Association between xenobiotic gene polymorphisms and non-Hodgkin's lymphoma risk

The last four decades have seen a significant increase in the incidence of non-Hodgkin's lymphoma (NHL) as a possible result of increasing environmental carcinogen exposure, particularly pesticides and solvents. Based on the increasing evidence for an association between carcinogen exposure-related cancer risk and xenobiotic gene polymorphisms, we have undertaken a case-control study of xenobiotic gene polymorphisms in individuals with a diagnosis of NHL. Polymorphisms of six xenobiotic genes (CYP1A1, GSTT1, GSTM1, PON1, NAT1, NAT2) were characterized in 169 individuals with NHL and 205 normal controls using polymerase chain reaction-based methods. Polymorphic frequencies were compared using Fisher's exact tests, and odds ratios for NHL risk were calculated. Among the NHL group, the incidence of GSTT1 null and PON1 BB genotypes were significantly increased compared with controls, 34% vs 14%, and 24% vs 11% respectively. Adjusted odds ratios calculated from multivariate analyses demonstrated that GSTT1 null conferred a fourfold increase in NHL risk (OR = 4.27; 95% CI, 2.40-7.61, P < 0.001) and PON1 BB a 2.9-fold increase (OR = 2.92; 95% CI, 1.49-5.72, P = 0.002). Furthermore, GSTT1 null combined with PON1 BB or GSTM1 null conferred an additional risk of NHL. This is the first time that a PON1 gene polymorphism has been shown to be associated with cancer risk. We conclude that the two polymorphisms, GSTT1 null and PON1 BB, are common genetic traits that pose low individual risk but may be important determinants of overall population NHL risk, particularly among groups exposed to NHL-related carcinogens.

"I can't believe I just said that": Using guided reflections with non-Indigenous pre-service teachers in Australia

This paper explores the use of guided narrative reflection as a strategy used with high-achieving non-Indigenous pre-service teachers in Australia on teaching practicum. We suggest that reflections (and subsequent dialogue) can provide opportunities for non-Indigenous preservice teachers to re-think their beliefs and actions in ways that may intervene in the teaching that often causes educational disadvantage for Aboriginal and Torres Strait Islander students.

The impact of heatwaves on mortality and emergency hospital admissions from non-external causes in Brisbane, Australia

Objectives Heatwaves can have significant health consequences resulting in increased mortality and morbidity. However, their impact on people living in tropical/subtropical regions remains largely unknown. This study assessed the impact of heatwaves on mortality and emergency hospital admissions (EHAs) from non-external causes (NEC) in Brisbane, a subtropical city in Australia. Methods We acquired daily data on weather, air pollution and EHAs for patients aged 15 years and over in Brisbane between January 1996 and December 2005, and on mortality between January 1996 and November 2004. A locally derived definition of heatwave (daily maximum ≥37°C for 2 or more consecutive days) was adopted. Case–crossover analyses were used to assess the impact of heatwaves on cause-specific mortality and EHAs. Results During heatwaves, there was a statistically significant increase in NEC mortality (OR 1.46; 95% CI 1.21 to 1.77), cardiovascular mortality (OR 1.89; 95% CI 1.44 to 2.48), diabetes mortality in those aged 75+ (OR 9.96; 95% CI 1.02 to 96.85), NEC EHAs (OR 1.15; 95% CI 1.07 to 1.23) and EHAs from renal diseases (OR 1.41; 95% CI 1.09 to 1.83). The elderly were found to be particularly vulnerable to heatwaves (eg, for NEC EHAs, OR 1.24 for 65–74-year-olds and 1.39 for those aged 75+). Conclusions Significant increases in NEC mortality and EHAs were observed during heatwaves in Brisbane where people are well accustomed to hot summer weather. The most vulnerable were the elderly and people with cardiovascular, renal or diabetic disease.

Higher-order non-linear analysis of steel structures. Part I : elastic second-order formulation

This paper presents a higher-order beam-column formulation that can capture the geometrically non-linear behaviour of steel framed structures which contain a multiplicity of slender members. Despite advances in computational frame software, analyses of large frames can still be problematic from a numerical standpoint and so the intent of the paper is to fulfil a need for versatile, reliable and efficient non-linear analysis of general steel framed structures with very many members. Following a comprehensive review of numerical frame analysis techniques, a fourth-order element is derived and implemented in an updated Lagrangian formulation, and it is able to predict flexural buckling, snap-through buckling and large displacement post-buckling behaviour of typical structures whose responses have been reported by independent researchers. The solutions are shown to be efficacious in terms of a balance of accuracy and computational expediency. The higher-order element forms a basis for augmenting the geometrically non-linear approach with material non-linearity through the refined plastic hinge methodology described in the companion paper.

Higher-order non-linear analysis of steel structures. Part II : refined plastic hinge formulation

In the companion paper, a fourth-order element formulation in an updated Lagrangian formulation was presented to handle geometric non-linearities. The formulation of the present paper extends this to include material non-linearity by proposing a refined plastic hinge approach to analyse large steel framed structures with many members, for which contemporary algorithms based on the plastic zone approach can be problematic computationally. This concept is an advancement of conventional plastic hinge approaches, as the refined plastic hinge technique allows for gradual yielding, being recognized as distributed plasticity across the element section, a condition of full plasticity, as well as including strain hardening. It is founded on interaction yield surfaces specified analytically in terms of force resultants, and achieves accurate and rapid convergence for large frames for which geometric and material non-linearity are significant. The solutions are shown to be efficacious in terms of a balance of accuracy and computational expediency. In addition to the numerical efficiency, the present versatile approach is able to capture different kinds of material and geometric non-linearities on general applications of steel structures, and thereby it offers an efficacious and accurate means of assessing non-linear behaviour of the structures for engineering practice.

Is sedation by non-anaesthetists really safe?

I read with great interest the editorial recently published in the British Journal of Anaesthesia that questioned whether sedation by non-anaesthetists is really safe. The authors noted their ‘grave concerns’ about the emerging practice of non-anaesthetist administered propofol (NAAP) during electrophysiology procedures. I offer the following insights into this issue.

The informed manager : exploring absorptive capacity in the non-profit sector

Being across new knowledge is critical to the survival of individual businesses. This study explored the way in which managers of small social services in Queensland identified important new knowledge and brought this into their organisations. New knowledge was found to be highly valued by managers with key resources allocated to knowledge seeking processes particularly in response to regulatory change. Knowledge absorption involved accessing multiple sources, and external professional networks were found to be critical to understanding and integrating new knowledge. The research highlighted the challenges in securing new knowledge and the importance of managers professional links.

A near-to-far non-parametric learning approach for estimating traversability in deformable terrain

It is well recognized that many scientifically interesting sites on Mars are located in rough terrains. Therefore, to enable safe autonomous operation of a planetary rover during exploration, the ability to accurately estimate terrain traversability is critical. In particular, this estimate needs to account for terrain deformation, which significantly affects the vehicle attitude and configuration. This paper presents an approach to estimate vehicle configuration, as a measure of traversability, in deformable terrain by learning the correlation between exteroceptive and proprioceptive information in experiments. We first perform traversability estimation with rigid terrain assumptions, then correlate the output with experienced vehicle configuration and terrain deformation using a multi-task Gaussian Process (GP) framework. Experimental validation of the proposed approach was performed on a prototype planetary rover and the vehicle attitude and configuration estimate was compared with state-of-the-art techniques. We demonstrate the ability of the approach to accurately estimate traversability with uncertainty in deformable terrain.

Capturing complex, non-linear team behaviours during competitive football performance

This study investigated changes in the complexity (magnitude and structure of variability) of the collective behaviours of association football teams during competitive performance. Raw positional data from an entire competitive match between two professional teams were obtained with the ProZone® tracking system. Five compound positional variables were used to investigate the collective patterns of performance of each team including: surface area, stretch index, team length, team width, and geometrical centre. Analyses involve the coefficient of variation (%CV) and approximate entropy (ApEn), as well as the linear association between both parameters. Collective measures successfully captured the idiosyncratic behaviours of each team and their variations across the six time periods of the match. Key events such as goals scored and game breaks (such as half time and full time) seemed to influence the collective patterns of performance. While ApEn values significantly decreased during each half, the %CV increased. Teams seem to become more regular and predictable, but with increased magnitudes of variation in their organisational shape over the natural course of a match.

IL-23R is epigenetically regulated and modulated by chemotherapy in non-small cell lung cancer

The Interleukin-23 (IL-23)/IL-23R signaling axis is an important inflammatory pathway, involved in the stimulation and regulation of the T helper (Th) 17 lymphocytes, resulting in the production of IL-17. Aside from auto-immunity, this cytokine has also been linked to carcinogenesis and polymorphisms in the IL-23R gene are associated with an increased risk for the development of a number of different cancers. Activation of the IL-23 pathway results in the up-regulation of STAT3 and it is thought that the pathological consequences associated with this are in part due to the production of IL-17. We have previously identified IL-23A as pro-proliferative and epigenetically regulated in non-small cell lung cancer (NSCLC). The current study aims to evaluate IL-23R in greater detail in NSCLC. We demonstrate that IL-23R is expressed and epigenetically regulated in NSCLC through histone post-translation modifications and CpG island methylation. In addition, Gemcitabine treatment, a chemotherapy drug used in the treatment of NSCLC, resulted in the up-regulation of the IL-23R. Furthermore, Apilimod (STA 5326), a small molecule which blocks the expression of IL-23 and IL-12, reduced the proliferative capacity of NSCLC cells, particularly in the adenocarcinoma (A549) sub-type. Apilimod is currently undergoing investigation in a number of clinical trials for the treatment of auto-immune conditions such as Crohn's disease and Rheumatoid Arthritis. Our results may have implications for treating NSCLC patients with Gemcitabine or epigenetic targeted therapies. However, Apilimod may possibly provide a new treatment avenue for NSCLC patients. Work is currently ongoing to further delineate the IL-23/IL-23R axis in this disease.

Thromboxane synthase expression and correlation with VEGF and angiogenesis in non-small cell lung cancer

Background Thromboxane synthase (TXS) metabolizes prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with angiogenesis and poor outcome. TXS has been identified as a potential therapeutic target in NSCLC. This study examines a link between TXS expression, angiogenesis, and survival in NSCLC. Methods TXS and VEGF metabolite levels were measured in NSCLC serum samples (n=46) by EIA. TXB2 levels were correlated with VEGF. A 204-patient TMA was stained for TXS, VEGF, and CD-31 expression. Expression was correlated with a range of clinical parameters, including overall survival. TXS expression was correlated with VEGF and CD-31. Stable TXS clones were generated and the effect of overexpression on tumor growth and angiogenesis markers was examined in-vitro and in-vivo (xenograft mouse model). Results Serum TXB2 levels were correlated with VEGF (p<0.05). TXS and VEGF were expressed to a varying degree in NSCLC tissue. TXS was associated with VEGF (p<0.0001) and microvessel density (CD-31; p<0.05). TXS and VEGF expression levels were higher in adenocarcinoma (p<0.0001) and female patients (p<0.05). Stable overexpression of TXS increased VEGF secretion in-vitro. While no significant association with patient survival was observed for either TXS or VEGF in our patient cohort, TXS overexpression significantly (p<0.05) increased tumor growth in-vivo. TXS overexpression was also associated with higher levels of VEGF, microvessel density, and reduced apoptosis in xenograft tumors. Conclusion TXS promotes tumor growth in-vivo in NSCLC, an effect which is at least partly mediated through increased tumor angiogenesis.

High coexpression of both EGFR and IGF1R correlates with poor patient prognosis in resected non-small-cell lung cancer

Background Recent experimental and biomarker evidence indicates that the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor 1 (IGF1R) interact in the pathogenesis of malignant epithelial tumors, including lung cancer. This study examines the expression of both receptors and their prognostic significance in surgically resected non-small-cell lung cancer (NSCLC). Methods EGFR and IGF1R expression were evaluated in 184 patients with NSCLC (83 squamous cell carcinomas [SCCs], 83 adenocarcinomas [ADCs], and 18 other types) using immunohistochemical (IHC) analysis. Expression of both receptors was examined in matched fresh frozen normal and tumor tissues from 40 patients with NSCLC (20 SCCs and 20 ADCs) by Western blot analysis. Results High EGFR expression was detected in 51% of patients, and SCCs had higher EGFR expression than did non-SCCs (57.4% vs. 42.5%; P =.028). High IGF1R expression was observed in 53.8% of patients, with SCC having higher expression than non-SCC (62.6% vs. 37.3%; P =.0004). A significant association was shown between EGFR and IGF1R protein overexpression (P <.005). Patients with high expression of both receptors had a poorer overall survival (OS) (P =.04). Higher EGFR and IGF1R expression was detected in resected tumors relative to matched normal tissues (P =.0004 and P =.0009), with SCC having higher expression levels than ADC. Conclusion Our findings indicate a close interrelationship between EGFR and IGF1R. Coexpression of both receptors correlates with poor survival. This subset of patients may benefit from treatments cotargeting EGFR and IGF1R. © 2014 Elsevier Inc. All rights reserved.

Targeted therapies in non-small cell lung cancer

The majority of non-small cell lung cancer (NSCLC) patients present with advanced disease and with a 5 year survival rate of <15% for these patients, treatment outcomes are considered extremely disappointing. Standard chemotherapy regimens provide some improvement to ~40% of patients. However, intrinsic and acquired chemoresistance are a significant problem and hinder sustained long term benefits of such treatments. Advances in proteomic and genomic profiling have increased our understanding of the aberrant molecular mechanisms that are driving an individual's tumour. The increased sensitivity of these technologies has enabled molecular profiling at the stage of initial biopsy thus paving the way for a more personalised approach to the treatment of cancer patients. Improvements in diagnostics together with a wave of new targeted small molecule inhibitors and monoclonal antibodies have revolutionised the treatment of cancer. To date there are essentially three targeted agents approved for clinical use in NSCLC. The tyrosine kinase inhibitor (TKI) erlotinib, which targets the epidermal growth factor receptor (EGFR) TK domain, has proven to be an effective treatment strategy in patients who harbour activating mutations in the EGFR TK domain. Bevacizumab a monoclonal antibody targeting the vascular endothelial growth factor (VEGF) can improve survival, response rates, and progression-free survival when used in combination with chemotherapy. Crizotinib, a small-molecule drug, inhibits the tyrosine kinase activity of the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) fusion protein, resulting in decreased tumour cell growth, migration, and invasiveness in patients with locally advanced or metastatic NSCLC. The clinical relevance of several other targeted agents are under investigation in distinct molecular subsets of patients with key "driver" mutations including: KRAS, HER2, BRAF, MET, PIK3CA, AKT1,MAP2K1, ROS1 and RET. Often several pathways are activated simultaneously and crosstalk between pathways allows tumour cells to escape the inhibition of a single targeted agent. This chapter will explore the clinical development of currently available targeted therapies for NSCLC as well as those in clinical trials and will examine the synergy between cytotoxic therapies.

Acquired differential regulation of caspase-8 in cisplatin-resistant non-small-cell lung cancer

Failure to efficiently induce apoptosis contributes to cisplatin resistance in non-small-cell lung cancer (NSCLC). Although BCL-2-associated X protein (BAX) and BCL-2 antagonist killer (BAK) are critical regulators of the mitochondrial apoptosis pathway, their requirement has not been robustly established in relation to cisplatin. Here, we show that cisplatin can efficiently bypass mitochondrial apoptosis block caused by loss of BAX and BAK, via activation of the extrinsic death receptor pathway in some model cell lines. Apoptosis resistance following cisplatin can only be observed when both extrinsic and intrinsic pathways are blocked, consistent with redundancy between mitochondrial and death receptor pathways in cisplatin-induced apoptosis. In H460 NSCLC cells, caspase-8 cleavage was shown to be induced by cisplatin and is dependent on death receptor 4, death receptor 5, Fas-associated protein with death domain, acid sphingomyelinase and ceramide synthesis. In contrast, cisplatin-resistant cells fail to activate caspase-8 via this pathway despite conserving sensitivity to death ligand-driven activation. Accordingly, caspase-8 activation block acquired during cisplatin resistance, can be bypassed by death receptor agonism.

Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer

OBJECTIVES: Four randomized phase II/III trials investigated the addition of cetuximab to platinum-based, first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). A meta-analysis was performed to examine the benefit/risk ratio for the addition of cetuximab to chemotherapy. MATERIALS AND METHODS: The meta-analysis included individual patient efficacy data from 2018 patients and individual patient safety data from 1970 patients comprising respectively the combined intention-to-treat and safety populations of the four trials. The effect of adding cetuximab to chemotherapy was measured by hazard ratios (HRs) obtained using a Cox proportional hazards model and odds ratios calculated by logistic regression. Survival rates at 1 year were calculated. All applied models were stratified by trial. Tests on heterogeneity of treatment effects across the trials and sensitivity analyses were performed for all endpoints. RESULTS: The meta-analysis demonstrated that the addition of cetuximab to chemotherapy significantly improved overall survival (HR 0.88, p=0.009, median 10.3 vs 9.4 months), progression-free survival (HR 0.90, p=0.045, median 4.7 vs 4.5 months) and response (odds ratio 1.46, p<0.001, overall response rate 32.2% vs 24.4%) compared with chemotherapy alone. The safety profile of chemotherapy plus cetuximab in the meta-analysis population was confirmed as manageable. Neither trials nor patient subgroups defined by key baseline characteristics showed significant heterogeneity for any endpoint. CONCLUSION: The addition of cetuximab to platinum-based, first-line chemotherapy for advanced NSCLC significantly improved outcome for all efficacy endpoints with an acceptable safety profile, indicating a favorable benefit/risk ratio.