COX-derived prostanoid pathways in gastrointestinal cancer development and progression : novel targets for prevention and intervention

Arachidonic acid metabolism through cyclooxygenase (COX) pathways leads to the generation of biologically active eicosanoids. Eicosanoid expression levels vary during development and progression of gastrointestinal (GI) malignancies. COX-2 is the major COX-isoform responsible for G.I. cancer development/progression. COX-2 expression increases during progression from a normal to cancerous state. Evidence from observational studies has demonstrated that chronic NSAID use reduces the risk of cancer development, while both incidence and risk of death due to G.I. cancers were significantly reduced by daily aspirin intake. A number of randomized controlled trials (APC trial, Prevention of Sporadic Adenomatous Polyps trial, APPROVe trial) have also shown a significant protective effect in patients receiving selective COX-2 inhibitors. However, chronic use of selective COX-2 inhibitors at high doses was associated with increased cardiovascular risk, while NSAIDs have also been associated with increased risk. More recently, downstream effectors of COX-signaling have been investigated in cancer development/progression. PGE 2, which binds to both EP and PPAR receptors, is the major prostanoid implicated in the carcinogenesis of G.I. cancers. The role of TXA 2 in G.I. cancers has also been examined, although further studies are required to uncover its role in carcinogenesis. Other prostanoids investigated include PGD 2 and its metabolite 15d-PGJ2, PGF 1α and PGI 2. Targeting these prostanoids in G.I. cancers has the promise of avoiding cardiovascular toxicity associated with chronic selective COX-2 inhibition, while maintaining anti-tumor reactivity.A progressive sequence from normal to pre-malignant to a malignant state has been identified in G.I. cancers. In this review, we will discuss the role of the COX-derived prostanoids in G.I. cancer development and progression. Targeting these downstream prostanoids for chemoprevention and/or treatment of G.I. cancers will also be discussed. Finally, we will highlight the latest pre-clinical technologies as well as avenues for future investigation in this highly topical research field. © 2011 Elsevier B.V.

The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer

Prostacyclin synthase and thromboxane synthase signaling via arachidonic acid metabolism affects a number of tumor cell survival pathways such as cell proliferation, apoptosis, tumor cell invasion and metastasis, and angiogenesis. However, the effects of these respective synthases differ considerably with respect to the pathways described. While prostacyclin synthase is generally believed to be anti-tumor, a pro-carcinogenic role for thromboxane synthase has been demonstrated in a variety of cancers. The balance of oppositely-acting COX-derived prostanoids influences many processes throughout the body, such as blood pressure regulation, clotting, and inflammation. The PGI2/TXA2 ratio is of particular interest in-vivo, with the corresponding synthases shown to be differentially regulated in a variety of disease states. Pharmacological inhibition of thromboxane synthase has been shown to significantly inhibit tumor cell growth, invasion, metastasis and angiogenesis in a range of experimental models. In direct contrast, prostacyclin synthase overexpression has been shown to be chemopreventive in a murine model of the disease, suggesting that the expression and activity of this enzyme may protect against tumor development. In this review, we discuss the aberrant expression and known functions of both prostacyclin synthase and thromboxane synthase in cancer. We discuss the effects of these enzymes on a range of tumor cell survival pathways, such as tumor cell proliferation, induction of apoptosis, invasion and metastasis, and tumor cell angiogenesis. As downstream signaling pathways of these enzymes have also been implicated in cancer states, we examine the role of downstream effectors of PGIS and TXS activity in tumor growth and progression. Finally, we discuss current therapeutic strategies aimed at targeting these enzymes for the prevention/treatment of cancer. © 2010 Elsevier B.V. All rights reserved.

Development and validation of anthropometric prediction equations for estimation of lean body mass and appendicular lean soft tissue in Indian men and women

Lean body mass (LBM) and muscle mass remains difficult to quantify in large epidemiological studies due to non-availability of inexpensive methods. We therefore developed anthropometric prediction equations to estimate the LBM and appendicular lean soft tissue (ALST) using dual energy X-ray absorptiometry (DXA) as a reference method. Healthy volunteers (n= 2220; 36% females; age 18-79 y) representing a wide range of body mass index (14-44 kg/m2) participated in this study. Their LBM including ALST was assessed by DXA along with anthropometric measurements. The sample was divided into prediction (60%) and validation (40%) sets. In the prediction set, a number of prediction models were constructed using DXA measured LBM and ALST estimates as dependent variables and a combination of anthropometric indices as independent variables. These equations were cross-validated in the validation set. Simple equations using age, height and weight explained > 90% variation in the LBM and ALST in both men and women. Additional variables (hip and limb circumferences and sum of SFTs) increased the explained variation by 5-8% in the fully adjusted models predicting LBM and ALST. More complex equations using all the above anthropometric variables could predict the DXA measured LBM and ALST accurately as indicated by low standard error of the estimate (LBM: 1.47 kg and 1.63 kg for men and women, respectively) as well as good agreement by Bland Altman analyses. These equations could be a valuable tool in large epidemiological studies assessing these body compartments in Indians and other population groups with similar body composition.

Colloidal drug probe : method development and validation for adhesion force measurement using atomic force microscopy

This study demonstrates a novel technique of preparing drug colloid probes to determine the adhesion force between the drug salbutamol sulphate (SS) and the surfaces of polymer microparticles to be used as carriers for the dispersion of drug particles from a dry powder inhaler (DPI) formulation. Initially model silica probes of approximately 4 μm size, similar to a drug particle used in DPI formulations, were coated with a saturated SS solution with the aid of capillary forces acting between the silica probe and the drug solution. The developed method of ensuring a smooth and uniform layer of SS on the silica probe was validated using X-Ray Photoelectron Spectroscopy (XPS) and Scanning Electron Microscopy (SEM). Using the same technique, silica microspheres preattached on the AFM cantilever were coated with SS. The adhesion forces between the silica probe and drug coated silica (drug probe) and polymer surfaces (hydrophilic and hydrophobic) were determined. Our experimental results showed that the technique for preparing the drug probe was robust and can be used to determine the adhesion force between hydrophilic/hydrophobic drug probe and carrier surfaces to gain a better understanding on drug carrier adhesion forces in DPI formulations.

Development and validation of a pregnancy symptoms inventory

Background Physical symptoms are common in pregnancy and are predominantly associated with normal physiological changes. These symptoms have a social and economic cost, leading to absenteeism from work and additional medical interventions. There is currently no simple method for identifying common pregnancy related problems in the antenatal period. A validated tool, for use by pregnancy care providers would be useful. The aim of this study was to develop and validate a Pregnancy Symptoms Inventory for use by health professionals. Methods A list of symptoms was generated via expert consultation with health professionals. Focus groups were conducted with pregnant women. The inventory was tested for face validity and piloted for readability and comprehension. For test-re-test reliability, the tool was administered to the same women 2 to 3 days apart. Finally, midwives trialled the inventory for 1 month and rated its usefulness on a 10cm visual analogue scale (VAS). Results A 41-item Likert inventory assessing how often symptoms occurred and what effect they had, was developed. Individual item test re-test reliability was between .51 to 1, the majority (34 items) scoring ≥0.70. The top four “often” reported symptoms were urinary frequency (52.2%), tiredness (45.5%), poor sleep (27.5%) and back pain (19.5%). Among the women surveyed, 16.2% claimed to sometimes or often be incontinent. Referrals to the incontinence nurse increased > 8 fold during the study period. Conclusions The PSI provides a comprehensive inventory of pregnancy related symptoms, with a mechanism for assessing their effect on function. It was robustly developed, with good test re-test reliability, face validity, comprehension and readability. This provides a validated tool for assessing the impact of interventions in pregnancy.

Development and validation of anthropometric prediction equations for estimation of body fat in Indonesian men

Body composition of 292 males aged between 18 and 65 years was measured using the deuterium oxide dilution technique. Participants were divided into development (n=146) and cross-validation (n=146) groups. Stature, body weight, skinfold thickness at eight sites, girth at five sites, and bone breadth at four sites were measured and body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-stature ratio (WSR) calculated. Equations were developed using multiple regression analyses with skinfolds, breadth and girth measures, BMI, and other indices as independent variables and percentage body fat (%BF) determined from deuterium dilution technique as the reference. All equations were then tested in the cross-validation group. Results from the reference method were also compared with existing prediction equations by Durnin and Womersley (1974), Davidson et al (2011), and Gurrici et al (1998). The proposed prediction equations were valid in our cross-validation samples with r=0.77- 0.86, bias 0.2-0.5%, and pure error 2.8-3.6%. The strongest was generated from skinfolds with r=0.83, SEE 3.7%, and AIC 377.2. The Durnin and Womersley (1974) and Davidson et al (2011) equations significantly (p<0.001) underestimated %BF by 1.0 and 6.9% respectively, whereas the Gurrici et al (1998) equation significantly (p<0.001) overestimated %BF by 3.3% in our cross-validation samples compared to the reference. Results suggest that the proposed prediction equations are useful in the estimation of %BF in Indonesian men.

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.

A participatory framework for researching and evaluating communication for development and social change

The growing dominance of project planning cycles and results-based management in development over the past 20 years has significant implications for the effective evaluation of communication for development and social change and the sustainability of these processes. These approaches to development and evaluation usually give priority to the linear, logical framework (or log frame) approach promoted by many development institutions. This tends to emphasize upward accountability approaches to development and its evaluation, so that development is driven by exogenous rather than endogenous models of development and social change. Such approaches are underpinned by ideas of preplanning, and predetermination of what successful out -comes look like. In this way, outcomes of complex interventions tend to be reduced to simple, cause-effect processes and the categorization of things, including people (Chambers and Pettit 2004; Eyben 2011). This runs counter to communication for development approaches, which prioritize engagement, relationships, empowerment and dialogue as important components for positive social change.

Law, ethics and pandemic preparedness : the importance of cross-jurisdictional and cross-cultural perspectives

OBJECTIVE To explore social equity, health planning, regulatory and ethical dilemmas in responding to a pandemic influenza (H5N1) outbreak, and the adequacy of protocols and standards such as the International Health Regulations (2005). APPROACH This paper analyses the role of legal and ethical considerations for pandemic preparedness, including an exploration of the relevance of cross-jurisdictional and cross-cultural perspectives in assessing the validity of goals for harmonisation of laws and policies both within and between nations. Australian and international experience is reviewed in various areas, including distribution of vaccines during a pandemic, the distribution of authority between national and local levels of government, and global and regional equity issues for poorer countries. CONCLUSION This paper finds that questions such as those of distributional justice (resource allocation) and regulatory frameworks raise important issues about the cultural and ethical acceptability of planning measures. Serious doubt is cast on a 'one size fits all' approach to international planning for managing a pandemic. It is concluded that a more nuanced approach than that contained in international guidelines may be required if an effective response is to be constructed internationally. IMPLICATIONS The paper commends the wisdom of reliance on 'soft law', international guidance that leaves plenty of room for each nation to construct its response in conformity with its own cultural and value requirements.

Law, ethics and pandemic preparedness : the importance of cross-jurisdictional and cross-cultural perspectives

Objective To explore social equity, health planning, regulatory and ethical dilemmas in responding to a pandemic influenza (H5N1) outbreak, and the adequacy of protocols and standards such as the International Health Regulations (2005). Approach This paper analyses the role of legal and ethical considerations for pandemic preparedness, including an exploration of the relevance of cross-jurisdictional and cross-cultural perspectives in assessing the validity of goals for harmonisation of laws and policies both within and between nations. Australian and international experience is reviewed in various areas, including distribution of vaccines during a pandemic, the distribution of authority between national and local levels of government, and global and regional equity issues for poorer countries. Conclusion This paper finds that questions such as those of distributional justice (resource allocation) and regulatory frameworks raise important issues about the cultural and ethical acceptability of planning measures. Serious doubt is cast on a ‘one size fits all’ approach to international planning for managing a pandemic. It is concluded that a more nuanced approach than that contained in international guidelines may be required if an effective response is to be constructed internationally. Implications The paper commends the wisdom of reliance on ‘soft law’, international guidance that leaves plenty of room for each nation to construct its response in conformity with its own cultural and value requirements.

Environmental indicators for sustainable road development and operation

Road construction, maintenance and operation are activities that impact the environment by way of energy use, resource consumption and emission. Components such as construction material, transportation, street lighting, rolling resistance, traffic congestion during works, albedo and end-of-life processing impact the environment at different phases of the life of a road. With a view to promote sustainable development, a few sustainability rating schemes, e.g. Infrastructure Sustainability and Invest (Australia), Envision and Greenroads (USA), and CEEQUAL (UK) have been developed, that can assess road projects. These schemes address environmental areas such as: energy and emission, land, water, materials, discharges into surroundings, waste and ecology as factors for sustainable development. This paper assesses different rating schemes based on a defined comprehensive life cycle assessment (LCA) system boundary for road projects to identify different environmental indicators that address sustainable road development and operation. The findings indicate that new indicators are required to address different environmental components during the operation phase of roads.

Management of multiple heterogeneous UAVs using capability and autonomy visualisation: theory, experiment and result

The interest in utilising multiple heterogeneous Unmanned Aerial Vehicles (UAVs) in close proximity is growing rapidly. As such, many challenges are presented in the effective coordination and management of these UAVs; converting the current n-to-1 paradigm (n operators operating a single UAV) to the 1-to-n paradigm (one operator managing n UAVs). This paper introduces an Information Abstraction methodology used to produce the functional capability framework initially proposed by Chen et al. and its Level Of Detail (LOD) indexing scale. This framework was validated through comparing the operator workload and Situation Awareness (SA) of three experiment scenarios involving multiple autonomously heterogeneous UAVs. The first scenario was set in a high LOD configuration with highly abstracted UAV functional information; the second scenario was set in a mixed LOD configuration; and the final scenario was set in a low LOD configuration with maximal UAV functional information. Results show that there is a significant statistical decrease in operator workload when a UAV’s functional information is displayed at its physical form (low LOD - maximal information) when comparing to the mixed LOD configuration.