Acquisition of estrogen independence and antiestrogen resistance in breast cancer : association with the invasive and metastatic phenotype

A significant percentage of human breast cancer (HBC) is dependent upon the ovarian hormone estrogen for its onset and progression. The presence or lack of estrogen receptors (ERs) in human breast cancer is an important determinant both of prognosis and of choice of treatment - a poorer prognosis being associated with ER–ve disease. Cell lines established from human breast cancer provide models for breast cancer in various stages of progression (Engel & Young 1978). When grown as tumors in athymic nude mice, these lines represent the major in vivo experimental model for HBC studies (Brünner et al 1987). The ease of both in vitro and in vivo maintenance, the human derivation of the tissue, and the similarities in plasma estrogen levels between ovariectomized nude mice and postmenopausal women (Seibert et al. 1983, Brünner et al. 1986), make the growth of human breast cancer cell lines in nude mice an attractive...

The biology of breast tumor progression : acquisition of hormone independence and resistance to cytotoxic drugs

Many breast tumors appear to follow a predictable clinical pattern, being initially responsive to endocrine therapy and to cytotoxic chemotherapy but ultimately exhibiting a phenotype resistant to both modalities. Using the MCF-7 human breast cancer cell line as an example of an 'early' phenotype (estrogen and progesterone receptor positive, steroid responsive, low metastatic potential), we have isolated and characterized a series of hormone-independent but hormone-responsive variants (MIII and MCF7/LCC1). However, these variants remain responsive to both antiestrogens and cytotoxic drugs (methotrexate and colchicine). MIII and MCF7/LCCl cells appear to mimic some of the critical aspects of the early progression to a more aggressive phenotype. An examination of the phenotype of these cells suggests that some hormone-independent breast cancer cells are derived from hormone-dependent parental cells. The development of a hormone-independent phenotype can arise independently of acquisition of a cytotoxic drug resistant phenotype.

Epithelial-mesenchymal transition and mesenchymal-epithelial transition are essential for the acquisition of stem cell properties in hTERT-immortalised oral epithelial cells

BACKGROUND INFORMATION: Evidence has shown that mesenchymal-epithelial transition (MET) and epithelial-mesenchymal transition (EMT) are linked to stem cell properties. We currently lack a model showing how the occurrence of MET and EMT in immortalised cells influences the maintenance of stem cell properties. Thus, we established a project aiming to investigate the roles of EMT and MET in the acquisition of stem cell properties in immortalised oral epithelial cells. RESULTS: In this study, a retroviral transfection vector (pLXSN-hTERT) was used to immortalise oral epithelial cells by insertion of the hTERT gene (hTERT(+)-oral mucosal epithelial cell line [OME]). The protein and RNA expression of EMT transcriptional factors (Snail, Slug and Twist), their downstream markers (E-cadherin and N-cadherin) and embryonic stem cell markers (OCT4, Nanog and Sox2) were studied by reverse transcription PCR and Western blots in these cells. Some EMT markers were detected at both mRNA and protein levels. Adipocytes and bone cells were noted in the multi-differentiation assay, showing that the immortal cells underwent EMT. The differentiation assay for hTERT(+)-OME cells revealed the recovery of epithelial phenotypes, implicating the presence of MET. The stem cell properties were confirmed by the detection of appropriate markers. Altered expression of alpha-tubulin and gamma-tubulin in both two-dimensional-cultured (without serum) and three-dimensional-cultured hTERT(+)-OME spheroids indicated the re-programming of cytoskeleton proteins which is attributed to MET processes in hTERT(+)-OME cells. CONCLUSIONS: EMT and MET are essential for hTERT-immortalised cells to maintain their epithelial stem cell properties.

Dual acquisition of 18F-FMISO and 18F-FDOPA

Metabolic imaging using positron emission tomography (PET) has found increasing clinical use for the management of infiltrating tumours such as glioma. However, the heterogeneous biological nature of tumours and intrinsic treatment resistance in some regions means that knowledge of multiple biological factors is needed for effective treatment planning. For example, the use of 18F-FDOPA to identify infiltrative tumour and 18F-FMISO for localizing hypoxic regions. Performing multiple PET acquisitions is impractical in many clinical settings, but previous studies suggest multiplexed PET imaging could be viable. The fidelity of the two signals is affected by the injection interval, scan timing and injected dose. The contribution of this work is to propose a framework to explicitly trade-off signal fidelity with logistical constraints when designing the imaging protocol. The particular case of estimating 18F-FMISO from a single frame prior to injection of 18F-FDOPA is considered. Theoretical experiments using simulations for typical biological scenarios in humans demonstrate that results comparable to a pair of single-tracer acquisitions can be obtained provided protocol timings are carefully selected. These results were validated using a pre-clinical data set that was synthetically multiplexed. The results indicate that the dual acquisition of 18F-FMISO and 18F-FDOPA could be feasible in the clinical setting. The proposed framework could also be used to design protocols for other tracers.

A constraints-led perspective to understanding skill acquisition and game play: A basis for integration of motor learning theory and physical education praxis?

Background: In order to design appropriate environments for performance and learning of movement skills, physical educators need a sound theoretical model of the learner and of processes of learning. In physical education, this type of modelling informs the organization of learning environments and effective and efficient use of practice time. An emerging theoretical framework in motor learning, relevant to physical education, advocates a constraints-led perspective for acquisition of movement skills and game play knowledge. This framework shows how physical educators could use task, performer and environmental constraints to channel acquisition of movement skills and decision making behaviours in learners. From this viewpoint, learners generate specific movement solutions to satisfy the unique combination of constraints imposed on them, a process which can be harnessed during physical education lessons. Purpose: In this paper the aim is to provide an overview of the motor learning approach emanating from the constraints-led perspective, and examine how it can substantiate a platform for a new pedagogical framework in physical education: nonlinear pedagogy. We aim to demonstrate that it is only through theoretically valid and objective empirical work of an applied nature that a conceptually sound nonlinear pedagogy model can continue to evolve and support research in physical education. We present some important implications for designing practices in games lessons, showing how a constraints-led perspective on motor learning could assist physical educators in understanding how to structure learning experiences for learners at different stages, with specific focus on understanding the design of games teaching programmes in physical education, using exemplars from Rugby Union and Cricket. Findings: Research evidence from recent studies examining movement models demonstrates that physical education teachers need a strong understanding of sport performance so that task constraints can be manipulated so that information-movement couplings are maintained in a learning environment that is representative of real performance situations. Physical educators should also understand that movement variability may not necessarily be detrimental to learning and could be an important phenomenon prior to the acquisition of a stable and functional movement pattern. We highlight how the nonlinear pedagogical approach is student-centred and empowers individuals to become active learners via a more hands-off approach to learning. Summary: A constraints-based perspective has the potential to provide physical educators with a framework for understanding how performer, task and environmental constraints shape each individual‟s physical education. Understanding the underlying neurobiological processes present in a constraints-led perspective to skill acquisition and game play can raise awareness of physical educators that teaching is a dynamic 'art' interwoven with the 'science' of motor learning theories.

Image acquisition and manipulation protocols for CT-PET fusion to improve the accuracy of gross tumour volume localisation for 3D conformal radiotherapy for lung cancer

Aims: To develop clinical protocols for acquiring PET images, performing CT-PET registration and tumour volume definition based on the PET image data, for radiotherapy for lung cancer patients and then to test these protocols with respect to levels of accuracy and reproducibility. Method: A phantom-based quality assurance study of the processes associated with using registered CT and PET scans for tumour volume definition was conducted to: (1) investigate image acquisition and manipulation techniques for registering and contouring CT and PET images in a radiotherapy treatment planning system, and (2) determine technology-based errors in the registration and contouring processes. The outcomes of the phantom image based quality assurance study were used to determine clinical protocols. Protocols were developed for (1) acquiring patient PET image data for incorporation into the 3DCRT process, particularly for ensuring that the patient is positioned in their treatment position; (2) CT-PET image registration techniques and (3) GTV definition using the PET image data. The developed clinical protocols were tested using retrospective clinical trials to assess levels of inter-user variability which may be attributed to the use of these protocols. A Siemens Somatom Open Sensation 20 slice CT scanner and a Philips Allegro stand-alone PET scanner were used to acquire the images for this research. The Philips Pinnacle3 treatment planning system was used to perform the image registration and contouring of the CT and PET images. Results: Both the attenuation-corrected and transmission images obtained from standard whole-body PET staging clinical scanning protocols were acquired and imported into the treatment planning system for the phantom-based quality assurance study. Protocols for manipulating the PET images in the treatment planning system, particularly for quantifying uptake in volumes of interest and window levels for accurate geometric visualisation were determined. The automatic registration algorithms were found to have sub-voxel levels of accuracy, with transmission scan-based CT-PET registration more accurate than emission scan-based registration of the phantom images. Respiration induced image artifacts were not found to influence registration accuracy while inadequate pre-registration over-lap of the CT and PET images was found to result in large registration errors. A threshold value based on a percentage of the maximum uptake within a volume of interest was found to accurately contour the different features of the phantom despite the lower spatial resolution of the PET images. Appropriate selection of the threshold value is dependant on target-to-background ratios and the presence of respiratory motion. The results from the phantom-based study were used to design, implement and test clinical CT-PET fusion protocols. The patient PET image acquisition protocols enabled patients to be successfully identified and positioned in their radiotherapy treatment position during the acquisition of their whole-body PET staging scan. While automatic registration techniques were found to reduce inter-user variation compared to manual techniques, there was no significant difference in the registration outcomes for transmission or emission scan-based registration of the patient images, using the protocol. Tumour volumes contoured on registered patient CT-PET images using the tested threshold values and viewing windows determined from the phantom study, demonstrated less inter-user variation for the primary tumour volume contours than those contoured using only the patient’s planning CT scans. Conclusions: The developed clinical protocols allow a patient’s whole-body PET staging scan to be incorporated, manipulated and quantified in the treatment planning process to improve the accuracy of gross tumour volume localisation in 3D conformal radiotherapy for lung cancer. Image registration protocols which factor in potential software-based errors combined with adequate user training are recommended to increase the accuracy and reproducibility of registration outcomes. A semi-automated adaptive threshold contouring technique incorporating a PET windowing protocol, accurately defines the geometric edge of a tumour volume using PET image data from a stand alone PET scanner, including 4D target volumes.

Entrepreneurial growth : the role of international knowledge acquisition as moderated by firm age

In line with repeated recent calls for research on specific forms of growth rather than on an undifferentiated notion of “total growth,” our study contributes to the understanding of entrepreneurial growth. By this we mean growth through expansion into new geographic markets and/or via the introduction of new products or services. Building on Penrose's theory of the growth of the firm and on the research streams she has in part inspired, we investigate the impact of knowledge acquisition from international markets on entrepreneurial growth both at home and abroad. We further suggest that the effects of international knowledge acquisition on entrepreneurial growth will vary with firm age. Utilizing longitudinal data on 138 small and medium-sized enterprises (SMEs), we find that the acquisition of knowledge from international markets fuels growth through market development, and that this effect is stronger for international expansion than domestic expansion. Our results also show that firm age negatively moderates the relationship between international knowledge acquisition and entrepreneurial growth via the introduction of new products or services. Specifically, international knowledge acquisition has a positive effect on growth via new products/services development in young firms, but a negative effect in mature firms. We assume this reflects changes over time in how international knowledge is managed.

Australian pharmacists' understanding of their continuing professional development obligations

Background The adoption of continuing professional development (CPD) in Australia is still relatively new [expand]. There is limited information on how Australian pharmacists have engaged with the CPD requirements for registration. Aim To explore Australian registered pharmacists’ understanding and engagement with the requirement for CPD credits for registration. Method The Pharmacy Board of Australia’s CPD requirements for registration was used as a guide to design an online survey to ascertain Australian pharmacists understanding and engagement in the acquisition of CPD credits for registration. Results A total of 278 pharmacists responded to the survey – 66% were female and 30% were male (4% did not disclose their gender). 63% of respondents felt that it would not be difficult to acquire 40 CPD credits annually; with pharmacists identifying that Group 1 activities were a preferred way of acquiring CPD credits. The majority of pharmacists (91%) believed that they knew what the current CPD requirements for general registration are and 77% felt that there has been enough guidance provided to assist them. Despite this, 26% of participants had never used self directed learning plans and 38% did not know how to undertake self-directed learning. 76% of participants were under the common misconception that CPD is synonymous with continuing education. Conclusion The majority of registered pharmacists believe they understand and can engage in the acquisition of CPD credits for registration. However, some aspects of the process was not understood. The key link of how this process aims to develop individual practice needs to be further developed within the profession.

The dynamics of expertise acquisition in sport : the role of affective learning design

Objectives The aim of this position paper is to discuss the role of affect in designing learning experiences to enhance expertise acquisition in sport. The design of learning environments and athlete development programmes are predicated on the successful sampling and simulation of competitive performance conditions during practice. This premise is captured by the concept of representative learning design, founded on an ecological dynamics approach to developing skill in sport, and based on the individual-environment relationship. In this paper we discuss how the effective development of expertise in sport could be enhanced by the consideration of affective constraints in the representative design of learning experiences. Conclusions Based on previous theoretical modelling and practical examples we delineate two key principles of Affective Learning Design: (i) the design of emotion-laden learning experiences that effectively simulate the constraints of performance environments in sport; (ii) recognising individualised emotional and coordination tendencies that are associated with different periods of learning. Considering the role of affect in learning environments has clear implications for how sport psychologists, athletes and coaches might collaborate to enhance the acquisition of expertise in sport.

Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA

We report that tumor cells devoid of their mitochondrial genome (mtDNA) show delayed tumor growth and that tumor formation is associated with acquisition of mtDNA from host cells. This leads to partial recovery of mitochondrial function in cells derived from primary tumors grown from cells without mtDNA and a shorter lag in tumor growth. Cell lines from circulating tumor cells showed further recovery of mitochondrial respiration and an intermediate lag to tumor growth, while cells from lung metastases exhibited full restoration of respiratory function and no lag in tumor growth. Stepwise assembly of mitochondrial respiratory supercomplexes was correlated with acquisition of respiratory function. Our findings indicate horizontal transfer of mtDNA from host cells in the tumor microenvironment to tumor cells with compromised respiratory function to re-establish respiration and tumor-initiating efficacy. These results suggest a novel pathophysiological process for overcoming mtDNA damage and support the notion of high plasticity of malignant cells.

An international comparison of the continuing professional development process (CPD) in Australia, New Zealand and the United Kingdom

Background: The Pharmacy Board of Australia stipulated that for renewal of registration, pharmacists must have accrued a minimum of 20 CPD credits over the 2010-11 registration years (1). Mandatory CPD is not new in Pharmacy. The UK and New Zealand have both established systems of CPD in recent years. The purpose of this study is to investigate established CPD processes in the UK and New Zealand with the view to making recommendations for the implementation of the CPD process in Australia. Objectives: To compare the acquisition and guidance on documentation of CPD credit points in Australia, New Zealand and the United Kingdom. Methodology: A comparative online search of the websites of each of the registering authorities was undertaken. Any practice standards or guidelines which relate to registration or continuing professional development were analysed and compared. Results: In New Zealand the Pharmacy Council require Pharmacists to have a minimum of 12 outcome credits over a 3-year period for recertification (2, 3). The outcome credit related to each CPD action and is based on relevance to the pharmacist and their practice. It is graded between one, for CPD which has occasional relevance to practice and three which have considerable relevance to practice. There are examples of completed CPD recording sheets on their website (8). In the UK, The General Pharmaceutical Council require Pharmacists to make a minimum of nine CPD entries per year (4) and detailed guidance on how to record CPD activities is provided (5,7). The Pharmacy Board of Australia divides CPD activities into three groups (6). Of the 20 credits required annually only 10 can be gained from group one activities, which is information accessed without assessment. There is only brief guidance on the recording of CPD. Discussion: The GPhC in the UK provided the most comprehensive guidance on acquisition of CPD credit points and documentation (5,7) The Pharmacy Council of New Zealand made CPD points relevant to practice.(2,8) The Pharmacy Board of Australia provided limited information for pharmacists on CPD activities, which may impede pharmacist participation. Information may assist in increasing pharmacists’ engagement in CPD activities. In conclusion, there is variation between the three countries in the amount and type of information provided about CPD requirements.

Firm social, cultural and intellectual capital : strategic indicators of international client satisfaction

Despite the increasing significance of the construction industry as an emerging sector of the Australian economy, there is inadequate research performed on construction design firms in terms of theoretical and empirical foundations. Although past research has identified the barriers and success factors for firm market entry, evidence suggests that to date no research has explicitly explored the sustainability of construction design firms in international markets. SMEs and their approach to firm internationalisation differ significantly from large manufacturing firms and a vast majority of construction design firms operate as SMEs. This paper develops a sustainable business model for construction design SMEs, which rely upon the development of clear Client Following (CF) versus Market Seeking (MS) strategies to support internal firm strategic and operational management. The understanding of these strategies is vital as the application of either will shape the design management approach of firms, which would in turn impact on the sustainability of these firms in foreign markets. Long-term sustainability of firms in international markets relies heavily upon client satisfaction. Client and project team participants’ communication during various design processes has often been problematic and the added difficulty of communicating across international boundaries further compounds the problem of capturing and maintaining client’s requirements. Therefore this paper develops a model for economic sustainability of Australian construction design firms working in international markets by exploring factors that affect client satisfaction across international boundaries, through the development of business performance indicators. These include not only the critical financial capital but also other ‘softer’ indicators, namely: social, cultural and intellectual capital. These act as a firm’s measure of success and the acquisition of this type of capital will provide significant advantages to firms’ success, hence sustainability in international markets.

Dynamics of multi-articular coordination in neurobiological systems

Although previous work in nonlinear dynamics on neurobiological coordination and control has provided valuable insights from studies of single joint movements in humans, researchers have shown increasing interest in coordination of multi-articular actions. Multi-articular movement models have provided valuable insights on neurobiological systems conceptualised as degenerate, adaptive complex systems satisfying the constraints of dynamic environments. In this paper, we overview empirical evidence illustrating the dynamics of adaptive movement behavior in a range of multi-articular actions including kicking, throwing, hitting and balancing. We model the emergence of creativity and the diversity of neurobiological action in the meta-stable region of self organising criticality. We examine the influence on multi-articular actions of decaying and emerging constraints in the context of skill acquisition. We demonstrate how, in this context, transitions between preferred movement patterns exemplify the search for and adaptation of attractor states within the perceptual motor workspace as a function of practice. We conclude by showing how empirical analyses of neurobiological coordination and control have been used to establish a nonlinear pedagogical framework for enhancing acquisition of multi-articular actions.

Mutation frequency of non-ESBL phenotype SENTRY (Asia-Pacific) isolates of Klebsiella pneumoniae conversion to an ESBL positive phenotype

Extended spectrum β-lactamases or ESBLs, which are derived from non-ESBL precursors by point mutation of β-lactamase genes (bla), are spreading rapidly all over the world and have caused considerable problems in the treatment of infections caused by bacteria which harbour them. The mechanism of this resistance is not fully understood and a better understanding of these mechanisms might significantly impact on choosing proper diagnostic and treatment strategies. Previous work on SHV β-lactamase gene, blaSHV, has shown that only Klebsiella pneumoniae strains which contain plasmid-borne blaSHV are able to mutate to phenotypically ESBL-positive strains and there was also evidence of an increase in blaSHV copy number. Therefore, it was hypothesised that although specific point mutation is essential for acquisition of ESBL activity, it is not yet enough, and blaSHV copy number amplification is also essential for an ESBL-positive phenotype, with homologous recombination being the likely mechanism of blaSHV copy number expansion. In this study, we investigated the mutation rate of non-ESBL expressing K. pneumoniae isolates to an ESBL-positive status by using the MSS-maximum likelihood method. Our data showed that blaSHV mutation rate of a non-ESBL expressing isolate is lower than the mutation rate of the other single base changes on the chromosome, even with a plasmid-borne blaSHV gene. On the other hand, mutation rate from a low MIC ESBL-positive (≤ 8 µg/mL for cefotaxime) to high MIC ESBL-positive (≥16 µg/mL for cefotaxime) is very high. This is because only gene copy number increase is needed which is probably mediated by homologous recombination that typically takes place at a much higher frequencies than point mutations. Using a subinhibitory concentration of novobiocin, as a homologous recombination inhibitor, revealed that this is the case.

Beating the urge : implications of research into substance-related desires

Despite the advent of improved pharmacological treatments to alleviate substance-related desires, psychological approaches will continue to be required. However, the current psychological treatment that most specifically focuses on desires and their management—cue exposure (CE)—has not lived up to its original promise. This paper argues that current psychological approaches to desire do not adequately incorporate our knowledge about the factors that trigger, maintain, and terminate episodes of desire. It asserts that the instigation and maintenance of desires involve both associative and elaborative processes. Understanding the processes triggering the initiation of intrusive thoughts may assist in preventing some episodes, but occasional intrusions will be inevitable. A demonstration of the ineffectiveness of thought suppression may discourage its use as a coping strategy for desire-related intrusions, and mindfulness meditation plus cognitive therapy may help in accepting their occurrence and letting them go. Competing tasks may be used to reduce elaboration of desires, and competing sensory images may have particular utility. The application of these procedures during episodes that are elicited in the clinic may allow the acquisition of more effective strategies to address desires in the natural environment.