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.

Corporate reputation and financial performance : underlying dimensions of corporate reputation and their relation to sustained financial performance

This thesis examined the relationship between firms' corporate reputation and their future financial performance. Corporate reputation was represented by measuring the level of senior executives' attention to a number of intangible firm' resources (e.g. financial reputation, service culture) within firms' annual reports over a 17 year period. Initial findings suggested there was only a small relationship between reputation and future performance which lead to a reformulation of the problem. Reputation was posited to be a source of corporate resilience that helped firms with stronger reputations to sustain superior financial performance in times of difficulty, as well as allowing them to rebound more quickly from performance decline. Results suggest this interpretation of corporate reputation as well as indicating that industry sectors operate in different reputational 'domains' in which the relative importance of financial versus stakeholder aspects of corporate reputation varies.

Blast response and failure analysis of pile foundations subjected to surface explosion

This paper presents the response of pile foundations to ground shocks induced by surface explosion using fully coupled and non-linear dynamic computer simulation techniques together with different material models for the explosive, air, soil and pile. It uses the Arbitrary Lagrange Euler coupling formulation with proper state material parameters and equations. Blast wave propagation in soil, horizontal pile deformation and pile damage are presented to facilitate failure evaluation of piles. Effects of end restraint of pile head and the number and spacing of piles within a group on their blast response and potential failure are investigated. The techniques developed and applied in this paper and its findings provide valuable information on the blast response and failure evaluation of piles and will provide guidance in their future analysis and design.

Mathematical investigation of the interactions between the inflammatory response and mechanical aspects of dermal wound repair

Dermal wound repair involves complex interactions between cells, cytokines and mechanics to close injuries to the skin. In particular, we investigate the contribution of fibroblasts, myofibroblasts, TGFβ, collagen and local tissue mechanics to wound repair in the human dermis. We develop a morphoelastic model where a realistic representation of tissue mechanics is key, and a fibrocontractive model that involves a reasonable approximation to the true kinetics of the important bioactive species. We use each of these descriptions to elucidate the mechanisms that generate pathologies such as hypertrophic scars, contractures and keloids. We find that for hypertrophic scar and contracture development, factors regulating the myofibroblast phenotype are critical, with heightened myofibroblast activation, reduced myofibroblast apoptosis or prolonged inflammation all predicted as mediators for scar hypertrophy and contractures. Prevention of these pathologies is predicted when myofibroblast apoptosis is induced, myofibroblast activation is blocked or TGFβ is neutralised. To investigate keloid invasion, we develop a caricature representation of the fibrocontractive model and find that TGFβ spread is the driving factor behind keloid growth. Blocking activation of TGFβ is found to cause keloid regression. Thus, we recommend myofibroblasts and TGFβ as targets for clinicians when developing intervention strategies for prevention and cure of fibrotic scars.

Cortisol shifts financial risk preferences

Risk taking is central to human activity. Consequently, it lies at the focal point of behavioral sciences such as neuroscience, economics, and finance. Many influential models from these sciences assume that financial risk preferences form a stable trait. Is this assumption justified and, if not, what causes the appetite for risk to fluctuate? We have previously found that traders experience a sustained increase in the stress hormone cortisol when the amount of uncertainty, in the form of market volatility, increases. Here we ask whether these elevated cortisol levels shift risk preferences. Using a double-blind, placebo-controlled, cross-over protocol we raised cortisol levels in volunteers over eight days to the same extent previously observed in traders. We then tested for the utility and probability weighting functions underlying their risk taking, and found that participants became more risk averse. We also observed that the weighting of probabilities became more distorted among men relative to women. These results suggest that risk preferences are highly dynamic. Specifically, the stress response calibrates risk taking to our circumstances, reducing it in times of prolonged uncertainty, such as a financial crisis. Physiology-induced shifts in risk preferences may thus be an under-appreciated cause of market instability.

Shadow boxing with an imaginary enemy : a response to “law and order blues”

In our rejoinder to Don Weatherburn's paper, “Law and Order Blues”, we do not take issue with his advocacy of the need to take crime seriously and to foster a more rational approach to the problems it poses. Where differences do emerge is (1) with his claim that he is willing to do so whilst we (in our different ways) are not; and (2) on the question of what this involves. Of particular concern is the way in which his argument proceeds by a combination of simple misrepresentation of the positions it seeks to disparage, and silence concerning issues of real substance where intellectual debate and exchange would be welcome and useful. Our paper challenges, in turn, the misrepresentation of Indermaur's analysis of trends in violent crime, the misrepresentation of Hogg and Brown's Rethinking Law and Order, the misrepresentation of the findings of some of the research into the effectiveness of punitive policies and the silence on sexual assault in “Law and Order Blues”. We suggest that his silence on sexual assault reflects a more widespread unwillingness to acknowledge the methodological problems that arise in the measurement of crime because such problems severely limit the extent to which confident assertions can be made about prevalence and trends.

Web based surveillance systems could improve disease detection and the response to emerging disease events

The Chinese government should be commended for its open, concerted, and rapid response to the recent H7N9 influenza outbreak. However, the first known case was not reported until 48 days after disease onset.1 Although the difficulties in detecting the virus and the lack of suitable diagnostic methods have been the focus of discussion,2 systematic limitations that may have contributed to this delay have hardly been discussed. The detection speed of surveillance systems is limited by the highly structured nature of information flow and hierarchical organisation of these systems. Flu surveillance usually relies on notification to a central authority of laboratory confirmed cases or presentations to sentinel practices for flu-like illness. Each step in this pathway presents a bottleneck at which information and time can be lost; this limitation must be dealt with...

Typology of phishing email victims based on their behavioural response

A victim of phishing emails could be subjected to money loss and identity theft. This paper investigates the different types of phishing email victims, with the goal of increasing such victims' defences. To obtain this kind of information, an experiment which involves sending a phishing email to participants is conducted. Quantitative and qualitative methods are also used to collect users' information. A model for detecting deception has been employed to understand victims' behaviour. This paper reports the qualitative results. The findings suggest that victims of phishing emails do not always exhibit the same vulnerability. The cause of being a victim is a result of three weaknesses in the detection process: (1) lack of knowledge; (2) weak confirmation channel, and; (3) victims' high propensity towards risk-taking. Therefore, it is suggested that users be provided with suitable confirmation channels and be more risk averse in their behaviour so that they would not fall victim to phishing emails.

Demand-side response model to avoid spike of electricity price

The aim of this work is to develop a demand-side-response model, which assists electricity consumers exposed to the market price to independently and proactively manage air-conditioning peak electricity demand. The main contribution of this research is to show how consumers can optimize the energy cost caused by the air conditioning load considering to several cases e.g. normal price, spike price, and the probability of a price spike case. This model also investigated how air-conditioning applies a pre-cooling method when there is a substantial risk of a price spike. The results indicate the potential of the scheme to achieve financial benefits for consumers and target the best economic performance for electrical generation distribution and transmission. The model was tested with Queensland electricity market data from the Australian Energy Market Operator and Brisbane temperature data from the Bureau of Statistics regarding hot days from 2011 to 2012.

Agility in consumer retail: sense-response alignment through the eyes of customers

In hyper competition, firms that are agile: sensing and responding better to customer requirements tend to be more successful and achieve supernormal profits. In spite of the widely accepted importance of customer agility, research is limited on this construct. The limited research also has predominantly focussed on the firm’s perspective of agility. However, we propose that the customers are better positioned to determine how well a firm is responding to their requirements (aka a firm’s customer agility). Taking the customers’ stand point, we address the issue of sense and respond alignment in two perspectives-matching and mediating. Based on data collected from customers in a field study, we tested hypothesis pertaining to the two methods of alignment using polynomial regression and response surface methodology. The results provide a good explanation for the role of both forms of alignment on customer satisfaction. Implication for research and practice are discussed.

Behavioural Inhibition System response to conflicting advertisement cues: Road safety messages vs. motor vehicle promotional advertisements

This study assessed the revised Behavioural Inhibition System (BIS), as conceptualised by Gray and McNaughton’s (2000) revised RST, by exposing participants to a loss-framed road safety message (emphasising the negative consequences of speeding behaviour) and a high performance motor vehicle promotional advertisement. Licensed young drivers (N = 40, aged 17–25 years) were randomly allocated to view either the message or both the message and advertisement. Participants then completed a computerised lexical decision task prior to completing three personality measures: Corr-Cooper RST-PQ, CARROT and Q-Task. It was predicted that those with a stronger BIS would demonstrate greater processing of these mixed message cues compared to weaker BIS individuals, and that this BIS effect would only be observed in the mixed cues condition (due to simultaneous activation of the incentive and punishment systems). Preliminary findings will be discussed in the context of the influence of personality traits on health message processing.

Non-response bias in randomized control experiments in criminology : putting the Queensland Community Engagement Trial (QCET) under a microscope

Objectives The goal of this article is to examine whether or not the results of the Queensland Community Engagement Trial (QCET)-a randomized controlled trial that tested the impact of procedural justice policing on citizen attitudes toward police-were affected by different types of nonresponse bias. Method We use two methods (Cochrane and Elffers methods) to explore nonresponse bias: First, we assess the impact of the low response rate by examining the effects of nonresponse group differences between the experimental and control conditions and pooled variance under different scenarios. Second, we assess the degree to which item response rates are influenced by the control and experimental conditions. Results Our analysis of the QCET data suggests that our substantive findings are not influenced by the low response rate in the trial. The results are robust even under extreme conditions, and statistical significance of the results would only be compromised in cases where the pooled variance was much larger for the nonresponse group and the difference between experimental and control conditions was greatly diminished. We also find that there were no biases in the item response rates across the experimental and control conditions. Conclusion RCTs that involve field survey responses-like QCET-are potentially compromised by low response rates and how item response rates might be influenced by the control or experimental conditions. Our results show that the QCET results were not sensitive to the overall low response rate across the experimental and control conditions and the item response rates were not significantly different across the experimental and control groups. Overall, our analysis suggests that the results of QCET are robust and any biases in the survey responses do not significantly influence the main experimental findings.

Mandate for remote sensing education and the remote sensing core curriculum

Consensus was developed by the remote sensing community during the 1980s and early 1990s regarding the need for an organized approach to teaching remote sensing fundamentals for collegiate institutions. Growth of the remote sensing industry might be seriously hampered without concerted efforts to bolster the capacity to teach state-of-the-practice remote sensing theory and practice to the next generation of professionals. A concerted effort of educators, researchers, government, and industry began in 1992 to meet these demands leading to the creation of the Remote Sensing Core Curriculum. The RSCC is currently sustained by cooperative efforts of the ASPRS, ICRSE, NASA, NCGIA, and others in the remote sensing community. Growth of the RSCC into the K-12 community resulted from its Internet teaching foundation that enables comprehensive and response reference links to the whole of the education community.

Mechanical tension as a driver of connective tissue growth in vitro

We propose the progressive mechanical expansion of cell-derived tissue analogues as a novel, growth-based approach to in vitro tissue engineering. The prevailing approach to producing tissue in vitro is to culture cells in an exogenous “scaffold” that provides a basic structure and mechanical support. This necessarily pre-defines the final size of the implantable material, and specific signals must be provided to stimulate appropriate cell growth, differentiation and matrix formation. In contrast, surgical skin expansion, driven by increments of stretch, produces increasing quantities of tissue without trauma or inflammation. This suggests that connective tissue cells have the innate ability to produce growth in response to elevated tension. We posit that this capacity is maintained in vitro, and that order-of-magnitude growth may be similarly attained in self-assembling cultures of cells and their own extracellular matrix. The hypothesis that growth of connective tissue analogues can be induced by mechanical expansion in vitro may be divided into three components: (1) tension stimulates cell proliferation and extracellular matrix synthesis; (2) the corresponding volume increase will relax the tension imparted by a fixed displacement; (3) the repeated application of static stretch will produce sustained growth and a tissue structure adapted to the tensile loading. Connective tissues exist in a state of residual tension, which is actively maintained by resident cells such as fibroblasts. Studies in vitro and in vivo have demonstrated that cellular survival, reproduction, and matrix synthesis and degradation are regulated by the mechanical environment. Order-of-magnitude increases in both bone and skin volume have been achieved clinically through staged expansion protocols, demonstrating that tension-driven growth can be sustained over prolonged periods. Furthermore, cell-derived tissue analogues have demonstrated mechanically advantageous structural adaptation in response to applied loading. Together, these data suggest that a program of incremental stretch constitutes an appealing way to replicate tissue growth in cell culture, by harnessing the constituent cells’ innate mechanical responsiveness. In addition to offering a platform to study the growth and structural adaptation of connective tissues, tension-driven growth presents a novel approach to in vitro tissue engineering. Because the supporting structure is secreted and organised by the cells themselves, growth is not restricted by a “scaffold” of fixed size. This also minimises potential adverse reactions to exogenous materials upon implantation. Most importantly, we posit that the growth induced by progressive stretch will allow substantial volumes of connective tissue to be produced from relatively small initial cell numbers.

Learning and teaching epidemiology with audience response technology

Background The learning and teaching of epidemiology is core to many public health programs. Many students find the content of epidemiology, and specifically risk of bias assessment, challenging to learn. Howbeit, learning is enhanced when knowledge is able to be acquired from an active-learning, hands-on experience. Methods The innovative use of wireless audience response technology “clickers” was incorporated into the lectures of the university’s post-graduate epidemiology units and the tailored epidemiological modules delivered for professional disciplines (e.g. optometry). Clickers were used to apply several pedagogical approaches of active learning including peer-instruction and real-world simulation. Students were also assessed for their gain in knowledge within the lecture (pre-post) and their perceptions of how the use of clickers helped them learn. The routine university-wide end of semester Insight Survey provided further information of the student’s satisfaction with the approach. Results The technology was useful in identifying deficits of knowledge of key concepts either before or after instruction. Where key concepts were re-tested post-lecture, as expected, knowledge increased significantly and provided immediate feed-back to students. Across the lecture series, typically 85% of students identified the technology helped them learn, increased their opportunity to interact with the lecturer, and recommend their use for future classes. The Insight Survey report identified 93% of respondents identified the unit in which clickers were consistently used provided good learning opportunities. Numerous student comments supported the teaching method. Conclusions Epidemiological subject matter lends itself to incorporation of audience response technology. The use of the technology to facilitate interactive voting provides an instant response and participation of everyone to enhance the classroom experience. The pedagogical approach increases students’ knowledge and increases their satisfaction with the unit.