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.

Community wide interventions for increasing physical activity

Background Multi-strategic community wide interventions for physical activity are increasingly popular but their ability to achieve population level improvements is unknown. Objectives To evaluate the effects of community wide, multi-strategic interventions upon population levels of physical activity. Search methods We searched the Cochrane Public Health Group Segment of the Cochrane Register of Studies,The Cochrane Library, MEDLINE, MEDLINE in Process, EMBASE, CINAHL, LILACS, PsycINFO, ASSIA, the British Nursing Index, Chinese CNKI databases, EPPI Centre (DoPHER, TRoPHI), ERIC, HMIC, Sociological Abstracts, SPORTDiscus, Transport Database and Web of Science (Science Citation Index, Social Sciences Citation Index, Conference Proceedings Citation Index). We also scanned websites of the EU Platform on Diet, Physical Activity and Health; Health-Evidence.org; the International Union for Health Promotion and Education; the NIHR Coordinating Centre for Health Technology (NCCHTA); the US Centre for Disease Control and Prevention (CDC) and NICE and SIGN guidelines. Reference lists of all relevant systematic reviews, guidelines and primary studies were searched and we contacted experts in the field. The searches were updated to 16 January 2014, unrestricted by language or publication status. Selection criteria Cluster randomised controlled trials, randomised controlled trials, quasi-experimental designs which used a control population for comparison, interrupted time-series studies, and prospective controlled cohort studies were included. Only studies with a minimum six-month follow up from the start of the intervention to measurement of outcomes were included. Community wide interventions had to comprise at least two broad strategies aimed at physical activity for the whole population. Studies which randomised individuals from the same community were excluded. Data collection and analysis At least two review authors independently extracted the data and assessed the risk of bias. Each study was assessed for the setting, the number of included components and their intensity. The primary outcome measures were grouped according to whether they were dichotomous (per cent physically active, per cent physically active during leisure time, and per cent physically inactive) or continuous (leisure time physical activity time (time spent)), walking (time spent), energy expenditure (as metabolic equivalents or METS)). For dichotomous measures we calculated the unadjusted and adjusted risk difference, and the unadjusted and adjusted relative risk. For continuous measures we calculated percentage change from baseline, unadjusted and adjusted. Main results After the selection process had been completed, 33 studies were included. A total of 267 communities were included in the review (populations between 500 and 1.9 million). Of the included studies, 25 were set in high income countries and eight were in low income countries. The interventions varied by the number of strategies included and their intensity. Almost all of the interventions included a component of building partnerships with local governments or non-governmental organisations (NGOs) (29 studies). None of the studies provided results by socio-economic disadvantage or other markers of equity. However, of those included studies undertaken in high income countries, 14 studies were described as being provided to deprived, disadvantaged or low socio-economic communities. Nineteen studies were identified as having a high risk of bias, 10 studies were unclear, and four studies had a low risk of bias. Selection bias was a major concern with these studies, with only five studies using randomisation to allocate communities. Four studies were judged as being at low risk of selection bias although 19 studies were considered to have an unclear risk of bias. Twelve studies had a high risk of detection bias, 13 an unclear risk and four a low risk of bias. Generally, the better designed studies showed no improvement in the primary outcome measure of physical activity at a population level. All four of the newly included, and judged to be at low risk of bias, studies (conducted in Japan, United Kingdom and USA) used randomisation to allocate the intervention to the communities. Three studies used a cluster randomised design and one study used a stepped wedge design. The approach to measuring the primary outcome of physical activity was better in these four studies than in many of the earlier studies. One study obtained objective population representative measurements of physical activity by accelerometers, while the remaining three low-risk studies used validated self-reported measures. The study using accelerometry, conducted in low income, high crime communities of USA, emphasised social marketing, partnership with police and environmental improvements. No change in the seven-day average daily minutes of moderate to vigorous physical activity was observed during the two years of operation. Some program level effect was observed with more people walking in the intervention community, however this result was not evident in the whole community. Similarly, the two studies conducted in the United Kingdom (one in rural villages and the other in urban London; both using communication, partnership and environmental strategies) found no improvement in the mean levels of energy expenditure per person per week, measured from one to four years from baseline. None of the three low risk studies reporting a dichotomous outcome of physical activity found improvements associated with the intervention. Overall, there was a noticeable absence of reporting of benefit in physical activity for community wide interventions in the included studies. However, as a group, the interventions undertaken in China appeared to have the greatest possibility of success with high participation rates reported. Reporting bias was evident with two studies failing to report physical activity measured at follow up. No adverse events were reported.The data pertaining to cost and sustainability of the interventions were limited and varied. Authors' conclusions Although numerous studies have been undertaken, there is a noticeable inconsistency of the findings in the available studies and this is confounded by serious methodological issues within the included studies. The body of evidence in this review does not support the hypothesis that the multi-component community wide interventions studied effectively increased physical activity for the population, although some studies with environmental components observed more people walking. Plain language summary Community wide interventions for increasing physical activity Not having enough physical activity leads to poorer health. Regular physical activity can reduce the risk of chronic disease and improve one's health and wellbeing. The lack of physical activity is a common and in some cases a growing health problem. To address this, 33 studies have used improvement activities directed at communities, using more than one approach in a single program. When we first looked at the available research in 2011 we observed that there was a lack of good studies which could show whether this approach was beneficial or not. Some studies claimed that community wide programs improved physical activities and other studies did not. In this update we found four new studies that were of good quality; however none of these four studies increased physical activity levels for the population. Some studies reported program level effects such as observing more people walking, however the population level of physical activity had not increased. This review found that community wide interventions are very difficult to undertake, and it appears that they usually fail to provide a measurable benefit in physical activity for a population. It is apparent that many of the interventions failed to reach a substantial portion of the community, and we speculate that some single strategies included in the combination may lack individual effectiveness. Laički sažetak Intervencije u zajednici za povećanje tjelesne aktivnosti Nedostatna tjelesna aktivnost povezana je s lošijim zdravljem.Redovita tjelesna aktivnost može umanjiti rizik od kroničnih bolesti te poboljšati zdravlje i kvalitetu života pojedinca.Manjak tjelesne aktivnosti čest je problem, a učestalost tog problema se povećava.Cochrane sustavni pregled je analizirao 33 studije koje su istražile programe za povećanje tjelesne aktivnosti u zajednici, u kojima se koristilo više od jednog pristupa.Kad su prvi put pregledani dokazi iz istraživanja koja su bila dostupna 2011. godine, utvrđeno je da nema dovoljno dobrih studija koje bi mogle pokazati je li takav pristup koristan ili ne.Primjerice, neke studije tvrde da programi za povećanje tjelesne aktivnosti u zajednici poboljšavaju tjelesnu aktivnost pojedinaca u zajednici, a druge studije tvrde suprotno.U ovom obnovljenom sustavnom pregledu pronađene su 4 nove studije koje su bile visoke kvalitete, ail nijedna od tih studija nije pokazala da je istraživana intervencija dovela do povećanja tjelesne aktivnosti u zajednici.Neke su studije opisale učinak na način da je opisano da je uočeno da više ljudi u zajednici hoda, međutim, ukupna razina tjelesne aktivnosti u promatranoj populaciji nije se povećala.Ovaj sustavni pregled je utvrdio da je intervencije za povećanje tjelesne aktivnosti u zajednici teško provesti i čini se da one obično ne uspijevaju u svojoj namjeri da na mjerljiv način povećaju tjelesnu aktivnost u populaciji.Čini se da mnoge intervencije nisu uspjele doseći veći broj stanovnika u zajednici pa se može smatrati da neke od strategija uključene u analizirane kombinacije nisu zasebno učinkovite.

Characterization and Mapping of Patterned Ground in the Saginaw Lowlands, Michigan: Possible Evidence for Late-Wisconsin Permafrost

We identified, mapped, and characterized a widespread area (gt;1,020 km2) of patterned ground in the Saginaw Lowlands of Michigan, a wet, flat plain composed of waterlain tills, lacustrine deposits, or both. The polygonal patterned ground is interpreted as a possible relict permafrost feature, formed in the Late Wisconsin when this area was proximal to the Laurentide ice sheet. Cold-air drainage off the ice sheet might have pooled in the Saginaw Lowlands, which sloped toward the ice margin, possibly creating widespread but short-lived permafrost on this glacial lake plain. The majority of the polygons occur between the Glacial Lake Warren strandline (~14.8 cal. ka) and the shoreline of Glacial Lake Elkton (~14.3 cal. ka), providing a relative age bracket for the patterned ground. Most of the polygons formed in dense, wet, silt loam soils on flat-lying sites and take the form of reticulate nets with polygon long axes of 150 to 160 m and short axes of 60 to 90 m. Interpolygon swales, often shown as dark curvilinears on aerial photographs, are typically slightly lower than are the polygon centers they bound. Some portions of these interpolygon swales are infilled with gravel-free, sandy loam sediments. The subtle morphology and sedimentological characteristics of the patterned ground in the Saginaw Lowlands suggest that thermokarst erosion, rather than ice-wedge replacement, was the dominant geomorphic process associated with the degradation of the Late-Wisconsin permafrost in the study area and, therefore, was primarily responsible for the soil patterns seen there today.

Mississippi Delta subsidence primarily caused by compaction of Holocene strata

Coastal subsidence causes sea-level rise, shoreline erosion and wetland loss, which poses a threat to coastal populations. This is especially evident in the Mississippi Delta in the southern United States, which was devastated by Hurricane Katrina in 2005. The loss of protective wetlands is considered a critical factor in the extensive flood damage. The causes of subsidence in coastal Louisiana, attributed to factors as diverse as shallow compaction and deep crustal processes, remain controversial. Current estimates of subsidence rates vary by several orders of magnitude. Here, we use a series of radiocarbon-dated sediment cores from the Mississippi Delta to analyse late Holocene deposits and assess compaction rates. We find that millennial-scale compaction rates primarily associated with peat can reach 5mm per year, values that exceed recent model predictions. Locally and on timescales of decades to centuries, rates are likely to be 10 mm or more per year. We conclude that compaction of Holocene strata contributes significantly to the exceptionally high rates of relative sea-level rise and coastal wetland loss in the Mississippi Delta, and is likely to cause subsidence in other organic-rich and often densely populated coastal plains.

Bridging the gap: Exploring the barriers to using economic evidence in healthcare decision making and strategies for improving uptake

Evidence from economic evaluations is often not used to inform healthcare policy despite being well regarded by policy makers and physicians. This article employs the accessibility and acceptability framework to review the barriers to using evidence from economic evaluation in healthcare policy and the strategies used to overcome these barriers. Economic evaluations are often inaccessible to policymakers due to the absence of relevant economic evaluations, the time and cost required to conduct and interpret economic evaluations, and lack of expertise to evaluate quality and interpret results. Consistently reported factors that limit the translation of findings from economic evaluations into healthcare policy include poor quality of research informing economic evaluations, assumptions used in economic modelling, conflicts of interest, difficulties in transferring resources between sectors, negative attitudes to healthcare rationing, and the absence of equity considerations. Strategies to overcome these barriers have been suggested in the literature, including training, structured abstract databases, rapid evaluation, reporting checklists for journals, and considering factors other than cost effectiveness in economic evaluations, such as equity or budget impact. The factors that prevent or encourage decision makers to use evidence from economic evaluations have been identified, but the relative importance of these factors to decision makers is uncertain.

Physical, chemical, biological and ecotoxicological properties of wastewater discharged from Davis Station, Antarctica

The properties and toxicity of untreatedwastewater at Davis Station, East Antarctica,were investigated to inform decisions regarding the appropriate level of treatment for local discharge purposes and more generally, to better understand the risk associated with dispersal and impact of wastewaters in Antarctica. Suspended solids, nutrients (nitrogen, phosphorus), biological oxygen demand (BOD), metals, organic contaminants, surfactants and microbiological load were measured at various locations throughout the wastewater discharge system. Wastewater quality and properties varied greatly between buildings on station, each ofwhich has separate holding tanks. Nutrients, BOD and settleable solid levelswere higher than standard municipal wastewaters. Microbiological loads were typical of untreated wastewater. Contaminants detected in the wastewater included metals and persistent organic compounds, mainly polybrominated diphenyl ethers (PBDEs). The toxicity of wastewater was also investigated in laboratory bioassays using two local Antarctic marine invertebrates, the amphipod Paramoera walkeri and the microgastropod Skenella paludionoides. Animals were exposed to a range of wastewater concentrations from3% to 68% (test 1) or 63% (test 2) over 21 days with survival monitored daily. Significant mortality occurred in all concentrations of wastewater after 14 to 21 days, and at higher concentrations (50–68% wastewater) mortality occurred after only one day. Results indicate that the local receiving marine environment at Davis Station is at risk from existing wastewater discharges, and that advanced treatment is required both to remove contaminants shown to cause toxicity to biota, as well as to reduce the environmental risks associated with non-native micro-organisms in wastewater.

A recommendation system for predicting risks across multiple business process instances

This paper proposes a recommendation system that supports process participants in taking risk-informed decisions, with the goal of reducing risks that may arise during process execution. Risk reduction involves decreasing the likelihood and severity of a process fault from occurring. Given a business process exposed to risks, e.g. a financial process exposed to a risk of reputation loss, we enact this process and whenever a process participant needs to provide input to the process, e.g. by selecting the next task to execute or by filling out a form, we suggest to the participant the action to perform which minimizes the predicted process risk. Risks are predicted by traversing decision trees generated from the logs of past process executions, which consider process data, involved resources, task durations and other information elements like task frequencies. When applied in the context of multiple process instances running concurrently, a second technique is employed that uses integer linear programming to compute the optimal assignment of resources to tasks to be performed, in order to deal with the interplay between risks relative to different instances. The recommendation system has been implemented as a set of components on top of the YAWL BPM system and its effectiveness has been evaluated using a real-life scenario, in collaboration with risk analysts of a large insurance company. The results, based on a simulation of the real-life scenario and its comparison with the event data provided by the company, show that the process instances executed concurrently complete with significantly fewer faults and with lower fault severities, when the recommendations provided by our recommendation system are taken into account.

Social and cultural drivers of incentive effectiveness in infrastructure projects

Formal incentives systems aim to encourage improved performance by offering a reward for the achievement of project-specific goals. Despite argued benefits of incentive systems on project delivery outcomes, there remains debate over how incentive systems can be designed to encourage the formation of strong project relationships within a complex social system such as an infrastructure project. This challenge is compounded by the increasing emphasis in construction management research on the important mediating influence of technical and organisational context on project performance. In light of this challenge, the research presented in this paper focuses on the design of incentive systems in four infrastructure projects: two road reconstructions in the Netherlands and two building constructions in Australia. Based on a motivational theory frame, a cross case analysis is conducted to examine differences and similarities across social and cultural drivers impacting on the effectiveness of the incentive systems in light of infrastructure project context. Despite significant differences in case project characteristics, results indicate the projects’ experience similar social drivers impacting on incentive effectiveness. Significant value across the projects was placed on: varied performance goals and multiple opportunities to across the project team to pursue incentive rewards; fair risk allocation across contract parties; value-driven tender selection; improved design-build integration; and promotion of future work opportunities. However, differences across the contexts were identified. Results suggest future work opportunities were a more powerful social driver in upholding reputation and establishing strong project relationships in the Australian context. On the other hand, the relationship initiatives in the Dutch context seemed to be more broadly embraced resulting in a greater willingness to collaboratively manage project risk. Although there are limitations with this research in drawing generalizations across two sets of case projects, the results provide a strong base to explore the social and cultural influences on incentive effectiveness across different geographical and contextual boundaries in future research.

The effectiveness of psychosocial interventions for cognitive dysfunction in cancer patients who have received chemotherapy : a systematic review

Background: Chemotherapy-related cognitive dysfunction (CRCD) refers to problems with memory,attention span, or concentration, experienced by patients with cancer who have had chemotherapy. CRCD can have a significant negative effect on a patient’s quality of life. The exact cause of CRCD is unknown but is presumed to be multifactorial. Objective: To conduct a systematic review of the effectiveness of psychosocial interventions designed to treat CRCD. Methods: Participants of interest to the review were over 18 years of age, diagnosed with cancer, and receiving chemotherapy or had received chemotherapy in the past. Interventions of interest were methods to improve cognitive function. Included study designs were randomized controlled trials, quasi-experimental trials, and quantitative observational studies. The primary outcome of interest was level of cognitive function. A three-step search strategy was utilized to identify studies published from 1985 to 2011 from a wide range of databases. Joanna Briggs Institute systematic review methods were used but findings were analyzed using the Cochrane Collaboration Review Manager 5.1 program.Weightedmean differences with 95% confidence intervals were calculated from the continuous data. Results: Searching identified 3,109 potentially relevant articles and 120 full-text articles were retrieved. Two further papers were sourced from reference lists of retrieved articles. From 122 papers, six were suitable for critical appraisal and six were included in the analysis. Meta-analysis was conducted on two cognitive behavioral therapy (CBT) trials for the outcome of inability to concentrate. Significant effect was seen for one CBT intervention at 20 weeks (p = .004). Significant effect from CBT on quality of life was seen at 6-month follow-up (p < .05). Conclusions: Despite some evidence of an effect, there is insufficient evidence at this stage to strongly recommend any of the interventions to assist in decreasing the effects of CRCD, except in terms of improving quality of life.

Wide-band spectral power fluctuations characterize the response of simulated cortical networks to increasing stimulus intensity

The hippocampus is an anatomically distinct region of the medial temporal lobe that plays a critical role in the formation of declarative memories. Here we show that a computer simulation of simple compartmental cells organized with basic hippocampal connectivity is capable of producing stimulus intensity sensitive wide-band fluctuations of spectral power similar to that seen in real EEG. While previous computational models have been designed to assess the viability of the putative mechanisms of memory storage and retrieval, they have generally been too abstract to allow comparison with empirical data. Furthermore, while the anatomical connectivity and organization of the hippocampus is well defined, many questions regarding the mechanisms that mediate large-scale synaptic integration remain unanswered. For this reason we focus less on the specifics of changing synaptic weights and more on the population dynamics. Spectral power in four distinct frequency bands were derived from simulated field potentials of the computational model and found to depend on the intensity of a random input. The majority of power occurred in the lowest frequency band (3-6 Hz) and was greatest to the lowest intensity stimulus condition (1% maximal stimulus). In contrast, higher frequency bands ranging from 7-45 Hz show an increase in power directly related with an increase in stimulus intensity. This trend continues up to a stimulus level of 15% to 20% of the maximal input, above which power falls dramatically. These results suggest that the relative power of intrinsic network oscillations are dependent upon the level of activation and that above threshold levels all frequencies are damped, perhaps due to over activation of inhibitory interneurons.

Memory and Epileptogenesis in Complex Biological and Simulated Systems

Oscillations of neural activity may bind widespread cortical areas into a neural representation that encodes disparate aspects of an event. In order to test this theory we have turned to data collected from complex partial epilepsy (CPE) patients with chronically implanted depth electrodes. Data from regions critical to word and face information processing was analyzed using spectral coherence measurements. Similar analyses of intracranial EEG (iEEG) during seizure episodes display HippoCampal Formation (HCF)—NeoCortical (NC) spectral coherence patterns that are characteristic of specific seizure stages (Klopp et al. 1996). We are now building a computational memory model to examine whether spatio-temporal patterns of human iEEG spectral coherence emerge in a computer simulation of HCF cellular distribution, membrane physiology and synaptic connectivity. Once the model is reasonably scaled it will be used as a tool to explore neural parameters that are critical to memory formation and epileptogenesis.

Rapid production of a plasmid DNA encoding a malaria vaccine candidate via amino-functionalized poly(GMA-co-EDMA) monolith

Malaria is a global health problem; an effective vaccine is urgently needed. Due to the relative poverty and lack of infrastructure in malaria endemic areas, DNA-based vaccines that are stable at ambient temperatures and easy to formulate have great potential. While attention has been focused mainly on antigen selection, vector design and efficacy assessment, the development of a rapid and commercially viable process to manufacture DNA is generally overlooked. We report here a continuous purification technique employing an optimized stationary adsorbent to allow high-vaccine recovery, low-processing time, and, hence, high-productivity. A 40.0 mL monolithic stationary phase was synthesized and functionalized with amino groups from 2-Chloro-N,N- diethylethylamine hydrochloride for anion-exchange isolation of a plasmid DNA (pDNA) that encodes a malaria vaccine candidate, VR1020-PyMSP4/5. Physical characterization of the monolithic polymer showed a macroporous material with a modal pore diameter of 750 nm. The final vaccine product isolated after 3 min elution was homogeneous supercoiled plasmid with gDNA, RNA and protein levels in keeping with clinical regulatory standards. Toxicological studies of the pVR1020-PyMSP4/5 showed a minimum endotoxin level of 0.28 EU/m.g pDNA. This cost-effective technique is cGMP compatible and highly scalable for the production of DNA-based vaccines in commercial quantities, when such vaccines prove to be effective against malaria. © 2008 American Institute of Chemical Engineers.