Clinicopathological relevance of BRAF mutations in human cancer

BRAF represents one of the most frequently mutated protein kinase genes in human tumours. The mutation is commonly tested in pathology practice. BRAF mutation is seen in melanoma, papillary thyroid carcinoma (including papillary thyroid carcinoma arising from ovarian teratoma), ovarian serous tumours, colorectal carcinoma, gliomas, hepatobiliary carcinomas and hairy cell leukaemia. In these cancers, various genetic aberrations of the BRAF proto-oncogene, such as different point mutations and chromosomal rearrangements, have been reported. The most common mutation, BRAF V600E, can be detected by DNA sequencing and immunohistochemistry on formalin fixed, paraffin embedded tumour tissue. Detection of BRAF V600E mutation has the potential for clinical use as a diagnostic and prognostic marker. In addition, a great deal of research effort has been spent in strategies inhibiting its activity. Indeed, recent clinical trials involving BRAF selective inhibitors exhibited promising response rates in metastatic melanoma patients. Clinical trials are underway for other cancers. However, cutaneous side effects of treatment have been reported and therapeutic response to cancer is short-lived due to the emergence of several resistance mechanisms. In this review, we give an update on the clinical pathological relevance of BRAF mutation in cancer. It is hoped that the review will enhance the direction of future research and assist in more effective use of the knowledge of BRAF mutation in clinical practice.

Clinical impacts of mammalian target of rapamycin expression in human colorectal cancers

This study investigated the clinicopathologic roles of mammalian target of rapamycin (mTOR) expression and its relationship to carcinogenesis and tumor progression in a colorectal adenoma-adenocarcinoma model. Two colon cancer cell lines with different pathologic stages (SW480 and SW48) and 1 normal colonic epithelial cell line (FHC) were used, in addition to 119 colorectal adenocarcinomas and 32 adenomas. mTOR expression profiles at messenger RNA (mRNA) and protein levels were investigated in the cells and tissues using real-time quantification polymerase chain reaction and immunohistochemistry. The findings were correlated with the clinicopathologic features of the tumors. The colon cell line from stage III cancer (SW48) showed higher expression of mTOR mRNA than that from stage II cancer (SW480). At the tissue level, mTOR showed higher mRNA and protein expression in colorectal carcinoma than in adenoma. The mRNA and protein expression was correlated with each other in approximately one-third of the carcinomas and adenomas. High levels of mTOR mRNA expression were noted more in carcinoma or adenoma arising from the distal portion of the large intestine (P = .025 and .019, respectively). Within the colorectal cancer population, a high level of expression of mTOR mRNA was related to the presence of lymph node metastases (P = .031), advanced pathologic stage (P = .05), and presence of persistent disease or tumor recurrence (P = .035). To conclude, the study has indicated that mTOR is likely to be involved in the development and progression of colorectal cancer and is linked to cancer initiation, invasiveness, and progression.

Using the SWAP to connect water, human rights and mining

It is important that industries’ water interactions respect the human right to water. Historically, within the mining industry there has been a disconnect between the management of sites’ internal water interactions and the consequences of their external impacts, including human rights impacts. This poses a challenge for the mining industry as it attempts to put the Ruggie Guiding Principles for Business and Human Rights into practice, particularly as United Nations has recently recognised the human right to water. A technical framework such as the Minerals Council of Australia’s Water Accounting Framework (WAF) can help to bridge this disconnect and to integrate human rights considerations into business practice by connecting a site’s external and internal water interactions and by encouraging regular monitoring of performance. However, at present the connection is limited since the WAF lacks the capability to formalise a site’s social water context. This work presents the Social Water Assessment Protocol (SWAP), a scoping tool consisting of a set of questions organised into taxonomic themes that capture a site’s social water context and that can be combined with the WAF to better connect human rights with mine water interactions.

Telomerase activity : detection and clinical implications in human cancer

Telomerase is an extremely important enzyme required for the immortalisation of tumour cells. Because the gene is activated in the vast majority of tumour tissues and remains unused in most somatic cells, it represents a marker with huge diagnostic, prognostic and treatment implications in cancer. This article summarises the basic structure and functions of telomerase and considers its clinical implications in colorectal and other cancers.

Improving the railway’s understanding of accident causation through an integrated approach to human factors analysis and technical safety data recording

This paper describes a safety data recording and analysis system that has been developed to capture safety occurrences including precursors using high-definition forward-facing video from train cabs and data from other train-borne systems. The paper describes the data processing model and how events detected through data analysis are related to an underlying socio-technical model of accident causation. The integrated approach to safety data recording and analysis insures systemic factors that condition, influence or potentially contribute to an occurrence are captured both for safety occurrences and precursor events, providing a rich tapestry of antecedent causal factors that can significantly improve learning around accident causation. This can ultimately provide benefit to railways through the development of targeted and more effective countermeasures, better risk models and more effective use and prioritization of safety funds. Level crossing occurrences are a key focus in this paper with data analysis scenarios describing causal factors around near-miss occurrences. The paper concludes with a discussion on how the system can also be applied to other types of railway safety occurrences.

Social water assessment protocol : a step towards connecting mining, water and human rights

The human right to water has recently been recognised by both the United Nations General Assembly and the Human Rights Council. As the mining industry interacts with water on multiple levels, it is important that these interactions respect the human right to water. Currently, a disconnect exists between mine site water management practices and the recognition of water from a human rights perspective. The Minerals Council of Australia (MCA) Water Accounting Framework (WAF) has previously been used to strengthen the connection between water management and human rights. This article extends this connection through the use of a Social Water Assessment Protocol (SWAP). The SWAP is scoping tool consisting of a set of questions classified into taxonomic themes under leading topics with suggested sources of data that enable mine sites to better understand the local water context in which they operate. Three of the themes contained in the SWAP – gender, Indigenous peoples and health – are discussed to demonstrate how the protocol may be useful in assisting mining companies to consider their impacts on the human right to water.

Genome-wide analysis in a murine Dnmt1 knockdown model identifies epigenetically silenced genes in primary human pituitary tumors

DNA methylation at promoter CpG islands (CGI) is an epigenetic modification associated with inappropriate gene silencing in multiple tumor types. In the absence of a human pituitary tumor cell line, small interfering RNA-mediated knockdown of the maintenance methyltransferase DNA methyltransferase (cytosine 5)-1 (Dnmt1) was used in the murine pituitary adenoma cell line AtT-20. Sustained knockdown induced reexpression of the fully methylated and normally imprinted gene neuronatin (Nnat) in a time-dependent manner. Combined bisulfite restriction analysis (COBRA) revealed that reexpression of Nnat was associated with partial CGI demethylation, which was also observed at the H19 differentially methylated region. Subsequent genome-wide microarray analysis identified 91 genes that were significantly differentially expressed in Dnmt1 knockdown cells (10% false discovery rate). The analysis showed that genes associated with the induction of apoptosis, signal transduction, and developmental processes were significantly overrepresented in this list (P < 0.05). Following validation by reverse transcription-PCR and detection of inappropriate CGI methylation by COBRA, four genes (ICAM1, NNAT, RUNX1, and S100A10) were analyzed in primary human pituitary tumors, each displaying significantly reduced mRNA levels relative to normal pituitary (P < 0.05). For two of these genes, NNAT and S100A10, decreased expression was associated with increased promoter CGI methylation. Induced expression of Nnat in stable transfected AtT-20 cells inhibited cell proliferation. To our knowledge, this is the first report of array-based "epigenetic unmasking" in combination with Dnmt1 knockdown and reveals the potential of this strategy toward identifying genes silenced by epigenetic mechanisms across species boundaries.

Modelling the dynamics of Plasmodium falciparum histidine-rich protein 2 in human malaria to better understand malaria rapid diagnostic test performance

BACKGROUND: Effective diagnosis of malaria is a major component of case management. Rapid diagnostic tests (RDTs) based on Plasmodium falciparumhistidine-rich protein 2 (PfHRP2) are popular for diagnosis of this most virulent malaria infection. However, concerns have been raised about the longevity of the PfHRP2 antigenaemia following curative treatment in endemic regions. METHODS: A model of PfHRP2 production and decay was developed to mimic the kinetics of PfHRP2 antigenaemia during infections. Data from two human infection studies was used to fit the model, and to investigate PfHRP2 kinetics. Four malaria RDTs were assessed in the laboratory to determine the minimum detectable concentration of PfHRP2. RESULTS: Fitting of the PfHRP2 dynamics model indicated that in malaria naive hosts, P. falciparum parasites of the 3D7 strain produce 1.4 x 10(-)(1)(3) g of PfHRP2 per parasite per replication cycle. The four RDTs had minimum detection thresholds between 6.9 and 27.8 ng/mL. Combining these detection thresholds with the kinetics of PfHRP2, it is predicted that as few as 8 parasites/muL may be required to maintain a positive RDT in a chronic infection. CONCLUSIONS: The results of the model indicate that good quality PfHRP2-based RDTs should be able to detect parasites on the first day of symptoms, and that the persistence of the antigen will cause the tests to remain positive for at least seven days after treatment. The duration of a positive test result following curative treatment is dependent on the duration and density of parasitaemia prior to treatment and the presence and affinity of anti-PfHRP2 antibodies.

A comparative study of airborne particulate pollution at two bus stations of different site geography

Airborne particulate pollutant is considered to be one of the major harmful emissions produced by vehicle engines as it has been directly linked to serious health problems. Passengers spend long times at bus stations and may be exposed to high concentrations of pollution. Particle pollution at two bus stations in Brisbane, Australia were monitored. The two bus stations consisted of markedly different site geography and surroundings with one situated in a street canyon and the other elevated above ground level. The same flow of traffic operated through both stations. Real time measurements of ultrafine particle concentration, size distribution and meteorological conditions were carried out on the platform continuously over several days. The results showed that the particle number concentrations were significantly different at the two stations, suggesting that the layout of site geometry and surroundings was a dominant determining factor through the injection of fresh air into the station platforms and the rates of dilution.

Geographical distribution of human Schistosoma japonicum infection in the Philippines : tools to support disease control and further elimination

S. japonicum infection is believed to be endemic in 28 of the 80 provinces of the Philippines and the most recent data on schistosomiasis prevalence have shown considerable variability between provinces. In order to increase the efficient allocation of parasitic disease control resources in the country, we aimed to describe the small scale spatial variation in S. japonicum prevalence across the Philippines, quantify the role of the physical environment in driving the spatial variation of S. japonicum, and develop a predictive risk map of S. japonicum infection. Data on S. japonicum infection from 35,754 individuals across the country were geo-located at the barangay level and included in the analysis. The analysis was then stratified geographically for Luzon, the Visayas and Mindanao. Zero-inflated binomial Bayesian geostatistical models of S. japonicum prevalence were developed and diagnostic uncertainty was incorporated. Results of the analysis show that in the three regions, males and individuals aged ≥ 20 years had significantly higher prevalence of S. japonicum compared with females and children <5 years. The role of the environmental variables differed between regions of the Philippines. S. japonicum infection was widespread in the Visayas whereas it was much more focal in Luzon and Mindanao. This analysis revealed significant spatial variation in prevalence of S. japonicum infection in the Philippines. This suggests that a spatially targeted approach to schistosomiasis interventions, including mass drug administration, is warranted. When financially possible, additional schistosomiasis surveys should be prioritized to areas identified to be at high risk, but which were underrepresented in our dataset.

Correlates of perceiving human resource management as a 'problem' in smaller firms

In this paper we investigate factors likely to correlate with human resource management (HRM) being perceived as a problem in smaller firms. The owner-manager and firm characteristics identified recognise that managerial ‘problems’ can result from a firm’s phase of growth, as well as the way in which an owner-manager’s capacity and characteristics affect their interpretation of such. From a survey of 1200 smaller firms in south east Melbourne (Australia), we use logistic regression on data from 428 respondents to assess organisational and individual factors correlating with perceiving HRM, broadly defined, to be a problem. The highest odds of this occurring were associated with being a larger manufacturing firm which was in a phase of growth other than diversification and which had a long-tenured manager who based the firm’s competitive success on factors other than the quality of staff. Knowing these correlates means assistance to help solve the perceived ‘problem’ with HRM can be more effectively targeted.

Connecting theory, practice and place in today’s landscape : an education initiative

Since the establishment of Australia’s earliest formal studies in landscape architecture, landscape planning has been a traditional focus within post-graduate studies at QUT. Study in this area has evolved from an earlier emphasis on applied physical geography through to traditional techniques and processes in visual assessment and management. The emphasis on these techniques has shifted again to a more complex exploration of natural, economic, social and cultural landscapes. Recently, the School has explored more innovative and complex dimensions of human and natural landscapes. This has involved a focus on particular regions under pressure from local social and economic change. These have included the under-threat ‘picturesque’ landscapes of the Blackall Range and the Tweed Valley. Attempts to bridge the institution and the landscape have unearthed, through a studio focus, strong connections with notions of sustainable villages, roadside interpretation, way finding, local economic initiatives, special area creation, cultural heritage brokering and ecological enhancements. These initiatives have spanned both local practice interests and academic pursuits. Central to this exploration is the concept of problem solving through the investigation of the concept of ‘multiple scales’. An open, yet intensive program is being developed with a team of ‘futurist’ practitioners offering a range of experiences and perspectives to students. The program is being increasingly linked to design studios so that landscape planning and landscape design form a fabric of inquiry that works towards reclaiming complex landscapes.

Introduction : At the Intersection of Entrepreneurship and Human Resource Management

In recent years there has been a growing literature on human resource management (HRM) and smaller firms which has also encompassed firms that are growing and entrepreneurial. For example we have seen a special edition of Entrepreneurship Theory and Practice (Katz et al., 2000), two of Human Resource Management Review (Baron, 2003; Barrett and Mayson, 2006) and one of Human Resource Management (Huselid, 2003; Tansky and Heneman, 2003), with another of Human Resource Management (to be edited by Ribeiro, Roig and Tansky) scheduled for publication in 2010. In addition, symposia on the topic have been undertaken at the Academy of Management in 2005 (organized by Mayson) and in 2004 (organized by Hayton). Papers dealing with issues of HRM for new, small, growing and/or entrepreneurial firms have been presented at a range of different conferences, whether they are management oriented such as the Academy of Management (AoM) and its regional variants (for example, the British Academy of Management (BAM) or the Australian and New Zealand Academy of Management (ANZAM)), entrepreneurially focused ones like the Babson College Entrepreneurship Research conference or ones focused specifically on smaller firms such as the conferences of the Institute for Small Business and Entrepreneurship (ISBE) in the UK or the International Council for Small Business (ICSB) and its regional affiliates. With all these papers and all this discussion is there anything left to say? Well yes, we think there is and we are...

Human resource management and entrepreneurship : building theory at the intersection

In 2008 we brought together much work at the intersection of entrepreneurship and human resource management (HRM) (Barrett & Mayson, 2008), after calls for more research (Baron, 2003; Katz, Aldrich, Welbourne & Williams, 2000; Tansky & Heneman, 2003). More has been collated since (Soriano, Dobon & Tansky, 2010; Tansky, Soriano & Dobon, 2010). We think it is now time again to regroup, pull conversational threads together and have a critical look at recent research at the intersection of HRM and Entrepreneurship. As editors of International Handbook of Entrepreneurship and HRM (Barrett & Mayson, 2008) we were privileged to collect 23 wonderfully diverse chapters from scholars around the globe addressing a range of issues at the intersection of the two pertinent disciplines or fields: HRM and entrepreneurship. This edition represented a coalescing of ideas that had been swirling about for some time. In three sections, the first dealt with theory and research methods, the second with the nature of HRM in small and entrepreneurial firms and the third with the functional aspects of HRM. At the time we were aware that the handbook did not cover the entire field and many topics were left unexplored. For example, the topic of regulation was generally absent while issues such as career advancement, performance management, organisational change and gender, diversity and ethnicity were also missing. In essence, the majority of those contributions sought to develop an understanding of the context in which particular aspects of HRM can be played out.

Non-invasive techniques for imaging in-vivo human corneal sub basal nerve mapping and migration rate in diabetic neuropathy

Purpose Corneal confocal microscopy (CCM) is a rapid non-invasive ophthalmic technique, which has been shown to diagnose and stratify the severity of diabetic neuropathy. Current morphometric techniques assess individual static images of the subbasal nerve plexus; this work explores the potential for non-invasive assessment of the wide-field morphology and dynamic changes of this plexus in vivo. Methods In this pilot study, laser scanning CCM was used to acquire maps (using a dynamic fixation target and semi-automated tiling software) of the central corneal sub-basal nerve plexus in 4 diabetic patients with and 6 without neuropathy and in 2 control subjects. Nerve migration was measured in an additional 7 diabetic patients with neuropathy, 4 without neuropathy and in 2 control subjects by repeating a modified version of the mapping procedure within 2-8 weeks, thus facilitating re-identification of distinctive nerve landmarks in the 2 montages. The rate of nerve movement was determined from these data and normalised to a weekly rate (µm/week), using customised software. Results Wide-field corneal nerve fibre length correlated significantly with the Neuropathy Disability Score (r = -0.58, p < 0.05), vibration perception (r = -0.66, p < 0.05) and peroneal conduction velocity (r = 0.67, p < 0.05). Central corneal nerve fibre length did not correlate with any of these measures of neuropathy (p > 0.05 for all). The rate of corneal nerve migration was 14.3 ± 1.1 µm/week in diabetic patients with neuropathy, 19.7 ± 13.3µm/week in diabetic patients without neuropathy, and 24.4 ± 9.8µm/week in control subjects; however, these differences were not significantly different (p = 0.543). Conclusions Our data demonstrate that it is possible to capture wide-field images of the corneal nerve plexus, and to quantify the rate of corneal nerve migration by repeating this procedure over a number of weeks. Further studies on larger sample sizes are required to determine the utility of this approach for the diagnosis and monitoring of diabetic neuropathy.