Androgen-targeted therapy-induced epithelial mesenchymal plasticity and neuroendocrine transdifferentiation in prostate cancer : an opportunity for intervention

Androgens regulate biological pathways to promote proliferation, differentiation, and survival of benign and malignant prostate tissue. Androgen receptor (AR) targeted therapies exploit this dependence and are used in advanced prostate cancer to control disease progression. Contemporary treatment regimens involve sequential use of inhibitors of androgen synthesis or AR function. Although targeting the androgen axis has clear therapeutic benefit, its effectiveness is temporary, as prostate tumor cells adapt to survive and grow. The removal of androgens (androgen deprivation) has been shown to activate both epithelial-to-mesenchymal transition (EMT) and neuroendocrine transdifferentiation (NEtD) programs. EMT has established roles in promoting biological phenotypes associated with tumor progression (migration/invasion, tumor cell survival, cancer stem cell-like properties, resistance to radiation and chemotherapy) in multiple human cancer types. NEtD in prostate cancer is associated with resistance to therapy, visceral metastasis, and aggressive disease. Thus, activation of these programs via inhibition of the androgen axis provides a mechanism by which tumor cells can adapt to promote disease recurrence and progression. Brachyury, Axl, MEK, and Aurora kinase A are molecular drivers of these programs, and inhibitors are currently in clinical trials to determine therapeutic applications. Understanding tumor cell plasticity will be important in further defining the rational use of androgen-targeted therapies clinically and provides an opportunity for intervention to prolong survival of men with metastatic prostate cancer.

Estimating the burden of disease attributable to lead exposure in South Africa in 2000

Objectives To estimate the burden of disease attributable to lead exposure in South Africa in 2000. Design World Health Organization comparative risk assessment (CRA) methodology was followed. Recent community studies were used to derive mean blood lead concentrations in adults and children in urban and rural areas. Population-attributable fractions were calculated and applied to revised burden of disease estimates for the relevant disease categories for South Africa in the year 2000. Monte Carlo simulation-modelling techniques were used for the uncertainty analysis. Setting South Africa. Subjects Children under 5 and adults 30 years and older. Outcome measures Cardiovascular mortality and disability-adjusted life years (DALYs) in adults 30 years and older and mild mental disability DALYs in children under 5 years. Results Lead exposure was estimated to cause 1 428 deaths (95% uncertainty interval 1 086-1 772) or 0.27% (95% uncertainty interval: 0.21 - 0.34%) of all deaths in South Africa in 2000. Burden of disease attributed to lead exposure was dominated by mild mental disability in young children, accounting for 75% of the total 58 939 (95% uncertainty interval 55 413 - 62 500) attributable DALYs. Cardiovascular disease in adults accounted for the remainder of the burden. Conclusions Even with the phasing out of leaded petrol, exposure to lead from its ongoing addition to paint, paraoccupational exposure and its use in backyard 'cottage industries' will continue to be an important public health hazard in South Africa for decades. Young children, especially those from disadvantaged communities, remain particularly vulnerable to lead exposure and poisoning.

Mitochondrial membrane potential in a small subset of artemisinin-induced dormant plasmodium falciparum parasites in vitro

Artemisinin induced dormancy is a proposed mechanism for failures of mono-therapy and is linked with artemisinin resistance in Plasmodium falciparum. The biological characterization and dynamics of dormant parasites are not well understood. Here we report that following dihydroartemisinin (DHA) treatment in vitro, a small subset of morphologically dormant parasites was stained with rhodamine 123 (RH), a mitochondrial membrane potential (MMP) marker, and persisted to recovery. FACS sorted RH-positive parasites resumed growth at 10,000/well while RH-negative parasites failed to recover at 5 million/well. Furthermore, transcriptional activity for mitochondrial enzymes was only detected in RH-positive dormant parasites. Importantly, after treating dormant parasites with different concentrations of atovaquone, a mitochondrial inhibitor, the recovery of dormant parasites was delayed or stopped. This demonstrates that mitochondrial activity is critical for survival and regrowth of dormant parasites and that RH staining provides a means of identifying these parasites. These findings provide novel paths for studying and eradicating this dormant stage.

Novel polymer synthesis methodologies using combination of thermally and photochemically-induced nitroxide mediated polymerisation

The combination of thermally- and photochemically-induced polymerization using light sensitive alkoxyamines was investigated. The thermally driven polymerizations were performed via the cleavage of the alkoxyamine functionality, whereas the photochemically-induced polymerizations were carried out either by nitroxide mediated photo-polymerization (NMP2) or by a classical type II mechanism, depending on the structure of the light-sensitive alkoxyamine employed. Once the potential of the various structures as initiators of thermally- and photo-induced polymerizations was established, their use in combination for block copolymer syntheses was investigated. With each alkoxyamine investigated, block copolymers were successfully obtained and the system was applied to the post-modification of polymer coatings for application in patterning and photografting.

Sustainability of public health interventions to reduce the risk of dioxin exposure at severe dioxin hot spots in Vietnam

Severe dioxin contamination at Bien Hoa and Da Nang airbases, Vietnam is of international concern. Public Health risk reduction programs were implemented in Bien Hoa in 2007-2009 and in Da Nang in 2009-2011. In 2009 and 2011 we reported the encouraging results of these interventions in improving the knowledge, attitude and practices (KAP) of local residents in reducing the dioxin exposure risk through foods. In 2013 we revisited these dioxin hot spots, aimed to evaluate whether the results of the intervention were maintained and to identify factors affecting the sustainability of the programs. To assess this, 16 in-depth interviews, six focus group discussions, and pre and post intervention KAP surveys were undertaken. 800 respondents from six intervention wards and 200 respondents from Buu Long Ward (the control site) were randomly selected to participate in the surveys. The results showed that as of 2013, the programs were rated as "moderately sustained" with a score of 3.3 out of 5.0 (cut off points 2.5 to <3.5) for Bien Hoa, and "well sustained" with a score of 3.8 out of 5.0 (cut off points 3.5 to <4.5) for Da Nang. Most formal intervention program activities had ceased and dioxin risk communication activities were no longer integrated into local routine health education programs. However, the main outcomes were maintained and were better than that in the control ward. Migration, lack of official guidance from City People's Committees and local authorities as well as the politically sensitive nature of dioxin issues were the main challenges for the sustainability of the programs.

Elemental composition of ambient fine particles in urban schools : sources of children’s exposure

Currently, there is a limited understanding of the sources of ambient fine particles that contribute to the exposure of children at urban schools. Since the size and chemical composition of airborne particle are key parameters for determining the source as well as toxicity, PM1 particles (mass concentration of particles with an aerodynamic diameter less than 1 µm) were collected at 24 urban schools in Brisbane, Australia and their elemental composition determined. Based on the elemental composition four main sources were identified; secondary sulphates, biomass burning, vehicle and industrial emissions. The largest contributing source was industrial emissions and this was considered as the main source of trace elements in the PM1 that children were exposed to at school. PM1 concentrations at the schools were compared to the elemental composition of the PM2.5 particles (mass concentration of particles with an aerodynamic diameter less than 2.5 µm) from a previous study conducted at a suburban and roadside site in Brisbane. This comparison revealed that the more toxic heavy metals (V, Cr, Ni, Cu, Zn and Pb), mostly from vehicle and industrial emissions, were predominantly in the PM1 fraction. Thus, the results from this study points to PM1 as a potentially better particle size fraction for investigating the health effects of airborne particles.

Eye rubbing-induced changes in intraocular pressure and corneal thickness measured at five locations, in subjects with ocular allergy

AIM To assess the effects of eye rubbing on corneal thickness (CT) and intraocular pressure (IOP) measurements obtained 0-30min after habitual eye rubbing in symptomatic patients. METHODS Measurements of IOP and CT were obtained at five locations (central, temporal, superior, nasal and inferior) before, and every 5min for 30min interval after 30s of eye rubbing, for 25 randomly selected eyes of 14 subjects with ocular allergy and 11 age-matched normals. Differences in measurements were calculated in each group [Baseline measurements minus measurements recorded at each time interval after eye rubbing (for IOP), and for each corneal location (for CT)] and comparison were then made between groups (allergic versus control) for differences in any observed effects. RESULTS Within groups, baseline mean IOPs in the allergic patient-group (14.2±3.0 mm Hg) and in the control group (13.1±1.9 mm Hg) were similar at all times, after eye rubbing (P >0.05, for all). The maximum reduction in IOP was 0.8 mm Hg in the control subjects and the maximum increase was also 0.8 mm Hg in the allergic subjects. Between groups (allergic versus control), the changes in IOP remained under 1 mm Hg at all times (P=0.2) after 30min of eye rubbing. Between 0 and 30min of CT measurements after eye rubbing, the mean central CT (CCT), inferior CT (ICT), superior CT (SCT), temporal CT (TCT) and nasal CT (NCT) did not vary significantly from baseline values in the control and allergic-subject groups (P>0.05, for both). Between both groups, changes in CT were similar at all locations (P>0.05) except for the TC which was minimally thinner by about 4.4 µm (P=0.001) in the allergic subjects than in the control subjects, 30min following 30s of eye rubbing. CONCLUSION IOP measured in allergic subjects after 30s of habitual eye rubbing was comparable with that obtained in normal subjects at all times between 0 and 30min. Although, CT in the allergic subjects were similar to those of the control subjects at all times, it varied between +10 and -7.5 µm following eye rubbing, with the temporal cornea showing consistent reductions in thickness in the subjects with allergy. However, this reduction was minimal and was considered to not be clinically relevant.

Urban Aboriginal and Torres Strait Islander children's exposure to stressful events : a cross sectional study

Objectives To determine the frequency and types of stressful events experienced by urban Aboriginal and Torres Strait Islander children, and to explore the relationship between these experiences and the children’s physical health and parental concerns about their behaviour and learning ability. Design, setting and participants Cross-sectional study of Aboriginal and Torres Strait Islander children aged ≤ 14 years presenting to an urban Indigenous primary health care service in Brisbane for annual child health checks between March 2007 and March 2010. Main outcome measures Parental or carer report of stressful events ever occurring in the family that may have affected the child. Results Of 344 participating children, 175 (51%) had experienced at least one stressful event. Reported events included the death of a family member or close friend (40; 23%), parental divorce or separation (28; 16%), witness to violence or abuse (20; 11%), or incarceration of a family member (7; 4%). These children were more likely to have parents or carers concerned about their behaviour (P < 0.001) and to have a history of ear (P < 0.001) or skin (P = 0.003) infections. Conclusions Children who had experienced stressful events had poorer physical health and more parental concern about behavioural issues than those who had not. Parental disclosure in the primary health care setting of stressful events that have affected the child necessitates appropriate medical, psychological or social interventions to ameliorate both the immediate and potential lifelong negative impact. However, treating the impact of stressful events is insufficient without dealing with the broader political and societal issues that result in a clustering of stressful events in the Aboriginal and Torres Strait Islander population.

Bicycle commuting and exposure to air pollution: A questionnaire-based investigation of perceptions, symptoms and risk management strategies

Background An increase in bicycle commuting participation may improve public health and traffic congestion in cities. Information on air pollution exposure (such as perception, symptoms and risk management) contributes to the responsible promotion of bicycle commuting participation. Methods To determine perceptions, symptoms and willingness for specific exposure risk management strategies of exposure to air pollution, a questionnaire-based cross-sectional investigation was conducted with adult bicycle commuters (n = 153; age = 41 ± 11 yr; 28% female). Results Frequency of acute respiratory signs and symptoms are positively-associated with in- and post-commute compared to pre-commute time periods (p < 0.05); greater positive-association is with respiratory disorder compared to healthy, and female compared to male, participants. The perception (although not signs or symptoms) of in-commute exposure to air pollution is positive-associated with the estimated level of in-commute proximity to motorised traffic. The majority of participants indicated a willingness (which varied with health status and gender) to adopt risk management strategies (with certain practical features) if shown to be appropriate and effective. Conclusions While acute signs and symptoms of air pollution exposure are indicated with bicycle commuting, and more so in susceptible individuals, there is willingness to manage exposure risk by adopting effective strategies with desirable features.

Automatic camera exposure control

It is commonplace to use digital video cameras in robotic applications. These cameras have built-in exposure control but they do not have any knowledge of the environment, the lens being used, the important areas of the image and do not always produce optimal image exposure. Therefore, it is desirable and often necessary to control the exposure off the camera. In this paper we present a scheme for exposure control which enables the user application to determine the area of interest. The proposed scheme introduces an intermediate transparent layer between the camera and the user application which combines the information from these for optimal exposure production. We present results from indoor and outdoor scenarios using directional and fish-eye lenses showing the performance and advantages of this framework.

Cell type-dependent, infection-induced, aberrant DNA methylation in gastric cancer

Epigenetic changes correspond to heritable modifications of the chromatin structure, which do not involve any alteration of the DNA sequence but nonetheless affect gene expression. These mechanisms play an important role in cell differentiation, but aberrant occurrences are also associated with a number of diseases, including cancer and neural development disorders. In particular, aberrant DNA methylation induced by H. Pylori has been found to be a significant risk factor in gastric cancer. To investigate the sensitivity of different genes and cell types to this infection, a computational model of methylation in gastric crypts is developed. In this article, we review existing results from physical experiments and outline their limitations, before presenting the computational model and investigating the influence of its parameters.

Biophysical correlates of intrinsic and stress-induced morphological variability in lateral amygdaloid neurons: A computational study

Morphological and physiological characteristics of neurons located in the dorsolateral and two ventral subdivisions of the lateral amygdala (LA) have been compared in order to differentiate their roles in the formation and storage of fear memories (Alphs et al, SfN abs 623.1, 2003). Briefly, in these populations, significant differences are observed in input resistance, membrane time constant, firing frequency, dendritic tortuosity, numbers of primary dendrites, dendritic segments and dendritic nodes...

Different correlation of Sphingosine-1-Phosphate receptor 1 with receptor activator of nuclear factor kappa B ligand and regulatory T cells in rat periapical lesions

Introduction Sphingosine-1-phosphate receptor 1 (S1P1) is crucial for regulation of immunity and bone metabolism. This study aimed to investigate the expression of S1P1 in rat periapical lesions and its relationship with receptor activator of nuclear factor kappa B ligand (RANKL) and regulatory T (Treg) cells. Methods Periapical lesions were induced by pulp exposure in the first lower molars of 55 Wistar rats. Thirty rats were killed on days 0, 7, 14, 21, 28, and 35, and their mandibles were harvested for x-ray imaging, micro–computed tomography scanning, histologic observation, immunohistochemistry, enzyme histochemistry, and double immunofluorescence analysis. The remaining 25 rats were killed on days 0, 14, 21, 28, and 35, and mandibles were harvested for flow cytometry. Results The volume and area of the periapical lesions increased from day 0 to day 21 and then remained comparably stable after day 28. S1P1-positive cells were observed in the inflammatory periapical regions; the number of S1P1-positive cells peaked at day 14 and then decreased from day 21 to day 35. The distribution of S1P1-positive cells was positively correlated with the dynamics of RANKL-positive cells but was negatively correlated with that of Treg cells. Conclusions S1P1 expression was differentially correlated with RANKL and Treg cell infiltration in the periapical lesions and is therefore a contributing factor to the pathogenesis of such lesions.

The prevention, detection and management of cancer treatment-induced cardiotoxicity: a meta-review

Background The benefits associated with some cancer treatments do not come without risk. A serious side effect of some common cancer treatments is cardiotoxicity. Increased recognition of the public health implications of cancer treatment-induced cardiotoxicity has resulted in a proliferation of systematic reviews in this field to guide practice. Quality appraisal of these reviews is likely to limit the influence of biased conclusions from systematic reviews that have used poor methodology related to clinical decision-making. The aim of this meta-review is to appraise and synthesise evidence from only high quality systematic reviews focused on the prevention, detection or management of cancer treatment-induced cardiotoxicity. Methods Using Cochrane methodology, we searched databases, citations and hand-searched bibliographies. Two reviewers independently appraised reviews and extracted findings. A total of 18 high quality systematic reviews were subsequently analysed, 67 % (n = 12) of these comprised meta-analyses. Results One systematic review concluded that there is insufficient evidence regarding the utility of cardiac biomarkers for the detection of cardiotoxicity. The following strategies might reduce the risk of cardiotoxicity: 1) The concomitant administration of dexrazoxane with anthracylines; 2) The avoidance of anthracyclines where possible; 3) The continuous administration of anthracyclines (>6 h) rather than bolus dosing; and 4) The administration of anthracycline derivatives such as epirubicin or liposomal-encapsulated doxorubicin instead of doxorubicin. In terms of management, one review focused on medical interventions for treating anthracycline-induced cardiotoxicity during or after treatment of childhood cancer. Neither intervention (enalapril and phosphocreatine) was associated with statistically significant improvement in ejection fraction or mortality. Conclusion This review highlights the lack of high level evidence to guide clinical decision-making with respect to the detection and management of cancer treatment-associated cardiotoxicity. There is more evidence with respect to the prevention of this adverse effect of cancer treatment. This evidence, however, only applies to anthracycline-based chemotherapy in a predominantly adult population. There is no high-level evidence to guide clinical decision-making regarding the prevention, detection or management of radiation-induced cardiotoxicity.