allowing little competitive advantage. In contrast, Chinese designers who rest their attention on the domestic Chinese market find a disparate, highly competitive marketplace. The pillars of authenticity that for foreign fashion brands extend far into their cultural and creative histories, often for many decades in the case of Louis Vuitton, Hermes and Christian Dior do not yet exist in China in this era of rapid globalisation. Here, the cultural bedrock allows these same pillars to extend only thirty years or so into the past reaching the moments when Deng Xiaoping granted China’s creative entrepreneurs passage. To this end, interviews with fashion designers in Shanghai have been undertaken during the last twelve months for a PhD dissertation. Production of culture theory has been used to identify working methods, practices of production and the social and cultural milieu necessary for designers to achieve viability. Preliminary findings indicate that some fashion designers have adopted an as-yet unexplored strategy of business and brand development with a distinct Chinese aesthetic at its core, in contrast to the clichéd cultural iconography often viewed by Western viewers as representative of Chinese creativity. The development of this aesthetic is similar to the development of the Scandinavian design ethos that emerged during the 1950s.

The role of Ureaplasma urealyticum in adverse pregnancy outcome

We investigated Ureaplasma urealyticum genital tract colonisation rates in an Australian population to determine whether colonisation was associated with adverse pregnancy outcome. Women attending an antenatal clinic were evaluated for lower genital tract colonisation at their first antenatal visit (162 women) and at 28 weeks gestation (120 women). Placentas from 92 women were cultured. U. urealyticum was the predominant isolate from the lower (57.4%) and upper (17.4%) genital tract in this population of pregnant women. U. urealyticum was a persistent coloniser during mid-trimester of pregnancy (in 88% of women colonised) whereas M. hominis, G. vaginalis, and Group B streptococcus were present as transient flora of the lower genital tract. Lower genital tract colonisation during pregnancy was not directly associated with adverse pregnancy outcome. However preterm delivery in afebrile, asymptomatic women, could possibly be associated with chorioamnionitis (four of 16 preterm births). Screening of women with a history of preterm birth may prevent upper genital tract infections and preterm delivery.

Overdue choices : how information and role in decision-making influence women's preferences for induction for prolonged pregnancy

Background: Enabling women to make informed decisions is a crucial component of consumer-focused maternity care. Current evidence suggests that health care practitioners’ communication of care options may not facilitate patient involvement in decision-making. The aim of this study was to investigate the effect of specific variations in health caregiver communication on women’s preferences for induction of labor for prolonged pregnancy. Methods: A convenience sample of 595 female participants read a hypothetical scenario in which an obstetrician discusses induction of labor with a pregnant woman. Information provided on induction and the degree of encouragement for the woman’s involvement in decision-making was manipulated to create four experimental conditions. Participants indicated preference with respect to induction, their perceptions of the quality of information received, and other potential moderating factors. Results: Participants who received information that was directive in favor of medical intervention were significantly more likely to prefer induction than those given nondirective information. No effect of level of involvement in decision-making was found. Participants’ general trust in doctors moderated the relationship between health caregiver communication and preferences for induction, such that the influence of information provided on preferences for induction differed across levels of involvement in decision-making for women with a low trust in doctors, but not for those with high trust. Many women were not aware of the level of information required to make an informed decision. Conclusions: Our findings highlight the potential value of strategies such as patient decision aids and health care professional education to improve the quality of information available to women and their capacity for informed decision-making during pregnancy and birth. (BIRTH 39:3 September 2012)

Designing the future in wound care : the role of the nurse practitioner

The nurse practitioner is emerging as a new level and type of health care. Increasing specialisation and advanced educational opportunities in nursing and the inequality in access to health care for sectors of the community have established the conditions under which the nurse practitioner movement has strengthened both nationally and internationally. The boundaries of responsibility for nurses are changing, not only because of increased demands but also because nurses have demonstrated their competence in varied extended and expanded practice roles. The nurse practitioner role reflects the continuing development of the nursing profession and substantially extends the career path for clinical nurses. This paper describes an aspect of a large-scale investigation into the feasibility of the role of the nurse practitioner in the Australian Capital Territory (ACT) health care system. The paper reports on the trial of practice for a wound care nurse practitioner model in a tertiary institution. In the trial the wound care nurse practitioner worked in an extended practice role for 10 months. The nurse practitioner practice was supported, monitored and mentored by a clinical support team. Data were collected relating to a range of outcomes including definition of the scope of practice for the model, description of patient demographics and outcomes and the efficacy of the nurse practitioner service. The findings informed the development of clinical protocols that define the scope of practice and the parameters of the wound care nurse practitioner model and provided information on the efficacy of this model of health care for the tertiary care environment. The findings further suggest that this model brings expert wound care and case management to an at-risk patient population. Recommendations are made relating to ongoing research into the role of the wound care nurse practitioner model in the ACT health care system.

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.

Getting the point : the role of gesture in managing intersubjectivity in a design activity

This paper illustrates the complexity of pointing as it is employed in a design workshop. Using the method of interaction analysis, we argue that pointing is not merely employed to index, locate, or fix reference to an object. It also constitutes a practice for reestablishing intersubjectivity and solving interactional trouble such as misunderstandings or disagreements by virtue of enlisting something as part of the participants’ shared experience. We use this analysis to discuss implications for how such practices might be supported with computer mediation, arguing for a “bricolage” approach to systems development that emphasizes the provision of resources for users to collaboratively negotiate the accomplishment of intersubjectivity ra- ther than systems that try to support pointing as a specific gestural action.

The role of knowledge intermediaries in developing firm learning capabilities

Regional innovation systems (RISs) literature has emphasized the critical role of interactive learning and knowledge exchange amongst firms and a variety of spatially connected innovation institutions as the foundation of regional innovation. Knowledge intermediaries have been analysed in terms of the technology-transaction services they provide firms and/or knowledge producers such as universities and therefore the role they play in facilitating interaction within the RIS. However, innovation also depends on the capability of the firm to learn. Some studies have suggested that intermediaries also play a role in that regard as participation in intermediary knowledge transfer programmes can contribute to the development of firm capabilities for problem-solving and learning. Our research is based on two case study intermediary programmes involving interviews with facilitators and participants. Our data show that knowledge intermediaries affect organizational learning capabilities by impacting on firms' network relationships, internal and external communication channels and internal learning processes which in turn affect the ability to interpret and use knowledge within the firm. This suggests that the role of knowledge intermediaries might be greater than facilitating interactions in the innovation system, as knowledge intermediation may affect the ability of firms to learn and absorb knowledge from their environment.

Green crime and the role of environmental courts

Environmental issues continue to capture international headlines and remain the subject of intense intellectual, political and public debate. As a result, environmental law is widely recognised as the fastest growing area of international jurisprudence. This, combined with the rapid expansion of environmental agreements and policies, has created a burgeoning landscape of administrative, regulatory and judicial regimes. Emerging from these developments are increases in environmental offences, and more recently environmental crimes. The judicial processing of environmental or ‘green’ crimes is rapidly developing across many jurisdictions. Since 1979, Australia has played a lead role in criminal justice processing of environment offences through the New South Wales Land and Environment Court (NSW LEC). This article draws on case data, observations and interviews with court personnel, to examine the ways in which environmental justice is now administered through the existing court structures, and how it has changed since the Court’s inception.

Spatial modelling of population health screening : the role of accessibility in predicting expected patient flows

This paper describes a generalised linear mixed model (GLMM) approach for understanding spatial patterns of participation in population health screening, in the presence of multiple screening facilities. The models presented have dual focus, namely the prediction of expected patient flows from regions to services and relative rates of participation by region- service combination, with both outputs having meaningful implications for the monitoring of current service uptake and provision. The novelty of this paper lies with the former focus, and an approach for distributing expected participation by region based on proximity to services is proposed. The modelling of relative rates of participation is achieved through the combination of different random effects, as a means of assigning excess participation to different sources. The methodology is applied to participation data collected from a government-funded mammography program in Brisbane, Australia.

Cellular model systems to study the tumor biological role of kallikrein-related peptidases in ovarian and prostate cancer

Since the identification of the gene family of kallikrein related peptidases (KLKs), their function has been robustly studied at the biochemical level. In vitro biochemical studies have shown that KLK proteases are involved in a number of extracellular processes that initiate intracellular signaling pathways by hydrolysis, as reviewed in Chapters 8, 9, and 15, Volume 1. These events have been associated with more invasive phenotypes of ovarian, prostate, and other cancers. Concomitantly, aberrant expression of KLKs has been associated with poor prognosis of patients with ovarian and prostate cancer (Borgoño and Diamandis, 2004; Clements et al., 2004; Yousef and Diamandis, 2009), with prostate-specific antigen (PSA, KLK3) being a long standing, clinically employed biomarker for prostate cancer (Lilja et al., 2008). Data generated from patient samples in clinical studies, alongwith biochemical activity, suggests that KLKs function in the development and progression of these diseases. To bridge the gap between their function at the molecular level and the clinical need for efficacious treatment and prognostic biomarkers, functional assessment at the in vitro cellular level, using various culture models, is increasing, particularly in a three-dimensional (3D) context (Abbott, 2003; Bissell and Radisky, 2001; Pampaloni et al., 2007; Yamada and Cukierman, 2007).

Exo1 plays a major role in DNA end resection in humans and influences double-strand break repair and damage signaling decisions

The resection of DNA double-strand breaks (DSBs) to generate ssDNA tails is a pivotal event in the cellular response to these breaks. In the two-step model of resection, primarily elucidated in yeast, initial resection by Mre11-CtIP is followed by extensive resection by two distinct pathways involving Exo1 or BLM/WRN-Dna2. However, resection pathways and their exact contributions in humans in vivo are not as clearly worked out as in yeast. Here, we examined the contribution of Exo1 to DNA end resection in humans in vivo in response to ionizing radiation (IR) and its relationship with other resection pathways (Mre11-CtIP or BLM/WRN). We find that Exo1 plays a predominant role in resection in human cells along with an alternate pathway dependent on WRN. While Mre11 and CtIP stimulate resection in human cells, they are not absolutely required for this process and Exo1 can function in resection even in the absence of Mre11-CtIP. Interestingly, the recruitment of Exo1 to DNA breaks appears to be inhibited by the NHEJ protein Ku80, and the higher level of resection that occurs upon siRNA-mediated depletion of Ku80 is dependent on Exo1. In addition, Exo1 may be regulated by 53BP1 and Brca1, and the restoration of resection in BRCA1-deficient cells upon depletion of 53BP1 is dependent on Exo1. Finally, we find that Exo1-mediated resection facilitates a transition from ATM- to ATR-mediated cell cycle checkpoint signaling. Our results identify Exo1 as a key mediator of DNA end resection and DSB repair and damage signaling decisions in human cells.