: A Model System for Anti-Cancer Drug Discovery and Therapeutic Target Identification

The nematode Caenorhabditis elegans (C. elegans) offers a unique opportunity for biological and basic medical researches due to its genetic tractability and well-defined developmental lineage. It also provides an exceptional model for genetic, molecular, and cellular analysis of human disease-related genes. Recently, C. elegans has been used as an ideal model for the identification and functional analysis of drugs (or small-molecules) in vivo. In this review, we describe conserved oncogenic signaling pathways (Wnt, Notch, and Ras) and their potential roles in the development of cancer stem cells. During C. elegans germline development, these signaling pathways regulate multiple cellular processes such as germline stem cell niche specification, germline stem cell maintenance, and germ cell fate specification. Therefore, the aberrant regulations of these signaling pathways can cause either loss of germline stem cells or overproliferation of a specific cell type, resulting in sterility. This sterility phenotype allows us to identify drugs that can modulate the oncogenic signaling pathways directly or indirectly through a high-throughput screening. Current in vivo or in vitro screening methods are largely focused on the specific core signaling components. However, this phenotype-based screening will identify drugs that possibly target upstream or downstream of core signaling pathways as well as exclude toxic effects. Although phenotype-based drug screening is ideal, the identification of drug targets is a major challenge. We here introduce a new technique, called Drug Affinity Responsive Target Stability (DARTS). This innovative method is able to identify the target of the identified drug. Importantly, signaling pathways and their regulators in C. elegans are highly conserved in most vertebrates, including humans. Therefore, C. elegans will provide a great opportunity to identify therapeutic drugs and their targets, as well as to understand mechanisms underlying the formation of cancer

Reduction of Ischemia/Reperfusion Injury With Bendavia, a Mitochondria-Targeting Cytoprotective Peptide

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Association of cardiac and vascular changes with ambient PMin diabetic individuals

Background and Objective Exposure to fine airborne particles (PM2.5) has been shown to be responsible for cardiovascular and hematological effects, especially in older people with cardiovascular disease. Some epidemiological studies suggest that individuals with diabetes may be a particularly susceptible population. This study examined effects of short-term exposures to ambient PM2.5 on markers of systemic inflammation, coagulation, autonomic control of heart rate, and repolarization in 22 adults (mean age: 61 years) with type 2 diabetes. Methods Each individual was studied for four consecutive days with daily assessments of plasma levels of blood markers. Cardiac rhythm and electrocardiographic parameters were examined at rest and with 24-hour ambulatory ECG monitors. PM2.5 and meteorological data were measured daily on the rooftop of the patient exam site. Data were analyzed with models adjusting for season, weekday, meteorology, and a random intercept. To identify susceptible subgroups, effect modification was analyzed by clinical characteristics associated with insulin resistance as well as with oxidative stress and by medication intake. Results Interleukin (IL)-6 and tumor necrosis factor alpha showed a significant increase with a lag of two days (percent change of mean level: 20.2% with 95%-confidence interval [6.4; 34.1] and 13.1% [1.9; 24.4], respectively) in association with an increase of 10 μg/m3 in PM2.5. Obese participants as well as individuals with elevated glycosylated hemoglobin, lower adiponectin, higher ferritin or with glutathione S-transferase M1 null genotype showed higher IL-6 effects. Changes in repolarization were found immediately as well as up to four days after exposure in individuals without treatment with a beta-adrenergic receptor blocker. Conclusions Exposure to elevated levels of PM2.5 alters ventricular repolarization and thus may increase myocardial vulnerability to arrhythmias. Exposure to PM2.5 also increases systemic inflammation. Characteristics associated with insulin resistance or with oxidative stress were shown to enhance the association

The Influence of Resistance Exercise Training on the Levels of Anxiety in Ischemic Stroke

The aim of this pilot study was to analyze the effect of a strength training program on indicators of trait and state anxiety in patients with ischemic stroke. The subjects were divided into two groups: experimental group (EG) consisting of 11 subjects aged years and a control group (CG) with 13 subjects aged years. EG underwent 12 weeks of strength training, with a frequency of three times a week. For data collection, a State-Trait Anxiety Inventory (STAI) was used. Significant differences were found between pre- and posttest in EG for trait anxiety ( pretest posttest) and state anxiety ( pretest posttest) with no differences in CG for trait anxiety ( pretest posttest) and state anxiety ( pretest posttest). In the evaluation between the groups, significant differences were found for all indicators of trait anxiety ( EG; CG) and state anxiety ( EG; CG). This pilot study indicates that strength training may provide an improvement in trait and state anxiety more than one year after stroke

The influence of the level of physical activity and human development in the quality of life in survivors of stroke

<p>Abstract</p> <p>Background</p> <p>The association between physical activity and quality of life in stroke survivors has not been analyzed within a framework related to the human development index. This study aimed to identify differences in physical activity level and in the quality of life of stroke survivors in two cities differing in economic aspects of the human development index.</p> <p>Methods</p> <p>Two groups of subjects who had suffered a stroke at least a year prior to testing and showed hemiplegia or hemiparesis were studied: a group from Belo Horizonte (BH) with 48 people (51.5 ± 8.7 years) and one from Montes Claros (MC) with 29 subjects (55.4 ± 8.1 years). Subsequently, regardless of location, the groups were divided into Active and Insufficiently Active so their difference in terms of quality of life could be analyzed.</p> <p>Results</p> <p>There were no significant differences between BH and MCG when it came to four dimensions of physical health that were evaluated (physical functioning, physical aspect, pain and health status) or in the following four dimensions of mental health status (vitality, social aspect, emotional aspect and mental health). However, significantly higher mean values were found in Active when compared with Insufficiently Active individuals in various measures of physical health (physical functioning 56.2 ± 4.4 vs. 47.4 ± 6.9; physical aspect 66.5 ± 6.5 vs. 59.1 ± 6.7; pain 55.9 ± 6.2 vs. 47.7 ± 6.0; health status 67.2 ± 4.2 vs. 56.6 ± 7.8) (arbitrary units), and mental health (vitality 60.9 ± 6.8 vs. 54.1 ± 7.2; social aspect 60.4 ± 7.1 vs. 54.2 ± 7.4; emotional aspect 64.0 ± 5.5 vs. 58.1 ± 6.9; mental health status 66.2 ± 5.5 vs. 58.4 ± 7.5) (arbitrary units).</p> <p>Conclusions</p> <p>Despite the difference between the cities concerning HDI values, no significant differences in quality of life were found between BH and MCG. However, the Active group showed significantly better results, confirming the importance of active lifestyle to enhance quality of life in stroke survivors.</p

An appropriate tool for entrepreneurial learning in SMEs? The case of the 20Twenty Leadership Programme

The 20Twenty Leadership Programme was developed by Cardiff Metropolitan University as an executive education programme to be delivered within South Wales to small businesses. It is funded by the European Social Fund (ESF) and administered by the Welsh European Funding Office and has the key aim of developing SME’s growth potential via a range of leadership and management skills, including a focus on ‘soft’ skills. The focus of this paper is to place the 20Twenty Leadership Programme within the wider context of entrepreneurship policy and SME training initiatives in particular, and then to examine the rationale and delivery methods of the Programme in relation to these. It also reflects on the Programme’s success (or otherwise) to date where possible. Finally, the paper seeks to suggest fruitful areas of further research both in terms of the 20Twenty Leadership Programme itself, but also with regard to evaluation in relation to other parallel programmes, and to SME training initiatives more generally

Expansion of cardiac ischemia/reperfusion injury after instillation of three forms of multi-walled carbon nanotubes

Background The exceptional physical-chemical properties of carbon nanotubes have lead to their use in diverse commercial and biomedical applications. However, their utilization has raised concerns about human exposure that may predispose individuals to adverse health risks. The present study investigated the susceptibility to cardiac ischemic injury following a single exposure to various forms of multi-walled carbon nanotubes (MWCNTs). It was hypothesized that oropharyngeal aspiration of MWCNTs exacerbates myocardial ischemia and reperfusion injury (I/R injury). Methods Oropharyngeal aspiration was performed on male C57BL/6J mice with a single amount of MWCNT (0.01 - 100 μg) suspended in 100 μL of a surfactant saline (SS) solution. Three forms of MWCNTs were used in this study: unmodified, commercial grade (C-grade), and functionalized forms that were modified either by acid treatment (carboxylated, COOH) or nitrogenation (N-doped) and a SS vehicle. The pulmonary inflammation, serum cytokine profile and cardiac ischemic/reperfusion (I/R) injury were assessed at 1, 7 and 28 days post-aspiration. Results Pulmonary response to MWCNT oropharyngeal aspiration assessed by bronchoalveolar lavage fluid (BALF) revealed modest increases in protein and inflammatory cell recruitment. Lung histology showed modest tissue inflammation as compared to the SS group. Serum levels of eotaxin were significantly elevated in the carboxylated MWCNT aspirated mice 1 day post exposure. Oropharyngeal aspiration of all three forms of MWCNTs resulted in a time and/or dose-dependent exacerbation of myocardial infarction. The severity of myocardial injury varied with the form of MWCNTs used. The N-doped MWCNT produced the greatest expansion of the infarct at any time point and required a log concentration lower to establish a no effect level. The expansion of the I/R injury remained significantly elevated at 28 days following aspiration of the COOH and N-doped forms, but not the C-grade as compared to SS. Conclusion Our results suggest that oropharyngeal aspiration of MWCNT promotes increased susceptibility of cardiac tissue to ischemia/reperfusion injury without a significant pulmonary inflammatory response. The cardiac injury effects were observed at low concentrations of MWCNTs and presence of MWCNTs may pose a significant risk to the cardiovascular system

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

The dicer-like1 Homolog fuzzy tassel Is Required for the Regulation of Meristem Determinacy in the Inflorescence and Vegetative Growth in Maize

Plant architecture is determined by meristems that initiate leaves during vegetative development and flowers during reproductive development. Maize (Zea mays) inflorescences are patterned by a series of branching events, culminating in floral meristems that produce sexual organs. The maize fuzzy tassel (fzt) mutant has striking inflorescence defects with indeterminate meristems, fasciation, and alterations in sex determination. fzt plants have dramatically reduced plant height and shorter, narrower leaves with leaf polarity and phase change defects. We positionally cloned fzt and discovered that it contains a mutation in a dicer-like1 homolog, a key enzyme required for microRNA (miRNA) biogenesis. miRNAs are small noncoding RNAs that reduce target mRNA levels and are key regulators of plant development and physiology. Small RNA sequencing analysis showed that most miRNAs are moderately reduced in fzt plants and a few miRNAs are dramatically reduced. Some aspects of the fzt phenotype can be explained by reduced levels of known miRNAs, including miRNAs that influence meristem determinacy, phase change, and leaf polarity. miRNAs responsible for other aspects of the fzt phenotype are unknown and likely to be those miRNAs most severely reduced in fzt mutants. The fzt mutation provides a tool to link specific miRNAs and targets to discrete phenotypes and developmental roles.ECU Open Access Publishing Support Fun

Changing malaria intervention coverage, transmission and hospitalization in Kenya

<p>Abstract</p> <p>Background</p> <p>Reports of declining incidence of malaria disease burden across several countries in Africa suggest that the epidemiology of malaria across the continent is in transition. Whether this transition is directly related to the scaling of intervention coverage remains a moot point.</p> <p>Methods</p> <p>Paediatric admission data from eight Kenyan hospitals and their catchments have been assembled across two three-year time periods: September 2003 to August 2006 (pre-scaled intervention) and September 2006 to August 2009 (post-scaled intervention). Interrupted time series (ITS) models were developed adjusting for variations in rainfall and hospital use by surrounding communities to show changes in malaria hospitalization over the two periods. The temporal changes in factors that might explain changes in disease incidence were examined sequentially for each hospital setting, compared between hospital settings and ranked according to plausible explanatory factors.</p> <p>Results</p> <p>In six out of eight sites there was a decline in Malaria admission rates with declines between 18% and 69%. At two sites malaria admissions rates increased by 55% and 35%. Results from the ITS models indicate that before scaled intervention in September 2006, there was a significant month-to-month decline in the mean malaria admission rates at four hospitals (trend P < 0.05). At the point of scaled intervention, the estimated mean admission rates for malaria was significantly less at four sites compared to the pre-scaled period baseline. Following scaled intervention there was a significant change in the month-to-month trend in the mean malaria admission rates in some but not all of the sites. Plausibility assessment of possible drivers of change pre- versus post-scaled intervention showed inconsistent patterns however, allowing for the increase in rainfall in the second period, there is a suggestion that starting transmission intensity and the scale of change in ITN coverage might explain some but not all of the variation in effect size. At most sites where declines between observation periods were documented admission rates were changing before free mass ITN distribution and prior to the implementation of ACT across Kenya.</p> <p>Conclusion</p> <p>This study provides evidence of significant within and between location heterogeneity in temporal trends of malaria disease burden. Plausible drivers for changing disease incidence suggest a complex combination of mechanisms, not easily measured retrospectively.</p