A metastatic neuroendocrine anaplastic small cell tumor in a patient with multiple endocrine neoplasia type 1 syndrome : assessment of disease status and response to doxorubicin, cyclophosphamide, etoposide chemotherapy through scintigraphic imaging with 111In-pentetreotide

Extrapulmonary small cell and small cell neuroendocrine tumors of unknown primary site are, in general, aggressive neoplasms with a short median survival. Like small cell lung cancer (SCLC), they often are responsive to chemotherapy and radiotherapy. Small cell lung cancer and well differentiated neuroendocrine carcinomas of the gastrointestinal tract and pancreas tend to express somatostatin receptors. These tumors may be localized in patients by scintigraphic imaging using radiolabeled somatostatin analogues. A patient with an anaplastic neuroendocrine small cell tumor arising on a background of multiple endocrine neoplasia type 1 syndrome is reported. The patient had a known large pancreatic gastrinoma and previously treated parathyroid adenopathy. At presentation, there was small cell cancer throughout the liver and skeleton. Imaging with a radiolabeled somatostatin analogue, 111In- pentetreotide (Mallinckrodt Medical B. V., Petten, Holland), revealed all sites of disease detected by routine biochemical and radiologic methods. After six cycles of chemotherapy with doxorubicin, cyclophosphamide, and etoposide, there was almost complete clearance of the metastatic disease. 111In-pentetreotide scintigraphy revealed uptake consistent with small areas of residual disease in the liver, the abdomen (in mesenteric lymph nodes), and posterior thorax (in a rib). The primary gastrinoma present before the onset of the anaplastic small cell cancer showed no evidence of response to the treatment. The patient remained well for 1 year and then relapsed with brain, lung, liver, and skeletal metastases. Despite an initial response to salvage radiotherapy and chemotherapy with carboplatin and dacarbazine, the patient died 6 months later.

Investigating the association between sun exposure and folate degradation in the human body

This thesis is the first study to investigate the associations between sun exposure and folate degradation in a group of childbearing age women in a high UV environment. It examined whether the degree of sun exposure experienced by women influenced blood folate levels following a period of folic acid supplementation and found a strong significant relationship between increased sun exposure and folate degradation. This relationship has strong implications for public health and the thesis has provided a foundation for further research in this area.

Characteristics of nontuberculous mycobacteria from a municipal water distribution system and their relevance to human infections

This thesis documented pathogenic species of nontuberculous mycobacteria in the Brisbane water distribution system. When water and shower aerosol strains were compared with human strains of mycobacteria, the study found that the likelihood of acquiring infection from municipal water was specific for four main species. The method for isolation of mycobacteria from water was refined, followed by sampling from 220 sites across Brisbane. A variety of species (incl 15 pathogens) were identified and genotypically compared to human strains. For M. abscessus and M. lentiflavum, water strains clustered with human strains. Pathogenic strains of M. kansasii were found, though non-pathogenic strains dominated. Waterborne strains of M. fortuitum differed to human strains. Extensive home sampling of 20 patients with NTM disease, supported the theory that the risk of acquiring NTM from water or shower aerosols appears species specific for M. avium, M. kansasii, M. lentiflavum and M. abscessus.

The Role of Social and Human Capital Among Nascent Entrepreneurs

This study examines nascent entrepreneurship by comparing individuals engaged in nascent activities (n=380) with a control group (n=608), after screening a sample from the general population (n=30,427). The study then follows the developmental process of nascent entrepreneurs for 18 months. Bridging and bonding social capital, consisting of both strong and weak ties, was a robust predictor for nascent entrepreneurs, as well as for advancing through the start-up process. With regard to outcomes like first sale or showing a profit, only one aspect of social capital, viz. being a member of a business network, had a statistically significant positive effect. The study supports human capital in predicting entry into nascent entrepreneurship, but only weakly for carrying the start-up process towards successful completion.

Crizotinib versus chemotherapy in advanced ALK-positive lung cancer

BACKGROUND: In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK ) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. METHODS: We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. RESULTS: The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. CONCLUSIONS: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.) Copyright © 2013 Massachusetts Medical Society.

An extracellular signal-regulated kinase 2 survival pathway mediates resistance of human mesothelioma cells to asbestos-induced injury

We hypothesized that normal human mesothelial cells acquire resistance to asbestos-induced toxicity via induction of one or more epidermal growth factor receptor (EGFR) - linked survival pathways (phosphoinositol-3-kinase/AKT/ mammalian target of rapamycin and extracellular signal - regulated kinase [ERK] 1/2) during simian virus 40 (SV40) transformation and carcinogenesis. Both isolated HKNM-2 mesothelial cells and a telomerase-immortalized mesothelial line (LP9/TERT-1) were more sensitive to crocidolite asbestos toxicity than an SV40 Tag-immortalized mesothelial line (MET5A) and malignant mesothelioma cell lines (HMESO and PPM Mill). Whereas increases in phosphorylation of AKT (pAKT) were observed in MET5A cells in response to asbestos, LP9/TERT-1 cells exhibited dose-related decreases in pAKT levels. Pretreatment with an EGFR phosphorylation or mitogen-activated protein kinase kinase 1/2 inhibitor abrogated asbestos-induced phosphorylated ERK (pERK) 1/2 levels in both LP9/TERT-1 and MET5A cells as well as increases in pAKT levels in MET5A cells. Transient transfection of small interfering RNAs targeting ERK1, ERK2, or AKT revealed that ERK1/2 pathways were involved in cell death by asbestos in both cell lines. Asbestos-resistant HMESO or PPM Mill cells with high endogenous levels of ERKs or AKT did not show dose-responsive increases in pERK1/ERK1, pERK2/ERK2, or pAKT/AKT levels by asbestos. However, small hairpin ERK2 stable cell lines created from both malignant mesothelioma lines were more sensitive to asbestos toxicity than shERK1 and shControl lines, and exhibited unique, tumor-specific changes in endogenous cell death - related gene expression. Our results suggest that EGFR phosphorylation is causally linkedto pERK and pAKT activation by asbestos in normal and SV40 Tag - immortalized human mesothelial cells. They also indicate that ERK2 plays a role in modulating asbestos toxicity by regulating genes critical to cell injury and survival that are differentially expressed in human mesotheliomas.

Phase II trial of Oxaliplatin and 5-Fluorouracil/Leucovorin combination in epithelial ovarian carcinoma relapsing within 2 years of platinum-based therapy

Objective To evaluate the efficacy and toxicity of Oxaliplatin and 5-Fluorouracil (5-FU)/Leucovorin (LV) combination in ovarian cancer relapsing within 2 years of prior platinum-based chemotherapy in a phase II trial. Methods Eligible patients had at least one prior platinum-based chemotherapy regimen, elevated CA-125 ≥ 60 IU/l, radiological evidence of disease progression and adequate hepatic, renal and bone marrow function. Patients with raised CA-125 levels alone as marker of disease relapse were not eligible. Oxaliplatin (85 mg/m 2) was given on day 1, and 5-Fluorouracil (370 mg/m 2) and Leucovorin (30 mg) was given on days 1 and 8 of a 14-day cycle. Results Twenty-seven patients were enrolled. The median age was 57 years (range 42-74 years). The median platinum-free interval (PFI) was 5 months (range 0-17 months) with only 30% of patients being platinum sensitive (PFI > 6 months). Six patients (22%) had two prior regimens of chemotherapy. A total of 191 cycles were administered (median 7; range 2-12). All patients were evaluable for toxicity. The following grade 3/4 toxicities were noted: anemia 4%; neutropenia 15%; thrombocytopenia 11%; neurotoxicity 8%; lethargy 4%; diarrhea 4%; hypokalemia 11%; hypomagnesemia 11%. Among 27 enrolled patients, 20 patients were evaluable for response by WHO criteria and 25 patients were evaluable by Rustin's CA-125 criteria. The overall response rate (RR) by WHO criteria was 30% (95% CI: 15- 52) [three complete responses (CRs) and three partial responses (PRs)]. The CA-125 response rate was 56% (95% CI: 37-73). Significantly, a 25% (95% CI: 9-53) radiological and a 50% (95% CI: 28-72) CA-125 response rate were noted in platinum resistant patients (PFI < 6 months). The median response duration was 4 months (range 3-12) and the median overall survival was 10 months. Conclusion Oxaliplatin and 5-Fluorouracil/ Leucovorin combination has a good safety profile and is active in platinum-pretreated advanced epithelial ovarian cancer. © 2004 Elsevier Inc. All rights reserved.

Characterisation of a human skin equivalent model to study the effects of ultraviolet B radiation on keratinocytes

The incidences of skin cancers resulting from chronic ultraviolet radiation (UVR) exposure are on the incline both in Australia and globally. Hence, the cellular and molecular pathways associated with UVR-induced photocarcinogenesis urgently need to be elucidated, in order to develop more robust preventative and treatment strategies against skin cancers. In vitro investigations into the effects of UVR (in particular the highly-mutagenic UVB wavelength) have, to date, mainly involved the use of cell culture and animal models. However, these models possess biological disparities to native skin, which to some extent have limited their relevance to the in vivo situation. To address this, we characterised a 3-dimensional, tissue-engineered human skin equivalent (HSE) model (consisting of primary human keratinocytes cultured on a dermal-derived scaffold) as a representation of a more physiologically-relevant platform to study keratinocyte responses to UVB. Significantly, we demonstrate that this model retains several important epidermal properties of native skin. Moreover, UVB-irradiation of the HSE constructs was shown to induce key markers of photodamage in the HSE keratinocytes, including the formation of cyclobutane pyrimidine dimers, the activation of apoptotic pathways, the accumulation of p53 and the secretion of inflammatory cytokines. Importantly, we also demonstrate that the UVB-exposed HSE constructs retain the capacity for epidermal repair and regeneration following photodamage. Together, our results demonstrate the potential of this skin equivalent model as a tool to study various aspects of the acute responses of human keratinocytes to UVB radiation damage.

Positioning change management and international human resource management

This concept paper examines the positioning of Change Management (CM) in relation to IHRM, and suggests that the emerging field of CM should be seen as collaborative with HRM in providing for the dynamic needs of organisations in contemporary international conditions of uncertainty and environmental turbulence.

Pooled biological specimens for human biomonitoring of environmental chemicals : opportunities and limitations

Biomonitoring has become the ‘gold standard’ in assessing chemical exposures, and plays an important role in risk assessment. The pooling of biological specimens – combining multiple individual specimens into a single sample – can be used in biomonitoring studies to monitor levels of exposure and identify exposure trends, or to identify susceptible populations in a cost-effective manner. Pooled samples provide an estimate of central tendency, and may also reveal information about variation within the population. The development of a pooling strategy requires careful consideration of the type and number of samples collected, the number of pools required, and the number of specimens to combine per pool in order to maximize the type and robustness of the data. Creative pooling strategies can be used to explore exposure-outcome associations, and extrapolation from other larger studies can be useful in identifying elevated exposures in specific individuals. The use of pooled specimens is advantageous as it saves significantly on analytical costs, may reduce the time and resources required for recruitment, and in certain circumstances, allows quantification of samples approaching the limit of detection. In addition, use of pooled samples can provide population estimates while avoiding ethical difficulties that may be associated with reporting individual results.

The human cost of change : tales from the campus about personal change fatigue, resistance, and resilience

For the last decade, one question has haunted me: what helps people to cope with large-scale organisational change in their workplace? This study explores the construct of personal change resilience, and its potential for identifying solutions to the problems of change fatigue and change resistance. The thesis has emerged from the fields of change management, leadership, training, mentoring, evaluation, management and trust within the context of higher education in Australia at the beginning of the twenty-first century. In this thesis I present a theoretical model of the factors to consider in increasing peoples’ personal change resilience as they navigate large-scale organisational change at work, thereby closing a gap in the literature on the construct of change resilience. The model presented is based on both the literature in the realms of business and education, and on the findings of the research. In this thesis, an autoethnographic case study of two Australian university projects is presented as one narrative, resulting in a methodological step forward in the use of multiple research participants’ stories in the development of a single narrative. The findings describe the experiences of workers in higher education and emphasise the importance of considerate management in the achievement of positive experiences of organisational change. This research makes a significant contribution to new knowledge in three ways. First, it closes a gap in the literature in the realm of change management around personal change resilience as a solution to the problem of change fatigue by presenting models of both change failure and personal change resilience. Second, it is methodologically innovative in the use of personae to tell the stories of multiple participants in one coherent tale presented as a work of ethnographic fiction seen through an autoethnographic lens. By doing so, it develops a methodology for giving a voice to those to whom change is done in the workplace. Third, it provides a perspective on organisational change management from the view of the actual workers affected by change, thereby adding to the literature that currently exists, which is based on the views of those with responsibility for leading or managing change rather than those it affects. This thesis is intended as a practical starting point for conversations by actual change managers in higher education, and it is written in such a way as to help them see how theory can be applied in real life, and how empowering and enabling the actual working staff members, and engaging with them in a considerate way before, during and even after the change process, can help to make them resilient enough to cope with the change, rather than leaving them burned out or disengaged and no longer a well-functioning member of the institution. This thesis shows how considerately managed large-scale organisational change can result in positive outcomes for both the organisation and the individuals who work in it.

Robust recognition of human behaviour in challenging environments

Novel techniques have been developed for the automatic recognition of human behaviour in challenging environments using information from visual and infra-red camera feeds. The techniques have been applied to two interesting scenarios: Recognise drivers' speech using lip movements and recognising audience behaviour, while watching a movie, using facial features and body movements. Outcome of the research in these two areas will be useful in the improving the performance of voice recognition in automobiles for voice based control and for obtaining accurate movie interest ratings based on live audience response analysis.

Exchanging data between Digital Human Modelling systems : a review of data formats

Digital human modeling (DHM) systems underwent significant development within the last years. They achieved constantly growing importance in the field of ergonomic workplace design, product development, product usability, ergonomic research, ergonomic education, audiovisual marketing and the entertainment industry. They help to design ergonomic products as well as healthy and safe socio-technical work systems. In the domain of scientific DHM systems, no industry specific standard interfaces are defined which could facilitate the exchange of 3D solid body data, anthropometric data or motion data. The focus of this article is to provide an overview of requirements for a reliable data exchange between different DHM systems in order to identify suitable file formats. Examples from the literature are discussed in detail. Methods: As a first step a literature review is conducted on existing studies and file formats for exchanging data between different DHM systems. The found file formats can be structured into different categories: static 3D solid body data exchange, anthropometric data exchange, motion data exchange and comprehensive data exchange. Each file format is discussed and advantages as well as disadvantages for the DHM context are pointed out. Case studies are furthermore presented, which show first approaches to exchange data between DHM systems. Lessons learnt are shortly summarized. Results: A selection of suitable file formats for data exchange between DHM systems is determined from the literature review.