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.

Feeling it out : Clark Beaumont

This catalogue essay was written to accompany Clark Beaumont's 2014 exhibition at Kings Artist Run in Melbourne, 'Feeling It Out'. It contextualises Clark Beaumont's work within a history of women's participation and achievement in modern and contemporary art, and suggests that this body of work may work through issues of anxiety, ambivalence and doubt about the art world.

Review : "The Culture of Curating and the Curating of Culture(s)", Paul O’Neill (2012)

Paul O'Neill's book, 'The Culture of Curating and the Curating of Culture(s)provides a concise overview of how curating has changed art and how art has changed curating. The book is divided into three sections, each dealing with a key transitional development: (1) the historical development of curatorial discourse; (2) the influence of the Biennial phenomenon and, finally, (3) how art and curating have converged since the 1990s. This review discusses the publication as a significant contribution to the development of a curatorial history and discourse.

Differential Regulation of Clusterin Isoforms by the Androgen Receptor

Clusterin (CLU) was initially reported as an androgen-repressed gene which is now shown to be an androgen-regulated ATP-independent cytoprotective molecular chaperone. CLU binds to a wide variety of client proteins to potently inhibit stress-induced protein aggregation and chaperone or stabilise conformations of proteins at times of cell stress. CLU is an enigmatic protein, being ascribed both pro- and anti-apoptotic roles. Recent evidence has shown that both secreted (sCLU) and nuclear (nCLU) isoforms can be produced, and that protein function is dependent on the sub-cellular localisation. We and others have shown that sCLU is cytoprotective, while nCLU is pro-apoptotic. It now seems likely that the apparently dichotomous functions of CLU result from the expression of different but related CLU isoforms and splice variants, and that cell survival depends in part on the relative expression of pro- versus anti-apoptotic CLU proteins. In cancer cells, increased sCLU expression is associated with increased resistance to apoptotic triggers and treatment resistance. CLU is a stress-induced protein upregulated after apoptotic triggers like androgen ablation and chemotherapy. Treatment strategies targeting stress-associated increases in sCLU expression enhance treatment-induced apoptosis and delay the emergence of androgen independence. Differential regulation of CLU isoforms and splice variants by androgens may be a pathway whereby cancer cells develop treatment resistance and evade apoptosis.

Longitudinal think aloud study of a novice programmer

Recent research from within a neo-Piagetian perspective proposes that novice programmers pass through the sensorimotor and preoperational stages before being able to reason at the concrete operational stage. However, academics traditionally teach and assess introductory programming as if students commence at the concrete operational stage. In this paper, we present results from a series of think aloud sessions with a single student, known by the pseudonym “Donald”. We conducted the sessions mainly over one semester, with an additional session three semesters later. Donald first manifested predominately sensorimotor reasoning, followed by preoperational reasoning, and finally concrete operational reasoning. This longitudinal think aloud study of Donald is the first direct observational evidence of a novice programmer progressing through the neo-Piagetian stages.

RMAA safety performance : how does it compare with Greenfield projects?

Gross value of cons truction work in the repair , maintenance, minor alte ration and addition (RMAA) sector in Hong Kong has expanded dramatically by 58% from 1998 to 2007, accounting for over 53% of the whole construction market in 2007. Unfortunately, the portion of industrial accidents arising from this sector also increased substantially during the same period. It is important to improve the safety performance of the RMAA sector. This paper has set out the objectives to examine safety statistics of RMAA works; to compare them with those of green field projects; and more importantly, to highlight potential hurdles en countered in the process of comparison and finally to provide effective recommendations for overcoming these impediments. To strive for continuous safety improvement of RMAA works, comparable safety statistics should be compiled for this sector.

Staurosporine augments EGF-mediated EMT in PMC42-LA cells through actin depolymerisation, focal contact size reduction and Snail1 induction : a model for cross-modulation

Background A feature of epithelial to mesenchymal transition (EMT) relevant to tumour dissemination is the reorganization of actin cytoskeleton/focal contacts, influencing cellular ECM adherence and motility. This is coupled with the transcriptional repression of E-cadherin, often mediated by Snail1, Snail2 and Zeb1/δEF1. These genes, overexpressed in breast carcinomas, are known targets of growth factor-initiated pathways, however it is less clear how alterations in ECM attachment cross-modulate to regulate these pathways. EGF induces EMT in the breast cancer cell line PMC42-LA and the kinase inhibitor staurosporine (ST) induces EMT in embryonic neural epithelial cells, with F-actin de-bundling and disruption of cell-cell adhesion, via inhibition of aPKC. Methods PMC42-LA cells were treated for 72 h with 10 ng/ml EGF, 40 nM ST, or both, and assessed for expression of E-cadherin repressor genes (Snail1, Snail2, Zeb1/δEF1) and EMT-related genes by QRT-PCR, multiplex tandem PCR (MT-PCR) and immunofluorescence +/- cycloheximide. Actin and focal contacts (paxillin) were visualized by confocal microscopy. A public database of human breast cancers was assessed for expression of Snail1 and Snail2 in relation to outcome. Results When PMC42-LA were treated with EGF, Snail2 was the principal E-cadherin repressor induced. With ST or ST+EGF this shifted to Snail1, with more extreme EMT and Zeb1/δEF1 induction seen with ST+EGF. ST reduced stress fibres and focal contact size rapidly and independently of gene transcription. Gene expression analysis by MT-PCR indicated that ST repressed many genes which were induced by EGF (EGFR, CAV1, CTGF, CYR61, CD44, S100A4) and induced genes which alter the actin cytoskeleton (NLF1, NLF2, EPHB4). Examination of the public database of breast cancers revealed tumours exhibiting higher Snail1 expression have an increased risk of disease-recurrence. This was not seen for Snail2, and Zeb1/δEF1 showed a reverse correlation with lower expression values being predictive of increased risk. Conclusion ST in combination with EGF directed a greater EMT via actin depolymerisation and focal contact size reduction, resulting in a loosening of cell-ECM attachment along with Snail1-Zeb1/δEF1 induction. This appeared fundamentally different to the EGF-induced EMT, highlighting the multiple pathways which can regulate EMT. Our findings add support for a functional role for Snail1 in invasive breast cancer.

Carcinoma invasion and metastasis : a role for epithelial-mesenchymal transition?

Carcinogenesis involves the accretion of unprogrammed genetic and epigenetic changes, which lead to dysregulation of the normal control of cell number. But a key clinical turning point in carcinoma progression is the establishment by emigrant cells of secondary growth sites (i.e., metastasis). The metastatic “cascade” comprises numerous steps, including escape from the primary tumor site, penetration of local stroma, entry of local vascular or lymphatic vessels (intravasation), aggregation with platelets, interaction with and adhesion to distant endothelia, extravasation, recolonization, and expansion ( 1), all the time avoiding effective immune clearance and being able to survive in these multiple contexts...

Contribution of fibroblast and mast cell (afferent) and tumor (efferent) IL-6 effects within the tumor microenvironment

Hyperactive inflammatory responses following cancer initiation have led to cancer being described as a 'wound that never heals'. These inflammatory responses elicit signals via NFκB leading to IL-6 production, and IL-6 in turn has been shown to induce epithelial to mesenchymal transition in breast cancer cells in vitro, implicating a role for this cytokine in cancer cell invasion. We previously have shown that conditioned medium derived from cancer-associated fibroblasts induced an Epithelial to Mesenchymal transition (EMT) in PMC42-LA breast cancer cells and we have now identify IL-6 as present in this medium. We further show that IL-6 is expressed approximately 100 fold higher in a cancer-associated fibroblast line compared to normal fibroblasts. Comparison of mouse-specific (stroma) and human-specific (tumor) IL-6 mRNA expression from MCF-7, MDA MB 468 and MDA MB 231 xenografts also indicated the stroma rather than tumor as a significantly higher source of IL-6 expression. Mast cells (MCs) feature in inflammatory cancer-associated stroma, and activated MCs secrete IL-6. We observed a higher MC index (average number of mast cells per xenograft section/average tumor size) in MDA MB 468 compared to MDA MB 231 xenografts, where all MC were observed to be active (degranulating). This higher MC index correlated with greater mouse-specific IL-6 expression in the MDA MB 468 xenografts, implicating MC as an important source of stromal IL-6. Furthermore, immunohistochemistry on these xenografts for pSTAT3, which lies downstream of the IL-6 receptor indicated frequent correlations between pSTAT3 and mast cell positive cells. Analysis of publically available databases for IL-6 expression in patient tissue revealed higher IL-6 in laser capture microdissected stroma compared to adjacent tissue epithelium from patients with inflammatory breast cancer (IBC) and invasive non-inflammatory breast cancer (non-IBC) and we show that IL-6 expression was significantly higher in Basal versus Luminal molecular/phenotypic groupings of breast cancer cell lines. Finally, we discuss how afferent and efferent IL-6 pathways may participate in a positive feedback cycle to dictate tumor progression.

Epidermal growth factor-induced epithelio-mesenchymal transition in human breast carcinoma cells

PMC42-LA cells display an epithelial phenotype: the cells congregate into pavement epithelial sheets in which E-cadherin and β-catenin are localized at cell-cell borders. They abundantly express cytokeratins, although 5% to 10% of the cells also express the mesenchymal marker vimentin. Stimulation of PMC42-LA cells with epidermal growth factor (EGF) leads to epithelio-mesenchymal transition-like changes including up-regulation of vimentin and down-regulation of E-cadherin. Vimentin expression is seen in virtually all cells, and this increase is abrogated by treatment of cells with an EGF receptor antagonist. The expression of the mesenchyme-associated extracellular matrix molecules fibronectin and chondroitin sulfate proteoglycan also increase in the presence of EGF. PMC42-LA cells adhere rapidly to collagen I, collagen IV, and laminin-1 substrates and markedly more slowly to fibronectin and vitronectin. EGF increases the speed of cell adhesion to most of these extracellular matrix molecules without altering the order of adhesive preference. EGF also caused a time-dependent increase in the motility of PMC42-LA cells, commensurate with the degree of vimentin staining. The increase in motility was at least partly chemokinetic, because it was evident both with and without chemoattractive stimuli. Although E-cadherin staining at cell-cell junctions disappeared in response to EGF, β-catenin persisted at the cell periphery. Further analysis revealed that N-cadherin was present at the cell-cell junctions of untreated cells and that expression was increased after EGF treatment. N- and E-cadherin are not usually coexpressed in human carcinoma cell lines but can be coexpressed in embryonic tissues, and this may signify an epithelial cell population prone to epithelio-mesenchymal-like responses.

STI-GMaS : an open-source environment for simulation of sexually-transmitted infections

Background Sexually-transmitted pathogens often have severe reproductive health implications if treatment is delayed or absent, especially in females. The complex processes of disease progression, namely replication and ascension of the infection through the genital tract, span both extracellular and intracellular physiological scales, and in females can vary over the distinct phases of the menstrual cycle. The complexity of these processes, coupled with the common impossibility of obtaining comprehensive and sequential clinical data from individual human patients, makes mathematical and computational modelling valuable tools in developing our understanding of the infection, with a view to identifying new interventions. While many within-host models of sexually-transmitted infections (STIs) are available in existing literature, these models are difficult to deploy in clinical/experimental settings since simulations often require complex computational approaches. Results We present STI-GMaS (Sexually-Transmitted Infections – Graphical Modelling and Simulation), an environment for simulation of STI models, with a view to stimulating the uptake of these models within the laboratory or clinic. The software currently focuses upon the representative case-study of Chlamydia trachomatis, the most common sexually-transmitted bacterial pathogen of humans. Here, we demonstrate the use of a hybrid PDE–cellular automata model for simulation of a hypothetical Chlamydia vaccination, demonstrating the effect of a vaccine-induced antibody in preventing the infection from ascending to above the cervix. This example illustrates the ease with which existing models can be adapted to describe new studies, and its careful parameterisation within STI-GMaS facilitates future tuning to experimental data as they arise. Conclusions STI-GMaS represents the first software designed explicitly for in-silico simulation of STI models by non-theoreticians, thus presenting a novel route to bridging the gap between computational and clinical/experimental disciplines. With the propensity for model reuse and extension, there is much scope within STI-GMaS to allow clinical and experimental studies to inform model inputs and drive future model development. Many of the modelling paradigms and software design principles deployed to date transfer readily to other STIs, both bacterial and viral; forthcoming releases of STI-GMaS will extend the software to incorporate a more diverse range of infections.

Promoting resilience in children with intellectual disability : a randomized controlled trial in Australian schools

Children with intellectual disability are more vulnerable to adverse developmental outcomes because of the lifelong risks associated with cognitive impairment. Difficulties with learning and adaptive behaviour inevitably produce considerable personal, social and economic disadvantage. Of concern is consistent evidence that psychiatric disorders affect a substantial proportion of people with intellectual disability. The estimated prevalence rate of between 35 and 49 % is three times that found in the general population (Wallander, Dekker, & Koot, 2006). Until recently, mental illness has been relatively neglected for people with intellectual disability, especially in relation to prevention or early detection (Kolaitis, 2008) and most research to date has been descriptive rather than focused on intervention (Bouras, 2013). Yet a considerable body of evidence demonstrates that efficacious interventions do exist for preventing psychopathology and enhancing resilience in typically developing children and adolescents (see Mallin, Walker, & Levin, 2013 for a review). In order to prevent the high comorbidity of intellectual disability and psychopathology, there is a compelling need for evidence-based practices that promote the resilience of individuals with intellectual disability (Matson, Terlonge, & Minshawi, 2008). In this chapter, we describe a randomized controlled trial of an intervention that was designed to enhance the resilience of a group of children with mild intellectual disability as they prepared to make the transition to high school. We report results from our evaluation of this intervention, and reflect on the difficulties of providing successful interventions for children whose lives are complicated not only by intellectual disability, but also by a range of contextual disadvantages.

Artists and their worlds

A catalogue essay written for 'Tall Tales and Other Adventures: a University of Southern Queensland, Dogwood Crossing, Miles and Flying Arts research project.'

Frontier thinking : fear of the frock?

Stylish women, Dr Gertrude Langer, Margaret Cilento, and Joy Roggenkamp, didn't fit the mythology of modern art in Brisbane, typified by rugged artists like Ian Fairweather and Jon Molvig. Courtney Pedersen considers the place of fashion, urbanity, and women in the mid-century avant-garde.

Phosphoprotein pathway mapping: Akt/Mammalian target of rapamycin activation is negatively associated with childhood rhabdomyosarcoma survival

Mapping of protein signaling networks within tumors can identify new targets for therapy and provide a means to stratify patients for individualized therapy. Despite advances in combination chemotherapy, the overall survival for childhood rhabdomyosarcoma remains ∼60%. A critical goal is to identify functionally important protein signaling defects associated with treatment failure for the 40% nonresponder cohort. Here, we show, by phosphoproteomic network analysis of microdissected tumor cells, that interlinked components of the Akt/mammalian target of rapamycin (mTOR) pathway exhibited increased levels of phosphorylation for tumors of patients with short-term survival. Specimens (n = 59) were obtained from the Children's Oncology Group Intergroup Rhabdomyosarcoma Study (IRS) IV, D9502 and D9803, with 12-year follow-up. High phosphorylation levels were associated with poor overall and poor disease-free survival: Akt Ser473 (overall survival P < 0.001, recurrence-free survival P < 0.0009), 4EBP1 Thr37/46 (overall survival P < 0.0110, recurrence-free survival P < 0.0106), eIF4G Ser1108 (overall survival P < 0.0017, recurrence-free survival P < 0.0072), and p70S6 Thr389 (overall survival P < 0.0085, recurrence-free survival P < 0.0296). Moreover, the findings support an altered interrelationship between the insulin receptor substrate (IRS-1) and Akt/mTOR pathway proteins (P < 0.0027) for tumors from patients with poor survival. The functional significance of this pathway was tested using CCI-779 in a mouse xenograft model. CCI-779 suppressed phosphorylation of mTOR downstream proteins and greatly reduced the growth of two different rhabdomyosarcoma (RD embryonal P = 0.00008; Rh30 alveolar P = 0.0002) cell lines compared with controls. These results suggest that phosphoprotein mapping of the Akt/mTOR pathway should be studied further as a means to select patients to receive mTOR/IRS pathway inhibitors before administration of chemotherapy.