The role of the arachidonic acid pathway in NSCLC development and progression : novel approaches for therapeutic intervention

Arachidonic acid metabolism through cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P-450 epoxygenase (EPOX) pathways is responsible for the formation of biologically active eicosanoids, including prostanoids, leukotrienes, hydroxyeicosatetraenoic acid, epoxyeicosatrienoic acid and hydroperoxyeicosatetraenoic acids. Altered eicosanoid expression levels are commonly observed during tumour development and progression of a range of malignancies, including non-small cell lung cancer (NSCLC). Arachidonic acid-derived eicosanoids affect a range of biological phenomena to modulate tumour processes such as cell growth, survival, angiogenesis, cell adhesion, invasion and migration and metastatic potential. Numerous studies have demonstrated that eicosanoids modulate NSCLC development and progression, while targeting these pathways has generally been shown to inhibit tumour growth/progression. Modulation of these arachidonic acid-derived pathways for the prevention and/or treatment of NSCLC has been the subject of significant interest over the past number of years, with a number of clinical trials examining the potential of COX and LOX inhibitors in combination with traditional and novel molecular approaches. However, results from these trials have been largely disappointing. Furthermore, enthusiasm for the use of selective COX-2 inhibitors for cancer prevention/treatment waned, due to their association with adverse cardiovascular events in chemoprevention trials. While COX and LOX targeting may both retain promise for NSCLC prevention and/or treatment, there is an urgent need to understand the downstream signalling mechanisms through which these and other arachidonic acid-derived signalling pathways mediate their effects on tumourigenesis. This will allow for development of safer and potentially more effective strategies for NSCLC prevention and/or treatment. Chemoprevention studies with PGI2 analogues have demonstrated considerable promise, while binding to/signalling through PGE2 receptors have also been the subject of interest for NSCLC treatment. In this chapter, the role of the eicosanoid signalling pathways in non-small cell lung cancer will be discussed. In particular, the effect of the eicosanoids on tumour cell proliferation, their roles in induction of cell death, effects on angiogenesis, migration, invasion and their regulation of the immune response will be assessed, with signal transduction pathways involved in these processes also discussed. Finally, novel approaches targeting these arachidonic acid-derived eicosanoids (using pharmacological or natural agents) for chemoprevention and/or treatment of NSCLC will be outlined. Elucidating the molecular mechanisms underlying the effects of specific or general arachidonic acid pathway modulators may lead to the design of biologically and pharmacologically targeted therapeutic strategies for NSCLC prevention/treatment, which may be used alone or in combination with conventional therapies.

Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations

Purpose The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS). Patients and Methods In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs). Results A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatmentrelated adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain. Conclusion Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

Symptom control and quality of life in lux-lung 3 : a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations

Purpose Patient-reported symptoms and health-related quality of life (QoL) benefits were investigated in a randomized, phase III trial of afatinib or cisplatin/pemetrexed. Patients and Methods Three hundred forty-five patients with advanced epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma were randomly assigned 2:1 to afatinib 40 mg per day or up to six cycles of cisplatin/pemetrexed. Lung cancer symptoms and health-related QoL were assessed every 21 days until progression using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Lung Cancer-13 questionnaires. Analyses of cough, dyspnea, and pain were preplanned, including percentage of patients who improved on therapy, time to deterioration of symptoms, and change in symptoms over time. Results Questionnaire compliance was high. Compared with chemotherapy, afatinib significantly delayed the time to deterioration for cough (hazard ratio [HR], 0.60; 95% CI, 0.41 to 0.87; P = .007) and dyspnea (HR, 0.68; 95% CI, 0.50 to 0.93; P = .015), but not pain (HR, 0.83; 95% CI, 0.62 to 1.10; P = .19). More patients on afatinib (64%) versus chemotherapy (50%) experienced improvements in dyspnea scores (P lt; .010). Differences in mean scores over time significantly favored afatinib over chemotherapy for cough (P lt; .001) and dyspnea (P = .001). Afatinib showed significantly better mean scores over time in global health status/QoL (P = .015) and physical (P = .001), role (P = .004), and cognitive (P lt; .007) functioning compared with chemotherapy. Fatigue and nausea were worse with chemotherapy, whereas diarrhea, dysphagia, and sore mouth were worse with afatinib (all P = .01). Conclusion In patients with lung adenocarcinoma with EGFR mutations, first-line afatinib was associated with better control of cough and dyspnea compared with chemotherapy, although diarrhea, dysphagia, and sore mouth were worse. Global health status/QoL was also improved over time with afatinib compared with chemotherapy.

The emergence of Leptospira borgpetersenii serovar Arborea as the dominant infecting serovar following the summer of natural disasters in Queensland, Australia 2011

The following research reports the emergence of Leptospira borgpetersenii serovar Arborea as the dominant infecting serovar following the summer of disasters and the ensuing clean up in Queensland, Australia during 2011. For the 12 month period (1 January to 31 December) L. borgpetersenii serovar Arborea accounted for over 49% of infections. In response to a flooding event public health officials need to issue community wide announcements warning the population about the dangers of leptospirosis and other water borne diseases. Communication with physicians working in the affected community should also be increased to update physicians with information such as clinical presentation of leptospirosis and other waterborne diseases. These recommendations will furnish public health officials with considerations for disease management when dealing with future disaster management programs.

Patterns of social capital associated with transit oriented development

In policy circles, transit oriented development (TOD) is believed to enhance social capital, however empirical evidence of this relationship is lacking. This research compares levels of social capital between TOD vs. non-TOD areas in Brisbane, Australia. Using a Two Step cluster analysis technique, three types of neighbourhood groupings were identified based on net employment density, net residential density, land use diversity, intersection density, and public transport accessibility: TODs, transit adjacent development (TADs) and traditional suburbs. Two dimensions of social capital were measured (trust and reciprocity, connections with neighbours) based on factor analysis of eight items representing elements of social capital. Multivariate regression analyses were conducted to identify links between the distributions of the dimensions of social capital on areas defined as TODs, TADs, and traditional suburbs controlling for socio-demographics and environmental factors. Results show that individuals living in TODs had a significantly higher level of trust and reciprocity and connections with neighbours compared with residents of TADs. It appears that TODs may foster the development of social sustainability.

Australian baby boomers switched to more environment friendly modes of transport during the global financial crisis

The global financial crisis (GFC) in 2008 rocked local, regional, and state economies throughout the world. Several intermediate outcomes of the GFC have been well documented in the literature including loss of jobs and reduced income. Relatively little research has, however, examined the impacts of the GFC on individual level travel behaviour change. To address this shortcoming, HABITAT panel data were employed to estimate a multinomial logit model to examine mode switching behaviour between 2007 (pre-GFC) and 2009 (post-GFC) of a baby boomers cohort in Brisbane, Australia—a city within a developed country that has been on many metrics the least affected by the GFC. In addition, a Poisson regression model was estimated to model the number of trips made by individuals in 2007, 2008, and 2009. The South East Queensland Travel Survey datasets were used to develop this model. Four linear regression models were estimated to assess the effects of the GFC on time allocated to travel during a day: one for each of the three travel modes including public transport, active transport, less environmentally friendly transport; and an overall travel time model irrespective of mode. The results reveal that individuals were more likely to switch to public transport who lost their job or whose income reduced between 2007 and 2009. Individuals also made significantly fewer trips in 2008 and 2009 compared to 2007. Individuals spent significantly less time using less environmentally friendly transport but more time using public transport in 2009. Baby boomers switched to more environmentally friendly travel modes during the GFC.

Detecting and Analyzing Linear Structures in Biomedical Images : A Case Study Using Corneal Nerve Fibers

Diabetic peripheral neuropathy (DPN) is one of the most common long-term complications of diabetes. The accurate detection and quantification of DPN are important for defining at-risk patients, anticipating deterioration, and assessing new therapies. Current methods of detecting and quantifying DPN, such as neurophysiology, lack sensitivity, require expert assessment and focus primarily on large nerve fibers. However, the earliest damage to nerve fibers in diabetic neuropathy is to the small nerve fibers. At present, small nerve fiber damage is currently assessed using skin/nerve biopsy; both are invasive technique and are not suitable for repeated investigations.

Nutrition screening and assessment in Parkinson's disease : a comparison of methods

Background & Aims Nutrition screening and assessment enable early identification of malnourished people and those at risk of malnutrition. Appropriate assessment tools assist with informing and monitoring nutrition interventions. Tool choice needs to be appropriate to the population and setting. Methods Community-dwelling people with Parkinson’s disease (>18 years) were recruited. Body mass index (BMI) was calculated from weight and height. Participants were classified as underweight according to World Health Organisation (WHO) (≤18.5kg/m2) and age specific (<65 years,≤18.5kg/m2; ≥65 years,≤23.5kg/m2) cut-offs. The Mini-Nutritional Assessment (MNA) screening (MNA-SF) and total assessment scores were calculated. The Patient-Generated Subjective Global Assessment (PG-SGA), including the Subjective Global Assessment (SGA), was performed. Sensitivity, specificity, positive predictive value, negative predictive value and weighted kappa statistic of each of the above compared to SGA were determined. Results Median age of the 125 participants was 70.0(35-92) years. Age-specific BMI (Sn 68.4%, Sp 84.0%) performed better than WHO (Sn 15.8%, Sp 99.1%) categories. MNA-SF performed better (Sn 94.7%, Sp 78.3%) than both BMI categorisations for screening purposes. MNA had higher specificity but lower sensitivity than PG-SGA (MNA Sn 84.2%, Sp 87.7%; PG-SGA Sn 100.0%, Sp 69.8%). Conclusions BMI lacks sensitivity to identify malnourished people with Parkinson’s disease and should be used with caution. The MNA-SF may be a better screening tool in people with Parkinson’s disease. The PG-SGA performed well and may assist with informing and monitoring nutrition interventions. Further research should be conducted to validate screening and assessment tools in Parkinson’s disease.  

Food reward sensitivity predicts overconsumption of high-fat snack food

Overconsumption of snack foods has been linked to rising rates of obesity, with our ‘obesogenic’ environment and its abundance of palatable, high-calorie foods and associated cues especially implicated. However, it is clear that some individuals are particularly susceptible to overconsumption and weight gain. It was hypothesised that individuals sensitive to the rewarding properties of palatable foods, and associated stimuli, would show elevated consumption. Snack food intake was measured in 50 adults (mean age 34.5 years, BMI 23.9 kg/m2, 56% female) in a repeated measures design, both with and without a ‘food cue’. Trait (BIS/BAS scales), behavioural (computerised CARROT) and food reward were assessed. Sensitivity to food reward, but not generalised reward, was positively associated with snack food intake. This relationship was not affected by the presence of a food cue. Findings are discussed in the context of implications for weight management.

Thinking Pedagogically

Despite the dominancy of medical explanations for difficult child behavior, the shifting sands that lie beneath the ADHD construct provide an unstable foundation for educational practice. It can be somewhat liberating to remember that “attention deficit hyperactivity disorder” is a label (one of many, including minimal brain damage and hyperkinetic reaction of childhood) that the medical domain has coined to both group and describe certain challenging behaviors exhibited by children and young people (see Smith, Chapter 2). The label is but one conceptualization of what these behaviors mean and, despite the existence of powerful lobby groups, it may not be the best way forward. In what follows, I present an alternative typology to the medical conceptualization by describing some common issues that bring this group of children to attention. In an effort to introduce educationally useful responses to students who are difficult to teach, I will then outline what classroom teachers need to recognize in order to work with these students and realize their potential. To assist teachers in thinking pedagogically, these observations are coupled with well-known and relevant qualities of good teaching to remind teachers of what they already know and to reacquaint them with the power of that knowledge.

Much confusion about inclusion in Australia's largest education system

Over the last three decades, growing international recognition of the right of students with a disability to attend their local school has prompted change in the formation of education policies, schooling structures and pedagogical practice. Inclusion, as the movement has become known, has since been taken up and developed to different degrees in different regions and to differing degrees of success. Yet, despite sincere attempts to better include students with physical, sensory and intellectual disabilities, new and different forms of exclusion have arisen since the late 1990s; particularly for students with social, emotional and/or behavioural difficulties. In this lecture, Dr Linda Graham reports on findings from a three year ARC Discovery project to consider the impact of inclusion on the New South Wales government schooling sector, Australia’s largest education system.

Efficient selective identity-based encryption without random oracles

We construct two efficient Identity-Based Encryption (IBE) systems that admit selective-identity security reductions without random oracles in groups equipped with a bilinear map. Selective-identity secure IBE is a slightly weaker security model than the standard security model for IBE. In this model the adversary must commit ahead of time to the identity that it intends to attack, whereas in an adaptive-identity attack the adversary is allowed to choose this identity adaptively. Our first system—BB1—is based on the well studied decisional bilinear Diffie–Hellman assumption, and extends naturally to systems with hierarchical identities, or HIBE. Our second system—BB2—is based on a stronger assumption which we call the Bilinear Diffie–Hellman Inversion assumption and provides another approach to building IBE systems. Our first system, BB1, is very versatile and well suited for practical applications: the basic hierarchical construction can be efficiently secured against chosen-ciphertext attacks, and further extended to support efficient non-interactive threshold decryption, among others, all without using random oracles. Both systems, BB1 and BB2, can be modified generically to provide “full” IBE security (i.e., against adaptive-identity attacks), either using random oracles, or in the standard model at the expense of a non-polynomial but easy-to-compensate security reduction.

Kamouflage : loss-resistant password management

We introduce Kamouflage: a new architecture for building theft-resistant password managers. An attacker who steals a laptop or cell phone with a Kamouflage-based password manager is forced to carry out a considerable amount of online work before obtaining any user credentials. We implemented our proposal as a replacement for the built-in Firefox password manager, and provide performance measurements and the results from experiments with large real-world password sets to evaluate the feasibility and effectiveness of our approach. Kamouflage is well suited to become a standard architecture for password managers on mobile devices.

Lattice basis delegation in fixed dimension and shorter-ciphertext hierarchical IBE

We present a technique for delegating a short lattice basis that has the advantage of keeping the lattice dimension unchanged upon delegation. Building on this result, we construct two new hierarchical identity-based encryption (HIBE) schemes, with and without random oracles. The resulting systems are very different from earlier lattice-based HIBEs and in some cases result in shorter ciphertexts and private keys. We prove security from classic lattice hardness assumptions.