WorldWideScience

Sample records for intervention targets identified

  1. Negative symptoms and social cognition: identifying targets for psychological interventions.

    Science.gov (United States)

    Lincoln, Tania M; Mehl, Stephanie; Kesting, Marie-Luise; Rief, Winfried

    2011-09-01

    How to improve treatment for negative symptoms is a continuing topic of debate. Suggestions have been made to advance psychological understanding of negative symptoms by focusing on the social cognitive processes involved in symptom formation and maintenance. Following the recommendations by the National Institute of Mental Health workshop on social cognition in schizophrenia, this study investigated associations between negative symptoms and various aspects of social cognition including Theory of Mind (ToM), attribution, empathy, self-esteem, and interpersonal self-concepts in 75 patients with schizophrenia spectrum disorders and 75 healthy controls. Negative symptoms were significantly associated with difficulties in ToM, less readiness to be empathic, lower self-esteem, less self-serving bias, negative self-concepts related to interpersonal abilities, and dysfunctional acceptance beliefs. Different aspects of social cognition were mildly to moderately correlated and interacted in their impact on negative symptoms: Difficulties in ToM were associated with negative symptoms in persons with low but not in persons with medium or high levels of self-esteem. Taken together, the social cognition variables and their hypothesized interaction explained 39% of the variance in negative symptoms after controlling for neurocognition and depression. The results highlight the relevance of self-concepts related to social abilities, dysfunctional beliefs, and global self-worth alone and in interaction with ToM deficits for negative symptoms and thereby provide a helpful basis for advancing psychosocial interventions.

  2. Large Dog Relinquishment to Two Municipal Facilities in New York City and Washington, D.C.: Identifying Targets for Intervention

    Science.gov (United States)

    Weiss, Emily; Slater, Margaret; Garrison, Laurie; Drain, Natasha; Dolan, Emily; Scarlett, Janet M.; Zawistowski, Stephen L.

    2014-01-01

    Simple Summary While the overall trend in euthanasia has been decreasing nationally, large dogs are at a higher risk of euthanasia than other-sized dogs in most animal shelters in the United States. We hypothesized that one way to increase the lives saved with regard to large dogs in shelters is to keep them home in the first place when possible. Our research is the first to collect data in New York City and Washington, D.C., identifying the process leading to the owner relinquishment of large dogs. We found that targets for interventions to decrease large dog relinquishment are likely different in each community. Abstract While the overall trend in euthanasia has been decreasing nationally, large dogs are at a higher risk of euthanasia than other sized dogs in most animal shelters in the United States. We hypothesized one way to increase the lives saved with respect to these large dogs is to keep them home when possible. In order to develop solutions to decrease relinquishment, a survey was developed to learn more about the reasons owners relinquish large dogs. The survey was administered to owners relinquishing their dogs at two large municipal facilities, one in New York City and one in Washington, D.C. There were 157 responses between the two facilities. We found both significant similarities and differences between respondents and their dogs from the two cities. We identified opportunities to potentially support future relinquishers and found that targets for interventions are likely different in each community. PMID:26480315

  3. Large Dog Relinquishment to Two Municipal Facilities in New York City and Washington, D.C.: Identifying Targets for Intervention

    Directory of Open Access Journals (Sweden)

    Emily Weiss

    2014-07-01

    Full Text Available While the overall trend in euthanasia has been decreasing nationally, large dogs are at a higher risk of euthanasia than other sized dogs in most animal shelters in the United States. We hypothesized one way to increase the lives saved with respect to these large dogs is to keep them home when possible. In order to develop solutions to decrease relinquishment, a survey was developed to learn more about the reasons owners relinquish large dogs. The survey was administered to owners relinquishing their dogs at two large municipal facilities, one in New York City and one in Washington, D.C. There were 157 responses between the two facilities. We found both significant similarities and differences between respondents and their dogs from the two cities. We identified opportunities to potentially support future relinquishers and found that targets for interventions are likely different in each community.

  4. Applying the Theoretical Domains Framework to identify barriers and targeted interventions to enhance nurses' use of electronic medication management systems in two Australian hospitals.

    Science.gov (United States)

    Debono, Deborah; Taylor, Natalie; Lipworth, Wendy; Greenfield, David; Travaglia, Joanne; Black, Deborah; Braithwaite, Jeffrey

    2017-03-27

    Medication errors harm hospitalised patients and increase health care costs. Electronic Medication Management Systems (EMMS) have been shown to reduce medication errors. However, nurses do not always use EMMS as intended, largely because implementation of such patient safety strategies requires clinicians to change their existing practices, routines and behaviour. This study uses the Theoretical Domains Framework (TDF) to identify barriers and targeted interventions to enhance nurses' appropriate use of EMMS in two Australian hospitals. This qualitative study draws on in-depth interviews with 19 acute care nurses who used EMMS. A convenience sampling approach was used. Nurses working on the study units (N = 6) in two hospitals were invited to participate if available during the data collection period. Interviews inductively explored nurses' experiences of using EMMS (step 1). Data were analysed using the TDF to identify theory-derived barriers to nurses' appropriate use of EMMS (step 2). Relevant behaviour change techniques (BCTs) were identified to overcome key barriers to using EMMS (step 3) followed by the identification of potential literature-informed targeted intervention strategies to operationalise the identified BCTs (step 4). Barriers to nurses' use of EMMS in acute care were represented by nine domains of the TDF. Two closely linked domains emerged as major barriers to EMMS use: Environmental Context and Resources (availability and properties of computers on wheels (COWs); technology characteristics; specific contexts; competing demands and time pressure) and Social/Professional Role and Identity (conflict between using EMMS appropriately and executing behaviours critical to nurses' professional role and identity). The study identified three potential BCTs to address the Environmental Context and Resources domain barrier: adding objects to the environment; restructuring the physical environment; and prompts and cues. Seven BCTs to address Social

  5. A mixed-methods study identifying key intervention targets to improve participation in daily living activities in primary Sjögren's syndrome patients.

    Science.gov (United States)

    Hackett, Katie L; Deane, Katherine H O; Newton, Julia L; Deary, Vincent; Bowman, Simon; Rapley, Tim; Ng, Wan-Fai

    2018-02-06

    Functional ability and participation in life situations are compromised in many primary Sjögren's syndrome (PSS) patients. This study aims to identify the key barriers and priorities to participation in daily living activities, in order to develop potential future interventions. Group concept mapping (GCM), a semi-quantitative, mixed-methods, approach was used to identify and structure ideas from UK PSS patients, adults living with a PSS patient (AHMs) and health care professionals (HCPs). Brainstorming generated ideas, which were summarised into a final set of statements. Participants individually arranged these statements into themes and rated each statement for importance. Multidimensional scaling and hierarchical cluster analysis were applied to sorted and rated data to produce visual representations of the ideas (concept maps), enabling identification of agreed priority areas for interventions. 121 patients, 43 AHMs and 67 HCPs took part. 463 ideas were distilled down to 94 statements. These statements were grouped into seven clusters; 'Patient empowerment', 'Symptoms', 'Wellbeing', 'Access and coordination of healthcare', 'Knowledge and support', 'Public awareness and support' and 'Family and friends'. Patient empowerment and Symptoms were rated as priority conceptual themes. Important statements within priority clusters indicate patients should be taken seriously and supported to self-manage symptoms of oral and ocular dryness, fatigue, pain and poor sleep. Our data highlighted that in addition to managing PSS symptoms; interventions aiming to improve patient empowerment, general wellbeing, access to healthcare, patient education and social support are important to facilitate improved participation in daily living activities. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  6. Intervention Targets for Youth with Disabilities in Foster Care

    Science.gov (United States)

    Harwick, Robin; Tyre, Ashli; Beisse, Kay; Thomas, Cathy

    2015-01-01

    This article will focus on students with disabilities in foster care to help school psychologists identify effective school-based interventions for these students. We will report our findings from three independent studies and then apply the findings to suggest targeted interventions for these students that are intended to improve educational and…

  7. Identifying potential programs and platforms to deliver multiple micronutrient interventions.

    Science.gov (United States)

    Olney, Deanna K; Rawat, Rahul; Ruel, Marie T

    2012-01-01

    This article reviews the potential of four broad types of platforms, health, agriculture, market-based, and social protection programs, to deliver multiple micronutrient (MMN) interventions (supplementation, fortification, and dietary modification). We assessed the platforms' potential based on seven performance criteria related to programs within these platforms: 1) targeting, 2) efficacy of interventions, 3) quality of implementation, 4) utilization, 5) impact, 6) coverage, and 7) sustainability. We highlight one type of program per platform to illustrate strengths and weaknesses for delivering MMN interventions, identify critical knowledge gaps, and highlight what is needed to increase effectiveness for delivering MMN interventions. We found that all four platforms have the potential to effectively deliver MMN interventions if the following key program elements are addressed: 1) strong behavior change communication strategies to increase demand and proper utilization of services/products; 2) supply side interventions to ensure consistent availability of high quality interventions, products, and well-trained staff; 3) rigorous evaluations of effectiveness, quality of delivery, and impact pathways to generate best practices for replication and scale-up; and 4) timely dissemination of evaluation results to ensure use by program implementers and policy makers. The diversification of delivery platforms, which simultaneously addresses multiple determinants of MMN deficiencies and expands coverage, is needed to accelerate progress in reducing MMN deficiencies.

  8. Systematic review of universal and targeted workplace interventions for depression.

    Science.gov (United States)

    Wan Mohd Yunus, Wan Mohd Azam; Musiat, Peter; Brown, June S L

    2018-01-01

    Depression is increasingly being recognised as a significant mental health problem in the workplace contributing to productivity loss and economic burden to organisations. This paper reviews recently published randomised controlled trials (RCTs) of universal and targeted interventions to reduce depression in the workplace. Studies were identified through searches of EMBASE, MEDLINE/PubMed, PsycINFO, PsycARTICLES Full Text, and Global Health and Social Policy and Practice databases. Studies were included if they included an RCT of a workplace intervention for employees targeting depression as the primary outcome. Twenty-two published RCTs investigating interventions utilising various therapeutic approaches were identified. The cognitive behavioural therapy (CBT) approach is the most frequently used in the workplace, while interventions that combine different therapeutic approaches showed the most promising results. A universal intervention in the workplace that combines CBT and coping flexibility recorded the highest effect size (d=1.45 at 4 months' follow-up). Most interventions were delivered in group format and showed low attrition rates compared with other delivery formats. Although all studies reviewed were RCTs, the quality of reporting is low. Interventions using different therapeutic approaches with different modes of delivery have been used. Most of these interventions were shown to reduce depression levels among employees in the workplace, particularly those that combine more than one therapeutic approaches. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  9. Parameter trajectory analysis to identify treatment effects of pharmacological interventions.

    Directory of Open Access Journals (Sweden)

    Christian A Tiemann

    Full Text Available The field of medical systems biology aims to advance understanding of molecular mechanisms that drive disease progression and to translate this knowledge into therapies to effectively treat diseases. A challenging task is the investigation of long-term effects of a (pharmacological treatment, to establish its applicability and to identify potential side effects. We present a new modeling approach, called Analysis of Dynamic Adaptations in Parameter Trajectories (ADAPT, to analyze the long-term effects of a pharmacological intervention. A concept of time-dependent evolution of model parameters is introduced to study the dynamics of molecular adaptations. The progression of these adaptations is predicted by identifying necessary dynamic changes in the model parameters to describe the transition between experimental data obtained during different stages of the treatment. The trajectories provide insight in the affected underlying biological systems and identify the molecular events that should be studied in more detail to unravel the mechanistic basis of treatment outcome. Modulating effects caused by interactions with the proteome and transcriptome levels, which are often less well understood, can be captured by the time-dependent descriptions of the parameters. ADAPT was employed to identify metabolic adaptations induced upon pharmacological activation of the liver X receptor (LXR, a potential drug target to treat or prevent atherosclerosis. The trajectories were investigated to study the cascade of adaptations. This provided a counter-intuitive insight concerning the function of scavenger receptor class B1 (SR-B1, a receptor that facilitates the hepatic uptake of cholesterol. Although activation of LXR promotes cholesterol efflux and -excretion, our computational analysis showed that the hepatic capacity to clear cholesterol was reduced upon prolonged treatment. This prediction was confirmed experimentally by immunoblotting measurements of SR-B1

  10. Targeting Cancer Metabolism: Dietary and Pharmacologic Interventions.

    Science.gov (United States)

    Vernieri, Claudio; Casola, Stefano; Foiani, Marco; Pietrantonio, Filippo; de Braud, Filippo; Longo, Valter

    2016-12-01

    Most tumors display oncogene-driven reprogramming of several metabolic pathways, which are crucial to sustain their growth and proliferation. In recent years, both dietary and pharmacologic approaches that target deregulated tumor metabolism are beginning to be considered for clinical applications. Dietary interventions exploit the ability of nutrient-restricted conditions to exert broad biological effects, protecting normal cells, organs, and systems, while sensitizing a wide variety of cancer cells to cytotoxic therapies. On the other hand, drugs targeting enzymes or metabolites of crucial metabolic pathways can be highly specific and effective, but must be matched with a responsive tumor, which might rapidly adapt. In this review, we illustrate how dietary and pharmacologic therapies differ in their effect on tumor growth, proliferation, and metabolism and discuss the available preclinical and clinical evidence in favor of or against each of them. We also indicate, when appropriate, how to optimize future investigations on metabolic therapies on the basis of tumor- and patient-related characteristics. To our knowledge, this is the first review article that comprehensively analyzes the preclinical and preliminary clinical experimental foundations of both dietary and pharmacologic metabolic interventions in cancer therapy. Among several promising therapies, we propose treatment personalization on the basis of tumor genetics, tumor metabolism, and patient systemic metabolism.Cancer Discov; 6(12); 1315-33. ©2016 AACR. ©2016 American Association for Cancer Research.

  11. Identifying molecular targets of lifestyle modifications in colon cancer prevention

    Directory of Open Access Journals (Sweden)

    Molly Marie Derry

    2013-05-01

    Full Text Available One in four deaths in the United States is cancer-related, and colorectal cancer (CRC is the second leading cause of cancer-associated deaths. Screening strategies are utilized but have not reduced disease incidence or mortality. In this regard, there is an interest in cancer preventive strategies focusing on lifestyle intervention, where specific etiologic factors involved in cancer initiation, promotion, and progression could be targeted. For example, exposure to dietary carcinogens, such as nitrosamines and polycyclic aromatic hydrocarbons influences colon carcinogenesis. Furthermore, dietary deficiencies could alter sensitivity to genetic damage and influence carcinogen metabolism contributing to CRC. High alcohol consumption increases the risk of mutations including the fact that acetaldehyde, an ethanol metabolite, is classified as a group 1 carcinogen. Tobacco smoke exposure is also a risk factor for cancer development; ~20% of CRCs are associated with smoking. Additionally, obese patients have a higher risk of cancer development, which is further supported by the fact that physical activity decreases CRC risk by 55%. Similarly, chronic inflammatory conditions also increase the risk of CRC development. Moreover, the circadian clock alters digestion and regulates other biochemical, physiological and behavioral processes that could positively influence CRC. Taken together, colon carcinogenesis involves a number of etiological factors, and therefore, to create effective preventive strategies, molecular targets need to be identified and beleaguered prior to disease progression. With this in mind, the following is a comprehensive review identifying downstream target proteins of the above lifestyle risk factors, which are modulated during colon carcinogenesis and could be targeted for CRC prevention by novel agents including phytochemicals.

  12. Targeting cancer metabolism: dietary and pharmacological interventions

    Science.gov (United States)

    Vernieri, Claudio; Casola, Stefano; Foiani, Marco; Pietrantonio, Filippo; de Braud, Filippo; Longo, Valter

    2016-01-01

    Most tumors display oncogene-driven reprogramming of several metabolic pathways, which are crucial to sustain their growth and proliferation. In recent years, both dietary and pharmacological approaches that target deregulated tumor metabolism are beginning to be considered for clinical applications. Dietary interventions exploit the ability of nutrient-restricted conditions to exert broad biological effects, protecting normal cells, organs and systems, while sensitizing a wide variety of cancer cells to cytotoxic therapies. On the other hand, drugs targeting enzymes or metabolites of crucial metabolic pathways can be highly specific and effective, but must be matched with a responsive tumor, which might rapidly adapt. In this Review, we illustrate how dietary and pharmacological therapies differ in their effect on tumor growth, proliferation and metabolism, and discuss the available preclinical and clinical evidence in favor or against each of them. We also indicate, when appropriate, how to optimize future investigations on metabolic therapies on the basis of tumor- and patient-related characteristics. PMID:27872127

  13. Identifying unexpected therapeutic targets via chemical-protein interactome.

    Directory of Open Access Journals (Sweden)

    Lun Yang

    Full Text Available Drug medications inevitably affect not only their intended protein targets but also other proteins as well. In this study we examined the hypothesis that drugs that share the same therapeutic effect also share a common therapeutic mechanism by targeting not only known drug targets, but also by interacting unexpectedly on the same cryptic targets. By constructing and mining an Alzheimer's disease (AD drug-oriented chemical-protein interactome (CPI using a matrix of 10 drug molecules known to treat AD towards 401 human protein pockets, we found that such cryptic targets exist. We recovered from CPI the only validated therapeutic target of AD, acetylcholinesterase (ACHE, and highlighted several other putative targets. For example, we discovered that estrogen receptor (ER and histone deacetylase (HDAC, which have recently been identified as two new therapeutic targets of AD, might already have been targeted by the marketed AD drugs. We further established that the CPI profile of a drug can reflect its interacting character towards multi-protein sets, and that drugs with the same therapeutic attribute will share a similar interacting profile. These findings indicate that the CPI could represent the landscape of chemical-protein interactions and uncover "behind-the-scenes" aspects of the therapeutic mechanisms of existing drugs, providing testable hypotheses of the key nodes for network pharmacology or brand new drug targets for one-target pharmacology paradigm.

  14. Being targeted: Young women's experience of being identified for a teenage pregnancy prevention programme

    OpenAIRE

    Sorhaindo, Annik; Bonell, Chris; Fletcher, Adam; Jessiman, Patricia; Keogh, Peter; Mitchell, Kirstin

    2016-01-01

    Research on the unintended consequences of targeting ‘high-risk’ young people for health interventions is limited. Using qualitative data from an evaluation of the Teens & Toddlers Pregnancy Prevention programme, we explored how young women experienced being identified as at risk for teenage pregnancy to understand the processes via which unintended consequences may occur. Schools' lack of transparency regarding the targeting strategy and criteria led to feelings of confusion and mistrust...

  15. Integrating intervention targets offered by homeostatic theory.

    Science.gov (United States)

    Annunziato, Rachel A; Grossman, Stephanie L

    2016-01-01

    Marks presents "homeostatic theory" which proposes that weight gain is fostered by a "Circle of Discontent" consisting of body dissatisfaction, negative affect, and overconsumption. This innovative framework offers potential intervention approaches, including victim-blaming, stigma, and discrimination, as well as devalorizing the thin-ideal. Our article discusses possible ways that clinical health psychologists based in university settings may be uniquely positioned to consider and implement large-scale programs that have shown great promise for addressing these core issues.

  16. Interventions Targeting Mental Health Self-Stigma: A Review and Comparison

    Science.gov (United States)

    Yanos, Philip T.; Lucksted, Alicia; Drapalski, Amy L.; Roe, David; Lysaker, Paul

    2014-01-01

    Objective With growing awareness of the impact of mental illness self-stigma, interest has arisen in the development of interventions to combat it. The present article briefly reviews and compares interventions targeting self-stigma to clarify the similarities and important differences between the interventions. Methods We conducted a narrative review of published literature on interventions targeting self-stigma. Results Six intervention approaches (Healthy Self-Concept, Self-Stigma Reduction Program, Ending Self-Stigma, Narrative Enhancement and Cognitive Therapy, Coming Out Proud, and Anti-Stigma Photo-Voice Intervention) were identified and are discussed, and data is reviewed on format, group-leader backgrounds, languages, number of sessions, primary mechanisms of action, and the current state of data on their efficacy. Conclusions and Implications for Practice We conclude with a discussion of common elements and important distinctions between the interventions and a consideration of which interventions might be best suited to particular populations or settings. PMID:25313530

  17. Identifying targets for quality improvement in hospital antibiotic prescribing

    NARCIS (Netherlands)

    Spreuwel, P.C. van; Blok, H.; Langelaar, M.F.; Kullberg, B.J.; Mouton, J.W.; Natsch, S.S.

    2015-01-01

    OBJECTIVES: To audit antibiotic use in a university hospital and to identify targets for quality improvement in a setting with low antibiotic use and resistance rates. METHODOLOGY: A point-prevalence survey (PPS), using a patient-based audit tool for antibiotic use, was executed in the Radboud

  18. Integrating intervention targets offered by homeostatic theory

    Directory of Open Access Journals (Sweden)

    Rachel A Annunziato

    2016-02-01

    Full Text Available Marks presents “homeostatic theory” which proposes that weight gain is fostered by a “Circle of Discontent” consisting of body dissatisfaction, negative affect, and overconsumption. This innovative framework offers potential intervention approaches, including victim-blaming, stigma, and discrimination, as well as devalorizing the thin-ideal. Our article discusses possible ways that clinical health psychologists based in university settings may be uniquely positioned to consider and implement large-scale programs that have shown great promise for addressing these core issues.

  19. Proteomic and Genetic Approaches Identify Syk as an AML Target

    Science.gov (United States)

    Hahn, Cynthia K.; Berchuck, Jacob E.; Ross, Kenneth N.; Kakoza, Rose M.; Clauser, Karl; Schinzel, Anna C.; Ross, Linda; Galinsky, Ilene; Davis, Tina N.; Silver, Serena J.; Root, David E.; Stone, Richard M.; DeAngelo, Daniel J.; Carroll, Martin; Hahn, William C.; Carr, Steven A.; Golub, Todd R.; Kung, Andrew L.; Stegmaier, Kimberly

    2009-01-01

    SUMMARY Cell-based screening can facilitate rapid identification of compounds inducing complex cellular phenotypes. Advancing a compound toward the clinic, however, generally requires identification of precise mechanisms of action. We previously found that epidermal growth factor receptor (EGFR) inhibitors induce acute myeloid leukemia (AML) differentiation via a non-EGFR mechanism. In this report, we integrated proteomic and RNAi-based strategies to identify their off-target anti-AML mechanism. These orthogonal approaches identified Syk as a target in AML. Genetic and pharmacological inactivation of Syk with a drug in clinical trial for other indications promoted differentiation of AML cells and attenuated leukemia growth in vivo. These results demonstrate the power of integrating diverse chemical, proteomic, and genomic screening approaches to identify therapeutic strategies for cancer. PMID:19800574

  20. Identifying problematic drugs based on the characteristics of their targets.

    Science.gov (United States)

    Lopes, Tiago J S; Shoemaker, Jason E; Matsuoka, Yukiko; Kawaoka, Yoshihiro; Kitano, Hiroaki

    2015-01-01

    Identifying promising compounds during the early stages of drug development is a major challenge for both academia and the pharmaceutical industry. The difficulties are even more pronounced when we consider multi-target pharmacology, where the compounds often target more than one protein, or multiple compounds are used together. Here, we address this problem by using machine learning and network analysis to process sequence and interaction data from human proteins to identify promising compounds. We used this strategy to identify properties that make certain proteins more likely to cause harmful effects when targeted; such proteins usually have domains commonly found throughout the human proteome. Additionally, since currently marketed drugs hit multiple targets simultaneously, we combined the information from individual proteins to devise a score that quantifies the likelihood of a compound being harmful to humans. This approach enabled us to distinguish between approved and problematic drugs with an accuracy of 60-70%. Moreover, our approach can be applied as soon as candidate drugs are available, as demonstrated with predictions for more than 5000 experimental drugs. These resources are available at http://sourceforge.net/projects/psin/.

  1. Identifying problematic drugs based on the characteristics of their targets

    Directory of Open Access Journals (Sweden)

    Tiago Jose eDa Silva Lopes

    2015-09-01

    Full Text Available Identifying promising compounds during the early stages of drug development is a major challenge for both academia and the pharmaceutical industry. The difficulties are even more pronounced when we consider multi-target pharmacology, where the compounds often target more than one protein, or multiple compounds are used together. Here, we address this problem by using machine learning and network analysis to process sequence and interaction data from human proteins to identify promising compounds. We used this strategy to identify properties that make certain proteins more likely to cause harmful effects when targeted; such proteins usually have domains commonly found throughout the human proteome. Additionally, since currently marketed drugs hit multiple targets simultaneously, we combined the information from individual proteins to devise a score that quantifies the likelihood of a compound being harmful to humans. This approach enabled us to distinguish between approved and problematic drugs with an accuracy of 60%¬–70%. Moreover, our approach can be applied as soon as candidate drugs are available, as demonstrated with predictions for more than 5000 experimental drugs. These resources are available at http://sourceforge.net/projects/psin/.

  2. Translating Genetic Research into Preventive Intervention: The Baseline Target Moderated Mediator Design

    Science.gov (United States)

    Howe, George W.; Beach, Steven R. H.; Brody, Gene H.; Wyman, Peter A.

    2016-01-01

    In this paper we present and discuss a novel research approach, the baseline target moderated mediation (BTMM) design, that holds substantial promise for advancing our understanding of how genetic research can inform prevention research. We first discuss how genetically informed research on developmental psychopathology can be used to identify potential intervention targets. We then describe the BTMM design, which employs moderated mediation within a longitudinal study to test whether baseline levels of intervention targets moderate the impact of the intervention on change in that target, and whether change in those targets mediates causal impact of preventive or treatment interventions on distal health outcomes. We next discuss how genetically informed BTMM designs can be applied to both microtrials and full-scale prevention trials. We use simulated data to illustrate a BTMM, and end with a discussion of some of the advantages and limitations of this approach. PMID:26779062

  3. Translating genetic research into preventive intervention: The baseline target moderated mediator design

    Directory of Open Access Journals (Sweden)

    George W. Howe

    2016-01-01

    Full Text Available In this paper we present and discuss a novel research approach, the baseline target moderated mediation (BTMM design, that holds substantial promise for advancing our understanding of how genetic research can inform prevention research. We first discuss how genetically informed research on developmental psychopathology can be used to identify potential intervention targets. We then describe the BTMM design, which employs moderated mediation within a longitudinal study to test whether baseline levels of intervention targets moderate the impact of the intervention on change in that target, and whether change in those targets mediates causal impact of preventive or treatment interventions on distal health outcomes. We next discuss how genetically informed BTMM designs can be applied to both microtrials and full-scale prevention trials. We end with a discussion of some of the advantages and limitations of this approach.

  4. A SYSTEMATIC REVIEW OF INTERVENTIONS TARGETING PATERNAL MENTAL HEALTH IN THE PERINATAL PERIOD.

    Science.gov (United States)

    Rominov, Holly; Pilkington, Pamela D; Giallo, Rebecca; Whelan, Thomas A

    2016-05-01

    Interventions targeting parents' mental health in the perinatal period are critical due to potential consequences of perinatal mental illness for the parent, the infant, and their family. To date, most programs have targeted mothers. This systematic review explores the current status and evidence for intervention programs aiming to prevent or treat paternal mental illness in the perinatal period. Electronic databases were systematically searched to identify peer-reviewed studies that described an intervention targeting fathers' mental health in the perinatal period. Mental health outcomes included depression, anxiety, and stress as well as more general measures of psychological functioning. Eleven studies were identified. Three of five psychosocial interventions and three massage-technique interventions reported significant effects. None of the couple-based interventions reported significant effects. A number of methodological limitations were identified, including inadequate reporting of study designs, and issues with the timing of interventions. The variability in outcomes measures across the studies made it difficult to evaluate the overall effectiveness of the interventions. Father-focused interventions aimed at preventing perinatal mood problems will be improved if future studies utilize more rigorous research strategies. © 2016 Michigan Association for Infant Mental Health.

  5. Opportunity of interventional radiology: advantages and application of interventional technique in biological target therapy

    International Nuclear Information System (INIS)

    Teng Gaojun; Lu Qin

    2007-01-01

    Interventional techniques not only provide opportunity of treatment for many diseases, but also alter the traditional therapeutic pattern. With the new century of wide application of biological therapies, interventional technique also shows extensive roles. The current biological therapy, including gene therapy, cell transplantation therapy, immunobiologic molecule therapy containing cell factors, tumor antibody or vaccine, recombined proteins, radioactive-particles and targeting materials therapy, can be locally administrated by interventional techniques. The combination of targeting biological therapies and high-targeted interventional technique holds advantages of minimal invasion, accurate delivery, vigorous local effect, and less systemic adverse reactions. Authors believe that the biological therapy may arise a great opportunity for interventional radiology, therefore interventional colleagues should grasp firmly and promptly for the development and extension in this field. (authors)

  6. Weight management interventions targeting young women: a systematic review.

    Science.gov (United States)

    Hutchesson, Melinda J; Hulst, Judith; Collins, Clare E

    2013-06-01

    Young women are at high risk of weight gain. The aim of this systematic review was to evaluate randomized controlled trials of weight management interventions specifically targeting young women. Nine databases were searched for randomized controlled trials conducted from 1980 to December 2011 that recruited women aged 18 to 35 years, evaluated a weight management intervention, and reported weight as the primary outcome. Eight studies of moderate to poor quality met the inclusion criteria. Three interventions were specifically designed for young women and compared behavioral weight gain prevention interventions to control groups. Four of the five remaining studies evaluated weight gain prevention interventions, including daily weighing with feedback (n=2), a science course (n=1), and an exercise programs (n=1). The single weight loss intervention lowered the energy density of the participants' diet (n=1). Intervention lengths ranged from 4 weeks to 1 year, and only three studies followed-up with participants after the intervention. Retention rates ranged from 54% to 100% at post-intervention follow-up, with over half of the studies' retention rates young women are limited in number and quality and are highly heterogeneous. Therefore, their overall effectiveness cannot be established at this time. High-quality randomized controlled trials evaluating interventions that are tailored to the unique needs of young women, and that can be disseminated broadly, are urgently needed to address the unmet needs of this high-risk group. Copyright © 2013 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.

  7. Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention

    Energy Technology Data Exchange (ETDEWEB)

    Smallwood, Heather S.; Duan, Susu; Morfouace, Marie; Rezinciuc, Svetlana; Shulkin, Barry L.; Shelat, Anang; Zink, Erika E.; Milasta, Sandra; Bajracharya, Resha; Oluwaseum, Ajayi J.; Roussel, Martine F.; Green, Douglas R.; Pasa-Tolic, Ljiljana; Thomas, Paul G.

    2017-05-01

    Influenza is a worldwide health and financial burden posing a significant risk to the immune-compromised, obese, diabetic, elderly, and pediatric populations. We identified increases in glucose metabolism in the lungs of pediatric patients infected with respiratory pathogens. Using quantitative mass spectrometry, we found metabolic changes occurring after influenza infection in primary human respiratory cells and validated infection-associated increases in c-Myc, glycolysis, and glutaminolysis. We confirmed these findings with a metabolic drug screen that identified the PI3K/mTOR inhibitor BEZ235 as a regulator of infectious virus production. BEZ235 treatment ablated the transient induction of c-Myc, restored PI3K/mTOR pathway homeostasis measured by 4E-BP1 and p85 phosphorylation, and reversed infection-induced changes in metabolism. Importantly, BEZ235 reduced infectious progeny but had no effect on the early stages of viral replication. BEZ235 significantly increased survival in mice, while reducing viral titer. We show metabolic reprogramming of host cells by influenza virus exposes targets for therapeutic intervention.

  8. Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention

    Directory of Open Access Journals (Sweden)

    Heather S. Smallwood

    2017-05-01

    Full Text Available Influenza is a worldwide health and financial burden posing a significant risk to the immune-compromised, obese, diabetic, elderly, and pediatric populations. We identified increases in glucose metabolism in the lungs of pediatric patients infected with respiratory pathogens. Using quantitative mass spectrometry, we found metabolic changes occurring after influenza infection in primary human respiratory cells and validated infection-associated increases in c-Myc, glycolysis, and glutaminolysis. We confirmed these findings with a metabolic drug screen that identified the PI3K/mTOR inhibitor BEZ235 as a regulator of infectious virus production. BEZ235 treatment ablated the transient induction of c-Myc, restored PI3K/mTOR pathway homeostasis measured by 4E-BP1 and p85 phosphorylation, and reversed infection-induced changes in metabolism. Importantly, BEZ235 reduced infectious progeny but had no effect on the early stages of viral replication. BEZ235 significantly increased survival in mice, while reducing viral titer. We show metabolic reprogramming of host cells by influenza virus exposes targets for therapeutic intervention.

  9. Pharmacy students' ability to identify plagiarism after an educational intervention.

    Science.gov (United States)

    Degeeter, Michelle; Harris, Kira; Kehr, Heather; Ford, Carolyn; Lane, Daniel C; Nuzum, Donald S; Compton, Cynthia; Gibson, Whitney

    2014-03-12

    Objective. To determine if an educational intervention in a doctor of pharmacy (PharmD) degree program increases pharmacy students' ability to identify plagiarism. Methods. First-year (P1), second-year (P2), and third-year (P3) pharmacy students attended an education session during which types of plagiarism and methods for avoiding plagiarism were reviewed. Students completed a preintervention assessment immediately prior to the session and a postintervention assessment the following semester to measure their ability. Results. Two hundred fifty-two students completed both preintervention and postintervention assessments. There was a 4% increase from preintervention to postintervention in assessment scores for the overall student sample (pplagiarism can significantly improve students' ability to identify plagiarism.

  10. Pharmacy Students’ Ability to Identify Plagiarism After an Educational Intervention

    Science.gov (United States)

    Harris, Kira; Kehr, Heather; Ford, Carolyn; Lane, Daniel C.; Nuzum, Donald S.; Compton, Cynthia; Gibson, Whitney

    2014-01-01

    Objective. To determine if an educational intervention in a doctor of pharmacy (PharmD) degree program increases pharmacy students’ ability to identify plagiarism. Methods. First-year (P1), second-year (P2), and third-year (P3) pharmacy students attended an education session during which types of plagiarism and methods for avoiding plagiarism were reviewed. Students completed a preintervention assessment immediately prior to the session and a postintervention assessment the following semester to measure their ability. Results. Two hundred fifty-two students completed both preintervention and postintervention assessments. There was a 4% increase from preintervention to postintervention in assessment scores for the overall student sample (pplagiarism can significantly improve students’ ability to identify plagiarism. PMID:24672066

  11. Identifying microRNAs and transcript targets in Jatropha seeds.

    Science.gov (United States)

    Galli, Vanessa; Guzman, Frank; de Oliveira, Luiz F V; Loss-Morais, Guilherme; Körbes, Ana P; Silva, Sérgio D A; Margis-Pinheiro, Márcia M A N; Margis, Rogério

    2014-01-01

    MicroRNAs, or miRNAs, are endogenously encoded small RNAs that play a key role in diverse plant biological processes. Jatropha curcas L. has received significant attention as a potential oilseed crop for the production of renewable oil. Here, a sRNA library of mature seeds and three mRNA libraries from three different seed development stages were generated by deep sequencing to identify and characterize the miRNAs and pre-miRNAs of J. curcas. Computational analysis was used for the identification of 180 conserved miRNAs and 41 precursors (pre-miRNAs) as well as 16 novel pre-miRNAs. The predicted miRNA target genes are involved in a broad range of physiological functions, including cellular structure, nuclear function, translation, transport, hormone synthesis, defense, and lipid metabolism. Some pre-miRNA and miRNA targets vary in abundance between the three stages of seed development. A search for sequences that produce siRNA was performed, and the results indicated that J. curcas siRNAs play a role in nuclear functions, transport, catalytic processes and disease resistance. This study presents the first large scale identification of J. curcas miRNAs and their targets in mature seeds based on deep sequencing, and it contributes to a functional understanding of these miRNAs.

  12. Identifying microRNAs and transcript targets in Jatropha seeds.

    Directory of Open Access Journals (Sweden)

    Vanessa Galli

    Full Text Available MicroRNAs, or miRNAs, are endogenously encoded small RNAs that play a key role in diverse plant biological processes. Jatropha curcas L. has received significant attention as a potential oilseed crop for the production of renewable oil. Here, a sRNA library of mature seeds and three mRNA libraries from three different seed development stages were generated by deep sequencing to identify and characterize the miRNAs and pre-miRNAs of J. curcas. Computational analysis was used for the identification of 180 conserved miRNAs and 41 precursors (pre-miRNAs as well as 16 novel pre-miRNAs. The predicted miRNA target genes are involved in a broad range of physiological functions, including cellular structure, nuclear function, translation, transport, hormone synthesis, defense, and lipid metabolism. Some pre-miRNA and miRNA targets vary in abundance between the three stages of seed development. A search for sequences that produce siRNA was performed, and the results indicated that J. curcas siRNAs play a role in nuclear functions, transport, catalytic processes and disease resistance. This study presents the first large scale identification of J. curcas miRNAs and their targets in mature seeds based on deep sequencing, and it contributes to a functional understanding of these miRNAs.

  13. Identifying targets for preventing epilepsy using systems biology.

    Science.gov (United States)

    Loeb, Jeffrey A

    2011-06-27

    While there are a plethora of medications that block seizures, these same drugs have little effect on preventing or curing epilepsy. This suggests that the molecular pathways for epileptogenesis are distinct from those that produce acute seizures and therefore will require the identification of novel truly 'antiepileptic' therapeutics. Identification and testing of potential antiepileptic drug targets first in animal models and then in humans is thus becoming an important next step in the battle against epilepsy. In focal forms of human epilepsy the battle, however, is complicated by the large and varied types of brain abnormalities capable of producing a state of chronic, recurrent seizures. Unfortunately, once the epileptic state develops, it often persists to produce a life-long seizure disorder that can only be suppressed by anticonvulsant medications, and cured only in some through surgical resection of the seizure focus. While deductive approaches to drug target identification use our current state of knowledge, based mostly on animal models of epileptogenesis, a growing reductionist approach often referred to as systems biology takes advantage of newer high-throughput technologies to profile large numbers and types of molecules simultaneously. Some of these approaches, such as functional genomics, proteomics, and metabolomics have been undertaken in both human and animal epileptic brain tissues and are beginning to hone in on new therapeutic targets. While these methods are highly sensitive, this same sensitivity also produces a high rate of false positives due to variables other than those of interest. The experimental design, therefore, needs to be tightly controlled to reduce these unintended results that can be misleading. Most importantly, epileptogenic targets need to be validated in animal models of epileptogenesis, so that, if successful, these new methods have the potential to identify unbiased, important new therapeutics. Copyright © 2011 Elsevier

  14. Identifying rural food deserts: Methodological considerations for food environment interventions.

    Science.gov (United States)

    Lebel, Alexandre; Noreau, David; Tremblay, Lucie; Oberlé, Céline; Girard-Gadreau, Maurie; Duguay, Mathieu; Block, Jason P

    2016-06-09

    Food insecurity in an important public health issue and affects 13% of Canadian households. It is associated with poor accessibility to fresh, diverse and affordable food products. However, measurement of the food environment is challenging in rural settings since the proximity of food supply sources is unevenly distributed. The objective of this study was to develop a methodology to identify food deserts in rural environments. In-store evaluations of 25 food products were performed for all food stores located in four contiguous rural counties in Quebec. The quality of food products was estimated using four indices: freshness, affordability, diversity and the relative availability. Road network distance between all residences to the closest food store with a favourable score on the four dimensions was mapped to identify residential clusters located in deprived communities without reasonable access to a "good" food source. The result was compared with the food desert parameters proposed by the US Department of Agriculture (USDA), as well as with the perceptions of a group of regional stakeholders. When food quality was considered, food deserts appeared more prevalent than when only the USDA definition was used. Objective measurements of the food environment matched stakeholders' perceptions. Food stores' characteristics are different in rural areas and require an in-store estimation to identify potential rural food deserts. The objective measurements of the food environment combined with the field knowledge of stakeholders may help to shape stronger arguments to gain the support of decision-makers to develop relevant interventions.

  15. Genetic Approaches To Identifying Novel Osteoporosis Drug Targets.

    Science.gov (United States)

    Brommage, Robert

    2015-10-01

    During the past two decades effective drugs for treating osteoporosis have been developed, including anti-resorptives inhibiting bone resorption (estrogens, the SERM raloxifene, four bisphosphonates, RANKL inhibitor denosumab) and the anabolic bone forming daily injectable peptide teriparatide. Two potential drugs (odanacatib and romosozumab) are in late stage clinical development. The most pressing unmet need is for orally active anabolic drugs. This review describes the basic biological studies involved in developing these drugs, including the animal models employed for osteoporosis drug development. The genomics revolution continues to identify potential novel osteoporosis drug targets. Studies include human GWAS studies and identification of mutant genes in subjects having abnormal bone mass, mouse QTL and gene knockouts, and gene expression studies. Multiple lines of evidence indicate that Wnt signaling plays a major role in regulating bone formation and continued study of this complex pathway is likely to lead to key discoveries. In addition to the classic Wnt signaling targets DKK1 and sclerostin, LRP4, LRP5/LRP6, SFRP4, WNT16, and NOTUM can potentially be targeted to modulate Wnt signaling. Next-generation whole genome and exome sequencing, RNA-sequencing and CRISPR/CAS9 gene editing are new experimental techniques contributing to understanding the genome. The International Knockout Mouse Consortium efforts to knockout and phenotype all mouse genes are poised to accelerate. Accumulating knowledge will focus attention on readily accessible databases (Big Data). Efforts are underway by the International Bone and Mineral Society to develop an annotated Skeletome database providing information on all genes directly influencing bone mass, architecture, mineralization or strength. © 2015 Wiley Periodicals, Inc.

  16. Identifying radiotherapy target volumes in brain cancer by image analysis.

    Science.gov (United States)

    Cheng, Kun; Montgomery, Dean; Feng, Yang; Steel, Robin; Liao, Hanqing; McLaren, Duncan B; Erridge, Sara C; McLaughlin, Stephen; Nailon, William H

    2015-10-01

    To establish the optimal radiotherapy fields for treating brain cancer patients, the tumour volume is often outlined on magnetic resonance (MR) images, where the tumour is clearly visible, and mapped onto computerised tomography images used for radiotherapy planning. This process requires considerable clinical experience and is time consuming, which will continue to increase as more complex image sequences are used in this process. Here, the potential of image analysis techniques for automatically identifying the radiation target volume on MR images, and thereby assisting clinicians with this difficult task, was investigated. A gradient-based level set approach was applied on the MR images of five patients with grades II, III and IV malignant cerebral glioma. The relationship between the target volumes produced by image analysis and those produced by a radiation oncologist was also investigated. The contours produced by image analysis were compared with the contours produced by an oncologist and used for treatment. In 93% of cases, the Dice similarity coefficient was found to be between 60 and 80%. This feasibility study demonstrates that image analysis has the potential for automatic outlining in the management of brain cancer patients, however, more testing and validation on a much larger patient cohort is required.

  17. Small molecule screening identifies targetable zebrafish pigmentation pathways

    DEFF Research Database (Denmark)

    Colanesi, Sarah; Taylor, Kerrie L; Temperley, Nicholas D

    2012-01-01

    Small molecules complement genetic mutants and can be used to probe pigment cell biology by inhibiting specific proteins or pathways. Here, we present the results of a screen of active compounds for those that affect the processes of melanocyte and iridophore development in zebrafish and investig......Small molecules complement genetic mutants and can be used to probe pigment cell biology by inhibiting specific proteins or pathways. Here, we present the results of a screen of active compounds for those that affect the processes of melanocyte and iridophore development in zebrafish...... and investigate the effects of a few of these compounds in further detail. We identified and confirmed 57 compounds that altered pigment cell patterning, number, survival, or differentiation. Additional tissue targets and toxicity of small molecules are also discussed. Given that the majority of cell types...

  18. Neural Regulation of Pancreatic Cancer: A Novel Target for Intervention

    International Nuclear Information System (INIS)

    Chang, Aeson; Kim-Fuchs, Corina; Le, Caroline P.; Hollande, Frédéric; Sloan, Erica K.

    2015-01-01

    The tumor microenvironment is known to play a pivotal role in driving cancer progression and governing response to therapy. This is of significance in pancreatic cancer where the unique pancreatic tumor microenvironment, characterized by its pronounced desmoplasia and fibrosis, drives early stages of tumor progression and dissemination, and contributes to its associated low survival rates. Several molecular factors that regulate interactions between pancreatic tumors and their surrounding stroma are beginning to be identified. Yet broader physiological factors that influence these interactions remain unclear. Here, we discuss a series of preclinical and mechanistic studies that highlight the important role chronic stress plays as a physiological regulator of neural-tumor interactions in driving the progression of pancreatic cancer. These studies propose several approaches to target stress signaling via the β-adrenergic signaling pathway in order to slow pancreatic tumor growth and metastasis. They also provide evidence to support the use of β-blockers as a novel therapeutic intervention to complement current clinical strategies to improve cancer outcome in patients with pancreatic cancer

  19. MicroRNA: an Emerging Therapeutic Target and Intervention Tool

    Directory of Open Access Journals (Sweden)

    Decheng Yang

    2008-06-01

    Full Text Available MicroRNAs (miRNAs are a class of short non-coding RNAs with posttranscriptional regulatory functions. To date, more than 600 human miRNAs have been experimentally identified, and estimated to regulate more than one third of cellular messenger RNAs. Accumulating evidence has linked the dysregulated expression patterns of miRNAs to a variety of diseases, such as cancer, neurodegenerative diseases, cardiovascular diseases and viral infections. MiRNAs provide its particular layer of network for gene regulation, thus possessing the great potential both as a novel class of therapeutic targets and as a powerful intervention tool. In this regard, synthetic RNAs that contain the binding sites of miRNA have been shown to work as a “decoy” or “miRNA sponge” to inhibit the function of specific miRNAs. On the other hand, miRNA expression vectors have been used to restore or overexpress specific miRNAs to achieve a long-term effect. Further, double-stranded miRNA mimetics for transient replacement have been experimentally validated. Endogenous precursor miRNAs have also been used as scaffolds for the induction of RNA interference. This article reviews the recent progress on this emerging technology as a powerful tool for gene regulation studies and particularly as a rationale strategy for design of therapeutics.

  20. Neural Regulation of Pancreatic Cancer: A Novel Target for Intervention

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Aeson [Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052 (Australia); Kim-Fuchs, Corina [Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052 (Australia); Department of Visceral Surgery and Medicine, University Hospital Bern, Bern 3010 (Switzerland); Le, Caroline P. [Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052 (Australia); Hollande, Frédéric [Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052 (Australia); Department of Pathology, University of Melbourne, Parkville 3010 (Australia); Sloan, Erica K., E-mail: erica.sloan@monash.edu [Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052 (Australia); Cousins Center for PNI, UCLA Semel Institute, Jonsson Comprehensive Cancer Center, and UCLA AIDS Institute, University of California Los Angeles, Los Angeles, CA 90095 (United States); Peter MacCallum Cancer Centre, Division of Cancer Surgery, East Melbourne, Victoria 3002 (Australia)

    2015-07-17

    The tumor microenvironment is known to play a pivotal role in driving cancer progression and governing response to therapy. This is of significance in pancreatic cancer where the unique pancreatic tumor microenvironment, characterized by its pronounced desmoplasia and fibrosis, drives early stages of tumor progression and dissemination, and contributes to its associated low survival rates. Several molecular factors that regulate interactions between pancreatic tumors and their surrounding stroma are beginning to be identified. Yet broader physiological factors that influence these interactions remain unclear. Here, we discuss a series of preclinical and mechanistic studies that highlight the important role chronic stress plays as a physiological regulator of neural-tumor interactions in driving the progression of pancreatic cancer. These studies propose several approaches to target stress signaling via the β-adrenergic signaling pathway in order to slow pancreatic tumor growth and metastasis. They also provide evidence to support the use of β-blockers as a novel therapeutic intervention to complement current clinical strategies to improve cancer outcome in patients with pancreatic cancer.

  1. Mobile Interventions Targeting Risky Drinking Among University Students: A Review.

    Science.gov (United States)

    Berman, Anne H; Gajecki, Mikael; Sinadinovic, Kristina; Andersson, Claes

    Mobile interventions based on text messages, automated telephone programs (interactive voice response (IVR)), and smartphone apps offer a new approach targeting hazardous alcohol use in university students. This review covers seven recent studies involving college or university students that evaluated intervention efficacy in comparison to controls: four using text messages, one using IVR, and two smartphone apps. Only the study evaluating IVR reported positive results for the primary outcome. Two of the text message studies reported positive results on secondary outcomes, while the other two reported no differences in comparison to control groups. For smartphone apps, one study reported positive results on secondary outcomes, while the other showed no differences in comparison to controls for a web-based app and negative results for a native app. Further development of mobile interventions is needed for this at-risk population, both in terms of intervention content and use of robust research designs.

  2. Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

    Directory of Open Access Journals (Sweden)

    Yuri Pevzner

    2015-08-01

    Full Text Available Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

  3. Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

    Directory of Open Access Journals (Sweden)

    Yuri Pevzner

    2014-05-01

    Full Text Available Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

  4. Meta-analysis of targeted small-group reading interventions.

    Science.gov (United States)

    Hall, Matthew S; Burns, Matthew K

    2018-02-01

    Small-group reading interventions are commonly used in schools but the components that make them effective are still debated or unknown. The current study meta-analyzed 26 small-group reading intervention studies that resulted in 27 effect sizes. Findings suggested a moderate overall effect for small-group reading interventions (weighted g=0.54). Interventions were more effective if they were targeted to a specific skill (g=0.65), then as part of a comprehensive intervention program that addressed multiple skills (g=0.35). There was a small correlation between intervention effects and group size (r=0.21) and duration (r=0.11). Small-group interventions led to a larger median effect size (g=0.64) for elementary-aged students than for those in middle or high school (g=0.20), but the two confidence intervals overlapped. Implications for research and practice are discussed. Copyright © 2017 Society for the Study of School Psychology. Published by Elsevier Ltd. All rights reserved.

  5. Cancer therapeutic target genes identified on chromosome 20q

    Directory of Open Access Journals (Sweden)

    Editorial Office

    2016-08-01

    Full Text Available An integrated quantitative genome data analysis was recently able to pinpoint 18 genes on human chromosome 20q that could potentially serve as novel molecular targets for cancer therapy. Researchers Antoine M Snijders and Jian-Hua Mao from Lawrence Berkeley National Laboratory’s Biological Systems and Engineering Division in Berkeley, California, United States, in their study published by the journal Advances in Modern Oncology Research (AMOR sought to compare the amounts of individual mRNAs – messenger RNAs that specify the amino acid sequence of the protein products of gene expression – in cancerous human tissues with corresponding normal tissues. The duo conducted a meta-analysis of genes on chromosome 20q that are found to be consistently upregulated across different human tumor types, while collecting gene transcript data of normal and tumor tissues across 11 different tumor types including brain, breast, colon, gastric, head and neck, liver, lung, ovarian, cervix, pancreas, and prostate cancers. “We calculated the differential expression of all 301 genes present on chromosome 20q for which gene transcript data was available. We then filtered for genes that were upregulated in tumors by at least 1.5 fold (p < 0.05 in seven or more tumor types,” they said. The resulting analysis identified 18 genes – some such as AURKA, UBE2C, TPX2, FAM83D, ZNF217, SALL4 and MMP9 have been previously known to potentially cause cancer. The 18-gene signature is revealed by the study to have robustly elevated levels across human cancers. “We observed significant association of our signature with disease-free survival in all 18 independent data… These data indicated that our signature is broadly predictive for disease-free survival, independent of tumor type,” the researchers said. In certain cases, Snijders and Mao found that increased gene expression was associated with better prognosis. “For example, the increased expressions of MMP9 and

  6. Developing Internet interventions to target the individual impact of stigma in health conditions

    Directory of Open Access Journals (Sweden)

    Neil Thomas

    2015-09-01

    Full Text Available A number of health problems are associated with significant stigma, a social phenomenon in which individuals become the object of negative stereotypes. In addition to experiencing negative reactions from others, stigmatised individuals and groups can experience harmful consequences when they internalise these negative prevailing attitudes. The objective of this paper was to consider the potential to develop Internet-based health-related interventions explicitly targeting the effects of stigma on the individual. A review of the literature was conducted to synthesise current conceptualisations of stigma and self-stigma across a number of groups, and to identify current intervention developments. Self-stigma reduction strategies developed for in-person services include cognitive reframing, myth busting, contact with other members of the stigmatised group, and disclosure promotion. The development and provision of interventions targeting self-stigma within an online environment is in its infancy. Our review considers there to be particular potential of online interventions for this target, associated with the capacity of the Internet to promote having contact with peers within one’s stigmatised group, and for user interaction and empowerment. We conclude that self-stigma is a domain in which there is significant potential for innovation with health-related interventions, and provide a number of recommendations for online intervention development.

  7. Identifying determinants of effective complementary feeding behaviour change interventions in developing countries

    Science.gov (United States)

    Fabrizio, Cecilia S; van Liere, Marti; Pelto, Gretel

    2014-01-01

    As stunting moves to the forefront of the global agenda, there is substantial evidence that behaviour change interventions (BCI) can improve infant feeding practices and growth. However, this evidence has not been translated into improved outcomes on a national level because we do not know enough about what makes these interventions work, for whom, when, why, at what cost and for how long. Our objective was to examine the design and implementation of complementary feeding BCI, from the peer-reviewed literature, to identify generalisable key determinants. We identified 29 studies that evaluated BCI efficacy or effectiveness, were conducted in developing countries, and reported outcomes on infant and young children aged 6–24 months. Two potential determinants emerged: (1) effective studies used formative research to identify cultural barriers and enablers to optimal feeding practices, to shape the intervention strategy, and to formulate appropriate messages and mediums for delivery; (2) effective studies delineated the programme impact pathway to the target behaviour change and assessed intermediary behaviour changes to learn what worked. We found that BCI that used these developmental and implementation processes could be effective despite heterogeneous approaches and design components. Our analysis was constrained, however, by the limited published data on how design and implementation were carried out, perhaps because of publishing space limits. Information on cost-effectiveness, sustainability and scalability was also very limited. We suggest a more comprehensive reporting process and a more strategic research agenda to enable generalisable evidence to accumulate. PMID:24798264

  8. Being targeted: Young women's experience of being identified for a teenage pregnancy prevention programme.

    Science.gov (United States)

    Sorhaindo, Annik; Bonell, Chris; Fletcher, Adam; Jessiman, Patricia; Keogh, Peter; Mitchell, Kirstin

    2016-06-01

    Research on the unintended consequences of targeting 'high-risk' young people for health interventions is limited. Using qualitative data from an evaluation of the Teens & Toddlers Pregnancy Prevention programme, we explored how young women experienced being identified as at risk for teenage pregnancy to understand the processes via which unintended consequences may occur. Schools' lack of transparency regarding the targeting strategy and criteria led to feelings of confusion and mistrust among some young women. Black and minority ethnic young women perceived that the assessment of their risk was based on stereotyping. Others felt their outgoing character was misinterpreted as signifying risk. To manage these imposed labels, stigma and reputational risks, young women responded to being targeted by adopting strategies, such as distancing, silence and refusal. To limit harmful consequences, programmes could involve prospective participants in determining their need for intervention or introduce programmes for young people at all levels of risk. Copyright © 2016 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

  9. Identifying missed opportunities for early intervention among HIV ...

    African Journals Online (AJOL)

    Background and design. HIV is a major contributor to childhood morbidity and mortality in South Africa. We describe HIV prevalence, disease profile, outcome and missed opportunities for early intervention in a cohort of HIV-infected children admitted to Chris Hani Baragwanath Hospital's general paediatric wards between ...

  10. Improving child survival through environmental and nutritional interventions: the importance of targeting interventions toward the poor.

    Science.gov (United States)

    Gakidou, Emmanuela; Oza, Shefali; Vidal Fuertes, Cecilia; Li, Amy Y; Lee, Diana K; Sousa, Angelica; Hogan, Margaret C; Vander Hoorn, Stephen; Ezzati, Majid

    2007-10-24

    The United Nations Millennium Development Goals (MDGs) set targets related to important global poverty, health, and sustainability issues. A critical but underinvestigated question for planning and allocating resources toward the MDGs is how interventions related to one MDG might affect progress toward other goals. To estimate the reduction in child mortality as a result of interventions related to the environmental and nutritional MDGs (improving child nutrition and providing clean water, sanitation, and fuels) and to estimate how the magnitude and distribution of the effects of interventions vary based on the economic status of intervention recipients. Population-level comparative risk assessment modeling the mortality effects of interventions on child nutrition and environmental risk factors, stratified by economic status. Data on economic status, child underweight, water and sanitation, and household fuels were from the nationally representative Demographic and Health Surveys for 42 countries in Latin America and the Caribbean, South Asia, and sub-Saharan Africa. Data on disease-specific child mortality were from the World Health Organization. Data on the hazardous effects of each MDG-related risk factor were from systematic reviews and meta-analyses of epidemiological studies. Child mortality, stratified by comparable international quintiles of economic status. Implementing interventions that improve child nutrition and provide clean water and sanitation and clean household fuels to all children younger than 5 years would result in an estimated annual reduction in child deaths of 49,700 (14%) in Latin America and the Caribbean, 0.80 million (24%) in South Asia, and 1.47 million (31%) in sub-Saharan Africa. These benefits are equivalent to 30% to 48% of the current regional gaps toward the MDG target on reducing child mortality. Fifty percent coverage of the same environmental and nutritional interventions, as envisioned by the MDGs, would reduce child

  11. Identifying targets for preventing epilepsy using systems biology

    OpenAIRE

    Loeb, Jeffrey A.

    2011-01-01

    While there are a plethora of medications that block seizures, these same drugs have little effect on preventing or curing epilepsy. This suggests that the molecular pathways for epileptogenesis are distinct from those that produce acute seizures and therefore will require the identification of novel truly ‘antiepileptic’ therapeutics. Identification and testing of potential antiepileptic drug targets first in animal models and then in humans is thus becoming an important next step in the bat...

  12. Using a behaviour change techniques taxonomy to identify active ingredients within trials of implementation interventions for diabetes care.

    Science.gov (United States)

    Presseau, Justin; Ivers, Noah M; Newham, James J; Knittle, Keegan; Danko, Kristin J; Grimshaw, Jeremy M

    2015-04-23

    Methodological guidelines for intervention reporting emphasise describing intervention content in detail. Despite this, systematic reviews of quality improvement (QI) implementation interventions continue to be limited by a lack of clarity and detail regarding the intervention content being evaluated. We aimed to apply the recently developed Behaviour Change Techniques Taxonomy version 1 (BCTTv1) to trials of implementation interventions for managing diabetes to assess the capacity and utility of this taxonomy for characterising active ingredients. Three psychologists independently coded a random sample of 23 trials of healthcare system, provider- and/or patient-focused implementation interventions from a systematic review that included 142 such studies. Intervention content was coded using the BCTTv1, which describes 93 behaviour change techniques (BCTs) grouped within 16 categories. We supplemented the generic coding instructions within the BCTTv1 with decision rules and examples from this literature. Less than a quarter of possible BCTs within the BCTTv1 were identified. For implementation interventions targeting providers, the most commonly identified BCTs included the following: adding objects to the environment, prompts/cues, instruction on how to perform the behaviour, credible source, goal setting (outcome), feedback on outcome of behaviour, and social support (practical). For implementation interventions also targeting patients, the most commonly identified BCTs included the following: prompts/cues, instruction on how to perform the behaviour, information about health consequences, restructuring the social environment, adding objects to the environment, social support (practical), and goal setting (behaviour). The BCTTv1 mapped well onto implementation interventions directly targeting clinicians and patients and could also be used to examine the impact of system-level interventions on clinician and patient behaviour. The BCTTv1 can be used to characterise

  13. Multilevel Interventions Targeting Obesity: Research Recommendations for Vulnerable Populations.

    Science.gov (United States)

    Stevens, June; Pratt, Charlotte; Boyington, Josephine; Nelson, Cheryl; Truesdale, Kimberly P; Ward, Dianne S; Lytle, Leslie; Sherwood, Nancy E; Robinson, Thomas N; Moore, Shirley; Barkin, Shari; Cheung, Ying Kuen; Murray, David M

    2017-01-01

    The origins of obesity are complex and multifaceted. To be successful, an intervention aiming to prevent or treat obesity may need to address multiple layers of biological, social, and environmental influences. NIH recognizes the importance of identifying effective strategies to combat obesity, particularly in high-risk and disadvantaged populations with heightened susceptibility to obesity and subsequent metabolic sequelae. To move this work forward, the National Heart, Lung, and Blood Institute, in collaboration with the NIH Office of Behavioral and Social Science Research and NIH Office of Disease Prevention convened a working group to inform research on multilevel obesity interventions in vulnerable populations. The working group reviewed relevant aspects of intervention planning, recruitment, retention, implementation, evaluation, and analysis, and then made recommendations. Recruitment and retention techniques used in multilevel research must be culturally appropriate and suited to both individuals and organizations. Adequate time and resources for preliminary work are essential. Collaborative projects can benefit from complementary areas of expertise and shared investigations rigorously pretesting specific aspects of approaches. Study designs need to accommodate the social and environmental levels under study, and include appropriate attention given to statistical power. Projects should monitor implementation in the multiple venues and include a priori estimation of the magnitude of change expected within and across levels. The complexity and challenges of delivering interventions at several levels of the social-ecologic model require careful planning and implementation, but hold promise for successful reduction of obesity in vulnerable populations. Copyright © 2016. Published by Elsevier Inc.

  14. Improving medication adherence with a targeted, technology-driven disease management intervention.

    Science.gov (United States)

    Lawrence, David B; Allison, Wanda; Chen, Joyce C; Demand, Michael

    2008-06-01

    Treatment adherence is critical in managing chronic disease, but achieving it remains an elusive goal across many prevalent conditions. As part of its care management strategy, BlueCross BlueShield of South Carolina (BCBSSC) implemented the Longitudinal Adherence Treatment Evaluation program, a behavioral intervention to improve medication adherence among members with cardiovascular disease and/or diabetes. The objectives of this study were to 1) assess the effectiveness of telephonic intervention in influencing reinitiation of medication therapy, and 2) evaluate the rate and timing of medication reinitiation. BCBSSC applied algorithms against pharmacy claims data to identify patients prescribed targeted medications who were 60 or more days overdue for refills. This information was provided to care managers to address during their next patient contact. Care managers received focused training on techniques for medication behavior change, readiness to change, motivational interviewing, and active listening. Training also addressed common barriers to adherence and available resources, including side effect management, mail order benefits, drug assistance programs, medication organizers, and reminder systems. Overdue refills were tracked for 12 months, with medication reinitiation followed for an additional 3 months. In the intervention group, 94 patients were identified with 123 instances of late medication refills. In the age- and gender-matched comparison group, 61 patients were identified with 76 late refills. The intervention group had a significantly higher rate of medication reinitiation (59.3%) than the control group (42.1%; P < 0.05). Time to reinitiation was significantly shorter in the intervention group, 59.5 (+/- 69.0) days vs. 107.4 (+/- 109) days for the control group (P < 0.05). This initiative demonstrated that a targeted disease management intervention promoting patient behavior change increased the number of patients who reinitiated therapy after a

  15. The Targeted Reading Intervention (TRI): A Classroom Teacher Tier 2 Intervention to Help Struggling Readers in Early Elementary School

    Science.gov (United States)

    Vernon-Feagans, Lynne; Amendum, Steve; Kainz, Kirsten; Ginsburg, Marnie

    2009-01-01

    The two studies presented in this report were designed to test the effectiveness of a new diagnostic-based reading intervention for classroom teachers, called the Targeted Reading Intervention (TRI). This TRI Tier 2 intervention stressed diagnostic teaching as the key to helping struggling readers make rapid progress in reading in the regular…

  16. Parental Factors Associated with Child Post-traumatic Stress Following Injury: A Consideration of Intervention Targets

    Directory of Open Access Journals (Sweden)

    Anna E. Wise

    2017-08-01

    Full Text Available Post-traumatic stress disorder (PTSD symptoms are relatively common following pediatric traumatic injury and are related to poor long-term child outcomes. However, due to concerns regarding the efficacy of early child preventive interventions, and difficulty intervening with injured and medicated children soon after the event, it is not feasible to provide early psychological interventions to children exposed to traumatic injury. Parental PTSD symptoms and reactions to the child’s traumatic injury impact child outcomes and provide potential targets for early intervention to reduce child symptom development without involving the child. The authors conducted a review of the literature using Psycinfo and Pubmed research databases (publication years = 1990–2017 and identified 65 published studies relevant to the topic of the review. The present review considers parent factors [parenting styles, parental post-traumatic pathology (PTS, adaptive and maladaptive coping strategies, and communication regarding the traumatic injury] and their impact on child PTS. We focus specifically on factors amenable to intervention. We further review moderators of these relationships (e.g., child age and gender, parent gender and conclude that it is unlikely that a one-size-fits-all approach to treatment will be successful. Rather, it is necessary to consider the age and gender of parent child dyads in designing and providing targeted interventions to families following the traumatic injury of a child.

  17. Using Market Research to Characterize College Students and Identify Potential Targets for Influencing Health Behaviors

    Science.gov (United States)

    Berg, Carla J.; Ling, Pamela M.; Guo, Hongfei; Windle, Michael; Thomas, Janet L.; Ahluwalia, Jasjit S.; An, Lawrence C.

    2013-01-01

    Marketing campaigns, such as those developed by the tobacco industry, are based on market research, which defines segments of a population by assessing psychographic characteristics (i.e., attitudes, interests). This study uses a similar approach to define market segments of college smokers, to examine differences in their health behaviors (smoking, drinking, binge drinking, exercise, diet), and to determine the validity of these segments. A total of 2,265 undergraduate students aged 18–25 years completed a 108-item online survey in fall 2008 assessing demographic, psychographic (i.e., attitudes, interests), and health-related variables. Among the 753 students reporting past 30-day smoking, cluster analysis was conducted using 21 psychographic questions and identified three market segments – Stoic Individualists, Responsible Traditionalists, and Thrill-Seeking Socializers. We found that segment membership was related to frequency of alcohol use, binge drinking, and limiting dietary fat. We then developed three messages targeting each segment and conducted message testing to validate the segments on a subset of 73 smokers representing each segment in spring 2009. As hypothesized, each segment indicated greater relevance and salience for their respective message. These findings indicate that identifying qualitatively different subgroups of young adults through market research may inform the development of engaging interventions and health campaigns targeting college students. PMID:25264429

  18. Using Market Research to Characterize College Students and Identify Potential Targets for Influencing Health Behaviors.

    Science.gov (United States)

    Berg, Carla J; Ling, Pamela M; Guo, Hongfei; Windle, Michael; Thomas, Janet L; Ahluwalia, Jasjit S; An, Lawrence C

    2010-12-01

    Marketing campaigns, such as those developed by the tobacco industry, are based on market research, which defines segments of a population by assessing psychographic characteristics (i.e., attitudes, interests). This study uses a similar approach to define market segments of college smokers, to examine differences in their health behaviors (smoking, drinking, binge drinking, exercise, diet), and to determine the validity of these segments. A total of 2,265 undergraduate students aged 18-25 years completed a 108-item online survey in fall 2008 assessing demographic, psychographic (i.e., attitudes, interests), and health-related variables. Among the 753 students reporting past 30-day smoking, cluster analysis was conducted using 21 psychographic questions and identified three market segments - Stoic Individualists, Responsible Traditionalists, and Thrill-Seeking Socializers. We found that segment membership was related to frequency of alcohol use, binge drinking, and limiting dietary fat. We then developed three messages targeting each segment and conducted message testing to validate the segments on a subset of 73 smokers representing each segment in spring 2009. As hypothesized, each segment indicated greater relevance and salience for their respective message. These findings indicate that identifying qualitatively different subgroups of young adults through market research may inform the development of engaging interventions and health campaigns targeting college students.

  19. Target and identify: triazene linker helps identify azidation sites of labelled proteins via click and cleave strategy.

    Science.gov (United States)

    Lohse, Jonas; Schindl, Alexandra; Danda, Natasha; Williams, Chris P; Kramer, Karl; Kuster, Bernhard; Witte, Martin D; Médard, Guillaume

    2017-10-31

    A method for identifying probe modification of proteins via tandem mass spectrometry was developed. Azide bearing molecules are immobilized on functionalised sepharose beads via copper catalysed Huisgen-type click chemistry and selectively released under acidic conditions by chemical cleavage of the triazene linkage. We applied this method to identify the modification site of targeted-diazotransfer on BirA.

  20. Complementary Approaches to Existing Target Based Drug Discovery for Identifying Novel Drug Targets

    Directory of Open Access Journals (Sweden)

    Suhas Vasaikar

    2016-11-01

    Full Text Available In the past decade, it was observed that the relationship between the emerging New Molecular Entities and the quantum of R&D investment has not been favorable. There might be numerous reasons but few studies stress the introduction of target based drug discovery approach as one of the factors. Although a number of drugs have been developed with an emphasis on a single protein target, yet identification of valid target is complex. The approach focuses on an in vitro single target, which overlooks the complexity of cell and makes process of validation drug targets uncertain. Thus, it is imperative to search for alternatives rather than looking at success stories of target-based drug discovery. It would be beneficial if the drugs were developed to target multiple components. New approaches like reverse engineering and translational research need to take into account both system and target-based approach. This review evaluates the strengths and limitations of known drug discovery approaches and proposes alternative approaches for increasing efficiency against treatment.

  1. Identifying the Right Disease Targets to Develop Better Drugs, Faster | NIH MedlinePlus the Magazine

    Science.gov (United States)

    ... this page please turn JavaScript on. Identifying the Right Disease Targets to Develop Better Drugs, Faster Past ... reason is that we're not selecting the right biological changes to target from the start. How ...

  2. Influence of prior sexual risk experience on response to intervention targeting multiple risk behaviors among adolescents.

    Science.gov (United States)

    Wu, Ying; Burns, James J; Stanton, Bonita F; Li, Xiaoming; Harris, Carole V; Galbraith, Jennifer; Wei, Liang

    2005-01-01

    To identify correlates of sexual risk variations among African-American adolescents, and to examine the influence of prior sexual experience on response to a HIV risk-reduction intervention. Eight hundred seventeen African-American youth aged 13 to 16 years living in and around urban public housing in Baltimore were recruited to participate in a HIV risk-reduction intervention targeting multiple risk behaviors. An instrument designed to measure three levels of sexual risk ("abstinent," "protected sex" [having sex with a condom], and "unprotected sex" [having sex without a condom]) was administered at baseline, 6 months and 12 months postintervention. Multiple regression analyses were conducted to identify predictors of the degree of sexual risk using longitudinal data. Repeated measure analyses were conducted to assess behavioral changes over time among the three groups. Data confirmed the co-variation of sexual risk behavior and other problem behaviors among adolescents, cross-sectionally and longitudinally. After exposure to an 8-session risk-reduction intervention, youth engaging in the highest degree of sexual risk demonstrated the greatest reduction in both sexual risk and other risks. These improvements were seen at both 6 months and 12 months postintervention. Youth who were abstinent at baseline maintained the lowest levels in risk involvement throughout the study period when compared with sexually active youth. However, abstinent youth risk involvement significantly increased at 6 months and 12 months after baseline. Youth engaging in protected sex at baseline demonstrated a significant increase in non-condom use and a significant decrease in multiple risk involvement over time. Results support HIV risk-reduction intervention efforts that target multiple risk behaviors. Response of adolescents to the intervention is directly related to the sexual risk behavior at baseline. These data may suggest that the response to risk behavior intervention depends in

  3. Pilot evaluation of a web-based intervention targeting sexual health service access.

    Science.gov (United States)

    Brown, K E; Newby, K; Caley, M; Danahay, A; Kehal, I

    2016-04-01

    Sexual health service access is fundamental to good sexual health, yet interventions designed to address this have rarely been implemented or evaluated. In this article, pilot evaluation findings for a targeted public health behavior change intervention, delivered via a website and web-app, aiming to increase uptake of sexual health services among 13-19-year olds are reported. A pre-post questionnaire-based design was used. Matched baseline and follow-up data were identified from 148 respondents aged 13-18 years. Outcome measures were self-reported service access, self-reported intention to access services and beliefs about services and service access identified through needs analysis. Objective service access data provided by local sexual health services were also analyzed. Analysis suggests the intervention had a significant positive effect on psychological barriers to and antecedents of service access among females. Males, who reported greater confidence in service access compared with females, significantly increased service access by time 2 follow-up. Available objective service access data support the assertion that the intervention may have led to increases in service access. There is real promise for this novel digital intervention. Further evaluation is planned as the model is licensed to and rolled out by other local authorities in the United Kingdom. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  4. Identifying Human Genome-Wide CNV, LOH and UPD by Targeted Sequencing of Selected Regions.

    Directory of Open Access Journals (Sweden)

    Wei Li

    Full Text Available Copy-number variations (CNV, loss of heterozygosity (LOH, and uniparental disomy (UPD are large genomic aberrations leading to many common inherited diseases, cancers, and other complex diseases. An integrated tool to identify these aberrations is essential in understanding diseases and in designing clinical interventions. Previous discovery methods based on whole-genome sequencing (WGS require very high depth of coverage on the whole genome scale, and are cost-wise inefficient. Another approach, whole exome genome sequencing (WEGS, is limited to discovering variations within exons. Thus, we are lacking efficient methods to detect genomic aberrations on the whole genome scale using next-generation sequencing technology. Here we present a method to identify genome-wide CNV, LOH and UPD for the human genome via selectively sequencing a small portion of genome termed Selected Target Regions (SeTRs. In our experiments, the SeTRs are covered by 99.73%~99.95% with sufficient depth. Our developed bioinformatics pipeline calls genome-wide CNVs with high confidence, revealing 8 credible events of LOH and 3 UPD events larger than 5M from 15 individual samples. We demonstrate that genome-wide CNV, LOH and UPD can be detected using a cost-effective SeTRs sequencing approach, and that LOH and UPD can be identified using just a sample grouping technique, without using a matched sample or familial information.

  5. Targeted Metabolomics Identifies Pharmacodynamic Biomarkers for BIO 300 Mitigation of Radiation-Induced Lung Injury.

    Science.gov (United States)

    Jones, Jace W; Jackson, Isabel L; Vujaskovic, Zeljko; Kaytor, Michael D; Kane, Maureen A

    2017-12-01

    Biomarkers serve a number of purposes during drug development including defining the natural history of injury/disease, serving as a secondary endpoint or trigger for intervention, and/or aiding in the selection of an effective dose in humans. BIO 300 is a patent-protected pharmaceutical formulation of nanoparticles of synthetic genistein being developed by Humanetics Corporation. The primary goal of this metabolomic discovery experiment was to identify biomarkers that correlate with radiation-induced lung injury and BIO 300 efficacy for mitigating tissue damage based upon the primary endpoint of survival. High-throughput targeted metabolomics of lung tissue from male C57L/J mice exposed to 12.5 Gy whole thorax lung irradiation, treated daily with 400 mg/kg BIO 300 for either 2 weeks or 6 weeks starting 24 h post radiation exposure, were assayed at 180 d post-radiation to identify potential biomarkers. A panel of lung metabolites that are responsive to radiation and able to distinguish an efficacious treatment schedule of BIO 300 from a non-efficacious treatment schedule in terms of 180 d survival were identified. These metabolites represent potential biomarkers that could be further validated for use in drug development of BIO 300 and in the translation of dose from animal to human.

  6. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.

    Science.gov (United States)

    Zuber, Johannes; Shi, Junwei; Wang, Eric; Rappaport, Amy R; Herrmann, Harald; Sison, Edward A; Magoon, Daniel; Qi, Jun; Blatt, Katharina; Wunderlich, Mark; Taylor, Meredith J; Johns, Christopher; Chicas, Agustin; Mulloy, James C; Kogan, Scott C; Brown, Patrick; Valent, Peter; Bradner, James E; Lowe, Scott W; Vakoc, Christopher R

    2011-08-03

    Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.

  7. Targeting Policy for Obesity Prevention: Identifying the Critical Age for Weight Gain in Women

    Directory of Open Access Journals (Sweden)

    Trevor J. B. Dummer

    2012-01-01

    Full Text Available The obesity epidemic requires the development of prevention policy targeting individuals most likely to benefit. We used self-reported prepregnancy body weight of all women giving birth in Nova Scotia between 1988 and 2006 to define obesity and evaluated socioeconomic, demographic, and temporal trends in obesity using linear regression. There were 172,373 deliveries in this cohort of 110,743 women. Maternal body weight increased significantly by 0.5 kg per year from 1988, and lower income and rural residence were both associated significantly with increasing obesity. We estimated an additional 82,000 overweight or obese women in Nova Scotia in 2010, compared to the number that would be expected from obesity rates of just two decades ago. The critical age for weight gain was identified as being between 20 and 24 years. This age group is an important transition age between adolescence and adulthood when individuals first begin to accept responsibility for food planning, purchasing, and preparation. Policy and public health interventions must target those most at risk, namely, younger women and the socially deprived, whilst tackling the marketing of low-cost energy-dense foods at the expense of healthier options.

  8. Can Targeted Intervention Mitigate Early Emotional and Behavioral Problems?: Generating Robust Evidence within Randomized Controlled Trials.

    Directory of Open Access Journals (Sweden)

    Orla Doyle

    Full Text Available This study examined the impact of a targeted Irish early intervention program on children's emotional and behavioral development using multiple methods to test the robustness of the results. Data on 164 Preparing for Life participants who were randomly assigned into an intervention group, involving home visits from pregnancy onwards, or a control group, was used to test the impact of the intervention on Child Behavior Checklist scores at 24-months. Using inverse probability weighting to account for differential attrition, permutation testing to address small sample size, and quantile regression to characterize the distributional impact of the intervention, we found that the few treatment effects were largely concentrated among boys most at risk of developing emotional and behavioral problems. The average treatment effect identified a 13% reduction in the likelihood of falling into the borderline clinical threshold for Total Problems. The interaction and subgroup analysis found that this main effect was driven by boys. The distributional analysis identified a 10-point reduction in the Externalizing Problems score for boys at the 90th percentile. No effects were observed for girls or for the continuous measures of Total, Internalizing, and Externalizing problems. These findings suggest that the impact of this prenatally commencing home visiting program may be limited to boys experiencing the most difficulties. Further adoption of the statistical methods applied here may help to improve the internal validity of randomized controlled trials and contribute to the field of evaluation science more generally.ISRCTN Registry ISRCTN04631728.

  9. Rational polypharmacology: systematically identifying and engaging multiple drug targets to promote axon growth

    Science.gov (United States)

    Al-Ali, Hassan; Lee, Do-Hun; Danzi, Matt C.; Nassif, Houssam; Gautam, Prson; Wennerberg, Krister; Zuercher, Bill; Drewry, David H.; Lee, Jae K.; Lemmon, Vance P.; Bixby, John L.

    2016-01-01

    Mammalian Central Nervous System (CNS) neurons regrow their axons poorly following injury, resulting in irreversible functional losses. Identifying therapeutics that encourage CNS axon repair has been difficult, in part because multiple etiologies underlie this regenerative failure. This suggests a particular need for drugs that engage multiple molecular targets. Although multi-target drugs are generally more effective than highly selective alternatives, we lack systematic methods for discovering such drugs. Target-based screening is an efficient technique for identifying potent modulators of individual targets. In contrast, phenotypic screening can identify drugs with multiple targets; however, these targets remain unknown. To address this gap, we combined the two drug discovery approaches using machine learning and information theory. We screened compounds in a phenotypic assay with primary CNS neurons and also in a panel of kinase enzyme assays. We used learning algorithms to relate the compounds’ kinase inhibition profiles to their influence on neurite outgrowth. This allowed us to identify kinases that may serve as targets for promoting neurite outgrowth, as well as others whose targeting should be avoided. We found that compounds that inhibit multiple targets (polypharmacology) promote robust neurite outgrowth in vitro. One compound with exemplary polypharmacology, was found to promote axon growth in a rodent spinal cord injury model. A more general applicability of our approach is suggested by its ability to deconvolve known targets for a breast cancer cell line, as well as targets recently shown to mediate drug resistance. PMID:26056718

  10. Interstitial cells of Cajal as targets for pharmacological intervention in gastrointestinal motor disorders

    DEFF Research Database (Denmark)

    Huizinga, J D; Thuneberg, L; Vanderwinden, J M

    1997-01-01

    Interstitial cells of Cajal (ICCs) have recently been identified as the pacemaker cells for contractile activity of the gastrointestinal tract. These cells generate the electrical 'slow-wave' activity that determines the characteristic frequency of phasic contractions of the stomach, intestine...... through the gut organs. Here Jan Huizinga, Lars Thuneberg, Jean-Marie Vanderwinden and Jüri Rumessen, suggest that, as ICCs are unique to the gut, they might be ideal targets for pharmacological intervention in gastrointestinal motility disorders, which are very common and costly....

  11. Effects of an Emotional Literacy Intervention for Students Identified with Bullying Behaviour

    Science.gov (United States)

    Knowler, Claire; Frederickson, Norah

    2013-01-01

    The effectiveness of a 12-week, small group emotional literacy (EL) intervention in reducing bullying behaviour in school was evaluated. Participants were 50 primary school pupils identified through peer nomination as engaging in bullying behaviours. The intervention was implemented in schools already engaged with a universal social and emotional…

  12. Periostin: a promising target of therapeutical intervention for prostate cancer

    Directory of Open Access Journals (Sweden)

    Ding Weihong

    2011-06-01

    RNA-Periostin LNCap cells growed slowly in vitro and in vivo. The tissues of xenografts as PCa were verificated by HE staining. Additionally, the weak positive Periostin expressed tumor cells could be seen in the tissues of 6 xenografts from the group of down-regulated Periostin LNCap cells which had a significant decrease of the amount of Periostin compared to the other two group. Furthermore, our results demonstrated that sliencing Periostin could inhibit migration of LNCap cells in vitro. Conclusions Our data indicates that Periostin as an up-regulated protein in PCa may be a promising target of therapeutical intervention for PCa in future.

  13. A systematic review of suicide prevention interventions targeting indigenous peoples in Australia, United States, Canada and New Zealand.

    Science.gov (United States)

    Clifford, Anton C; Doran, Christopher M; Tsey, Komla

    2013-05-13

    Indigenous peoples of Australia, Canada, United States and New Zealand experience disproportionately high rates of suicide. As such, the methodological quality of evaluations of suicide prevention interventions targeting these Indigenous populations should be rigorously examined, in order to determine the extent to which they are effective for reducing rates of Indigenous suicide and suicidal behaviours. This systematic review aims to: 1) identify published evaluations of suicide prevention interventions targeting Indigenous peoples in Australia, Canada, United States and New Zealand; 2) critique their methodological quality; and 3) describe their main characteristics. A systematic search of 17 electronic databases and 13 websites for the period 1981-2012 (inclusive) was undertaken. The reference lists of reviews of suicide prevention interventions were hand-searched for additional relevant studies not identified by the electronic and web search. The methodological quality of evaluations of suicide prevention interventions was assessed using a standardised assessment tool. Nine evaluations of suicide prevention interventions were identified: five targeting Native Americans; three targeting Aboriginal Australians; and one First Nation Canadians. The main intervention strategies employed included: Community Prevention, Gatekeeper Training, and Education. Only three of the nine evaluations measured changes in rates of suicide or suicidal behaviour, all of which reported significant improvements. The methodological quality of evaluations was variable. Particular problems included weak study designs, reliance on self-report measures, highly variable consent and follow-up rates, and the absence of economic or cost analyses. There is an urgent need for an increase in the number of evaluations of preventive interventions targeting reductions in Indigenous suicide using methodologically rigorous study designs across geographically and culturally diverse Indigenous

  14. Legislative, educational, policy and other interventions targeting physicians' interaction with pharmaceutical companies: a systematic review.

    Science.gov (United States)

    Alkhaled, Lina; Kahale, Lara; Nass, Hala; Brax, Hneine; Fadlallah, Racha; Badr, Kamal; Akl, Elie A

    2014-07-01

    Pharmaceutical company representatives likely influence the prescribing habits and professional behaviour of physicians. The objective of this study was to systematically review the effects of interventions targeting practising physicians' interactions with pharmaceutical companies. We included observational studies, non-randomised controlled trials (non-RCTs) and RCTs evaluating legislative, educational, policy or other interventions targeting the interactions between physicians and pharmaceutical companies. The search strategy included an electronic search of MEDLINE and EMBASE. Two reviewers performed duplicate and independent study selection, data abstraction and assessment of risk of bias. We assessed the risk of bias in each included study. We summarised the findings narratively because the nature of the data did not allow a meta-analysis to be conducted. We assessed the quality of evidence by outcome using the GRADE methodology. Of 11 189 identified citations, one RCT and three observational studies met the eligibility criteria. All four studies specifically targeted one type of interaction with pharmaceutical companies, that is, interactions with drug representatives. The RCT provided moderate quality evidence of no effect of a 'collaborative approach' between the pharmaceutical industry and a health authority. The three observational studies provided low quality evidence suggesting a positive effect of policies aiming to reduce interaction between physicians and pharmaceutical companies (by restricting free samples, promotional material, and meetings with pharmaceutical company representatives) on prescription behaviour. We identified too few studies to allow strong conclusions. Available evidence suggests a potential impact of policies aiming to reduce interaction between physicians and drug representatives on physicians' prescription behaviour. We found no evidence concerning interventions affecting other types of interaction with pharmaceutical

  15. Increasing Early Detection of Prostate Cancer in African American Men Through a Culturally Targeted Print Intervention

    Science.gov (United States)

    2006-03-01

    the early detection of PCa among AA men are critical. Although culturally targeted health interventions have been found to be effective there are no...AD_________________ Award Number: W81XWH-04-1-0026 TITLE: Increasing Early Detection of Prostate...Cancer in African American Men Through a Culturally Targeted Print Intervention PRINCIPAL INVESTIGATOR: Hayley Thompson, Ph.D

  16. Considerations for biomarker-targeted intervention strategies for tuberculosis disease prevention.

    Science.gov (United States)

    Fiore-Gartland, Andrew; Carpp, Lindsay N; Naidoo, Kogieleum; Thompson, Ethan; Zak, Daniel E; Self, Steve; Churchyard, Gavin; Walzl, Gerhard; Penn-Nicholson, Adam; Scriba, Thomas J; Hatherill, Mark

    2018-03-01

    Current diagnostic tests for Mycobacterium tuberculosis (MTB) infection have low prognostic specificity for identifying individuals who will develop tuberculosis (TB) disease, making mass preventive therapy strategies targeting all MTB-infected individuals impractical in high-burden TB countries. Here we discuss general considerations for a risk-targeted test-and-treat strategy based on a highly specific transcriptomic biomarker that can identify individuals who are most likely to progress to active TB disease as well as individuals with TB disease who have not yet presented for medical care. Such risk-targeted strategies may offer a rapid, ethical and cost-effective path towards decreasing the burden of TB disease and interrupting transmission and would also be critical to achieving TB elimination in countries nearing elimination. We also discuss design considerations for a Correlate of Risk Targeted Intervention Study (CORTIS), which could provide proof-of-concept for the strategy. One such study in South Africa is currently enrolling 1500 high-risk and 1700 low-risk individuals, as defined by biomarker status, and is randomizing high-risk participants to TB preventive therapy or standard of care treatment. All participants are monitored for progression to active TB with primary objectives to assess efficacy of the treatment and performance of the biomarker. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  17. Enhanced surveillance of Staphylococcus aureus bacteraemia to identify targets for infection prevention.

    Science.gov (United States)

    Morris, A K; Russell, C D

    2016-06-01

    Surveillance of Staphylococcus aureus bacteraemia (SAB) in Scotland is limited to the number of infections per 100,000 acute occupied bed-days and susceptibility to meticillin. To demonstrate the value of enhanced SAB surveillance to identify targets for infection prevention. Prospective cohort study of all patients identified with SAB over a five-year period in a single health board in Scotland. All patients were reviewed at the bedside by a clinical microbiologist. In all, 556 SAB episodes were identified: 261 (46.6%) were hospital-acquired; 209 (37.9%) were healthcare-associated; 80 (14.4%) were community-acquired; and in six (1.1%) the origin of infection was not hospital-acquired, but could not be separated into healthcare-associated or community-acquired. These were classified as non-hospital-acquired. Meticillin-resistant S. aureus (MRSA) bacteraemia was associated with hospital-acquired and healthcare-associated infections. In addition, there was a significantly higher 30-day mortality associated with hospital-acquired (31.4%) and healthcare-associated (16.3%) infections compared to community-acquired SAB (8.7%). Vascular access devices were associated with hospital-acquired SAB and peripheral venous cannulas were the source for most of these (43.9%). Community-acquired infections were associated with intravenous drug misuse, respiratory tract infections and skeletal and joint infections. Skin and soft tissue infections were more widely seen in healthcare-associated infections. The data indicate that enhanced surveillance of SAB by origin of infection and source of bacteraemia has implications for infection prevention, empirical antibiotic therapy, and health improvement interventions. Copyright © 2016 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

  18. Targeting Premalignant Lesions: Implications for Early Breast Cancer Detection and Intervention

    Science.gov (United States)

    2016-04-01

    1 AWARD NUMBER: W81XWH-14-1-0032 TITLE: Targeting Premalignant Lesions: Implications for Early Breast Cancer Detection and Intervention ...therapeutically intervene to successfully inhibit or even reverse tumor progression. 15. SUBJECT TERMS Breast cancer, Premalignant lesions, early intervention ...INTRODUCTION: Difficulty in managing treatment of advanced stage breast cancer has led to the goal for detection and intervention of early -stage disease

  19. Improving Student Outcomes in Higher Education: The Science of Targeted Intervention.

    Science.gov (United States)

    Harackiewicz, Judith M; Priniski, Stacy J

    2018-01-04

    Many theoretically based interventions have been developed over the past two decades to improve educational outcomes in higher education. Based in social-psychological and motivation theories, well-crafted interventions have proven remarkably effective because they target specific educational problems and the processes that underlie them. In this review, we evaluate the current state of the literature on targeted interventions in higher education with an eye to emerging theoretical and conceptual questions about intervention science. We review three types of interventions, which focus on the value students perceive in academic tasks, their framing of academic challenges, and their personal values, respectively. We consider interventions that (a) target academic outcomes (e.g., grades, major or career plans, course taking, retention) in higher education, as well as the pipeline to college, and (b) have been evaluated in at least two studies. Finally, we discuss implications for intervention science moving forward.

  20. Can Social Functioning in Schizophrenia Be Improved through Targeted Social Cognitive Intervention?

    Directory of Open Access Journals (Sweden)

    David L. Roberts

    2012-01-01

    Full Text Available Efforts to use cognitive remediation in psychosocial intervention for schizophrenia have increasingly incorporated social cognition as a treatment target. A distinction can be made in this work between “broad-based” interventions, which integrate social cognitive training within a multicomponent suite of intervention techniques and “targeted” interventions; which aim to enhance social cognition alone. Targeted interventions have the potential advantage of being more efficient than broad-based interventions; however, they also face difficult challenges. In particular, targeted interventions may be less likely to achieve maintenance and generalization of gains made in treatment. A novel potential solution to this problem is described which draws on the social psychological literature on social cognition.

  1. Targeting Premalignant Lesions - Implications for Early Breast Cancer Detection and Intervention

    Science.gov (United States)

    2017-04-01

    AWARD NUMBER: W81XWH-14-1-0032 TITLE: Targeting Premalignant Lesions - Implications for Early Breast Cancer Detection and Intervention PRINCIPAL...INTRODUCTION: Difficulty in managing treatment of advanced stage breast cancer has led to the goal for detection and intervention of early -stage...Furthermore, these probes will be used to develop targeted therapeutic nanoparticles for early intervention in breast cancer. 2. KEYWORDS

  2. Screen Time Weight-loss Intervention Targeting Children at Home (SWITCH: process evaluation of a randomised controlled trial intervention

    Directory of Open Access Journals (Sweden)

    Louise Foley

    2016-05-01

    Full Text Available Abstract Background The Screen Time Weight-loss Intervention Targeting Children at Home (SWITCH trial tested a family intervention to reduce screen-based sedentary behaviour in overweight children. The trial found no significant effect of the intervention on children’s screen-based sedentary behaviour. To explore these null findings, we conducted a pre-planned process evaluation, focussing on intervention delivery and uptake. Methods SWITCH was a randomised controlled trial of a 6-month family intervention to reduce screen time in overweight children aged 9–12 years (n = 251. Community workers met with each child’s primary caregiver to deliver the intervention content. Community workers underwent standard training and were monitored once by a member of the research team to assess intervention delivery. The primary caregiver implemented the intervention with their child, and self-reported intervention use at 3 and 6 months. An exploratory analysis determined whether child outcomes at 6 months varied by primary caregiver use of the intervention. Results Monitoring indicated that community workers delivered all core intervention components to primary caregivers. However, two thirds of primary caregivers reported using any intervention component “sometimes” or less frequently at both time points, suggesting that intervention uptake was poor. Additionally, analyses indicated no effect of primary caregiver intervention use on child outcomes at 6 months, suggesting the intervention itself lacked efficacy. Conclusions Poor uptake, and the efficacy of the intervention itself, may have played a role in the null findings of the SWITCH trial on health behaviour and body composition. Trial registration The trial was registered in the Australian and New Zealand Clinical Trials Registry (no. ACTRN12611000164998 ; registration date: 10/02/2011.

  3. Using GIS Mapping to Target Public Health Interventions: Examining Birth Outcomes Across GIS Techniques.

    Science.gov (United States)

    MacQuillan, E L; Curtis, A B; Baker, K M; Paul, R; Back, Y O

    2017-08-01

    With advances in spatial analysis techniques, there has been a trend in recent public health research to assess the contribution of area-level factors to health disparity for a number of outcomes, including births. Although it is widely accepted that health disparity is best addressed by targeted, evidence-based and data-driven community efforts, and despite national and local focus in the U.S. to reduce infant mortality and improve maternal-child health, there is little work exploring how choice of scale and specific GIS visualization technique may alter the perception of analyses focused on health disparity in birth outcomes. Retrospective cohort study. Spatial analysis of individual-level vital records data for low birthweight and preterm births born to black women from 2007 to 2012 in one mid-sized Midwest city using different geographic information systems (GIS) visualization techniques [geocoded address records were aggregated at two levels of scale and additionally mapped using kernel density estimation (KDE)]. GIS analyses in this study support our hypothesis that choice of geographic scale (neighborhood or census tract) for aggregated birth data can alter programmatic decision-making. Results indicate that the relative merits of aggregated visualization or the use of KDE technique depend on the scale of intervention. The KDE map proved useful in targeting specific areas for interventions in cities with smaller populations and larger census tracts, where they allow for greater specificity in identifying intervention areas. When public health programmers seek to inform intervention placement in highly populated areas, however, aggregated data at the census tract level may be preferred, since it requires lower investments in terms of time and cartographic skill and, unlike neighborhood, census tracts are standardized in that they become smaller as the population density of an area increases.

  4. Health service interventions targeting relatives of heart patients

    DEFF Research Database (Denmark)

    Nissen, Nina Konstantin; Madsen, Mette; Olsen Zwisler, Ann-Dorthe

    2008-01-01

    systematically reviewed to clarify what the health services do for relatives of heart patients and to assess the effects of interventions. We searched Medline, EMBASE, PsycINFO, CINAHL database, CSA and the Cochrane Library from January 2000 to March 2006. RESULTS: Only six scientific articles reported...

  5. Target-similarity search using Plasmodium falciparum proteome identifies approved drugs with anti-malarial activity and their possible targets.

    Directory of Open Access Journals (Sweden)

    Reagan M Mogire

    Full Text Available Malaria causes about half a million deaths annually, with Plasmodium falciparum being responsible for 90% of all the cases. Recent reports on artemisinin resistance in Southeast Asia warrant urgent discovery of novel drugs for the treatment of malaria. However, most bioactive compounds fail to progress to treatments due to safety concerns. Drug repositioning offers an alternative strategy where drugs that have already been approved as safe for other diseases could be used to treat malaria. This study screened approved drugs for antimalarial activity using an in silico chemogenomics approach prior to in vitro verification. All the P. falciparum proteins sequences available in NCBI RefSeq were mined and used to perform a similarity search against DrugBank, TTD and STITCH databases to identify similar putative drug targets. Druggability indices of the potential P. falciparum drug targets were obtained from TDR targets database. Functional amino acid residues of the drug targets were determined using ConSurf server which was used to fine tune the similarity search. This study predicted 133 approved drugs that could target 34 P. falciparum proteins. A literature search done at PubMed and Google Scholar showed 105 out of the 133 drugs to have been previously tested against malaria, with most showing activity. For further validation, drug susceptibility assays using SYBR Green I method were done on a representative group of 10 predicted drugs, eight of which did show activity against P. falciparum 3D7 clone. Seven had IC50 values ranging from 1 μM to 50 μM. This study also suggests drug-target association and hence possible mechanisms of action of drugs that did show antiplasmodial activity. The study results validate the use of proteome-wide target similarity approach in identifying approved drugs with activity against P. falciparum and could be adapted for other pathogens.

  6. Effects of an emotional literacy intervention for students identified with bullying behaviour.

    Science.gov (United States)

    Knowler, Claire; Frederickson, Norah

    2013-12-01

    The effectiveness of a 12-week, small group emotional literacy (EL) intervention in reducing bullying behaviour in school was evaluated. Participants were 50 primary school pupils identified through peer nomination as engaging in bullying behaviours. The intervention was implemented in schools already engaged with a universal social and emotional learning initiative, including an anti-bullying component. Within schools, participants were randomly assigned to an intervention or a wait-list comparison group. Response to the intervention was found to be dependent on baseline levels of EL. Only children whose baseline level was low showed a significant reduction in peer-rated bullying behaviour. No effect of the intervention was detected on victimisation or adjustment scores, although positive changes in adjustment were associated with increased EL.

  7. Targeted Immune Interventions for an HIV-1 Cure.

    Science.gov (United States)

    Perreau, Matthieu; Banga, Riddhima; Pantaleo, Giuseppe

    2017-10-01

    Combination antiretroviral therapy (cART) induces durable suppression of virus replication but is unable to eradicate HIV. Invariably, virus rebound follows treatment interruption and life-long cART is thus required. Advances have been made in our understanding of HIV latency, identification of HIV cell reservoirs, regulation of HIV-specific immune responses, as well as in the development of broad neutralizing antibodies and putative therapeutic vaccines. These have provided a scientific basis to explore alternative strategies that achieve durable suppression of viremia in the absence of cART, the so-called functional cure. Single intervention strategies have shown promise, albeit with limited efficacy. Consequently, a combination of interventions aiming to stimulate the immune response and prevent new rounds of viral infection and spreading may render the HIV functional cure a feasible goal. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Identifying the effects of environmental and policy change interventions on healthy eating.

    Science.gov (United States)

    Bowen, Deborah J; Barrington, Wendy E; Beresford, Shirley A A

    2015-03-18

    Obesity has been characterized as a disease. Strategies to change the incidence and prevalence of this disease include a focus on changing physical and social environments, over and above individual-level strategies, using a multilevel or systems approach. We focus our attention on evidence published between 2008 and 2013 on the effectiveness of interventions in nutrition environments, i.e., environmental interventions designed to influence the intake of healthful foods and amount of energy consumed. An overarching socioecological framework that has guided much of this research was used to characterize different types of environmental strategies. Intervention examples in each area of the framework are provided with a discussion of key findings and related conceptual and methodological issues. The emphasis in this review is on adults, but clearly this literature is only one part of the picture. Much research has been focused on child-specific interventions, including environmental interventions. Some evidence suggests effectiveness of policy-based or other types of interventions that aim to regulate or restructure environments to promote healthy dietary choices, and these strategies would apply to both children and adults. Opportunities to evaluate these policy changes in adults' social and physical environments are rare. Much of the existing research has been with children. As conceptual and methodological issues continue to be identified and resolved, we hope that future research in this domain will identify environmental strategies that can be included in intervention toolboxes to build healthy nutrition environments for both adults and children.

  9. Matrine Is Identified as a Novel Macropinocytosis Inducer by a Network Target Approach.

    Science.gov (United States)

    Zhang, Bo; Wang, Xin; Li, Yan; Wu, Min; Wang, Shu-Yan; Li, Shao

    2018-01-01

    Comprehensively understanding pharmacological functions of natural products is a key issue to be addressed for the discovery of new drugs. Unlike some single-target drugs, natural products always exert diverse therapeutic effects through acting on a "network" that consists of multiple targets, making it necessary to develop a systematic approach, e.g., network pharmacology, to reveal pharmacological functions of natural products and infer their mechanisms of action. In this work, to identify the "network target" of a natural product, we perform a functional analysis of matrine, a marketed drug in China extracted from a medical herb Ku-Shen ( Radix Sophorae Flavescentis ). Here, the network target of matrine was firstly predicted by drugCIPHER, a genome-wide target prediction method. Based on the network target of matrine, we performed a functional gene set enrichment analysis to computationally identify the potential pharmacological functions of matrine, most of which are supported by the literature evidence, including neurotoxicity and neuropharmacological activities of matrine. Furthermore, computational results demonstrated that matrine has the potential for the induction of macropinocytosis and the regulation of ATP metabolism. Our experimental data revealed that the large vesicles induced by matrine are consistent with the typical characteristics of macropinosome. Our verification results also suggested that matrine could decrease cellular ATP level. These findings demonstrated the availability and effectiveness of the network target strategy for identifying the comprehensive pharmacological functions of natural products.

  10. Targeted and Untargeted Metabolic Profiling of Wild Grassland Plants identifies Antibiotic and Anthelmintic Compounds Targeting Pathogen Physiology, Metabolism and Reproduction

    OpenAIRE

    French, Katherine E.; Harvey, Joe; McCullagh, James S. O.

    2018-01-01

    Plants traditionally used by farmers to manage livestock ailments could reduce reliance on synthetic antibiotics and anthelmintics but in many cases their chemical composition is unknown. As a case study, we analyzed the metabolite profiles of 17 plant species and 45 biomass samples from agricultural grasslands in England using targeted and untargeted metabolite profiling by liquid-chromatography mass spectrometry. We identified a range of plant secondary metabolites, including 32 compounds w...

  11. Targeted and untargeted metabolic profiling of wild grassland plants identifies antibiotic and anthelmintic compounds targeting pathogen physiology, metabolism and reproduction

    OpenAIRE

    French, KE; Harvey, J; Mccullagh, J

    2018-01-01

    Plants traditionally used by farmers to manage livestock ailments could reduce reliance on synthetic antibiotics and anthelmintics but in many cases their chemical composition is unknown. As a case study, we analyzed the metabolite profiles of 17 plant species and 45 biomass samples from agricultural grasslands in England using targeted and untargeted metabolite profiling by liquid‐chromatography mass‐spectrometry. We identified a range of plant secondary metabolites, including 32 compounds w...

  12. Screening and brief intervention targeting risky drinkers in Danish general practice - a pragmatic controlled trial

    DEFF Research Database (Denmark)

    Beich, A.; Gannik, D.; Saelan, H.

    2007-01-01

    AIMS: Recommendations for routine alcohol screening and brief counselling intervention in primary health care rest on results from intervention efficacy studies. By conducting a pragmatic controlled trial (PCT), we aimed at evaluating the effectiveness of the WHO recommendations for screening......-14 months. Outcome measures focused on patients' acceptance of screening and intervention and their self-reported alcohol consumption. RESULTS: Patient acceptance of screening and intervention -10.3% (N = 794) of the target population (N = 7, 691) explicitly refused screening. All intervention group...

  13. Intervention Integrity in the Low Countries: Interventions Targeting Social-Emotional Behaviors in the School

    Science.gov (United States)

    Taal, Margot; Ekels, Elles; van der Valk, Cindel; van der Molen, Maurits

    2017-01-01

    The current study presents a review of intervention studies conducted in the Low Countries (i.e., The Netherlands and Flanders) focusing on social-emotional behaviors in the school. The primary purpose of this review was to assess whether studies included an operational definition of the intervention under study and reported data on the…

  14. Identifying Early Target Cells of Nipah Virus Infection in Syrian Hamsters

    OpenAIRE

    Baseler, Laura; Scott, Dana P.; Saturday, Greg; Horne, Eva; Rosenke, Rebecca; Thomas, Tina; Meade-White, Kimberly; Haddock, Elaine; Feldmann, Heinz; de Wit, Emmie

    2016-01-01

    Background Nipah virus causes respiratory and neurologic disease with case fatality rates up to 100% in individual outbreaks. End stage lesions have been described in the respiratory and nervous systems, vasculature and often lymphoid organs in fatal human cases; however, the initial target organs of Nipah virus infection have not been identified. Here, we detected the initial target tissues and cells of Nipah virus and tracked virus dissemination during the early phase of infection in Syrian...

  15. Identifying a practice-based implementation framework for sustainable interventions for improving the evolving working environment

    DEFF Research Database (Denmark)

    Højberg, Helene; Nørregaard Rasmussen, Charlotte Diana; Osborne, Richard H.

    2018-01-01

    Our aim was to identify implementation components for sustainable working environment interventions in the nursing assistant sector to generate a framework to optimize the implementation of workplace improvement initiatives. The implementation framework was informed by: 1) an industry advisory......) An engaged workplace with mutual goals, 3) The intervention is sustainably fitted to the workplace, and 4) the intervention is an attractive choice. The highest rated component was “Engaged and Active Management” (mean 4.1) and the lowest rated was “Delivered in an Attractive Form” (mean 2.8). The framework...... provides new insights into implementation in an evolving working environment and is aiming to assist with addressing gaps in effectiveness of workplace interventions and implementation success....

  16. Factors affecting ambulance utilization for asthma attack treatment: understanding where to target interventions.

    Science.gov (United States)

    Raun, L H; Ensor, K B; Campos, L A; Persse, D

    2015-05-01

    Asthma is a serious, sometimes fatal condition, in which attacks vary in severity, potentially requiring emergency medical services (EMS) ambulance treatment. A portion of asthma attacks requiring EMS ambulance treatment may be prevented with improved education and access to care. The aim of this study was to identify areas of the city with high rates of utilization of EMS ambulance for treatment, and the demographics, socio-economic status, and time of day associated with these rates, to better target future interventions to prevent emergencies and reduce cost. A cross-sectional study was conducted on individuals in Houston, TX (USA) requiring ambulance treatment for asthma attacks from 2004 to 2011. 12,155 EMS ambulance-treated asthma attack cases were linked to census tracts. High rate treatment areas were identified with geospatial mapping. Census tract demographic characteristics of these high rate areas were compared with the remainder of the city using logistic regression. The association between case level demographics and the time of day of asthma attack within the high rate area was also assessed with logistic regression. EMS ambulance-treated high rate areas were identified and found to have a utilization incidence rate over six times higher per 100,000 people than the remainder of the city. There is an increased risk of location in this high rate area with a census tract level increase of percent of population: earning less than $10,000 yearly income (RR 1.21, 1.16-1.26), which is black (RR 1.08, 1.07-1.10), which is female (RR 1.34, 1.20-1.49) and have obtained less than a high school degree (RR 1.02, 1.01-1.03). Within the high rate area, case level data indicates an increased risk of requiring an ambulance after normal doctor office hours for men compared with women (RR 1.13, 1.03-1.22), for black compared with Hispanic ethnicity (RR 1.31, 1.08-1.59), or for adults (less than 41 and greater than 60) compared with children. Interventions to prevent

  17. Yeast-based assay identifies novel Shh/Gli target genes in vertebrate development

    Directory of Open Access Journals (Sweden)

    Milla Luis A

    2012-01-01

    Full Text Available Abstract Background The increasing number of developmental events and molecular mechanisms associated with the Hedgehog (Hh pathway from Drosophila to vertebrates, suggest that gene regulation is crucial for diverse cellular responses, including target genes not yet described. Although several high-throughput, genome-wide approaches have yielded information at the genomic, transcriptional and proteomic levels, the specificity of Gli binding sites related to direct target gene activation still remain elusive. This study aims to identify novel putative targets of Gli transcription factors through a protein-DNA binding assay using yeast, and validating a subset of targets both in-vitro and in-vivo. Testing in different Hh/Gli gain- and loss-of-function scenarios we here identified known (e.g., ptc1 and novel Hh-regulated genes in zebrafish embryos. Results The combined yeast-based screening and MEME/MAST analysis were able to predict Gli transcription factor binding sites, and position mapping of these sequences upstream or in the first intron of promoters served to identify new putative target genes of Gli regulation. These candidates were validated by qPCR in combination with either the pharmacological Hh/Gli antagonist cyc or the agonist pur in Hh-responsive C3H10T1/2 cells. We also used small-hairpin RNAs against Gli proteins to evaluate targets and confirm specific Gli regulation their expression. Taking advantage of mutants that have been identified affecting different components of the Hh/Gli signaling system in the zebrafish model, we further analyzed specific novel candidates. Studying Hh function with pharmacological inhibition or activation complemented these genetic loss-of-function approaches. We provide evidence that in zebrafish embryos, Hh signaling regulates sfrp2, neo1, and c-myc expression in-vivo. Conclusion A recently described yeast-based screening allowed us to identify new Hh/Gli target genes, functionally important in

  18. Matrine Is Identified as a Novel Macropinocytosis Inducer by a Network Target Approach

    Directory of Open Access Journals (Sweden)

    Bo Zhang

    2018-01-01

    Full Text Available Comprehensively understanding pharmacological functions of natural products is a key issue to be addressed for the discovery of new drugs. Unlike some single-target drugs, natural products always exert diverse therapeutic effects through acting on a “network” that consists of multiple targets, making it necessary to develop a systematic approach, e.g., network pharmacology, to reveal pharmacological functions of natural products and infer their mechanisms of action. In this work, to identify the “network target” of a natural product, we perform a functional analysis of matrine, a marketed drug in China extracted from a medical herb Ku-Shen (Radix Sophorae Flavescentis. Here, the network target of matrine was firstly predicted by drugCIPHER, a genome-wide target prediction method. Based on the network target of matrine, we performed a functional gene set enrichment analysis to computationally identify the potential pharmacological functions of matrine, most of which are supported by the literature evidence, including neurotoxicity and neuropharmacological activities of matrine. Furthermore, computational results demonstrated that matrine has the potential for the induction of macropinocytosis and the regulation of ATP metabolism. Our experimental data revealed that the large vesicles induced by matrine are consistent with the typical characteristics of macropinosome. Our verification results also suggested that matrine could decrease cellular ATP level. These findings demonstrated the availability and effectiveness of the network target strategy for identifying the comprehensive pharmacological functions of natural products.

  19. Psychostimulant and Sensory Stimulation Interventions That Target the Reading and Math Deficits of Students with ADHD

    Science.gov (United States)

    Zentall, Sydney S.; Tom-Wright, Kinsey; Lee, Jiyeon

    2013-01-01

    Objective: The purpose of this review of students with attention deficit hyperactivity disorder (ADHD) was to summarize the following: (1) academic deficits in math and reading, (2) possible theoretical contributors to these deficits, and (3) psychostimulant interventions that target math and reading, as well as, parallel interventions involving…

  20. Interventions targeting sexual and reproductive health and rights outcomes of young people living with HIV: a comprehensive review of current interventions from sub-Saharan Africa.

    Science.gov (United States)

    Pretorius, Leandri; Gibbs, Andrew; Crankshaw, Tamaryn; Willan, Samantha

    2015-01-01

    A growing number of young people (ages 10-24) are living with HIV (YPLWH) in sub-Saharan Africa (SSA). These YPLWH have particular needs and challenges related to their sexual and reproductive health and rights (SRHR). Contextual factors including gender inequalities, violence, stigma, and discrimination and lack of tailored services undermine YPLWH's SRHR. Understand the scope and impact of interventions targeting YPLWH to improve SRH-related outcomes in SSA. We undertook a review to synthesise evaluated interventions (qualitative, quantitative, or mixed methods) aimed at improving the SRH outcomes of YPLWH in SSA with outcomes based on a World Health Organization framework of comprehensive SRHR approaches for women living with HIV. Using inclusion criteria, only six interventions were identified. Interventions sought to improve a range of direct and indirect SRH outcomes, including sexual behaviour, adherence, disclosure, and mental health. Four overarching issues emerged: 1) all interventions were structured according to cognitive behavioural therapy theories of behaviour change - while showing promise they do not tackle the wider gender, social, and economic contexts that shape YPLWH's SRH; 2) 'significant others' were included in two of the interventions, but further work needs to consider how to leverage parental/guardian support appropriately; 3) interventions only accessed young people who were already linked to care, participants were likely to have better SRH outcomes than those potentially more vulnerable YPLWH; and 4) none of the interventions explored the sexuality of young people. There have been a limited number of evaluated interventions to strengthen SRH of YPLWH in SSA, and gaps exist in addressing the SRHR needs of YPLWH. Intervention approaches require greater scope and depth, including the need to address structural and contextual challenges.

  1. Interventions targeting sexual and reproductive health and rights outcomes of young people living with HIV: a comprehensive review of current interventions from sub-Saharan Africa

    Directory of Open Access Journals (Sweden)

    Leandri Pretorius

    2015-11-01

    Full Text Available Background: A growing number of young people (ages 10–24 are living with HIV (YPLWH in sub-Saharan Africa (SSA. These YPLWH have particular needs and challenges related to their sexual and reproductive health and rights (SRHR. Contextual factors including gender inequalities, violence, stigma, and discrimination and lack of tailored services undermine YPLWH's SRHR. Objective: Understand the scope and impact of interventions targeting YPLWH to improve SRH-related outcomes in SSA. Design: We undertook a review to synthesise evaluated interventions (qualitative, quantitative, or mixed methods aimed at improving the SRH outcomes of YPLWH in SSA with outcomes based on a World Health Organization framework of comprehensive SRHR approaches for women living with HIV. Using inclusion criteria, only six interventions were identified. Results: Interventions sought to improve a range of direct and indirect SRH outcomes, including sexual behaviour, adherence, disclosure, and mental health. Four overarching issues emerged: 1 all interventions were structured according to cognitive behavioural therapy theories of behaviour change – while showing promise they do not tackle the wider gender, social, and economic contexts that shape YPLWH's SRH; 2 ‘significant others’ were included in two of the interventions, but further work needs to consider how to leverage parental/guardian support appropriately; 3 interventions only accessed young people who were already linked to care, participants were likely to have better SRH outcomes than those potentially more vulnerable YPLWH; and 4 none of the interventions explored the sexuality of young people. Conclusions: There have been a limited number of evaluated interventions to strengthen SRH of YPLWH in SSA, and gaps exist in addressing the SRHR needs of YPLWH. Intervention approaches require greater scope and depth, including the need to address structural and contextual challenges.

  2. Detecting signatures of balancing selection to identify targets of anti-parasite immunity.

    Science.gov (United States)

    Weedall, Gareth D; Conway, David J

    2010-07-01

    Parasite antigen genes might evolve under frequency-dependent immune selection. The distinctive patterns of polymorphism that result can be detected using population genetic methods that test for signatures of balancing selection, allowing genes encoding important targets of immunity to be identified. Analyses can be complicated by population structures, histories and features of a parasite's genome. However, new sequencing technologies facilitate scans of polymorphism throughout parasite genomes to identify the most exceptional gene specific signatures. We focus on malaria parasites to illustrate challenges and opportunities for detecting targets of frequency-dependent immune selection to discover new potential vaccine candidates. Copyright 2010 Elsevier Ltd. All rights reserved.

  3. Chemical Genomics Identifies the PERK-Mediated Unfolded Protein Stress Response as a Cellular Target for Influenza Virus Inhibition

    Directory of Open Access Journals (Sweden)

    Sara Landeras-Bueno

    2016-04-01

    Full Text Available Influenza A viruses generate annual epidemics and occasional pandemics of respiratory disease with important consequences for human health and the economy. Therefore, a large effort has been devoted to the development of new anti-influenza virus drugs directed to viral targets, as well as to the identification of cellular targets amenable to anti-influenza virus therapy. Here we have addressed the identification of such potential cellular targets by screening collections of drugs approved for human use. We reasoned that screening with a green fluorescent protein-based recombinant replicon system would identify cellular targets involved in virus transcription/replication and/or gene expression and hence address an early stage of virus infection. By using such a strategy, we identified Montelukast (MK as an inhibitor of virus multiplication. MK inhibited virus gene expression but did not alter viral RNA synthesis in vitro or viral RNA accumulation in vivo. The low selectivity index of MK prevented its use as an antiviral, but it was sufficient to identify a new cellular pathway suitable for anti-influenza virus intervention. By deep sequencing of RNA isolated from mock- and virus-infected human cells, treated with MK or left untreated, we showed that it stimulates the PERK-mediated unfolded protein stress response. The phosphorylation of PERK was partly inhibited in virus-infected cells but stimulated in MK-treated cells. Accordingly, pharmacological inhibition of PERK phosphorylation led to increased viral gene expression, while inhibition of PERK phosphatase reduced viral protein synthesis. These results suggest the PERK-mediated unfolded protein response as a potential cellular target to modulate influenza virus infection.

  4. Identifying M&A targets and the information content of VC/PEs

    Directory of Open Access Journals (Sweden)

    Qingquan Tang

    2018-03-01

    Full Text Available The information gap in the M&A market hinders acquirers from effectively identifying high-quality targets. We examine whether VC/PEs convey information content in the M&A market and whether acquirers can use such information to identify high-quality targets. We show that VC/PEs have significant information content and can signal high-quality target companies via “certification”. When acquirers lack acquisition experience and targets are located in inferior information environments, VC/PE “certification” is more significant. The better reputation a VC/PE has, the more information it conveys. Syndicate VC/PEs convey stronger information than independent VC/PEs. We also find that acquirers do not pay higher premiums for high-quality targets. Overall, our results suggest that VC/PEs have value relevance in the M&A market, confirming their “certification” role. We present means for acquirers to select high-quality targets and investors to build efficient portfolios. Keywords: M&A, Certification, VC/PEs, Information content

  5. Breast Cancer Survivorship Care: Targeting a Colorectal Cancer Education Intervention

    Directory of Open Access Journals (Sweden)

    Sherri G. Homan

    2015-08-01

    Full Text Available Breast cancer survivors are at risk of developing a second primary cancer. Colorectal cancer (CRC is one of the leading second primary cancers, and it is often preventable. We developed a multi-component educational tool to inform and encourage women breast cancer survivors to engage in CRC screening. To assess the strengths and weakness of the tool and to improve the relevancy to the target audience, we convened four focus groups of women breast cancer survivors in Missouri. We also assessed the potential impact of the tool on the knowledge, attitudes, and beliefs regarding CRC and collected information on the barriers to CRC screening through pre- and post-focus groups’ questionnaires. A total of 43 women breast cancer survivors participated and provided very valuable suggestions on design and content to update the tool. Through the process and comparing pre- and post-focus group assessments, a significantly higher proportion of breast cancer survivors strongly agreed or agreed that CRC is preventable (78.6% vs. 96.9%, p = 0.02 and became aware that they were at a slightly increased risk for CRC (18.6% vs. 51.7%, p = 0.003. The most cited barrier was the complexity of preparation for colonoscopy.

  6. UP Finder: A COBRA toolbox extension for identifying gene overexpression strategies for targeted overproduction

    Directory of Open Access Journals (Sweden)

    Xi Wang

    2017-12-01

    Full Text Available Overexpression of key genes is a basic strategy for overproducing target products via metabolic engineering. Traditionally, identifying those key genes/pathways largely relies on the knowledge of biochemistry and bioinformatics. In this study, a modeling tool named UP Finder was developed to facilitate the rapid identification of gene overexpression strategies. It was based on the COBRA toolbox under MATLAB environment. All the key gene/pathway targets are identified in one click after simply loading a Systems Biology Markup Language model and specifying a metabolite as the targeted product. The outputs are also quantitatively ranked to show the preference for determining overexpression strategies in pathway design. Analysis examples for overproducing lycopene precursor in Escherichia coli and fatty acyl-ACP in the cyanobacterium Synechocystis sp. PCC 6803 by the UP Finder showed high degree of agreement with the reported key genes in the literatures.

  7. Factor Analysis of Therapist-Identified Treatment Targets in Community-Based Children's Mental Health.

    Science.gov (United States)

    Love, Allison R; Okado, Izumi; Orimoto, Trina E; Mueller, Charles W

    2018-01-01

    The present study used exploratory and confirmatory factor analyses to identify underlying latent factors affecting variation in community therapists' endorsement of treatment targets. As part of a statewide practice management program, therapist completed monthly reports of treatment targets (up to 10 per month) for a sample of youth (n = 790) receiving intensive in-home therapy. Nearly 75 % of youth were diagnosed with multiple co-occurring disorders. Five factors emerged: Disinhibition, Societal Rules Evasion, Social Engagement Deficits, Emotional Distress, and Management of Biodevelopmental Outcomes. Using logistic regression, primary diagnosis predicted therapist selection of Disinhibition and Emotional Distress targets. Client age predicted endorsement of Societal Rules Evasion targets. Practice-to-research implications are discussed.

  8. Identifying Neurofibromin-Specific Regulatory Nodes for Therapeutic Targeting in NF1

    Science.gov (United States)

    2016-10-01

    analysis and electron microscopy, as shown in Figure 9. Figure 9. Biophysical characterization of recombinant , full length neurofibromin. Left panel...libraries targeting cancer specific genetic alterations; ii) Identify recurrently mutated genes that regulate oncogenic pathways and drug responses...iii) Produce genetic interaction maps to uncover pathway relationships between candidate drivers. Overlap: None Funding Number: N/A PI

  9. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1

    DEFF Research Database (Denmark)

    Carvill, Gemma L; Heavin, Sinéad B; Yendle, Simone C

    2013-01-01

    Epileptic encephalopathies are a devastating group of epilepsies with poor prognosis, of which the majority are of unknown etiology. We perform targeted massively parallel resequencing of 19 known and 46 candidate genes for epileptic encephalopathy in 500 affected individuals (cases) to identify ...

  10. Identifying target groups for the prevention of depression in early adolescence: The TRAILS study

    NARCIS (Netherlands)

    Monshouwer, K.; Smit, H.F.E.; Ruiter, M.; Ormel, H.; Verhulst, F.; Vollebergh, w.; Oldehinkel, T.

    2012-01-01

    Background: Depression in adolescence is associated with long-term adverse consequences. The aim of the present study is to identify target groups at increased risk of developing depression in early adolescence, such that prevention is associated with the largest health benefit at population-level

  11. Identifying target groups for the prevention of depression in early adolescence : The TRAILS study

    NARCIS (Netherlands)

    Monshouwer, K.; Smit, F.; Ruiter, M.; Ormel, Johan; Verhulst, F.; Vollebergh, W.; Oldehinkel, T.

    Background: Depression in adolescence is associated with long-term adverse consequences. The aim of the present study is to identify target groups at increased risk of developing depression in early adolescence, such that prevention is associated with the largest health benefit at population-level

  12. Genomes2Drugs: identifies target proteins and lead drugs from proteome data.

    LENUS (Irish Health Repository)

    Toomey, David

    2009-01-01

    BACKGROUND: Genome sequencing and bioinformatics have provided the full hypothetical proteome of many pathogenic organisms. Advances in microarray and mass spectrometry have also yielded large output datasets of possible target proteins\\/genes. However, the challenge remains to identify new targets for drug discovery from this wealth of information. Further analysis includes bioinformatics and\\/or molecular biology tools to validate the findings. This is time consuming and expensive, and could fail to yield novel drugs if protein purification and crystallography is impossible. To pre-empt this, a researcher may want to rapidly filter the output datasets for proteins that show good homology to proteins that have already been structurally characterised or proteins that are already targets for known drugs. Critically, those researchers developing novel antibiotics need to select out the proteins that show close homology to any human proteins, as future inhibitors are likely to cross-react with the host protein, causing off-target toxicity effects later in clinical trials. METHODOLOGY\\/PRINCIPAL FINDINGS: To solve many of these issues, we have developed a free online resource called Genomes2Drugs which ranks sequences to identify proteins that are (i) homologous to previously crystallized proteins or (ii) targets of known drugs, but are (iii) not homologous to human proteins. When tested using the Plasmodium falciparum malarial genome the program correctly enriched the ranked list of proteins with known drug target proteins. CONCLUSIONS\\/SIGNIFICANCE: Genomes2Drugs rapidly identifies proteins that are likely to succeed in drug discovery pipelines. This free online resource helps in the identification of potential drug targets. Importantly, the program further highlights proteins that are likely to be inhibited by FDA-approved drugs. These drugs can then be rapidly moved into Phase IV clinical studies under \\'change-of-application\\' patents.

  13. Genomes2Drugs: identifies target proteins and lead drugs from proteome data.

    Directory of Open Access Journals (Sweden)

    David Toomey

    Full Text Available BACKGROUND: Genome sequencing and bioinformatics have provided the full hypothetical proteome of many pathogenic organisms. Advances in microarray and mass spectrometry have also yielded large output datasets of possible target proteins/genes. However, the challenge remains to identify new targets for drug discovery from this wealth of information. Further analysis includes bioinformatics and/or molecular biology tools to validate the findings. This is time consuming and expensive, and could fail to yield novel drugs if protein purification and crystallography is impossible. To pre-empt this, a researcher may want to rapidly filter the output datasets for proteins that show good homology to proteins that have already been structurally characterised or proteins that are already targets for known drugs. Critically, those researchers developing novel antibiotics need to select out the proteins that show close homology to any human proteins, as future inhibitors are likely to cross-react with the host protein, causing off-target toxicity effects later in clinical trials. METHODOLOGY/PRINCIPAL FINDINGS: To solve many of these issues, we have developed a free online resource called Genomes2Drugs which ranks sequences to identify proteins that are (i homologous to previously crystallized proteins or (ii targets of known drugs, but are (iii not homologous to human proteins. When tested using the Plasmodium falciparum malarial genome the program correctly enriched the ranked list of proteins with known drug target proteins. CONCLUSIONS/SIGNIFICANCE: Genomes2Drugs rapidly identifies proteins that are likely to succeed in drug discovery pipelines. This free online resource helps in the identification of potential drug targets. Importantly, the program further highlights proteins that are likely to be inhibited by FDA-approved drugs. These drugs can then be rapidly moved into Phase IV clinical studies under 'change-of-application' patents.

  14. Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets

    Science.gov (United States)

    Karube, K; Enjuanes, A; Dlouhy, I; Jares, P; Martin-Garcia, D; Nadeu, F; Ordóñez, G R; Rovira, J; Clot, G; Royo, C; Navarro, A; Gonzalez-Farre, B; Vaghefi, A; Castellano, G; Rubio-Perez, C; Tamborero, D; Briones, J; Salar, A; Sancho, J M; Mercadal, S; Gonzalez-Barca, E; Escoda, L; Miyoshi, H; Ohshima, K; Miyawaki, K; Kato, K; Akashi, K; Mozos, A; Colomo, L; Alcoceba, M; Valera, A; Carrió, A; Costa, D; Lopez-Bigas, N; Schmitz, R; Staudt, L M; Salaverria, I; López-Guillermo, A; Campo, E

    2018-01-01

    Genome studies of diffuse large B-cell lymphoma (DLBCL) have revealed a large number of somatic mutations and structural alterations. However, the clinical significance of these alterations is still not well defined. In this study, we have integrated the analysis of targeted next-generation sequencing of 106 genes and genomic copy number alterations (CNA) in 150 DLBCL. The clinically significant findings were validated in an independent cohort of 111 patients. Germinal center B-cell and activated B-cell DLBCL had a differential profile of mutations, altered pathogenic pathways and CNA. Mutations in genes of the NOTCH pathway and tumor suppressor genes (TP53/CDKN2A), but not individual genes, conferred an unfavorable prognosis, confirmed in the independent validation cohort. A gene expression profiling analysis showed that tumors with NOTCH pathway mutations had a significant modulation of downstream target genes, emphasizing the relevance of this pathway in DLBCL. An in silico drug discovery analysis recognized 69 (46%) cases carrying at least one genomic alteration considered a potential target of drug response according to early clinical trials or preclinical assays in DLBCL or other lymphomas. In conclusion, this study identifies relevant pathways and mutated genes in DLBCL and recognizes potential targets for new intervention strategies. PMID:28804123

  15. What works with men? A systematic review of health promoting interventions targeting men

    Directory of Open Access Journals (Sweden)

    Reid Garth

    2008-07-01

    Full Text Available Abstract Background Encouraging men to make more effective use of (preventive health services is considered one way of improving their health. The aim of this study was to appraise the available evidence of effective interventions aimed at improving men's health. Methods Systematic review of relevant studies identified through 14 electronic databases and other information resources. Results were pooled within health topic and described qualitatively. Results Of 11,749 citations screened, 338 articles were assessed and 27 met our inclusion criteria. Most studies were male sex-specific, i.e. prostate cancer screening and testicular self-examination. Other topics included alcohol, cardiovascular disease, diet and physical activity, skin cancer and smoking cessation. Twenty-three interventions were effective or partially effective and 18 studies satisfied all quality criteria. Conclusion Most of the existing evidence relates to male sex-specific health problems as opposed to general health concerns relevant to both men and women. There is little published evidence on how to improve men's uptake of services. We cannot conclude from this review that targeting men works better than providing services for all people. Large-scale studies are required to help produce evidence that is sufficiently robust to add to the small evidence base that currently exists in this field.

  16. Head-and-Neck Target Delineation Among Radiation Oncology Residents After a Teaching Intervention: A Prospective, Blinded Pilot Study

    International Nuclear Information System (INIS)

    Bekelman, Justin E.; Wolden, Suzanne; Lee, Nancy

    2009-01-01

    Purpose: We conducted this study to determine the feasibility of incorporating a teaching intervention on target delineation into the educational curriculum of a radiation oncology residency program and to assess the short-term effects on resident skills. Methods and Materials: The study schema consisted of a baseline evaluation, the teaching intervention, and a follow-up evaluation. At the baseline evaluation, the participants contoured three clinical tumor volumes (CTVs) (70 Gy, 59.4 Gy, and 54 Gy) on six contrast-enhanced axial computed tomography images of a de-identified patient with Stage T2N2bM0 squamous cell carcinoma of the right base of the tongue. The participants attended a series of head-and-neck oncology and anatomy seminars. The teaching intervention consisted of a didactic lecture and an interactive hands-on practical session designed to improve the knowledge and skills for target delineation in the head and neck. At the follow-up evaluation, the residents again contoured the CTVs. Results: Of the 14 eligible residents, 11 (79%) actually participated in the study. For all participants, but especially for those who had not had previous experience with head-and-neck target delineation, the teaching intervention was associated with improvement in the delineation of the node-negative neck (CTV 54 Gy contour). Regardless of clinical experience, participants had difficulty determining what should be included in the CTV 59.4 Gy contour to ensure adequate coverage of potential microscopic disease. Conclusion: Incorporating a teaching intervention into the education curriculum of a radiation oncology residency program is feasible and was associated with short-term improvements in target delineation skills. Subsequent interventions will require content refinement, additional validation, longer term follow-up, and multi-institutional collaboration

  17. Identifying quality improvement intervention publications - A comparison of electronic search strategies

    Directory of Open Access Journals (Sweden)

    Rubenstein Lisa V

    2011-08-01

    Full Text Available Abstract Background The evidence base for quality improvement (QI interventions is expanding rapidly. The diversity of the initiatives and the inconsistency in labeling these as QI interventions makes it challenging for researchers, policymakers, and QI practitioners to access the literature systematically and to identify relevant publications. Methods We evaluated search strategies developed for MEDLINE (Ovid and PubMed based on free text words, Medical subject headings (MeSH, QI intervention components, continuous quality improvement (CQI methods, and combinations of the strategies. Three sets of pertinent QI intervention publications were used for validation. Two independent expert reviewers screened publications for relevance. We compared the yield, recall rate, and precision of the search strategies for the identification of QI publications and for a subset of empirical studies on effects of QI interventions. Results The search yields ranged from 2,221 to 216,167 publications. Mean recall rates for reference publications ranged from 5% to 53% for strategies with yields of 50,000 publications or fewer. The 'best case' strategy, a simple text word search with high face validity ('quality' AND 'improv*' AND 'intervention*' identified 44%, 24%, and 62% of influential intervention articles selected by Agency for Healthcare Research and Quality (AHRQ experts, a set of exemplar articles provided by members of the Standards for Quality Improvement Reporting Excellence (SQUIRE group, and a sample from the Cochrane Effective Practice and Organization of Care Group (EPOC register of studies, respectively. We applied the search strategy to a PubMed search for articles published in 10 pertinent journals in a three-year period which retrieved 183 publications. Among these, 67% were deemed relevant to QI by at least one of two independent raters. Forty percent were classified as empirical studies reporting on a QI intervention. Conclusions The presented

  18. Direct molecular targets of resveratrol: identifying key interactions to unlock complex mechanisms.

    Science.gov (United States)

    Britton, Robert G; Kovoor, Christina; Brown, Karen

    2015-08-01

    To truly understand the mechanisms through which resveratrol exerts its biological effects, the key direct interactions between resveratrol and its target biomolecules must be identified. With an increasing number of biochemical tools to measure and quantify direct physical interactions between biomolecules, there have been around 20 proteins identified as having a specific affinity to resveratrol to date. Resveratrol has been described as a promiscuous molecule, and one would expect it to bind with numerous proteins, which would help explain why resveratrol appears to have so many health benefits and has been shown to act upon various different pathways related to a diverse range of conditions. The aim of this review is to present the direct protein targets of resveratrol that are currently known and highlight the consequences of direct binding and the methods used to identify the nature of these interactions. © 2015 New York Academy of Sciences.

  19. Identifying Family-Member-Specific Targets of Mono-ARTDs by Using a Chemical Genetics Approach.

    Science.gov (United States)

    Carter-O'Connell, Ian; Jin, Haihong; Morgan, Rory K; Zaja, Roko; David, Larry L; Ahel, Ivan; Cohen, Michael S

    2016-01-26

    ADP-ribosyltransferases (ARTD1-16) have emerged as major downstream effectors of NAD(+) signaling in the cell. Most ARTDs (ARTD7 and 8, 10-12, and 14-17) catalyze the transfer of a single unit of ADP-ribose from NAD(+) to target proteins, a process known as mono-ADP-ribosylation (MARylation). Progress in understanding the cellular functions of MARylation has been limited by the inability to identify the direct targets for individual mono-ARTDs. Here, we engineered mono-ARTDs to use an NAD(+) analog that is orthogonal to wild-type ARTDs. We profiled the MARylomes of ARTD10 and ARTD11 in vitro, identifying isoform-specific targets and revealing a potential role for ARTD11 in nuclear pore complex biology. We found that ARTD11 targeting is dependent on both its regulatory and catalytic domains, which has important implications for how ARTDs recognize their targets. We anticipate that our chemical genetic strategy will be generalizable to all mono-ARTD family members based on the similarity of the mono-ARTD catalytic domains. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Identifying Family-Member-Specific Targets of Mono-ARTDs by Using a Chemical Genetics Approach

    Directory of Open Access Journals (Sweden)

    Ian Carter-O’Connell

    2016-01-01

    Full Text Available ADP-ribosyltransferases (ARTD1–16 have emerged as major downstream effectors of NAD+ signaling in the cell. Most ARTDs (ARTD7 and 8, 10–12, and 14–17 catalyze the transfer of a single unit of ADP-ribose from NAD+ to target proteins, a process known as mono-ADP-ribosylation (MARylation. Progress in understanding the cellular functions of MARylation has been limited by the inability to identify the direct targets for individual mono-ARTDs. Here, we engineered mono-ARTDs to use an NAD+ analog that is orthogonal to wild-type ARTDs. We profiled the MARylomes of ARTD10 and ARTD11 in vitro, identifying isoform-specific targets and revealing a potential role for ARTD11 in nuclear pore complex biology. We found that ARTD11 targeting is dependent on both its regulatory and catalytic domains, which has important implications for how ARTDs recognize their targets. We anticipate that our chemical genetic strategy will be generalizable to all mono-ARTD family members based on the similarity of the mono-ARTD catalytic domains.

  1. Screening trematodes for novel intervention targets: a proteomic and immunological comparison of Schistosoma haematobium, Schistosoma bovis and Echinostoma caproni

    Science.gov (United States)

    HIGÓN, MELISSA; COWAN, GRAEME; NAUSCH, NORMAN; CAVANAGH, DAVID; OLEAGA, ANA; TOLEDO, RAFAEL; STOTHARD, J. RUSSELL; ANTÚNEZ, ORETO; MARCILLA, ANTONIO; BURCHMORE, RICHARD; MUTAPI, FRANCISCA

    2011-01-01

    SUMMARY With the current paucity of vaccine targets for parasitic diseases, particularly those in childhood, the aim of this study was to compare protein expression and immune cross-reactivity between the trematodes Schistosoma haematobium, S. bovis and Echinostoma caproni in the hope of identifying novel intervention targets. Native adult parasite proteins were separated by 2-dimensional gel electrophoresis and identified through electrospray ionisation tandem mass spectrometry to produce a reference gel. Proteins from differential gel electrophoresis analyses of the three parasite proteomes were compared and screened against sera from hamsters infected with S. haematobium and E. caproni following 2-dimensional Western blotting. Differential protein expression between the three species was observed with circa 5% of proteins from S. haematobium showing expression up-regulation compared to the other two species. There was 91% similarity between the proteomes of the two Schistosoma species and 81% and 78·6% similarity between S. haematobium and S. bovis versus E. caproni, respectively. Although there were some common cross-species antigens, species-species targets were revealed which, despite evolutionary homology, could be due to phenotypic plasticity arising from different host-parasite relationships. Nevertheless, this approach helps to identify novel intervention targets which could be used as broad-spectrum candidates for future use in human and veterinary vaccines. PMID:21729355

  2. Functional profiling of microtumors to identify cancer associated fibroblast-derived drug targets.

    Science.gov (United States)

    Horman, Shane R; To, Jeremy; Lamb, John; Zoll, Jocelyn H; Leonetti, Nicole; Tu, Buu; Moran, Rita; Newlin, Robbin; Walker, John R; Orth, Anthony P

    2017-11-21

    Recent advances in chemotherapeutics highlight the importance of molecularly-targeted perturbagens. Although these therapies typically address dysregulated cancer cell proteins, there are increasing therapeutic modalities that take into consideration cancer cell-extrinsic factors. Targeting components of tumor stroma such as vascular or immune cells has been shown to represent an efficacious approach in cancer treatment. Cancer-associated fibroblasts (CAFs) exemplify an important stromal component that can be exploited in targeted therapeutics, though their employment in drug discovery campaigns has been relatively minimal due to technical logistics in assaying for CAF-tumor interactions. Here we report a 3-dimensional multi-culture tumor:CAF spheroid phenotypic screening platform that can be applied to high-content drug discovery initiatives. Using a functional genomics approach we systematically profiled 1,024 candidate genes for CAF-intrinsic anti-spheroid activity; identifying several CAF genes important for development and maintenance of tumor:CAF co-culture spheroids. Along with previously reported genes such as WNT, we identify CAF-derived targets such as ARAF and COL3A1 upon which the tumor compartment depends for spheroid development. Specifically, we highlight the G-protein-coupled receptor OGR1 as a unique CAF-specific protein that may represent an attractive drug target for treating colorectal cancer. In vivo , murine colon tumor implants in OGR1 knockout mice displayed delayed tumor growth compared to tumors implanted in wild type littermate controls. These findings demonstrate a robust microphysiological screening approach for identifying new CAF targets that may be applied to drug discovery efforts.

  3. Identifying The Target Market For a New Floatation Therapy Service, Flowtion

    OpenAIRE

    Varpomaa, Jerry

    2016-01-01

    The purpose of this thesis was to probe and identify the most potential target market for a new kind of wellness-service for Flowtion, a state-of-the-art floatation therapy center, focusing on floatation tanks. To accomplish the main goal for this thesis, a survey was conducted using “Google Forms”. The survey was spread through social media (Facebook), and as a result 41 people answered. The survey helps Flowtion to define their most potential target segment, their behaviour and profile vari...

  4. Intervention modalities for targeting cognitive-motor interference in individuals with neurodegenerative disease: a systematic review.

    Science.gov (United States)

    Wajda, Douglas A; Mirelman, Anat; Hausdorff, Jeffrey M; Sosnoff, Jacob J

    2017-03-01

    Individuals with neurodegenerative disease (NDD) commonly have elevated cognitive-motor interference, change in either cognitive or motor performance (or both) when tasks are performed simultaneously, compared to healthy controls. Given that cognitive-motor interference is related to reduced community ambulation and elevated fall risk, it is a target of rehabilitation interventions. Areas covered: This review details the collective findings of previous dual task interventions in individuals with NDD. A total of 21 investigations focusing on 4 different neurodegenerative diseases and one NDD precursor (Parkinson's disease, multiple sclerosis, Alzheimer's disease (AD), dementia other than AD, and mild cognitive impairment) consisting of 721 participants were reviewed. Expert commentary: Preliminary evidence from interventions targeting cognitive-motor interference, both directly and indirectly, show promising results for improving CMI in individuals with neurodegenerative diseases. Methodological limitations, common to pilot investigations preclude firm conclusions. Well-designed randomized control trials targeting cognitive motor interference are warranted.

  5. Qualitative methods to ensure acceptability of behavioral and social interventions to the target population.

    Science.gov (United States)

    Ayala, Guadalupe X; Elder, John P

    2011-01-01

    This paper introduces qualitative methods for assessing the acceptability of an intervention. Acceptability refers to determining how well an intervention will be received by the target population and the extent to which the new intervention or its might meet the needs of the target population an d organizational setting. In this paper, we focus on two common qualitative methods for conducting acceptability research and their advantages and disadvantages: focus groups and interviews. We provide examples from our own research and other studies to demonstrate the use of these methods for conducting acceptability research and how one might adapt this approach for oral health research. We present emerging methods for conducting acceptability research, including the use of community-based participatory research, as well as the utility of conducting acceptability research for assessing the appropriateness of measures in intervention research.

  6. Evaluation of approaches to identify the targets of cellular immunity on a proteome-wide scale.

    Directory of Open Access Journals (Sweden)

    Fernanda C Cardoso

    Full Text Available BACKGROUND: Vaccine development against malaria and other complex diseases remains a challenge for the scientific community. The recent elucidation of the genome, proteome and transcriptome of many of these complex pathogens provides the basis for rational vaccine design by identifying, on a proteome-wide scale, novel target antigens that are recognized by T cells and antibodies from exposed individuals. However, there is currently no algorithm to effectively identify important target antigens from genome sequence data; this is especially challenging for T cell targets. Furthermore, for some of these pathogens, such as Plasmodium, protein expression using conventional platforms has been problematic but cell-free in vitro transcription translation (IVTT strategies have recently proved successful. Herein, we report a novel approach for proteome-wide scale identification of the antigenic targets of T cell responses using IVTT products. PRINCIPAL FINDINGS: We conducted a series of in vitro and in vivo experiments using IVTT proteins either unpurified, absorbed to carboxylated polybeads, or affinity purified through nickel resin or magnetic beads. In vitro studies in humans using CMV, EBV, and Influenza A virus proteins showed antigen-specific cytokine production in ELIspot and Cytometric Bead Array assays with cells stimulated with purified or unpurified IVTT antigens. In vitro and in vivo studies in mice immunized with the Plasmodium yoelii circumsporozoite DNA vaccine with or without IVTT protein boost showed antigen-specific cytokine production using purified IVTT antigens only. Overall, the nickel resin method of IVTT antigen purification proved optimal in both human and murine systems. CONCLUSIONS: This work provides proof of concept for the potential of high-throughput approaches to identify T cell targets of complex parasitic, viral or bacterial pathogens from genomic sequence data, for rational vaccine development against emerging and re

  7. Targeted parallel sequencing of large genetically-defined genomic regions for identifying mutations in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Liu Kun-hsiang

    2012-03-01

    Full Text Available Abstract Large-scale genetic screens in Arabidopsis are a powerful approach for molecular dissection of complex signaling networks. However, map-based cloning can be time-consuming or even hampered due to low chromosomal recombination. Current strategies using next generation sequencing for molecular identification of mutations require whole genome sequencing and advanced computational devises and skills, which are not readily accessible or affordable to every laboratory. We have developed a streamlined method using parallel massive sequencing for mutant identification in which only targeted regions are sequenced. This targeted parallel sequencing (TPSeq method is more cost-effective, straightforward enough to be easily done without specialized bioinformatics expertise, and reliable for identifying multiple mutations simultaneously. Here, we demonstrate its use by identifying three novel nitrate-signaling mutants in Arabidopsis.

  8. Secreted Frizzled-related protein 2 as a target in antifibrotic therapeutic intervention.

    Science.gov (United States)

    Mastri, Michalis; Shah, Zaeem; Hsieh, Karin; Wang, Xiaowen; Wooldridge, Bailey; Martin, Sean; Suzuki, Gen; Lee, Techung

    2014-03-15

    Progressive fibrosis is a pathological hallmark of many chronic diseases responsible for organ failure. Although there is currently no therapy on the market that specifically targets fibrosis, the dynamic fibrogenic process is known to be regulated by multiple soluble mediators that may be therapeutically intervened. The failing hamster heart exhibits marked fibrosis and increased expression of secreted Frizzled-related protein 2 (sFRP2) amenable to reversal by mesenchymal stem cell (MSC) therapy. Given the previous demonstration that sFRP2-null mice subjected to myocardial infarction exhibited reduced fibrosis and improved function, we tested whether antibody-based sFRP2 blockade might counteract the fibrogenic pathway and repair cardiac injury. Cardiomyopathic hamsters were injected intraperitoneally twice a week each with 20 μg of sFRP2 antibody. Echocardiography, histology, and biochemical analyses were performed after 1 mo. sFRP2 antibody increased left ventricular ejection fraction from 40 ± 1.2 to 49 ± 6.5%, whereas saline and IgG control exhibited a further decline to 37 ± 0.9 and 31 ± 3.2%, respectively. Functional improvement is associated with a ∼ 50% reduction in myocardial fibrosis, ∼ 65% decrease in apoptosis, and ∼ 75% increase in wall thickness. Consistent with attenuated fibrosis, both MSC therapy and sFRP2 antibody administration significantly increased the activity of myocardial matrix metalloproteinase-2. Gene expression analysis of the hamster heart and cultured fibroblasts identified Axin2 as a downstream target, the expression of which was activated by sFRP2 but inhibited by therapeutic intervention. sFRP2 blockade also increased myocardial levels of VEGF and hepatocyte growth factor (HGF) along with increased angiogenesis. These findings highlight the pathogenic effect of dysregulated sFRP2, which may be specifically targeted for antifibrotic therapy.

  9. Targeted and Untargeted Metabolic Profiling of Wild Grassland Plants identifies Antibiotic and Anthelmintic Compounds Targeting Pathogen Physiology, Metabolism and Reproduction.

    Science.gov (United States)

    French, Katherine E; Harvey, Joe; McCullagh, James S O

    2018-01-26

    Plants traditionally used by farmers to manage livestock ailments could reduce reliance on synthetic antibiotics and anthelmintics but in many cases their chemical composition is unknown. As a case study, we analyzed the metabolite profiles of 17 plant species and 45 biomass samples from agricultural grasslands in England using targeted and untargeted metabolite profiling by liquid-chromatography mass spectrometry. We identified a range of plant secondary metabolites, including 32 compounds with known antimicrobial/anthelmintic properties which varied considerably across the different plant samples. These compounds have been shown previously to target multiple aspects of pathogen physiology and metabolism in vitro and in vivo, including inhibition of quorum sensing in bacteria and egg viability in nematodes. The most abundant bioactive compounds were benzoic acid, myricetin, p-coumaric acid, rhamnetin, and rosmarinic acid. Four wild plants (Filipendula ulmaria (L.) Maxim., Prunella vulgaris L., Centuarea nigra L., and Rhinanthus minor L.) and two forage legumes (Medicago sativa L., Trifolium hybridium L.) contained high levels of these compounds. Forage samples from native high-diversity grasslands had a greater abundance of medicinal compounds than samples from agriculturally improved grasslands. Incorporating plants with antibiotic/anthelmintic compounds into livestock feeds may reduce global drug-resistance and preserve the efficacy of last-resort drugs.

  10. A target based approach identifies genomic predictors of breast cancer patient response to chemotherapy

    Directory of Open Access Journals (Sweden)

    Hallett Robin M

    2012-05-01

    Full Text Available Abstract Background The efficacy of chemotherapy regimens in breast cancer patients is variable and unpredictable. Whether individual patients either achieve long-term remission or suffer recurrence after therapy may be dictated by intrinsic properties of their breast tumors including genetic lesions and consequent aberrant transcriptional programs. Global gene expression profiling provides a powerful tool to identify such tumor-intrinsic transcriptional programs, whose analyses provide insight into the underlying biology of individual patient tumors. For example, multi-gene expression signatures have been identified that can predict the likelihood of disease reccurrence, and thus guide patient prognosis. Whereas such prognostic signatures are being introduced in the clinical setting, similar signatures that predict sensitivity or resistance to chemotherapy are not currently clinically available. Methods We used gene expression profiling to identify genes that were co-expressed with genes whose transcripts encode the protein targets of commonly used chemotherapeutic agents. Results Here, we present target based expression indices that predict breast tumor response to anthracycline and taxane based chemotherapy. Indeed, these signatures were independently predictive of chemotherapy response after adjusting for standard clinic-pathological variables such as age, grade, and estrogen receptor status in a cohort of 488 breast cancer patients treated with adriamycin and taxotere/taxol. Conclusions Importantly, our findings suggest the practicality of developing target based indices that predict response to therapeutics, as well as highlight the possibility of using gene signatures to guide the use of chemotherapy during treatment of breast cancer patients.

  11. A semantic problem solving environment for integrative parasite research: identification of intervention targets for Trypanosoma cruzi.

    Directory of Open Access Journals (Sweden)

    Priti P Parikh

    2012-01-01

    Full Text Available Research on the biology of parasites requires a sophisticated and integrated computational platform to query and analyze large volumes of data, representing both unpublished (internal and public (external data sources. Effective analysis of an integrated data resource using knowledge discovery tools would significantly aid biologists in conducting their research, for example, through identifying various intervention targets in parasites and in deciding the future direction of ongoing as well as planned projects. A key challenge in achieving this objective is the heterogeneity between the internal lab data, usually stored as flat files, Excel spreadsheets or custom-built databases, and the external databases. Reconciling the different forms of heterogeneity and effectively integrating data from disparate sources is a nontrivial task for biologists and requires a dedicated informatics infrastructure. Thus, we developed an integrated environment using Semantic Web technologies that may provide biologists the tools for managing and analyzing their data, without the need for acquiring in-depth computer science knowledge.We developed a semantic problem-solving environment (SPSE that uses ontologies to integrate internal lab data with external resources in a Parasite Knowledge Base (PKB, which has the ability to query across these resources in a unified manner. The SPSE includes Web Ontology Language (OWL-based ontologies, experimental data with its provenance information represented using the Resource Description Format (RDF, and a visual querying tool, Cuebee, that features integrated use of Web services. We demonstrate the use and benefit of SPSE using example queries for identifying gene knockout targets of Trypanosoma cruzi for vaccine development. Answers to these queries involve looking up multiple sources of data, linking them together and presenting the results.The SPSE facilitates parasitologists in leveraging the growing, but disparate

  12. Dengue vector management using insecticide treated materials and targeted interventions on productive breeding-sites in Guatemala

    Directory of Open Access Journals (Sweden)

    Rizzo Nidia

    2012-10-01

    Full Text Available Abstract Background In view of the epidemiological expansion of dengue worldwide and the availability of new tools and strategies particularly for controlling the primary dengue vector Aedes aegypti, an intervention study was set up to test the efficacy, cost and feasibility of a combined approach of insecticide treated materials (ITMs alone and in combination with appropriate targeted interventions of the most productive vector breeding-sites. Methods The study was conducted as a cluster randomized community trial using “reduction of the vector population” as the main outcome variable. The trial had two arms: 10 intervention clusters (neighborhoods and 10 control clusters in the town of Poptun Guatemala. Activities included entomological assessments (characteristics of breeding-sites, pupal productivity, Stegomyia indices at baseline, 6 weeks after the first intervention (coverage of window and exterior doorways made of PermaNet 2.0 netting, factory treated with deltamethrin at 55 mg/m2, and of 200 L drums with similar treated material and 6 weeks after the second intervention (combination of treated materials and other suitable interventions targeting productive breeding-sites i.e larviciding with Temephos, elimination etc.. The second intervention took place 17 months after the first intervention. The insecticide residual activity and the insecticidal content were also studied at different intervals. Additionally, information about demographic characteristics, cost of the intervention, coverage of houses protected and satisfaction in the population with the interventions was collected. Results At baseline (during the dry season a variety of productive container types for Aedes pupae were identified: various container types holding >20 L, 200 L drums, washbasins and buckets (producing 83.7% of all pupae. After covering 100% of windows and exterior doorways and a small number of drums (where the commercial cover could be fixed in 970 study

  13. Dengue vector management using insecticide treated materials and targeted interventions on productive breeding-sites in Guatemala.

    Science.gov (United States)

    Rizzo, Nidia; Gramajo, Rodrigo; Escobar, Maria Cabrera; Arana, Byron; Kroeger, Axel; Manrique-Saide, Pablo; Petzold, Max

    2012-10-30

    In view of the epidemiological expansion of dengue worldwide and the availability of new tools and strategies particularly for controlling the primary dengue vector Aedes aegypti, an intervention study was set up to test the efficacy, cost and feasibility of a combined approach of insecticide treated materials (ITMs) alone and in combination with appropriate targeted interventions of the most productive vector breeding-sites. The study was conducted as a cluster randomized community trial using "reduction of the vector population" as the main outcome variable. The trial had two arms: 10 intervention clusters (neighborhoods) and 10 control clusters in the town of Poptun Guatemala. Activities included entomological assessments (characteristics of breeding-sites, pupal productivity, Stegomyia indices) at baseline, 6 weeks after the first intervention (coverage of window and exterior doorways made of PermaNet 2.0 netting, factory treated with deltamethrin at 55 mg/m2, and of 200 L drums with similar treated material) and 6 weeks after the second intervention (combination of treated materials and other suitable interventions targeting productive breeding-sites i.e larviciding with Temephos, elimination etc.). The second intervention took place 17 months after the first intervention. The insecticide residual activity and the insecticidal content were also studied at different intervals. Additionally, information about demographic characteristics, cost of the intervention, coverage of houses protected and satisfaction in the population with the interventions was collected. At baseline (during the dry season) a variety of productive container types for Aedes pupae were identified: various container types holding >20 L, 200 L drums, washbasins and buckets (producing 83.7% of all pupae). After covering 100% of windows and exterior doorways and a small number of drums (where the commercial cover could be fixed) in 970 study households, tropical rains occurred in the area and

  14. Comparing methods of targeting obesity interventions in populations: An agent-based simulation.

    Science.gov (United States)

    Beheshti, Rahmatollah; Jalalpour, Mehdi; Glass, Thomas A

    2017-12-01

    Social networks as well as neighborhood environments have been shown to effect obesity-related behaviors including energy intake and physical activity. Accordingly, harnessing social networks to improve targeting of obesity interventions may be promising to the extent this leads to social multiplier effects and wider diffusion of intervention impact on populations. However, the literature evaluating network-based interventions has been inconsistent. Computational methods like agent-based models (ABM) provide researchers with tools to experiment in a simulated environment. We develop an ABM to compare conventional targeting methods (random selection, based on individual obesity risk, and vulnerable areas) with network-based targeting methods. We adapt a previously published and validated model of network diffusion of obesity-related behavior. We then build social networks among agents using a more realistic approach. We calibrate our model first against national-level data. Our results show that network-based targeting may lead to greater population impact. We also present a new targeting method that outperforms other methods in terms of intervention effectiveness at the population level.

  15. Posture and Locomotion Coupling: A Target for Rehabilitation Interventions in Persons with Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Marie-Laure Mille

    2012-01-01

    Full Text Available Disorders of posture, balance, and gait are debilitating motor manifestations of advancing Parkinson's disease requiring rehabilitation intervention. These problems often reflect difficulties with coupling or sequencing posture and locomotion during complex whole body movements linked with falls. Considerable progress has been made with demonstrating the effectiveness of exercise interventions for individuals with Parkinson's disease. However, gaps remain in the evidence base for specific interventions and the optimal content of exercise interventions. Using a conceptual theoretical framework and experimental findings, this perspective and review advances the viewpoint that rehabilitation interventions focused on separate or isolated components of posture, balance, or gait may limit the effectiveness of current clinical practices. It is argued that treatment effectiveness may be improved by directly targeting posture and locomotion coupling problems as causal factors contributing to balance and gait dysfunction. This approach may help advance current clinical practice and improve outcomes in rehabilitation for persons with Parkinson's disease.

  16. In silico mining identifies IGFBP3 as a novel target of methylation in prostate cancer.

    LENUS (Irish Health Repository)

    Perry, A S

    2007-05-21

    Promoter hypermethylation is central in deregulating gene expression in cancer. Identification of novel methylation targets in specific cancers provides a basis for their use as biomarkers of disease occurrence and progression. We developed an in silico strategy to globally identify potential targets of promoter hypermethylation in prostate cancer by screening for 5\\' CpG islands in 631 genes that were reported as downregulated in prostate cancer. A virtual archive of 338 potential targets of methylation was produced. One candidate, IGFBP3, was selected for investigation, along with glutathione-S-transferase pi (GSTP1), a well-known methylation target in prostate cancer. Methylation of IGFBP3 was detected by quantitative methylation-specific PCR in 49\\/79 primary prostate adenocarcinoma and 7\\/14 adjacent preinvasive high-grade prostatic intraepithelial neoplasia, but in only 5\\/37 benign prostatic hyperplasia (P < 0.0001) and in 0\\/39 histologically normal adjacent prostate tissue, which implies that methylation of IGFBP3 may be involved in the early stages of prostate cancer development. Hypermethylation of IGFBP3 was only detected in samples that also demonstrated methylation of GSTP1 and was also correlated with Gleason score > or =7 (P=0.01), indicating that it has potential as a prognostic marker. In addition, pharmacological demethylation induced strong expression of IGFBP3 in LNCaP prostate cancer cells. Our concept of a methylation candidate gene bank was successful in identifying a novel target of frequent hypermethylation in early-stage prostate cancer. Evaluation of further relevant genes could contribute towards a methylation signature of this disease.

  17. Novel modeling of combinatorial miRNA targeting identifies SNP with potential role in bone density.

    Directory of Open Access Journals (Sweden)

    Claudia Coronnello

    Full Text Available MicroRNAs (miRNAs are post-transcriptional regulators that bind to their target mRNAs through base complementarity. Predicting miRNA targets is a challenging task and various studies showed that existing algorithms suffer from high number of false predictions and low to moderate overlap in their predictions. Until recently, very few algorithms considered the dynamic nature of the interactions, including the effect of less specific interactions, the miRNA expression level, and the effect of combinatorial miRNA binding. Addressing these issues can result in a more accurate miRNA:mRNA modeling with many applications, including efficient miRNA-related SNP evaluation. We present a novel thermodynamic model based on the Fermi-Dirac equation that incorporates miRNA expression in the prediction of target occupancy and we show that it improves the performance of two popular single miRNA target finders. Modeling combinatorial miRNA targeting is a natural extension of this model. Two other algorithms show improved prediction efficiency when combinatorial binding models were considered. ComiR (Combinatorial miRNA targeting, a novel algorithm we developed, incorporates the improved predictions of the four target finders into a single probabilistic score using ensemble learning. Combining target scores of multiple miRNAs using ComiR improves predictions over the naïve method for target combination. ComiR scoring scheme can be used for identification of SNPs affecting miRNA binding. As proof of principle, ComiR identified rs17737058 as disruptive to the miR-488-5p:NCOA1 interaction, which we confirmed in vitro. We also found rs17737058 to be significantly associated with decreased bone mineral density (BMD in two independent cohorts indicating that the miR-488-5p/NCOA1 regulatory axis is likely critical in maintaining BMD in women. With increasing availability of comprehensive high-throughput datasets from patients ComiR is expected to become an essential

  18. Early detection of malaria foci for targeted interventions in endemic southern Zambia

    Directory of Open Access Journals (Sweden)

    Chime Nnenna

    2011-09-01

    Full Text Available Abstract Background Zambia has achieved significant reductions in the burden of malaria through a strategy of "scaling-up" effective interventions. Progress toward ultimate malaria elimination will require sustained prevention coverage and further interruption of transmission through active strategies to identify and treat asymptomatic malaria reservoirs. A surveillance system in Zambia's Southern Province has begun to implement such an approach. An early detection system could be an additional tool to identify foci of elevated incidence for targeted intervention. Methods Based on surveillance data collected weekly from 13 rural health centres (RHCs divided into three transmission zones, early warning thresholds were created following a technique successfully implemented in Thailand. Alert levels were graphed for all 52 weeks of a year using the mean and 95% confidence interval upper limit of a Poisson distribution of the weekly diagnosed malaria cases for every available week of historic data (beginning in Aug, 2008 at each of the sites within a zone. Annually adjusted population estimates for the RHC catchment areas served as person-time of weekly exposure. The zonal threshold levels were validated against the incidence data from each of the 13 respective RHCs. Results Graphed threshold levels for the three zones generally conformed to observed seasonal incidence patterns. Comparing thresholds with historic weekly incidence values, the overall percentage of aberrant weeks ranged from 1.7% in Mbabala to 36.1% in Kamwanu. For most RHCs, the percentage of weeks above threshold was greater during the high transmission season and during the 2009 year compared to 2010. 39% of weeks breaching alert levels were part of a series of three or more consecutive aberrant weeks. Conclusions The inconsistent sensitivity of the zonal threshold levels impugns the reliability of the alert system. With more years of surveillance data available, individual

  19. Vitiligo blood transcriptomics provides new insights into disease mechanisms and identifies potential novel therapeutic targets.

    Science.gov (United States)

    Dey-Rao, Rama; Sinha, Animesh A

    2017-01-28

    Significant gaps remain regarding the pathomechanisms underlying the autoimmune response in vitiligo (VL), where the loss of self-tolerance leads to the targeted killing of melanocytes. Specifically, there is incomplete information regarding alterations in the systemic environment that are relevant to the disease state. We undertook a genome-wide profiling approach to examine gene expression in the peripheral blood of VL patients and healthy controls in the context of our previously published VL-skin gene expression profile. We used several in silico bioinformatics-based analyses to provide new insights into disease mechanisms and suggest novel targets for future therapy. Unsupervised clustering methods of the VL-blood dataset demonstrate a "disease-state"-specific set of co-expressed genes. Ontology enrichment analysis of 99 differentially expressed genes (DEGs) uncovers a down-regulated immune/inflammatory response, B-Cell antigen receptor (BCR) pathways, apoptosis and catabolic processes in VL-blood. There is evidence for both type I and II interferon (IFN) playing a role in VL pathogenesis. We used interactome analysis to identify several key blood associated transcriptional factors (TFs) from within (STAT1, STAT6 and NF-kB), as well as "hidden" (CREB1, MYC, IRF4, IRF1, and TP53) from the dataset that potentially affect disease pathogenesis. The TFs overlap with our reported lesional-skin transcriptional circuitry, underscoring their potential importance to the disease. We also identify a shared VL-blood and -skin transcriptional "hot spot" that maps to chromosome 6, and includes three VL-blood dysregulated genes (PSMB8, PSMB9 and TAP1) described as potential VL-associated genetic susceptibility loci. Finally, we provide bioinformatics-based support for prioritizing dysregulated genes in VL-blood or skin as potential therapeutic targets. We examined the VL-blood transcriptome in context with our (previously published) VL-skin transcriptional profile to address

  20. Transcript profiling of Elf5+/- mammary glands during pregnancy identifies novel targets of Elf5.

    Directory of Open Access Journals (Sweden)

    Renee L Rogers

    Full Text Available BACKGROUND: Elf5, an epithelial specific Ets transcription factor, plays a crucial role in the pregnancy-associated development of the mouse mammary gland. Elf5(-/- embryos do not survive, however the Elf5(+/- mammary gland displays a severe pregnancy-associated developmental defect. While it is known that Elf5 is crucial for correct mammary development and lactation, the molecular mechanisms employed by Elf5 to exert its effects on the mammary gland are largely unknown. PRINCIPAL FINDINGS: Transcript profiling was used to investigate the transcriptional changes that occur as a result of Elf5 haploinsufficiency in the Elf5(+/- mouse model. We show that the development of the mouse Elf5(+/- mammary gland is delayed at a transcriptional and morphological level, due to the delayed increase in Elf5 protein in these glands. We also identify a number of potential Elf5 target genes, including Mucin 4, whose expression, is directly regulated by the binding of Elf5 to an Ets binding site within its promoter. CONCLUSION: We identify novel transcriptional targets of Elf5 and show that Muc4 is a direct target of Elf5, further elucidating the mechanisms through which Elf5 regulates proliferation and differentiation in the mammary gland.

  1. Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms.

    Science.gov (United States)

    Allen, Mary Ann; Andrysik, Zdenek; Dengler, Veronica L; Mellert, Hestia S; Guarnieri, Anna; Freeman, Justin A; Sullivan, Kelly D; Galbraith, Matthew D; Luo, Xin; Kraus, W Lee; Dowell, Robin D; Espinosa, Joaquin M

    2014-05-27

    The p53 transcription factor is a potent suppressor of tumor growth. We report here an analysis of its direct transcriptional program using Global Run-On sequencing (GRO-seq). Shortly after MDM2 inhibition by Nutlin-3, low levels of p53 rapidly activate ∼200 genes, most of them not previously established as direct targets. This immediate response involves all canonical p53 effector pathways, including apoptosis. Comparative global analysis of RNA synthesis vs steady state levels revealed that microarray profiling fails to identify low abundance transcripts directly activated by p53. Interestingly, p53 represses a subset of its activation targets before MDM2 inhibition. GRO-seq uncovered a plethora of gene-specific regulatory features affecting key survival and apoptotic genes within the p53 network. p53 regulates hundreds of enhancer-derived RNAs. Strikingly, direct p53 targets harbor pre-activated enhancers highly transcribed in p53 null cells. Altogether, these results enable the study of many uncharacterized p53 target genes and unexpected regulatory mechanisms.DOI: http://dx.doi.org/10.7554/eLife.02200.001. Copyright © 2014, Allen et al.

  2. Using Copy Number Alterations to Identify New Therapeutic Targets for Bladder Carcinoma

    Directory of Open Access Journals (Sweden)

    Donatella Conconi

    2016-02-01

    Full Text Available Bladder cancer represents the ninth most widespread malignancy throughout the world. It is characterized by the presence of two different clinical and prognostic subtypes: non-muscle-invasive bladder cancers (NMIBCs and muscle-invasive bladder cancers (MIBCs. MIBCs have a poor outcome with a common progression to metastasis. Despite improvements in knowledge, treatment has not advanced significantly in recent years, with the absence of new therapeutic targets. Because of the limitations of current therapeutic options, the greater challenge will be to identify biomarkers for clinical application. For this reason, we compared our array comparative genomic hybridization (array-CGH results with those reported in literature for invasive bladder tumors and, in particular, we focused on the evaluation of copy number alterations (CNAs present in biopsies and retained in the corresponding cancer stem cell (CSC subpopulations that should be the main target of therapy. According to our data, CCNE1, MYC, MDM2 and PPARG genes could be interesting therapeutic targets for bladder CSC subpopulations. Surprisingly, HER2 copy number gains are not retained in bladder CSCs, making the gene-targeted therapy less interesting than the others. These results provide precious advice for further study on bladder therapy; however, the clinical importance of these results should be explored.

  3. Chemical Genetic Screens Identify Kinase Inhibitor Combinations that Target Anti-Apoptotic Proteins for Cancer Therapy.

    Science.gov (United States)

    Contreras, Jacob I; Robb, Caroline M; King, Hannah M; Baxter, Jared; Crawford, Ayrianne J; Kour, Smit; Kizhake, Smitha; Sonawane, Yogesh A; Rana, Sandeep; Hollingsworth, Michael A; Luo, Xu; Natarajan, Amarnath

    2018-04-05

    The study presented here provides a framework for the discovery of unique inhibitor combinations that target the apoptosis network for cancer therapy. A pair of doxycycline (Dox)-inducible cell lines that specifically report on the ability of an inhibitor to induce apoptosis by targeting either the Mcl-1 arm or the Bcl-2/Bcl-xL/Bcl-w arm were used. Cell-based assays were optimized for high throughput screening (HTS) with caspase 3/7 as a read out. HTS with a 355-member kinase inhibitor library and the panel of Dox-inducible cell lines revealed that cyclin dependent kinase (CDK) inhibitors induced apoptosis by targeting the Mcl-1 arm, whereas PI3K inhibitors induced apoptosis by targeting the Bcl-2/Bcl-xL/Bcl-w arm. Validation studies identified unique combinations that synergistically inhibited growth and induced apoptosis in a panel of cancer cell lines. Since these inhibitors have been or are currently in clinical trials as single agents, the combinations can be rapidly translated to the clinics.

  4. Omen: identifying potential spear-phishing targets before the email is sent.

    Energy Technology Data Exchange (ETDEWEB)

    Wendt, Jeremy Daniel.

    2013-07-01

    We present the results of a two year project focused on a common social engineering attack method called "spear phishing". In a spear phishing attack, the user receives an email with information specifically focused on the user. This email contains either a malware-laced attachment or a link to download the malware that has been disguised as a useful program. Spear phishing attacks have been one of the most effective avenues for attackers to gain initial entry into a target network. This project focused on a proactive approach to spear phishing. To create an effective, user-specific spear phishing email, the attacker must research the intended recipient. We believe that much of the information used by the attacker is provided by the target organization's own external website. Thus when researching potential targets, the attacker leaves signs of his research in the webserver's logs. We created tools and visualizations to improve cybersecurity analysts' abilities to quickly understand a visitor's visit patterns and interests. Given these suspicious visitors and log-parsing tools, analysts can more quickly identify truly suspicious visitors, search for potential spear-phishing targeted users, and improve security around those users before the spear phishing email is sent.

  5. A new method of identifying target groups for pronatalist policy applied to Australia.

    Directory of Open Access Journals (Sweden)

    Mengni Chen

    Full Text Available A country's total fertility rate (TFR depends on many factors. Attributing changes in TFR to changes of policy is difficult, as they could easily be correlated with changes in the unmeasured drivers of TFR. A case in point is Australia where both pronatalist effort and TFR increased in lock step from 2001 to 2008 and then decreased. The global financial crisis or other unobserved confounders might explain both the reducing TFR and pronatalist incentives after 2008. Therefore, it is difficult to estimate causal effects of policy using econometric techniques. The aim of this study is to instead look at the structure of the population to identify which subgroups most influence TFR. Specifically, we build a stochastic model relating TFR to the fertility rates of various subgroups and calculate elasticity of TFR with respect to each rate. For each subgroup, the ratio of its elasticity to its group size is used to evaluate the subgroup's potential cost effectiveness as a pronatalist target. In addition, we measure the historical stability of group fertility rates, which measures propensity to change. Groups with a high effectiveness ratio and also high propensity to change are natural policy targets. We applied this new method to Australian data on fertility rates broken down by parity, age and marital status. The results show that targeting parity 3+ is more cost-effective than lower parities. This study contributes to the literature on pronatalist policies by investigating the targeting of policies, and generates important implications for formulating cost-effective policies.

  6. A new method of identifying target groups for pronatalist policy applied to Australia.

    Science.gov (United States)

    Chen, Mengni; Lloyd, Chris J; Yip, Paul S F

    2018-01-01

    A country's total fertility rate (TFR) depends on many factors. Attributing changes in TFR to changes of policy is difficult, as they could easily be correlated with changes in the unmeasured drivers of TFR. A case in point is Australia where both pronatalist effort and TFR increased in lock step from 2001 to 2008 and then decreased. The global financial crisis or other unobserved confounders might explain both the reducing TFR and pronatalist incentives after 2008. Therefore, it is difficult to estimate causal effects of policy using econometric techniques. The aim of this study is to instead look at the structure of the population to identify which subgroups most influence TFR. Specifically, we build a stochastic model relating TFR to the fertility rates of various subgroups and calculate elasticity of TFR with respect to each rate. For each subgroup, the ratio of its elasticity to its group size is used to evaluate the subgroup's potential cost effectiveness as a pronatalist target. In addition, we measure the historical stability of group fertility rates, which measures propensity to change. Groups with a high effectiveness ratio and also high propensity to change are natural policy targets. We applied this new method to Australian data on fertility rates broken down by parity, age and marital status. The results show that targeting parity 3+ is more cost-effective than lower parities. This study contributes to the literature on pronatalist policies by investigating the targeting of policies, and generates important implications for formulating cost-effective policies.

  7. Effect of a Targeted Women's Health Intervention in an Inner-City Emergency Department

    Directory of Open Access Journals (Sweden)

    Debra Houry

    2011-01-01

    Full Text Available Objective. To evaluate the effect of an Emergency Department (ED based, educational intervention for at-risk health behaviors. Methods. A randomized trial over a one-year period. African American women, aged 21–55, presenting to the ED waiting room were eligible. Each participant took a computer-based survey on health risk behaviors. Participants who screened positive on any of four validated scales (for IPV, nicotine, alcohol, or drug dependence were randomized to standard information about community resources (control or to targeted educational handouts based upon their screening results (intervention. Participants were surveyed at 3 months regarding contacts with community resources and harm-reduction actions. Results. 610 women were initially surveyed; 326 screened positive (13.7% for IPV, 40.1% for nicotine addiction, 26.6% for alcohol abuse, and 14.4% for drug abuse. 157 women were randomized to intervention and 169 to control. Among women who completed follow-up (=71, women in the Intervention Group were significantly more likely to have contacted local resources (37% versus 9%, =0.04 and were more likely to have taken risk-reducing action (97% versus 79%, =0.04. Conclusion. Targeted, brief educational interventions may be an effective method for targeting risk behaviors among vulnerable ED populations.

  8. Long-Term Effects of a Personality-Targeted Intervention to Reduce Alcohol Use in Adolescents

    Science.gov (United States)

    Conrod, Patricia J.; Castellanos-Ryan, Natalie; Mackie, Clare

    2011-01-01

    Objective: To examine the long-term effects of a personality-targeted intervention on drinking quantity and frequency (QF), problem drinking, and personality-specific motivations for alcohol use in early adolescence. Method: A randomized control trial was carried out with 364 adolescents (median age 14) recruited from 13 secondary schools with…

  9. Influence of controlled and uncontrolled interventions on Twitter in different target groups

    NARCIS (Netherlands)

    Maanen, P.P. van; Aarts, O.; Boertjes, E.; Wijn, R.

    2013-01-01

    In this paper the influence of interventions on Twitter users is studied. We define influence in a) number of participants, b) size of the audience, c) amount of activity, and d) reach. Influence is studied for four different target groups: a) politicians, b) journalists, c) employees and d) the

  10. The effect of interventions on Twitter in four target groups using different measures of influence

    NARCIS (Netherlands)

    Maanen, P.P. van; Wijn, R.; Boertjes, E.

    2014-01-01

    In this paper, the influence of interventions on Twitter users is studied. We define influence in (a) number of participants, (b) size of the audience, (c) amount of activity, and (d) reach. Influence is studied for four different target groups: (a) politicians, (b) journalists, (c) employees and

  11. Genome-wide gene expression dataset used to identify potential therapeutic targets in androgenetic alopecia

    Directory of Open Access Journals (Sweden)

    R. Dey-Rao

    2017-08-01

    Full Text Available The microarray dataset attached to this report is related to the research article with the title: “A genomic approach to susceptibility and pathogenesis leads to identifying potential novel therapeutic targets in androgenetic alopecia” (Dey-Rao and Sinha, 2017 [1]. Male-pattern hair loss that is induced by androgens (testosterone in genetically predisposed individuals is known as androgenetic alopecia (AGA. The raw dataset is being made publicly available to enable critical and/or extended analyses. Our related research paper utilizes the attached raw dataset, for genome-wide gene-expression associated investigations. Combined with several in silico bioinformatics-based analyses we were able to delineate five strategic molecular elements as potential novel targets towards future AGA-therapy.

  12. Process and Effects Evaluation of a Digital Mental Health Intervention Targeted at Improving Occupational Well-Being: Lessons From an Intervention Study With Failed Adoption.

    Science.gov (United States)

    Muuraiskangas, Salla; Harjumaa, Marja; Kaipainen, Kirsikka; Ermes, Miikka

    2016-05-11

    relief in stressful situations. The app was perceived as a toolkit for personal well-being that gives concrete instructions on how mindfulness can be practiced. However, many barriers to participate in the intervention were identified at the individual level, such as lack of time, lack of perceived need, and lack of perceived benefits. The findings suggest that neither the setting nor the approach used in this study were successful in adopting new digital interventions at the target organizations. Barriers were faced at both the organizational as well as the individual level. At the organizational level, top management needs to be involved in the intervention planning for fitting into the organization policies, the existing technology infrastructure, and also targeting the organizational goals. At the individual level, concretizing the benefits of the preventive intervention and arranging time for app use at the workplace are likely to increase adoption.

  13. A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Konstantinos Tzelepis

    2016-10-01

    Full Text Available Acute myeloid leukemia (AML is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as DOT1L, BCL2, and MEN1, and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose KAT2A as a candidate for downstream study. KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells. Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies.

  14. Intervention Strategies Used in Sport Injury Prevention Studies: A Systematic Review Identifying Studies Applying the Haddon Matrix.

    Science.gov (United States)

    Vriend, Ingrid; Gouttebarge, Vincent; Finch, Caroline F; van Mechelen, Willem; Verhagen, Evert A L M

    2017-10-01

    Prevention of sport injuries is crucial to maximise the health and societal benefits of a physically active lifestyle. To strengthen the translation and implementation of the available evidence base on effective preventive measures, a range of potentially relevant strategies should be considered. Our aim was to identify and categorise intervention strategies for the prevention of acute sport injuries evaluated in the scientific literature, applying the Haddon matrix, and identify potential knowledge gaps. Five electronic databases were searched (PubMed, EMBASE, SPORTDiscus, CINAHL, Cochrane) for studies that evaluated the effect of interventions on the occurrence of acute sport injuries. Studies were required to include a control group/condition, prospective data collection, and a quantitative injury outcome measure. A total of 155 studies were included, mostly randomised controlled trials (43%). The majority of studies (55%) focussed on strategies requiring a behavioural change on the part of athletes. Studies predominantly evaluated the preventive effect of various training programmes targeted at the 'pre-event' phase (n = 73) and the use of equipment to avoid injury in the 'event phase' (n = 29). A limited number of studies evaluated the preventive effect of strategies geared at rules and regulations (n = 14), and contextual modifications (n = 18). Studies specifically aimed at preventing re-injuries were a minority (n = 8), and were mostly related to ankle sprains (n = 5). Valuable insight into the extent of the evidence base of sport injury prevention studies was obtained for 20 potential intervention strategies. This approach can be used to monitor potential gaps in the knowledge base on sport injury prevention.

  15. Modulation of Lipid Droplet Metabolism—A Potential Target for Therapeutic Intervention in Flaviviridae Infections

    Directory of Open Access Journals (Sweden)

    Jingshu Zhang

    2017-11-01

    Full Text Available Lipid droplets (LDs are endoplasmic reticulum (ER-related dynamic organelles that store and regulate fatty acids and neutral lipids. They play a central role in cellular energy storage, lipid metabolism and cellular homeostasis. It has become evident that viruses have co-evolved in order to exploit host lipid metabolic pathways. This is especially characteristic of the Flaviviridae family, including hepatitis C virus (HCV and several flaviviruses. Devoid of an appropriate lipid biosynthetic machinery of their own, these single-strand positive-sense RNA viruses can induce dramatic changes in host metabolic pathways to establish a favorable environment for viral multiplication and acquire essential components to facilitate their assembly and traffic. Here we have reviewed the current knowledge on the intracellular life cycle of those from the Flaviviridae family, with particular emphasis on HCV and dengue virus (DENV, and their association with the biosynthesis and metabolism of LDs, with the aim to identify potential antiviral targets for development of novel therapeutic interventions.

  16. Identifying postpartum intervention approaches to prevent type 2 diabetes in women with a history of gestational diabetes

    Directory of Open Access Journals (Sweden)

    Abdul-Rahim Zainab S

    2011-03-01

    Full Text Available Abstract Background Women who develop gestational diabetes mellitus (GDM have an increased risk for the development of type 2 diabetes. Despite this "window of opportunity," few intervention studies have targeted postpartum women with a history of GDM. We sought perspectives of women with a history of GDM to identify a barriers and facilitators to healthy lifestyle changes postpartum, and b specific intervention approaches that would facilitate participation in a postpartum lifestyle intervention program. Methods We used mixed methods to gather data from women with a prior history of GDM, including focus groups and informant interviews. Analysis of focus groups relied on grounded theory and used open-coding to categorize data by themes, while frequency distributions were used for the informant interviews. Results Of 38 women eligible to participate in focus groups, only ten women were able to accommodate their schedules to attend a focus group and 15 completed informant interviews by phone. We analyzed data from 25 women (mean age 35, mean pre-pregnancy BMI 28, 52% Caucasian, 20% African American, 12% Asian, 8% American Indian, 8% refused to specify. Themes from the focus groups included concern about developing type 2 diabetes, barriers to changing diet, and barriers to increasing physical activity. In one focus group, women expressed frustration about feeling judged by their physicians during their GDM pregnancy. Cited barriers to lifestyle change were identified from both methods, and included time and financial constraints, childcare duties, lack of motivation, fatigue, and obstacles at work. Informants suggested facilitators for lifestyle change, including nutrition education, accountability, exercise partners/groups, access to gyms with childcare, and home exercise equipment. All focus group and informant interview participants reported access to the internet, and the majority expressed interest in an intervention program delivered

  17. Targeted next generation sequencing identifies clinically actionable mutations in patients with melanoma.

    Science.gov (United States)

    Jeck, William R; Parker, Joel; Carson, Craig C; Shields, Janiel M; Sambade, Maria J; Peters, Eldon C; Burd, Christin E; Thomas, Nancy E; Chiang, Derek Y; Liu, Wenjin; Eberhard, David A; Ollila, David; Grilley-Olson, Juneko; Moschos, Stergios; Neil Hayes, D; Sharpless, Norman E

    2014-07-01

    Somatic sequencing of cancers has produced new insight into tumorigenesis, tumor heterogeneity, and disease progression, but the vast majority of genetic events identified are of indeterminate clinical significance. Here, we describe a NextGen sequencing approach to fully analyzing 248 genes, including all those of known clinical significance in melanoma. This strategy features solution capture of DNA followed by multiplexed, high-throughput sequencing and was evaluated in 31 melanoma cell lines and 18 tumor tissues from patients with metastatic melanoma. Mutations in melanoma cell lines correlated with their sensitivity to corresponding small molecule inhibitors, confirming, for example, lapatinib sensitivity in ERBB4 mutant lines and identifying a novel activating mutation of BRAF. The latter event would not have been identified by clinical sequencing and was associated with responsiveness to a BRAF kinase inhibitor. This approach identified focal copy number changes of PTEN not found by standard methods, such as comparative genomic hybridization (CGH). Actionable mutations were found in 89% of the tumor tissues analyzed, 56% of which would not be identified by standard-of-care approaches. This work shows that targeted sequencing is an attractive approach for clinical use in melanoma. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Targeted interventions for improved equity in maternal and child health in low- and middle-income settings: a systematic review and meta-analysis.

    Science.gov (United States)

    Målqvist, Mats; Yuan, Beibei; Trygg, Nadja; Selling, Katarina; Thomsen, Sarah

    2013-01-01

    Targeted interventions to improve maternal and child health is suggested as a feasible and sometimes even necessary strategy to reduce inequity. The objective of this systematic review was to gather the evidence of the effectiveness of targeted interventions to improve equity in MDG 4 and 5 outcomes. We identified primary studies in all languages by searching nine health and social databases, including grey literature and dissertations. Studies evaluating the effect of an intervention tailored to address a structural determinant of inequity in maternal and child health were included. Thus general interventions targeting disadvantaged populations were excluded. Outcome measures were limited to indicators proposed for Millennium Development Goals 4 and 5. We identified 18 articles, whereof 15 evaluated various incentive programs, two evaluated a targeted policy intervention, and only one study evaluated an intervention addressing a cultural custom. Meta-analyses of the effectiveness of incentives programs showed a pooled effect size of RR 1.66 (95% CI 1.43-1.93) for antenatal care attendance (four studies with 2,476 participants) and RR 2.37 (95% CI 1.38-4.07) for health facility delivery (five studies with 25,625 participants). Meta-analyses were not performed for any of the other outcomes due to scarcity of studies. The targeted interventions aiming to improve maternal and child health are mainly limited to addressing economic disparities through various incentive schemes like conditional cash transfers and voucher schemes. This is a feasible strategy to reduce inequity based on income. More innovative action-oriented research is needed to speed up progress in maternal and child survival among the most disadvantaged populations through interventions targeting the underlying structural determinants of inequity.

  19. Intervention Efficacy in Trials Targeting Cannabis Use Disorders in Patients with Comorbid Psychosis

    DEFF Research Database (Denmark)

    Hjorthoj, Carsten Rygaard; Baker, Amanda; Fohlmann, Allan

    2014-01-01

    Introduction: Cannabis use disorders are highly prevalent in patients with schizophrenia and other psychoses, and are probably associated with a range of poor outcomes. Several trials have been conducted on this population, the results of which have been summarized in several systematic reviews...... but never in meta-analyses specifically regarding cannabis use. Methods: PubMed, PsycINFO, EMBASE, and The Cochrane Central Register of Controlled Trials were searched using predefined search terms. We included randomized trials of all types of interventions targeting cannabis use disorders in patients...... with schizophrenia spectrum disorders. We extracted information on intervention types, efficacy, trial characteristics, and risk of bias. Results: There was no evidence of an effect on frequency of cannabis use, but intervention effects of motivational intervention with or without cognitive behavior therapy were...

  20. Identifying novel targets of oncogenic EGF receptor signaling in lung cancer through global phosphoproteomics.

    Science.gov (United States)

    Zhang, Xu; Belkina, Natalya; Jacob, Harrys Kishore Charles; Maity, Tapan; Biswas, Romi; Venugopalan, Abhilash; Shaw, Patrick G; Kim, Min-Sik; Chaerkady, Raghothama; Pandey, Akhilesh; Guha, Udayan

    2015-01-01

    Mutations in the epidermal growth factor receptor (EGFR) kinase domain occur in 10-30% of lung adenocarcinoma and are associated with tyrosine kinase inhibitor (TKI) sensitivity. We sought to identify the immediate direct and indirect phosphorylation targets of mutant EGFRs in lung adenocarcinoma. We undertook SILAC strategy, phosphopeptide enrichment, and quantitative MS to identify dynamic changes of phosphorylation downstream of mutant EGFRs in lung adenocarcinoma cells harboring EGFR(L858R) and EGFR(L858R/T790M) , the TKI-sensitive, and TKI-resistant mutations, respectively. Top canonical pathways that were inhibited upon erlotinib treatment in sensitive cells, but not in the resistant cells include EGFR, insulin receptor, hepatocyte growth factor, mitogen-activated protein kinase, mechanistic target of rapamycin, ribosomal protein S6 kinase beta 1, and Janus kinase/signal transducer and activator of transcription signaling. We identified phosphosites in proteins of the autophagy network, such as ULK1 (S623) that is constitutively phosphorylated in these lung adenocarcinoma cells; phosphorylation is inhibited upon erlotinib treatment in sensitive cells, but not in resistant cells. Finally, kinase-substrate prediction analysis from our data indicated that substrates of basophilic kinases from, AGC and Calcium and calmodulin-dependent kinase groups, as well as STE group kinases were significantly enriched and those of proline-directed kinases from, CMGC and Casein kinase groups were significantly depleted among substrates that exhibited increased phosphorylation upon EGF stimulation and reduced phosphorylation upon TKI inhibition. This is the first study to date to examine global phosphorylation changes upon erlotinib treatment of lung adenocarcinoma cells and results from this study provide new insights into signaling downstream of mutant EGFRs in lung adenocarcinoma. All MS data have been deposited in the ProteomeXchange with identifier PXD001101 (http

  1. Clinical quality assurance surveillance and targeted interventions: managing unfavorable trends in a dental school clinic.

    Science.gov (United States)

    Hoover, Terry E; Kirk, Jeffrey; Fredekind, Richard E

    2007-06-01

    Dental schools establish quality assurance (QA) programs that are intended to improve patient care, comply with requirements of liability carriers and regulatory agencies, and maintain accreditation. Data collection, trend analysis, and interventions are typically used in QA programs to monitor and improve compliance. The purpose of this article is to discuss unfavorable trends and examine the effect of targeted interventions in three clinical operations: infection control, removable prosthodontics, and case reviews of students' patient care in progress (interim case reviews) at a U.S. dental school. Infection control compliance was evaluated and interventions were implemented beginning in 2002 to correct unfavorable trends in two protocols: placement of students' mobile supply cart and the use of overgloves. A predelivery esthetic consent was introduced in spring 2004 to decrease esthetic failures in removable prosthodontics. For interim case reviews, two areas received interventions going back to 2003: reevaluation following initial periodontal therapy and orthodontic screening. The data presented are not meant to show conclusive success of particular interventions, but to display broad trends and suggest methods to manage quality assurance parameters. These trends suggest we had better success with the interventions that were simple, valuable, measurable, and repeatable than with interventions that less fit these criteria.

  2. Autoantibodies targeting glomerular annexin A2 identify patients with proliferative lupus nephritis.

    Science.gov (United States)

    Caster, Dawn J; Korte, Erik A; Merchant, Michael L; Klein, Jon B; Wilkey, Daniel W; Rovin, Brad H; Birmingham, Dan J; Harley, John B; Cobb, Beth L; Namjou, Bahram; McLeish, Kenneth R; Powell, David W

    2015-12-01

    Patients with systemic lupus erythematosus (SLE) frequently develop lupus nephritis (LN), a complication frequently leading to end stage kidney disease. Immune complex deposition in the glomerulus is central to the development of LN. Using a targeted proteomic approach, we tested the hypothesis that autoantibodies targeting glomerular antigens contribute to the development of LN. Human podocyte and glomerular proteins were separated by SDS-PAGE and immunoblotted with sera from SLE patients with and without LN. The regions of those gels corresponding to reactive bands observed with sera from LN patients were analyzed using LC-MS/MS. LN reactive bands were seen at approximately 50 kDa in podocyte extracts and between 36 and 50 kDa in glomerular extracts. Those bands were analyzed by LC-MS/MS and 102 overlapping proteins were identified. Bioinformatic analysis determined that 36 of those proteins were membrane associated, including a protein previously suggested to contribute to glomerulonephritis and LN, annexin A2. By ELISA, patients with proliferative LN demonstrated significantly increased antibodies against annexin A2. Proteomic approaches identified multiple candidate antigens for autoantibodies in patients with LN. Serum antibodies against annexin A2 were significantly elevated in subjects with proliferative LN, validating those antibodies as potential biomarkers. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target.

    Science.gov (United States)

    Manguso, Robert T; Pope, Hans W; Zimmer, Margaret D; Brown, Flavian D; Yates, Kathleen B; Miller, Brian C; Collins, Natalie B; Bi, Kevin; LaFleur, Martin W; Juneja, Vikram R; Weiss, Sarah A; Lo, Jennifer; Fisher, David E; Miao, Diana; Van Allen, Eliezer; Root, David E; Sharpe, Arlene H; Doench, John G; Haining, W Nicholas

    2017-07-27

    Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPR-Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon-γ signalling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-κB signalling, antigen presentation and the unfolded protein response. In addition, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon-γ-mediated effects on antigen presentation and growth suppression. In vivo genetic screens in tumour models can identify new immunotherapy targets in unanticipated pathways.

  4. A novel mouse model identifies cooperating mutations and therapeutic targets critical for chronic myeloid leukemia progression

    Science.gov (United States)

    Giotopoulos, George; van der Weyden, Louise; Osaki, Hikari; Rust, Alistair G.; Gallipoli, Paolo; Meduri, Eshwar; Horton, Sarah J.; Chan, Wai-In; Foster, Donna; Prinjha, Rab K.; Pimanda, John E.; Tenen, Daniel G.; Vassiliou, George S.; Koschmieder, Steffen; Adams, David J.

    2015-01-01

    The introduction of highly selective ABL-tyrosine kinase inhibitors (TKIs) has revolutionized therapy for chronic myeloid leukemia (CML). However, TKIs are only efficacious in the chronic phase of the disease and effective therapies for TKI-refractory CML, or after progression to blast crisis (BC), are lacking. Whereas the chronic phase of CML is dependent on BCR-ABL, additional mutations are required for progression to BC. However, the identity of these mutations and the pathways they affect are poorly understood, hampering our ability to identify therapeutic targets and improve outcomes. Here, we describe a novel mouse model that allows identification of mechanisms of BC progression in an unbiased and tractable manner, using transposon-based insertional mutagenesis on the background of chronic phase CML. Our BC model is the first to faithfully recapitulate the phenotype, cellular and molecular biology of human CML progression. We report a heterogeneous and unique pattern of insertions identifying known and novel candidate genes and demonstrate that these pathways drive disease progression and provide potential targets for novel therapeutic strategies. Our model greatly informs the biology of CML progression and provides a potent resource for the development of candidate therapies to improve the dismal outcomes in this highly aggressive disease. PMID:26304963

  5. Identifying co-targets to fight drug resistance based on a random walk model

    Directory of Open Access Journals (Sweden)

    Chen Liang-Chun

    2012-01-01

    Full Text Available Abstract Background Drug resistance has now posed more severe and emergent threats to human health and infectious disease treatment. However, wet-lab approaches alone to counter drug resistance have so far still achieved limited success due to less knowledge about the underlying mechanisms of drug resistance. Our approach apply a heuristic search algorithm in order to extract active network under drug treatment and use a random walk model to identify potential co-targets for effective antibacterial drugs. Results We use interactome network of Mycobacterium tuberculosis and gene expression data which are treated with two kinds of antibiotic, Isoniazid and Ethionamide as our test data. Our analysis shows that the active drug-treated networks are associated with the trigger of fatty acid metabolism and synthesis and nicotinamide adenine dinucleotide (NADH-related processes and those results are consistent with the recent experimental findings. Efflux pumps processes appear to be the major mechanisms of resistance but SOS response is significantly up-regulation under Isoniazid treatment. We also successfully identify the potential co-targets with literature confirmed evidences which are related to the glycine-rich membrane, adenosine triphosphate energy and cell wall processes. Conclusions With gene expression and interactome data supported, our study points out possible pathways leading to the emergence of drug resistance under drug treatment. We develop a computational workflow for giving new insights to bacterial drug resistance which can be gained by a systematic and global analysis of the bacterial regulation network. Our study also discovers the potential co-targets with good properties in biological and graph theory aspects to overcome the problem of drug resistance.

  6. Gene silencing by RNA interference in Sarcoptes scabiei: a molecular tool to identify novel therapeutic targets.

    Science.gov (United States)

    Fernando, Deepani D; Marr, Edward J; Zakrzewski, Martha; Reynolds, Simone L; Burgess, Stewart T G; Fischer, Katja

    2017-06-10

    Scabies is one of the most common and widespread parasitic skin infections globally, affecting a large range of mammals including humans, yet the molecular biology of Sarcoptes scabiei is astonishingly understudied. Research has been hampered primarily due to the difficulty of sampling or culturing these obligatory parasitic mites. A further and major impediment to identify and functionally analyse potential therapeutic targets from the recently emerging molecular databases is the lack of appropriate molecular tools. We performed standard BLAST based searches of the existing S. scabiei genome databases using sequences of genes described to be involved in RNA interference in Drosophila and the mite model organism Tetranychus urticae. Experimenting with the S. scabiei mu-class glutathione S-transferase (SsGST-mu1) as a candidate gene we explored the feasibility of gene knockdown in S. scabiei by double-stranded RNA-interference (dsRNAi). We provide here an analysis of the existing S. scabiei draft genomes, confirming the presence of a double stranded RNA (dsRNA) - mediated silencing machinery. We report for the first time experimental gene silencing by RNA interference (RNAi) in S. scabiei. Non-invasive immersion of S. scabiei in dsRNA encoding an S. scabiei glutathione S-transferase mu-class 1 enzyme (SsGST-mu1) resulted in a 35% reduction in the transcription of the target gene compared to controls. A series of experiments identified the optimal conditions allowing systemic experimental RNAi without detrimental side effects on mite viability. This technique can now be used to address the key questions on the fundamental aspects of mite biology and pathogenesis, and to assess the potential therapeutic benefits of silencing S. scabiei target genes.

  7. Identifying Early Target Cells of Nipah Virus Infection in Syrian Hamsters.

    Directory of Open Access Journals (Sweden)

    Laura Baseler

    2016-11-01

    Full Text Available Nipah virus causes respiratory and neurologic disease with case fatality rates up to 100% in individual outbreaks. End stage lesions have been described in the respiratory and nervous systems, vasculature and often lymphoid organs in fatal human cases; however, the initial target organs of Nipah virus infection have not been identified. Here, we detected the initial target tissues and cells of Nipah virus and tracked virus dissemination during the early phase of infection in Syrian hamsters inoculated with a Nipah virus isolate from Malaysia (NiV-M or Bangladesh (NiV-B.Syrian hamsters were euthanized between 4 and 48 hours post intranasal inoculation and tissues were collected and analyzed for the presence of viral RNA, viral antigen and infectious virus. Virus replication was first detected at 8 hours post inoculation (hpi. Nipah virus initially targeted type I pneumocytes, bronchiolar respiratory epithelium and alveolar macrophages in the lung and respiratory and olfactory epithelium lining the nasal turbinates. By 16 hpi, virus disseminated to epithelial cells lining the larynx and trachea. Although the pattern of viral dissemination was similar for both virus isolates, the rate of spread was slower for NiV-B. Infectious virus was not detected in the nervous system or blood and widespread vascular infection and lesions within lymphoid organs were not observed, even at 48 hpi.Nipah virus initially targets the respiratory system. Virus replication in the brain and infection of blood vessels in non-respiratory tissues does not occur during the early phase of infection. However, virus replicates early in olfactory epithelium and may serve as the first step towards nervous system dissemination, suggesting that development of vaccines that block virus dissemination or treatments that can access the brain and spinal cord and directly inhibit virus replication may be necessary for preventing central nervous system pathology.

  8. Identifying Early Target Cells of Nipah Virus Infection in Syrian Hamsters.

    Science.gov (United States)

    Baseler, Laura; Scott, Dana P; Saturday, Greg; Horne, Eva; Rosenke, Rebecca; Thomas, Tina; Meade-White, Kimberly; Haddock, Elaine; Feldmann, Heinz; de Wit, Emmie

    2016-11-01

    Nipah virus causes respiratory and neurologic disease with case fatality rates up to 100% in individual outbreaks. End stage lesions have been described in the respiratory and nervous systems, vasculature and often lymphoid organs in fatal human cases; however, the initial target organs of Nipah virus infection have not been identified. Here, we detected the initial target tissues and cells of Nipah virus and tracked virus dissemination during the early phase of infection in Syrian hamsters inoculated with a Nipah virus isolate from Malaysia (NiV-M) or Bangladesh (NiV-B). Syrian hamsters were euthanized between 4 and 48 hours post intranasal inoculation and tissues were collected and analyzed for the presence of viral RNA, viral antigen and infectious virus. Virus replication was first detected at 8 hours post inoculation (hpi). Nipah virus initially targeted type I pneumocytes, bronchiolar respiratory epithelium and alveolar macrophages in the lung and respiratory and olfactory epithelium lining the nasal turbinates. By 16 hpi, virus disseminated to epithelial cells lining the larynx and trachea. Although the pattern of viral dissemination was similar for both virus isolates, the rate of spread was slower for NiV-B. Infectious virus was not detected in the nervous system or blood and widespread vascular infection and lesions within lymphoid organs were not observed, even at 48 hpi. Nipah virus initially targets the respiratory system. Virus replication in the brain and infection of blood vessels in non-respiratory tissues does not occur during the early phase of infection. However, virus replicates early in olfactory epithelium and may serve as the first step towards nervous system dissemination, suggesting that development of vaccines that block virus dissemination or treatments that can access the brain and spinal cord and directly inhibit virus replication may be necessary for preventing central nervous system pathology.

  9. A new method of identifying target groups for pronatalist policy applied to Australia

    Science.gov (United States)

    Chen, Mengni; Lloyd, Chris J.

    2018-01-01

    A country’s total fertility rate (TFR) depends on many factors. Attributing changes in TFR to changes of policy is difficult, as they could easily be correlated with changes in the unmeasured drivers of TFR. A case in point is Australia where both pronatalist effort and TFR increased in lock step from 2001 to 2008 and then decreased. The global financial crisis or other unobserved confounders might explain both the reducing TFR and pronatalist incentives after 2008. Therefore, it is difficult to estimate causal effects of policy using econometric techniques. The aim of this study is to instead look at the structure of the population to identify which subgroups most influence TFR. Specifically, we build a stochastic model relating TFR to the fertility rates of various subgroups and calculate elasticity of TFR with respect to each rate. For each subgroup, the ratio of its elasticity to its group size is used to evaluate the subgroup’s potential cost effectiveness as a pronatalist target. In addition, we measure the historical stability of group fertility rates, which measures propensity to change. Groups with a high effectiveness ratio and also high propensity to change are natural policy targets. We applied this new method to Australian data on fertility rates broken down by parity, age and marital status. The results show that targeting parity 3+ is more cost-effective than lower parities. This study contributes to the literature on pronatalist policies by investigating the targeting of policies, and generates important implications for formulating cost-effective policies. PMID:29425220

  10. Are suppressors of cytokine signaling proteins recently identified in atherosclerosis possible therapeutic targets?

    Science.gov (United States)

    Tang, Jingjing; Raines, Elaine W

    2005-10-01

    Atherosclerosis is a slowly progressing chronic inflammatory disease characterized by focal arterial lesions that can ultimately occlude the entire blood vessel and lead to sudden death. Lesions associated with cardiovascular events are those enriched in macrophages and other inflammatory cells. Activation of inflammatory cells within lesions induces the release of cytokines which promotes more inflammation and associated tissue damage if cytokine signaling pathways remain unregulated. Thus, pathways capable of suppressing proinflammatory cytokine signaling hold the potential to limit life-threatening cardiovascular events caused by atherogenesis. This review focuses on suppressors of cytokine signaling proteins recently identified in the atherosclerosis-prone ApoE(-/-) mouse and provides perspectives of their potential for intervention in atherosclerotic lesion progression.

  11. Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia.

    Science.gov (United States)

    Geng, Huimin; Brennan, Sarah; Milne, Thomas A; Chen, Wei-Yi; Li, Yushan; Hurtz, Christian; Kweon, Soo-Mi; Zickl, Lynette; Shojaee, Seyedmehdi; Neuberg, Donna; Huang, Chuanxin; Biswas, Debabrata; Xin, Yuan; Racevskis, Janis; Ketterling, Rhett P; Luger, Selina M; Lazarus, Hillard; Tallman, Martin S; Rowe, Jacob M; Litzow, Mark R; Guzman, Monica L; Allis, C David; Roeder, Robert G; Müschen, Markus; Paietta, Elisabeth; Elemento, Olivier; Melnick, Ari M

    2012-11-01

    Genetic lesions such as BCR-ABL1, E2A-PBX1, and MLL rearrangements (MLLr) are associated with unfavorable outcomes in adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Leukemia oncoproteins may directly or indirectly disrupt cytosine methylation patterning to mediate the malignant phenotype. We postulated that DNA methylation signatures in these aggressive B-ALLs would point toward disease mechanisms and useful biomarkers and therapeutic targets. We therefore conducted DNA methylation and gene expression profiling on a cohort of 215 adult patients with B-ALL enrolled in a single phase III clinical trial (ECOG E2993) and normal control B cells. In BCR-ABL1-positive B-ALLs, aberrant cytosine methylation patterning centered around a cytokine network defined by hypomethylation and overexpression of IL2RA(CD25). The E2993 trial clinical data showed that CD25 expression was strongly associated with a poor outcome in patients with ALL regardless of BCR-ABL1 status, suggesting CD25 as a novel prognostic biomarker for risk stratification in B-ALLs. In E2A-PBX1-positive B-ALLs, aberrant DNA methylation patterning was strongly associated with direct fusion protein binding as shown by the E2A-PBX1 chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq), suggesting that E2A-PBX1 fusion protein directly remodels the epigenome to impose an aggressive B-ALL phenotype. MLLr B-ALL featured prominent cytosine hypomethylation, which was linked with MLL fusion protein binding, H3K79 dimethylation, and transcriptional upregulation, affecting a set of known and newly identified MLL fusion direct targets with oncogenic activity such as FLT3 and BCL6. Notably, BCL6 blockade or loss of function suppressed proliferation and survival of MLLr leukemia cells, suggesting BCL6-targeted therapy as a new therapeutic strategy for MLLr B-ALLs. We conducted the first integrative epigenomic study in adult B-ALLs, as a correlative study to the ECOG E2993 phase III clinical trial. This

  12. Identifying eating behavior phenotypes and their correlates: A novel direction toward improving weight management interventions.

    Science.gov (United States)

    Bouhlal, Sofia; McBride, Colleen M; Trivedi, Niraj S; Agurs-Collins, Tanya; Persky, Susan

    2017-04-01

    Common reports of over-response to food cues, difficulties with calorie restriction, and difficulty adhering to dietary guidelines suggest that eating behaviors could be interrelated in ways that influence weight management efforts. The feasibility of identifying robust eating phenotypes (showing face, content, and criterion validity) was explored based on well-validated individual eating behavior assessments. Adults (n = 260; mean age 34 years) completed online questionnaires with measurements of nine eating behaviors including: appetite for palatable foods, binge eating, bitter taste sensitivity, disinhibition, food neophobia, pickiness and satiety responsiveness. Discovery-based visualization procedures that have the combined strengths of heatmaps and hierarchical clustering were used to investigate: 1) how eating behaviors cluster, 2) how participants can be grouped within eating behavior clusters, and 3) whether group clustering is associated with body mass index (BMI) and dietary self-efficacy levels. Two distinct eating behavior clusters and participant groups that aligned within these clusters were identified: one with higher drive to eat and another with food avoidance behaviors. Participants' BMI (p = 0.0002) and dietary self-efficacy (p behavior clusters showed content and criterion validity based on their association with BMI (associated, but not entirely overlapping) and dietary self-efficacy. Identifying eating behavior phenotypes appears viable. These efforts could be expanded and ultimately inform tailored weight management interventions. Published by Elsevier Ltd.

  13. Quantitative proteomics identify molecular targets that are crucial in larval settlement and metamorphosis of bugula neritina

    KAUST Repository

    Zhang, Huoming

    2011-01-07

    The marine invertebrate Bugula neritina has a biphasic life cycle that consists of a swimming larval stage and a sessile juvenile and adult stage. The attachment of larvae to the substratum and their subsequent metamorphosis have crucial ecological consequences. Despite many studies on this species, little is known about the molecular mechanism of these processes. Here, we report a comparative study of swimming larvae and metamorphosing individuals at 4 and 24 h postattachment using label-free quantitative proteomics. We identified more than 1100 proteins at each stage, 61 of which were differentially expressed. Specifically, proteins involved in energy metabolism and structural molecules were generally down-regulated, whereas proteins involved in transcription and translation, the extracellular matrix, and calcification were strongly up-regulated during metamorphosis. Many tightly regulated novel proteins were also identified. Subsequent analysis of the temporal and spatial expressions of some of the proteins and an assay of their functions indicated that they may have key roles in metamorphosis of B. neritina. These findings not only provide molecular evidence with which to elucidate the substantial changes in morphology and physiology that occur during larval attachment and metamorphosis but also identify potential targets for antifouling treatment. © 2011 American Chemical Society.

  14. Targeting the Akt1 allosteric site to identify novel scaffolds through virtual screening.

    Science.gov (United States)

    Yilmaz, Oya Gursoy; Olmez, Elif Ozkirimli; Ulgen, Kutlu O

    2014-02-01

    Preclinical data and tumor specimen studies report that AKT kinases are related to many human cancers. Therefore, identification and development of small molecule inhibitors targeting AKT and its signaling pathway can be therapeutic in treatment of cancer. Numerous studies report inhibitors that target the ATP-binding pocket in the kinase domains, but the similarity of this site, within the kinase family makes selectivity a major problem. The sequence identity amongst PH domains is significantly lower than that in kinase domains and developing more selective inhibitors is possible if PH domain is targeted. This in silico screening study is the first time report toward the identification of potential allosteric inhibitors expected to bind the cavity between kinase and PH domains of Akt1. Structural information of Akt1 was used to develop structure-based pharmacophore models comprising hydrophobic, acceptor, donor and ring features. The 3D structural information of previously identified allosteric Akt inhibitors obtained from literature was employed to develop a ligand-based pharmacophore model. Database was generated with drug like subset of ZINC and screening was performed based on 3D similarity to the selected pharmacophore hypotheses. Binding modes and affinities of the ligands were predicted by Glide software. Top scoring hits were further analyzed considering 2D similarity between the compounds, interactions with Akt1, fitness to pharmacophore models, ADME, druglikeness criteria and Induced-Fit docking. Using virtual screening methodologies, derivatives of 3-methyl-xanthine, quinoline-4-carboxamide and 2-[4-(cyclohexa-1,3-dien-1-yl)-1H-pyrazol-3-yl]phenol were proposed as potential leads for allosteric inhibition of Akt1. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma

    Science.gov (United States)

    Favoni, Roberto E; Daga, Antonio; Malatesta, Paolo; Florio, Tullio

    2012-01-01

    The incidence of human malignant pleural mesothelioma (hMPM) is still increasing worldwide. hMPM prognosis is poor even if the median survival time has been slightly improved after the introduction of the up-to-date chemotherapy. Nevertheless, large phase II/III trials support the combination of platinum derivatives and pemetrexed or raltitrexed, as preferred first-line schedule. Better understanding of the molecular machinery of hMPM will lead to the design and synthesis of novel compounds targeted against pathways identified as crucial for hMPM cell proliferation and spreading. Among them, several receptors tyrosine kinase show altered activity in subsets of hMPM. This observation suggests that these kinases might represent novel therapeutic targets in this chemotherapy-resistant disease. Over these foundations, several promising studies are ongoing at preclinical level and novel molecules are currently under evaluation as well. Yet, established tumour cell lines, used for decades to investigate the efficacy of anticancer agents, although still the main source of drug efficacy studies, after long-term cultures tend to biologically diverge from the original tumour, limiting the predictive potential of in vivo efficacy. Cancer stem cells (CSCs), a subpopulation of malignant cells capable of self-renewal and multilineage differentiation, are believed to play an essential role in cancer initiation, growth, metastasization and relapse, being responsible of chemo- and radiotherapy refractoriness. According to the current carcinogenesis theory, CSCs represent the tumour-initiating cell (TIC) fraction, the only clonogenic subpopulation able to originate a tumour mass. Consequently, the recently described isolation of TICs from hMPM, the proposed main pharmacological target for novel antitumoural drugs, may contribute to better dissect the biology and multidrug resistance pathways controlling hMPM growth. PMID:22289125

  16. Multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast.

    Science.gov (United States)

    Gatalica, Zoran; Vranic, Semir; Ghazalpour, Anatole; Xiu, Joanne; Ocal, Idris Tolgay; McGill, John; Bender, Ryan P; Discianno, Erin; Schlum, Aaron; Sanati, Souzan; Palazzo, Juan; Reddy, Sandeep; Pockaj, Barbara

    2016-01-12

    Malignant phyllodes tumor is a rare breast malignancy with sarcomatous overgrowth and with limited effective treatment options for recurrent and metastatic cases. Recent clinical trials indicated a potential for anti-angiogenic, anti-EGFR and immunotherapeutic approaches for patients with sarcomas, which led us to investigate these and other targetable pathways in malignant phyllodes tumor of the breast. Thirty-six malignant phyllodes tumors (including 8 metastatic tumors with two cases having matched primary and metastatic tumors) were profiled using gene sequencing, gene copy number analysis, whole genome expression, and protein expression. Whole genome expression analysis demonstrated consistent over-expression of genes involved in angiogenesis including VEGFA, Angiopoietin-2, VCAM1, PDGFRA, and PTTG1. EGFR protein overexpression was observed in 26/27 (96%) of cases with amplification of the EGFR gene in 8/24 (33%) cases. Two EGFR mutations were identified including EGFRvIII and a presumed pathogenic V774M mutation, respectively. The most common pathogenic mutations included TP53 (50%) and PIK3CA (15%). Cases with matched primary and metastatic tumors harbored identical mutations in both sites (PIK3CA/KRAS and RB1 gene mutations, respectively). Tumor expression of PD-L1 immunoregulatory protein was observed in 3/22 (14%) of cases. Overexpression of molecular biomarkers of increased angiogenesis, EGFR and immune checkpoints provides novel targeted therapy options in malignant phyllodes tumors of the breast.

  17. Kidney disease models: tools to identify mechanisms and potential therapeutic targets

    Science.gov (United States)

    Bao, Yin-Wu; Yuan, Yuan; Chen, Jiang-Hua; Lin, Wei-Qiang

    2018-01-01

    Acute kidney injury (AKI) and chronic kidney disease (CKD) are worldwide public health problems affecting millions of people and have rapidly increased in prevalence in recent years. Due to the multiple causes of renal failure, many animal models have been developed to advance our understanding of human nephropathy. Among these experimental models, rodents have been extensively used to enable mechanistic understanding of kidney disease induction and progression, as well as to identify potential targets for therapy. In this review, we discuss AKI models induced by surgical operation and drugs or toxins, as well as a variety of CKD models (mainly genetically modified mouse models). Results from recent and ongoing clinical trials and conceptual advances derived from animal models are also explored. PMID:29515089

  18. Integrated analysis of the molecular action of Vorinostat identifies epi-sensitised targets for combination therapy.

    Science.gov (United States)

    Hay, Jodie F; Lappin, Katrina; Liberante, Fabio; Kettyle, Laura M; Matchett, Kyle B; Thompson, Alexander; Mills, Ken I

    2017-09-15

    Several histone deacetylase inhibitors including Vorinostat have received FDA approval for the treatment of haematological malignancies. However, data from these trials indicate that Vorinostat has limited efficacy as a monotherapy, prompting the need for rational design of combination therapies. A number of epi-sensitised pathways, including sonic hedgehog (SHH), were identified in AML cells by integration of global patterns of histone H3 lysine 9 (H3K9) acetylation with transcriptomic analysis following Vorinostat-treatment. Direct targeting of the SHH pathway with SANT-1, following Vorinostat induced epi-sensitisation, resulted in synergistic cell death of AML cells. In addition, xenograft studies demonstrated that combination therapy induced a marked reduction in leukemic burden compared to control or single agents. Together, the data supports epi-sensitisation as a potential component of the strategy for the rational development of combination therapies in AML.

  19. Developing Targeted Health Service Interventions Using the PRECEDE-PROCEED Model: Two Australian Case Studies

    Directory of Open Access Journals (Sweden)

    Jane L. Phillips

    2012-01-01

    Full Text Available Aims and Objectives. This paper provides an overview of the applicability of the PRECEDE-PROCEED Model to the development of targeted nursing led chronic illness interventions. Background. Changing health care practice is a complex and dynamic process that requires consideration of social, political, economic, and organisational factors. An understanding of the characteristics of the target population, health professionals, and organizations plus identification of the determinants for change are also required. Synthesizing this data to guide the development of an effective intervention is a challenging process. The PRECEDE-PROCEED Model has been used in global health care settings to guide the identification, planning, implementation, and evaluation of various health improvement initiatives. Design. Using a reflective case study approach, this paper examines the applicability of the PRECEDE-PROCEED Model to the development of targeted chronic care improvement interventions for two distinct Australian populations: a rapidly expanding and aging rural population with unmet palliative care needs and a disadvantaged urban community at higher risk of cardiovascular disease. Results. The PRECEDE-PROCEED Model approach demonstrated utility across diverse health settings in a systematic planning process. In environments characterized by increasing health care needs, limited resources, and growing community expectations, adopting planning tools such as PRECEDE-PROCEED Model at a local level can facilitate the development of the most effective interventions. Relevance to Clinical Practice. The PRECEDE-PROCEED Model is a strong theoretical model that guides the development of realistic nursing led interventions with the best chance of being successful in existing health care environments.

  20. Increasing Early Detection of Prostate Cancer in African American Men through a Culturally Targeted Print Intervention

    Science.gov (United States)

    2008-06-01

    cancer . There are two forms of hormone therapy. One approach involves surgically removing the testicles . The other form of hormone therapy involves... Cancer in African American Men through a Culturally Targeted Print Intervention PRINCIPAL INVESTIGATOR: Hayley Thompson, Ph.D...COVERED (From - To) 1 Mar 2004 – 31 May 2008 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Increasing Early Detection of Prostate Cancer in African

  1. A systematic review of eHealth behavioral interventions targeting smoking, nutrition, alcohol, physical activity and/or obesity for young adults.

    Science.gov (United States)

    Oosterveen, Emilie; Tzelepis, Flora; Ashton, Lee; Hutchesson, Melinda J

    2017-06-01

    A systematic review of randomized control trials (RCT) was undertaken to evaluate the effectiveness of eHealth behavioral interventions aiming to improve smoking rates, nutrition behaviors, alcohol intake, physical activity levels and/or obesity (SNAPO) in young adults. Seven electronic databases were searched for RCTs published in English from 2000 to April 2015 and evaluating eHealth interventions aiming to change one or multiple SNAPO outcomes, and including young adult (18-35years) participants. Of 2,159 articles identified, 45 studies met the inclusion criteria. Most interventions targeted alcohol (n=26), followed by smoking (n=7), physical activity (n=4), obesity (n=4) and nutrition (n=1). Three interventions targeted multiple behaviors. The eHealth interventions were most often delivered via websites (79.5%). Most studies (n=32) compared eHealth interventions to a control group (e.g. waiting list control, minimal intervention), with the majority (n=23) showing a positive effect on a SNAPO outcome at follow-up. Meta-analysis demonstrated a significantly lower mean number of drinks consumed/week in brief web or computer-based interventions compared to controls (Mean Difference -2.43 [-3.54, -1.32], Pyoung adults, particularly in the short-term and for alcohol interventions. But there is insufficient evidence for their efficacy in the longer-term, as well as which mode of delivery is most effective. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  2. A Camp-based Intervention Targeting Independence Among Individuals with Spina Bifida

    Science.gov (United States)

    O’Mahar, Kerry; Jandasek, Barbara; Zukerman, Jill

    2010-01-01

    Objective To design and evaluate a camp-based intervention, the goal of which was to increase independence among children, adolescents, and adults with spina bifida. Methods An intervention targeting independence was embedded within a typical week long camp experience. The intervention consisted of the following: collaborative (i.e., parent and camper) goal identification, group sessions consisting of psycho-education and cognitive tools, and goal monitoring by camp counselors. Camper and parent report of demographic variables, goal attainment, spina bifida knowledge, and independence were gathered. Interventionist report of adherence to the treatment manual was also collected. Results Campers made significant gains in individual goals, management of spina bifida responsibilities, and independence with general spina bifida tasks, with medium effect sizes observed in goal attainment. Conclusions Results indicated that significant progress was made on individually oriented goals from pre- to post-camp. Design issues are discussed. PMID:20026569

  3. HLA ligandomics identifies histone deacetylase 1 as target for ovarian cancer immunotherapy.

    Science.gov (United States)

    Peper, Janet Kerstin; Bösmüller, Hans-Christian; Schuster, Heiko; Gückel, Brigitte; Hörzer, Helen; Roehle, Kevin; Schäfer, Richard; Wagner, Philipp; Rammensee, Hans-Georg; Stevanović, Stefan; Fend, Falko; Staebler, Annette

    2016-05-01

    The recent approval of clincially effective immune checkpoint inhibitors illustrates the potential of cancer immunotherapy. A challenging task remains the identification of specific targets guiding immunotherapy. Facilitated by technical advances, the direct identification of physiologically relevant targets is enabled by analyzing the HLA ligandome of cancer cells. Since recent publications demonstrate the immunogenicity of ovarian cancer (OvCa), immunotherapies, including peptide-based cancer vaccines, represent a promising treatment approach. To identify vaccine peptides, we employed a combined strategy of HLA ligandomics in high-grade serous OvCa samples and immunogenicity analysis. Only few proteins were naturally presented as HLA ligands on all samples analyzed, including histone deacetylase (HDAC) 1 and 2. In vitro priming of CD8(+) T cells demonstrated that two HDAC1/2-derived HLA ligands can induce T-cell responses, capable of killing HLA-matched tumor cells. High HDAC1 expression shown by immunohistochemistry in 136 high-grade serous OvCa patients associated with significantly reduced overall survival (OS), whereas patients with high numbers of CD3(+) tumor-infiltrating lymphocytes (TILs) in the tumor epithelium and CD8(+) TILs in the tumor stroma showed improved OS. However, correlating HDAC1 expression with TILs, high levels of TILs abrogated the impact of HDAC1 on OS. This study strengthens the role of HDAC1/2 as an important tumor antigen in OvCa, demonstrating its impact on OS in a large cohort of OvCa patients. We further identified two immunogenic HDAC1-derived peptides, which frequently induce multi-functional T-cell responses in many donors, suitable for future multi-peptide vaccine trials in OvCa patients.

  4. Identifying continuous quality improvement publications: what makes an improvement intervention ‘CQI’?

    Science.gov (United States)

    Hempel, Susanne; Lim, Yee-Wei; Danz, Marjorie S; Foy, Robbie; Suttorp, Marika J; Shekelle, Paul G; Rubenstein, Lisa V

    2011-01-01

    Background The term continuous quality improvement (CQI) is often used to refer to a method for improving care, but no consensus statement exists on the definition of CQI. Evidence reviews are critical for advancing science, and depend on reliable definitions for article selection. Methods As a preliminary step towards improving CQI evidence reviews, this study aimed to use expert panel methods to identify key CQI definitional features and develop and test a screening instrument for reliably identifying articles with the key features. We used a previously published method to identify 106 articles meeting the general definition of a quality improvement intervention (QII) from 9427 electronically identified articles from PubMed. Two raters then applied a six-item CQI screen to the 106 articles. Results Per cent agreement ranged from 55.7% to 75.5% for the six items, and reviewer-adjusted intra-class correlation ranged from 0.43 to 0.62. ‘Feedback of systematically collected data’ was the most common feature (64%), followed by being at least ‘somewhat’ adapted to local conditions (61%), feedback at meetings involving participant leaders (46%), using an iterative development process (40%), being at least ‘somewhat’ data driven (34%), and using a recognised change method (28%). All six features were present in 14.2% of QII articles. Conclusions We conclude that CQI features can be extracted from QII articles with reasonable reliability, but only a small proportion of QII articles include all features. Further consensus development is needed to support meaningful use of the term CQI for scientific communication. PMID:21727199

  5. Identifying continuous quality improvement publications: what makes an improvement intervention 'CQI'?

    Science.gov (United States)

    O'Neill, Sean M; Hempel, Susanne; Lim, Yee-Wei; Danz, Marjorie S; Foy, Robbie; Suttorp, Marika J; Shekelle, Paul G; Rubenstein, Lisa V

    2011-12-01

    The term continuous quality improvement (CQI) is often used to refer to a method for improving care, but no consensus statement exists on the definition of CQI. Evidence reviews are critical for advancing science, and depend on reliable definitions for article selection. As a preliminary step towards improving CQI evidence reviews, this study aimed to use expert panel methods to identify key CQI definitional features and develop and test a screening instrument for reliably identifying articles with the key features. We used a previously published method to identify 106 articles meeting the general definition of a quality improvement intervention (QII) from 9427 electronically identified articles from PubMed. Two raters then applied a six-item CQI screen to the 106 articles. Per cent agreement ranged from 55.7% to 75.5% for the six items, and reviewer-adjusted intra-class correlation ranged from 0.43 to 0.62. 'Feedback of systematically collected data' was the most common feature (64%), followed by being at least 'somewhat' adapted to local conditions (61%), feedback at meetings involving participant leaders (46%), using an iterative development process (40%), being at least 'somewhat' data driven (34%), and using a recognised change method (28%). All six features were present in 14.2% of QII articles. We conclude that CQI features can be extracted from QII articles with reasonable reliability, but only a small proportion of QII articles include all features. Further consensus development is needed to support meaningful use of the term CQI for scientific communication.

  6. Brief condom interventions targeting males in clinical settings: a meta-analysis.

    Science.gov (United States)

    Marcell, Arik V; Gibbs, Susannah; Lehmann, Harold P

    2016-02-01

    The objective of this study is to assess the effectiveness of brief clinic-based condom skills interventions that target males. We searched PubMed, Cumulative Index of Nursing and Allied Health Literature and PsychInfo for studies published from January 1980 through September 2014, using relevant search terms. We included studies if interventions taught about condoms lasting 60 min or shorter, used randomized or quasi-experimental design, were conducted in a clinical setting and targeted males. Two investigators sequentially reviewed abstracts. We abstracted and reviewed data from 16 studies that met the selection criteria. Where outcomes were poolable, we conducted meta-analyses using a random-effects model and I(2) index to assess heterogeneity. Outcome measures included condom knowledge, attitudes, behaviors, sexually transmitted infections (STIs)/human immunodeficiency virus and unintended pregnancy. Across studies, teaching about condoms was nested within sexual risk reduction curricula. Most interventions were one on one and conducted in STI clinics. Pooled analyses indicated that intervention receipt was associated with increases in percent of sex acts with condoms (standardized mean difference=0.29 [0.18, 0.41]; 0.19 [0.06, 0.33]) and reductions in STIs at 12-month follow-up or longer {odds ratio (OR)=0.82 [95% confidence interval: 0.67, 0.99]}. One study assessed unintended pregnancy and did not find an intervention effect. Study findings hold promise for considering brief condom skills interventions in clinical settings that can result in improvements in males' condom behaviors and possibly biological outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Identifying Effective Education Interventions in Sub-Saharan Africa: A Meta-Analysis of Rigorous Impact Evaluations

    Science.gov (United States)

    Conn, Katharine

    2014-01-01

    The aim of this dissertation is to identify effective educational interventions in Sub-Saharan African with an impact on student learning. This is the first meta-analysis in the field of education conducted for Sub-Saharan Africa. This paper takes an in-depth look at twelve different types of education interventions or programs and attempts to not…

  8. Targeted intervention: Computational approaches to elucidate and predict relapse in alcoholism.

    Science.gov (United States)

    Heinz, Andreas; Deserno, Lorenz; Zimmermann, Ulrich S; Smolka, Michael N; Beck, Anne; Schlagenhauf, Florian

    2017-05-01

    Alcohol use disorder (AUD) and addiction in general is characterized by failures of choice resulting in repeated drug intake despite severe negative consequences. Behavioral change is hard to accomplish and relapse after detoxification is common and can be promoted by consumption of small amounts of alcohol as well as exposure to alcohol-associated cues or stress. While those environmental factors contributing to relapse have long been identified, the underlying psychological and neurobiological mechanism on which those factors act are to date incompletely understood. Based on the reinforcing effects of drugs of abuse, animal experiments showed that drug, cue and stress exposure affect Pavlovian and instrumental learning processes, which can increase salience of drug cues and promote habitual drug intake. In humans, computational approaches can help to quantify changes in key learning mechanisms during the development and maintenance of alcohol dependence, e.g. by using sequential decision making in combination with computational modeling to elucidate individual differences in model-free versus more complex, model-based learning strategies and their neurobiological correlates such as prediction error signaling in fronto-striatal circuits. Computational models can also help to explain how alcohol-associated cues trigger relapse: mechanisms such as Pavlovian-to-Instrumental Transfer can quantify to which degree Pavlovian conditioned stimuli can facilitate approach behavior including alcohol seeking and intake. By using generative models of behavioral and neural data, computational approaches can help to quantify individual differences in psychophysiological mechanisms that underlie the development and maintenance of AUD and thus promote targeted intervention. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Screen-Time Weight-loss Intervention Targeting Children at Home (SWITCH): a randomized controlled trial.

    Science.gov (United States)

    Maddison, Ralph; Marsh, Samantha; Foley, Louise; Epstein, Leonard H; Olds, Timothy; Dewes, Ofa; Heke, Ihirangi; Carter, Karen; Jiang, Yannan; Mhurchu, Cliona Ni

    2014-09-10

    Screen-based activities, such as watching television (TV), playing video games, and using computers, are common sedentary behaviors among young people and have been linked with increased energy intake and overweight. Previous home-based sedentary behaviour interventions have been limited by focusing primarily on the child, small sample sizes, and short follow-up periods. The SWITCH (Screen-Time Weight-loss Intervention Targeting Children at Home) study aimed to determine the effect of a home-based, family-delivered intervention to reduce screen-based sedentary behaviour on body composition, sedentary behaviour, physical activity, and diet over 24 weeks in overweight and obese children. A two-arm, parallel, randomized controlled trial was conducted. Children and their primary caregiver living in Auckland, New Zealand were recruited via schools, community centres, and word of mouth. The intervention, delivered over 20 weeks, consisted of a face-to-face meeting with the parent/caregiver and the child to deliver intervention content, which focused on training and educating them to use a wide range of strategies designed to reduce their child's screen time. Families were given Time Machine TV monitoring devices to assist with allocating screen time, activity packages to promote alternative activities, online support via a website, and monthly newsletters. Control participants were given the intervention material on completion of follow-up. The primary outcome was change in children's BMI z-score from baseline to 24 weeks. Children (n = 251) aged 9-12 years and their primary caregiver were randomized to receive the SWITCH intervention (n = 127) or no intervention (controls; n = 124). There was no significant difference in change of zBMI between the intervention and control groups, although a favorable trend was observed (-0.016; 95% CI: -0.084, 0.051; p = 0.64). There were also no significant differences on secondary outcomes, except for a trend towards

  10. A Screening of UNF Targets Identifies Rnb, a Novel Regulator of Drosophila Circadian Rhythms.

    Science.gov (United States)

    Kozlov, Anatoly; Jaumouillé, Edouard; Machado Almeida, Pedro; Koch, Rafael; Rodriguez, Joseph; Abruzzi, Katharine C; Nagoshi, Emi

    2017-07-12

    Behavioral circadian rhythms are controlled by multioscillator networks comprising functionally different subgroups of clock neurons. Studies have demonstrated that molecular clocks in the fruit fly Drosophila melanogaster are regulated differently in clock neuron subclasses to support their specific functions (Lee et al., 2016; Top et al., 2016). The nuclear receptor unfulfilled ( unf ) represents a regulatory node that provides the small ventral lateral neurons (s-LNvs) unique characteristics as the master pacemaker (Beuchle et al., 2012). We previously showed that UNF interacts with the s-LNv molecular clocks by regulating transcription of the core clock gene period ( per ) (Jaumouillé et al., 2015). To gain more insight into the mechanisms by which UNF contributes to the functioning of the circadian master pacemaker, we identified UNF target genes using chromatin immunoprecipitation. Our data demonstrate that a previously uncharacterized gene CG7837 , which we termed R and B ( Rnb ), acts downstream of UNF to regulate the function of the s-LNvs as the master circadian pacemaker. Mutations and LNv-targeted adult-restricted knockdown of Rnb impair locomotor rhythms. RNB localizes to the nucleus, and its loss-of-function blunts the molecular rhythms and output rhythms of the s-LNvs, particularly the circadian rhythms in PDF accumulation and axonal arbor remodeling. These results establish a second pathway by which UNF interacts with the molecular clocks in the s-LNvs and highlight the mechanistic differences in the molecular clockwork within the pacemaker circuit. SIGNIFICANCE STATEMENT Circadian behavior is generated by a pacemaker circuit comprising diverse classes of pacemaker neurons, each of which contains a molecular clock. In addition to the anatomical and functional diversity, recent studies have shown the mechanistic differences in the molecular clockwork among the pacemaker neurons in Drosophila Here, we identified the molecular characteristics

  11. Applying Theory of Mind Concepts When Designing Interventions Targeting Social Cognition among Youth Offenders

    Science.gov (United States)

    Noel, Kristine K.; Westby, Carol

    2014-01-01

    This study employed a multiple baseline, across-participants, single-subject design to investigate the feasibility of an individual, narrative-based, social problem-solving intervention on the social problem-solving, narrative, and theory of mind (ToM) abilities of 3 incarcerated adolescent youth offenders identified as having emotional…

  12. Real-time non-rigid target tracking for ultrasound-guided clinical interventions

    Science.gov (United States)

    Zachiu, C.; Ries, M.; Ramaekers, P.; Guey, J.-L.; Moonen, C. T. W.; de Senneville, B. Denis

    2017-10-01

    Biological motion is a problem for non- or mini-invasive interventions when conducted in mobile/deformable organs due to the targeted pathology moving/deforming with the organ. This may lead to high miss rates and/or incomplete treatment of the pathology. Therefore, real-time tracking of the target anatomy during the intervention would be beneficial for such applications. Since the aforementioned interventions are often conducted under B-mode ultrasound (US) guidance, target tracking can be achieved via image registration, by comparing the acquired US images to a separate image established as positional reference. However, such US images are intrinsically altered by speckle noise, introducing incoherent gray-level intensity variations. This may prove problematic for existing intensity-based registration methods. In the current study we address US-based target tracking by employing the recently proposed EVolution registration algorithm. The method is, by construction, robust to transient gray-level intensities. Instead of directly matching image intensities, EVolution aligns similar contrast patterns in the images. Moreover, the displacement is computed by evaluating a matching criterion for image sub-regions rather than on a point-by-point basis, which typically provides more robust motion estimates. However, unlike similar previously published approaches, which assume rigid displacements in the image sub-regions, the EVolution algorithm integrates the matching criterion in a global functional, allowing the estimation of an elastic dense deformation. The approach was validated for soft tissue tracking under free-breathing conditions on the abdomen of seven healthy volunteers. Contact echography was performed on all volunteers, while three of the volunteers also underwent standoff echography. Each of the two modalities is predominantly specific to a particular type of non- or mini-invasive clinical intervention. The method demonstrated on average an accuracy of

  13. Adherence to the Obesity-related Lifestyle Intervention Targets in the IDEFICS Study

    DEFF Research Database (Denmark)

    Kovács, Eva; Siani, Alfonso; Konstabel, Kenn

    2014-01-01

    Background/objectives: To address behaviours associated with childhood obesity, certain target values are recommended that should be met to improve children’s health. In the IDEFICS (Identification and prevention of Dietary- and lifestyle-induced health Effects in Children and infantS) study such...... observed differences with respect to country, age and gender call for targeted intervention.......Background/objectives: To address behaviours associated with childhood obesity, certain target values are recommended that should be met to improve children’s health. In the IDEFICS (Identification and prevention of Dietary- and lifestyle-induced health Effects in Children and infantS) study.......9%. In general, children in northern countries and younger children showed better adherence to the recommendations. Only 1.1% of the children adhered to at least five of these recommendations. Conclusions: Current adherence of children to lifestyle recommendations to prevent childhood obesity is low where...

  14. Lifestyle interventions targeting body weight changes during the menopause transition: a systematic review.

    Science.gov (United States)

    Jull, Janet; Stacey, Dawn; Beach, Sarah; Dumas, Alex; Strychar, Irene; Ufholz, Lee-Anne; Prince, Stephanie; Abdulnour, Joseph; Prud'homme, Denis

    2014-01-01

    To determine the effectiveness of exercise and/or nutrition interventions and to address body weight changes during the menopause transition. A systematic review of the literature was conducted using electronic databases, grey literature, and hand searching. Two independent researchers screened for studies using experimental designs to evaluate the impact of exercise and/or nutrition interventions on body weight and/or central weight gain performed during the menopausal transition. Studies were quality appraised using Cochrane risk of bias. Included studies were analyzed descriptively. Of 3,564 unique citations screened, 3 studies were eligible (2 randomized controlled trials, and 1 pre/post study). Study quality ranged from low to high risk of bias. One randomized controlled trial with lower risk of bias concluded that participation in an exercise program combined with dietary interventions might mitigate body adiposity increases, which is normally observed during the menopause transition. The other two studies with higher risk of bias suggested that exercise might attenuate weight loss or weight gain and change abdominal adiposity patterns. High quality studies evaluating the effectiveness of interventions targeting body weight changes in women during their menopause transition are needed. Evidence from one higher quality study indicates an effective multifaceted intervention for women to minimize changes in body adiposity.

  15. A novel cognitive intervention for compulsive checking: Targeting maladaptive beliefs about memory.

    Science.gov (United States)

    Alcolado, Gillian M; Radomsky, Adam S

    2016-12-01

    Compulsive checking is one of the most common symptoms of obsessive-compulsive disorder (OCD). Recently it has been proposed that those who check compulsively may believe their memory is poor, rather than having an actual memory impairment. The current study sought to develop and assess a brief cognitive intervention focused on improving maladaptive beliefs about memory, as they pertain to both checking symptoms and memory performance. Participants (N = 24) with a diagnosis of OCD and clinical levels of checking symptomatology were randomly assigned either to receive two weekly 1-hour therapy sessions or to self-monitor during a similar waitlist period. Time spent checking, checking symptoms, maladaptive beliefs about memory, and visuospatial memory were assessed both pre- and post-treatment/waitlist. Results showed that compared to the waitlist condition, individuals in the treatment condition displayed significant decreases in their maladaptive beliefs about memory and checking symptoms from pre- to post-intervention. They also exhibited increased recall performance on a measure of visuospatial memory. Changes in beliefs about memory were predictors of reduced post-intervention checking, but were not predictive of increased post-intervention memory scores. The lack of long term follow-up data and use of a waitlist control leave questions about the stability and specificity of the intervention. Findings provide preliminary evidence that strategies targeting beliefs about memory may be worthy of inclusion in cognitive-behavioural approaches to treating compulsive checking. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Effects of a Workplace Intervention Targeting Psychosocial Risk Factors on Safety and Health Outcomes.

    Science.gov (United States)

    Hammer, Leslie B; Truxillo, Donald M; Bodner, Todd; Rineer, Jennifer; Pytlovany, Amy C; Richman, Amy

    2015-01-01

    The goal of this study was to test the effectiveness of a workplace intervention targeting work-life stress and safety-related psychosocial risk factors on health and safety outcomes. Data were collected over time using a randomized control trial design with 264 construction workers employed in an urban municipal department. The intervention involved family- and safety-supportive supervisor behavior training (computer-based), followed by two weeks of behavior tracking and a four-hour, facilitated team effectiveness session including supervisors and employees. A significant positive intervention effect was found for an objective measure of blood pressure at the 12-month follow-up. However, no significant intervention results were found for self-reported general health, safety participation, or safety compliance. These findings suggest that an intervention focused on supervisor support training and a team effectiveness process for planning and problem solving should be further refined and utilized in order to improve employee health with additional research on the beneficial effects on worker safety.

  17. Targeted nanotechnologies for cancer intervention: a patent review (2010-2016).

    Science.gov (United States)

    Pradeep, Priyamvada; Kumar, Pradeep; Choonara, Yahya E; Pillay, Viness

    2017-09-01

    In recent years, several active targeting nanostrategies have been patented for application in cancer theranostics. The versatility of nanostructures in terms of composition, manufacturability, functionalization, and matrix formation make them ideal for carrying large dose of bioactive contents, high density of targeting ligands on their surface, efficient delivery to the site of interest, and capable of forming multicomponent platforms. Areas covered: The patents were classified into polymeric and non-polymeric nanostructures and their applicability in addressing the targeting paradigm related to cancer intervention was explored. Specialized platforms such as nanoparticles, nanomicelles, nanocomposites, nanotubes, quantum dots, metal/silica particles, and dendrimers were cited as targeted nanostructures along with ligands such as antibody fragments, synthetic peptides, aptamers, small molecules, and folates. Here, we focused on patented targeted nanotechnological advances in recent years (2010-2016). Expert opinion: The formulation and performance prerequisites, available nanomaterial options, fabrication feasibility, and challenges and issues related with regulatory approval and patenting of cancer targeted nanocarriers are reviewed. Future research in this area should focus on clinically relevant bioactive combinations, better metastasis control, integration of imaging and theranostic techniques, predictive animal/pre-clinical models, maximal utilisation of extra- and intracellular tumor microenvironment for drug delivery, and exploring the metabolomic-, proteomic-, and genomic-based personalization of cancer nanomedicine.

  18. Catching moving targets: cancer stem cell hierarchies, therapy-resistance & considerations for clinical intervention.

    LENUS (Irish Health Repository)

    Gasch, Claudia

    2017-01-01

    It is widely believed that targeting the tumour-initiating cancer stem cell (CSC) component of malignancy has great therapeutic potential, particularly in therapy-resistant disease. However, despite concerted efforts, CSC-targeting strategies have not been efficiently translated to the clinic. This is partly due to our incomplete understanding of the mechanisms underlying CSC therapy-resistance. In particular, the relationship between therapy-resistance and the organisation of CSCs as Stem-Progenitor-Differentiated cell hierarchies has not been widely studied. In this review we argue that modern clinical strategies should appreciate that the CSC hierarchy is a dynamic target that contains sensitive and resistant components and expresses a collection of therapy-resisting mechanisms. We propose that the CSC hierarchy at primary presentation changes in response to clinical intervention, resulting in a recurrent malignancy that should be targeted differently. As such, addressing the hierarchical organisation of CSCs into our bench-side theory should expedite translation of CSC-targeting to bed-side practice. In conclusion, we discuss strategies through which we can catch these moving clinical targets to specifically compromise therapy-resistant disease.

  19. In vivo Labeling of Constellations of Functionally Identified Neurons for Targeted in vitro Recordings.

    Science.gov (United States)

    Lien, Anthony D; Scanziani, Massimo

    2011-01-01

    Relating the functional properties of neurons in an intact organism with their cellular and synaptic characteristics is necessary for a mechanistic understanding of brain function. However, while the functional properties of cortical neurons (e.g., tuning to sensory stimuli) are necessarily determined in vivo, detailed cellular and synaptic analysis relies on in vitro techniques. Here we describe an approach that combines in vivo calcium imaging (for functional characterization) with photo-activation of fluorescent proteins (for neuron labeling), thereby allowing targeted in vitro recording of multiple neurons with known functional properties. We expressed photo-activatable GFP rendered non-diffusible through fusion with a histone protein (H2B-PAGFP) in the mouse visual cortex to rapidly photo-label constellations of neurons in vivo at cellular and sub-cellular resolution using two-photon excitation. This photo-labeling method was compatible with two-photon calcium imaging of neuronal responses to visual stimuli, allowing us to label constellations of neurons with specific functional properties. Photo-labeled neurons were easily identified in vitro in acute brain slices and could be targeted for whole-cell recording. We also demonstrate that in vitro and in vivo image stacks of the same photo-labeled neurons could be registered to one another, allowing the exact in vivo response properties of individual neurons recorded in vitro to be known. The ability to perform in vitro recordings from neurons with known functional properties opens up exciting new possibilities for dissecting the cellular, synaptic, and circuit mechanisms that underlie neuronal function in vivo.

  20. A new peptide ligand for targeting human carbonic anhydrase IX, identified through the phage display technology.

    Directory of Open Access Journals (Sweden)

    Vasileios Askoxylakis

    2010-12-01

    Full Text Available Carbonic anhydrase IX (CAIX is a transmembrane enzyme found to be overexpressed in various tumors and associated with tumor hypoxia. Ligands binding this target may be used to visualize hypoxia, tumor manifestation or treat tumors by endoradiotherapy.Phage display was performed with a 12 amino acid phage display library by panning against a recombinant extracellular domain of human carbonic anhydrase IX. The identified peptide CaIX-P1 was chemically synthesized and tested in vitro on various cell lines and in vivo in Balb/c nu/nu mice carrying subcutaneously transplanted tumors. Binding, kinetic and competition studies were performed on the CAIX positive human renal cell carcinoma cell line SKRC 52, the CAIX negative human renal cell carcinoma cell line CaKi 2, the human colorectal carcinoma cell line HCT 116 and on human umbilical vein endothelial cells (HUVEC. Organ distribution studies were carried out in mice, carrying SKRC 52 tumors. RNA expression of CAIX in HCT 116 and HUVEC cells was investigated by quantitative real time PCR.In vitro binding experiments of (125I-labeled-CaIX-P1 revealed an increased uptake of the radioligand in the CAIX positive renal cell carcinoma cell line SKRC 52. Binding of the radioligand in the colorectal carcinoma cell line HCT 116 increased with increasing cell density and correlated with the mRNA expression of CAIX. Radioligand uptake was inhibited up to 90% by the unlabeled CaIX-P1 peptide, but not by the negative control peptide octreotide at the same concentration. No binding was demonstrated in CAIX negative CaKi 2 and HUVEC cells. Organ distribution studies revealed a higher accumulation in SKRC 52 tumors than in heart, spleen, liver, muscle, intestinum and brain, but a lower uptake compared to blood and kidney.These data indicate that CaIX-P1 is a promising candidate for the development of new ligands targeting human carbonic anhydrase IX.

  1. Effectiveness of interventions targeting frequent users of emergency departments: a systematic review.

    Science.gov (United States)

    Althaus, Fabrice; Paroz, Sophie; Hugli, Olivier; Ghali, William A; Daeppen, Jean-Bernard; Peytremann-Bridevaux, Isabelle; Bodenmann, Patrick

    2011-07-01

    Frequent users of emergency departments (EDs) are a relatively small group of vulnerable patients accounting for a disproportionally high number of ED visits. Our objective is to perform a systematic review of the type and effectiveness of interventions to reduce the number of ED visits by frequent users. We searched MEDLINE, EMBASE, CINAHL, PsychINFO, the Cochrane Library, and ISI Web of Science for randomized controlled trials, nonrandomized controlled trials, interrupted time series, and controlled and noncontrolled before-and-after studies describing interventions targeting adult frequent users of EDs. Primary outcome of interest was the reduction in ED use. We also explored costs analyses and various clinical (alcohol and drug use, psychiatric symptoms, mortality) and social (homelessness, insurance status, social security support) outcomes. We included 11 studies (3 randomized controlled trials, 2 controlled and 6 noncontrolled before-and-after studies). Heterogeneity in both study designs and definitions of frequent users precluded meta-analyses of the results. The most studied intervention was case management (n=7). Only 1 of 3 randomized controlled trials showed a significant reduction in ED use compared with usual care. Six of the 8 before-and-after studies reported a significant reduction in ED use, and 1 study showed a significant increase. ED cost reductions were demonstrated in 3 studies. Social outcomes such as reduction of homelessness were favorable in 3 of 3 studies, and clinical outcomes trended toward positive results in 2 of 3 studies. Interventions targeting frequent users may reduce ED use. Case management, the most frequently described intervention, reduced ED costs and seemed to improve social and clinical outcomes. It appears to be beneficial to patients and justifiable for hospitals to implement case management for frequent users in the framework of a clear and consensual definition of frequent users and standardized outcome measures

  2. Developing a multi-pollutant conceptual framework for the selection and targeting of interventions in water industry catchment management schemes.

    Science.gov (United States)

    Bloodworth, J W; Holman, I P; Burgess, P J; Gillman, S; Frogbrook, Z; Brown, P

    2015-09-15

    In recent years water companies have started to adopt catchment management to reduce diffuse pollution in drinking water supply areas. The heterogeneity of catchments and the range of pollutants that must be removed to meet the EU Drinking Water Directive (98/83/EC) limits make it difficult to prioritise areas of a catchment for intervention. Thus conceptual frameworks are required that can disaggregate the components of pollutant risk and help water companies make decisions about where to target interventions in their catchments to maximum effect. This paper demonstrates the concept of generalising pollutants in the same framework by reviewing key pollutant processes within a source-mobilisation-delivery context. From this, criteria are developed (with input from water industry professionals involved in catchment management) which highlights the need for a new water industry specific conceptual framework. The new CaRPoW (Catchment Risk to Potable Water) framework uses the Source-Mobilisation-Delivery concept as modular components of risk that work at two scales, source and mobilisation at the field scale and delivery at the catchment scale. Disaggregating pollutant processes permits the main components of risk to be ascertained so that appropriate interventions can be selected. The generic structure also allows for the outputs from different pollutants to be compared so that potential multiple benefits can be identified. CaRPow provides a transferable framework that can be used by water companies to cost-effectively target interventions under current conditions or under scenarios of land use or climate change. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  3. A Target Repurposing Approach Identifies N-myristoyltransferase as a New Candidate Drug Target in Filarial Nematodes

    Science.gov (United States)

    Villemaine, Estelle; Poole, Catherine B.; Chapman, Melissa S.; Pollastri, Michael P.; Wyatt, Paul G.; Carlow, Clotilde K. S.

    2014-01-01

    Myristoylation is a lipid modification involving the addition of a 14-carbon unsaturated fatty acid, myristic acid, to the N-terminal glycine of a subset of proteins, a modification that promotes their binding to cell membranes for varied biological functions. The process is catalyzed by myristoyl-CoA:protein N-myristoyltransferase (NMT), an enzyme which has been validated as a drug target in human cancers, and for infectious diseases caused by fungi, viruses and protozoan parasites. We purified Caenorhabditis elegans and Brugia malayi NMTs as active recombinant proteins and carried out kinetic analyses with their essential fatty acid donor, myristoyl-CoA and peptide substrates. Biochemical and structural analyses both revealed that the nematode enzymes are canonical NMTs, sharing a high degree of conservation with protozoan NMT enzymes. Inhibitory compounds that target NMT in protozoan species inhibited the nematode NMTs with IC50 values of 2.5–10 nM, and were active against B. malayi microfilariae and adult worms at 12.5 µM and 50 µM respectively, and C. elegans (25 µM) in culture. RNA interference and gene deletion in C. elegans further showed that NMT is essential for nematode viability. The effects observed are likely due to disruption of the function of several downstream target proteins. Potential substrates of NMT in B. malayi are predicted using bioinformatic analysis. Our genetic and chemical studies highlight the importance of myristoylation in the synthesis of functional proteins in nematodes and have shown for the first time that NMT is required for viability in parasitic nematodes. These results suggest that targeting NMT could be a valid approach for the development of chemotherapeutic agents against nematode diseases including filariasis. PMID:25188325

  4. Why use of interventions targeting outdoor biting mosquitoes will be necessary to achieve malaria elimination

    Directory of Open Access Journals (Sweden)

    Nicodem James Govella

    2012-06-01

    Full Text Available By definition, elimination of malaria means permanent reduction to zero of locally incidence of infections. Achieving this goal among other reasons, it requires fully understanding on where and when persons are most exposed to malaria vectors as these are fundamental for targeting interventions to achieve maximum impact. While elimination can be possible in some settings with low malaria transmission intensity and dominated with late and indoor biting of vectors using Long Lasting Insecticidal Nets (LLIN and Indoor Residual Spraying (IRs, it’s difficult and even impossible in areas with high and where majority of human exposure to transmission occurs outside human dwellings. Recently in response to wide spread use of LLIN and IRS, human risk of exposure to transmission is increasingly spread across the entire night so that much of it occurs outdoors and before bed time. This modification of vector populations and behaviour has now been reported from across Africa, Asia and from the Solomon Islands. Historical evidence shows that even in areas with intervention coverage exceeding 90% of human population it was so hard to even push prevalence down below the pre elimination threshold of 1% being compromised mainly with the outdoor residual transmission. Malaria control experts must however continue to deliver interventions that tackle indoor transmission but considerable amount of resources that target mosquitoes outside of houses and outside of sleeping hours will therefore be required to sustain and go beyond existing levels of malaria control and achieve elimination.

  5. Distribution and determinants of risk of teenage motherhood in three British longitudinal studies: implications for targeted prevention interventions.

    Science.gov (United States)

    Kneale, Dylan; Fletcher, Adam; Wiggins, Richard; Bonell, Chris

    2013-01-01

    In order to consider the potential contribution of universal versus targeted prevention interventions, the authors examined what is the distribution of established risk variables for teenage motherhood? from where in these distributions do births arise? and how does this distribution/determination of risk vary between studies? Secondary data analysis of three British longitudinal studies. For all cohorts and variables, the 'risk' category was the least frequent. Continuous risk factors were normally distributed. A high rate of teenage motherhood within a risk category often translated into low 'contribution' to the overall rate (eg, expectation to leave school at the minimum age among the 1989/1990-born cohort) and vice versa. Most young women had a low probability of teenage motherhood. For any targeting strategy, combining risk factors and a low threshold of predicted probability would be necessary to achieve adequate sensitivity. Assessing between-cohort applicability of findings, the authors find that the numbers of teenage parents is poorly estimated and estimates of the variability and direction of risk may also be inadequate. With reference to a number of established risk factors, there is not a core of easily identifiable multiply disadvantaged girls who go on to constitute the majority of teenage mothers in these studies. While individual risk factors are unlikely to enable targeting, a composite may have some limited potential, albeit with a low threshold for 'risk' and with the caveat that evidence from one population may not inform good targeting in another. It is likely that universal approaches will have more impact.

  6. Novel snail1 target proteins in human colon cancer identified by proteomic analysis.

    Directory of Open Access Journals (Sweden)

    María Jesús Larriba

    2010-04-01

    Full Text Available The transcription factor Snail1 induces epithelial-to-mesenchymal transition (EMT, a process responsible for the acquisition of invasiveness during tumorigenesis. Several transcriptomic studies have reported Snail1-regulated genes in different cell types, many of them involved in cell adhesion. However, only a few studies have used proteomics as a tool for the characterization of proteins mediating EMT.We identified by proteomic analysis using 2D-DIGE electrophoresis combined with MALDI-TOF-TOF and ESI-linear ion trap mass spectrometry a number of proteins with variable functions whose expression is modulated by Snail1 in SW480-ADH human colon cancer cells. Validation was performed by Western blot and immunofluorescence analyses. Snail1 repressed several members of the 14-3-3 family of phosphoserine/phosphothreonine binding proteins and also the expression of the Proliferation-associated protein 2G4 (PA2G4 that was mainly localized at the nuclear Cajal bodies. In contrast, the expression of two proteins involved in RNA processing, the Cleavage and polyadenylation specificity factor subunit 6 (CPSF6 and the Splicing factor proline/glutamine-rich (SFPQ, was higher in Snail1-expressing cells than in controls. The regulation of 14-3-3epsilon, 14-3-3tau, 14-3-3zeta and PA2G4 by Snail1 was reproduced in HT29 colon cancer cells. In addition, we found an inverse correlation between 14-3-3sigma and Snail1 expression in human colorectal tumors.We have identified a set of novel Snail1 target proteins in colon cancer that expand the cellular processes affected by Snail1 and thus its relevance for cell function and phenotype.

  7. Comprehensive analyses of ventricular myocyte models identify targets exhibiting favorable rate dependence.

    Directory of Open Access Journals (Sweden)

    Megan A Cummins

    2014-03-01

    Full Text Available Reverse rate dependence is a problematic property of antiarrhythmic drugs that prolong the cardiac action potential (AP. The prolongation caused by reverse rate dependent agents is greater at slow heart rates, resulting in both reduced arrhythmia suppression at fast rates and increased arrhythmia risk at slow rates. The opposite property, forward rate dependence, would theoretically overcome these parallel problems, yet forward rate dependent (FRD antiarrhythmics remain elusive. Moreover, there is evidence that reverse rate dependence is an intrinsic property of perturbations to the AP. We have addressed the possibility of forward rate dependence by performing a comprehensive analysis of 13 ventricular myocyte models. By simulating populations of myocytes with varying properties and analyzing population results statistically, we simultaneously predicted the rate-dependent effects of changes in multiple model parameters. An average of 40 parameters were tested in each model, and effects on AP duration were assessed at slow (0.2 Hz and fast (2 Hz rates. The analysis identified a variety of FRD ionic current perturbations and generated specific predictions regarding their mechanisms. For instance, an increase in L-type calcium current is FRD when this is accompanied by indirect, rate-dependent changes in slow delayed rectifier potassium current. A comparison of predictions across models identified inward rectifier potassium current and the sodium-potassium pump as the two targets most likely to produce FRD AP prolongation. Finally, a statistical analysis of results from the 13 models demonstrated that models displaying minimal rate-dependent changes in AP shape have little capacity for FRD perturbations, whereas models with large shape changes have considerable FRD potential. This can explain differences between species and between ventricular cell types. Overall, this study provides new insights, both specific and general, into the determinants of

  8. Identifying foods with good nutritional quality and price for the Opticourses intervention research project.

    Science.gov (United States)

    Dubois, Christophe; Tharrey, Marion; Darmon, Nicole

    2017-12-01

    People on a limited budget want to know the 'good price' of foods. Here we report the methodology used to produce an educational tool designed to help recognize foods with good nutritional quality and price, and assess the validity and relevancy of the tool. A 'Good Price Booklet' presenting a list of foods with good nutritional quality and price was constructed. The validity of the in-booklet prices was assessed by comparing them with prices actually paid by households from the Opticourses project. The relevancy of the booklet tool was assessed by semi-structured interviews with Opticourses participants. Socio-economically disadvantaged neighbourhoods of Marseille, France. Ninety-one participants collected household food-purchase receipts over a 1-month period. Based on the French food database, foods with higher-than-median nutritional quality were identified. After grouping similar foods, 100 foods were selected and their corresponding in-booklet prices were derived based on the distribution of average national prices by food group. Household food purchases data revealed that of the 2386 purchases of foods listed in the booklet, 67·1 % were bought at prices lower than the in-booklet prices. Nineteen semi-structured interviews showed that participants understood the tool and most continued using it more than a month after the intervention. A method was developed to ease the identification of foods with good nutritional quality and price. The Good Price Booklet is an effective tool to help guide people shopping on a low budget.

  9. High diversity of Cryptosporidium subgenotypes identified in Malaysian HIV/AIDS individuals targeting gp60 gene.

    Directory of Open Access Journals (Sweden)

    Asma Iqbal

    Full Text Available BACKGROUND: Currently, there is a lack of vital information in the genetic makeup of Cryptosporidium especially in developing countries. The present study aimed at determining the genotypes and subgenotypes of Cryptosporidium in hospitalized Malaysian human immunodeficiency virus (HIV positive patients. METHODOLOGY/PRINCIPAL FINDINGS: In this study, 346 faecal samples collected from Malaysian HIV positive patients were genetically analysed via PCR targeting the 60 kDa glycoprotein (gp60 gene. Eighteen (5.2% of 346 isolates were determined as Cryptosporidium positive with 72.2% (of 18 identified as Cryptosporidium parvum whilst 27.7% as Cryptosporidium hominis. Further gp60 analysis revealed C. parvum belonging to subgenotypes IIaA13G1R1 (2 isolates, IIaA13G2R1 (2 isolates, IIaA14G2R1 (3 isolates, IIaA15G2R1 (5 isolates and IIdA15G1R1 (1 isolate. C. hominis was represented by subgenotypes IaA14R1 (2 isolates, IaA18R1 (1 isolate and IbA10G2R2 (2 isolates. CONCLUSIONS/SIGNIFICANCE: These findings highlighted the presence of high diversity of Cryptosporidium subgenotypes among Malaysian HIV infected individuals. The predominance of the C. parvum subgenotypes signified the possibility of zoonotic as well as anthroponotic transmissions of cryptosporidiosis in HIV infected individuals.

  10. Generating political priority for regulatory interventions targeting obesity prevention: an Australian case study.

    Science.gov (United States)

    Baker, Phillip; Gill, Timothy; Friel, Sharon; Carey, Gemma; Kay, Adrian

    2017-03-01

    rationales to defer political priority. Overcoming these challenges may be important to future collective action efforts attempting to generate and sustain political priority for regulatory interventions targeting obesity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. A Narrative Review of Social Media and Game-Based Nutrition Interventions Targeted at Young Adults.

    Science.gov (United States)

    Nour, Monica; Yeung, Sin Hang; Partridge, Stephanie; Allman-Farinelli, Margaret

    2017-05-01

    The increased popularity of social media and mobile gaming among young adults provides an opportunity for innovative nutrition programs. This review evaluated the efficacy of these strategies in interventions targeted at 18- to 35-year-olds. The protocol was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Ten scientific databases, information technology conference proceedings, and gray literature were searched. Two reviewers conducted screening, data extraction, and quality assessments. Interventions were included if they used social media or electronic games. Comparisons were made pre- to post-intervention, or between intervention and control arms. Outcomes of interest included change in nutrition knowledge, attitudes, behavior, or weight and/or body composition. Eleven social media-based (randomized controlled trials [RCT] n=7) and six game-based [RCT n=1]) interventions were included. Overall quality of studies was low. Social media-based strategies included forum/blogs (n=5), Facebook (n=5), Twitter (n=1), YouTube (n=1), and chat rooms (n=1). Eight (RCT n=6) of 11 social media-based studies demonstrated improvements in outcomes. Findings suggested that social media may be more effective when combined with other strategies. Virtual reality games (n=3), web-based games (n=2), and a mobile application (n=1) were used in the gaming interventions. While a significant increase in knowledge was reported by three gaming studies (RCT=1), two used nonvalidated tools and longer-term measures of weight and behavioral outcomes were limited. The use of social media and gaming for nutrition promotion is in its infancy. Preliminary evidence suggests that these strategies have some utility for intervening with young adults. Further research using high-quality study designs is required, with measurement of outcomes over longer time periods. The systematic review protocol is registered with PROSPERO (registration number: CRD42015025427

  12. Can children identify and achieve goals for intervention? A randomized trial comparing two goal-setting approaches.

    Science.gov (United States)

    Vroland-Nordstrand, Kristina; Eliasson, Ann-Christin; Jacobsson, Helén; Johansson, Ulla; Krumlinde-Sundholm, Lena

    2016-06-01

    The efficacy of two different goal-setting approaches (children's self-identified goals and goals identified by parents) were compared on a goal-directed, task-oriented intervention. In this assessor-blinded parallel randomized trial, 34 children with disabilities (13 males, 21 females; mean age 9y, SD 1y 4mo) were randomized using concealed allocation to one of two 8-week, goal-directed, task-oriented intervention groups with different goal-setting approaches: (1) children's self-identified goals (n=18) using the Perceived Efficacy and Goal-Setting System, or (2) goals identified by parents (n=16) using the Canadian Occupational Performance Measure (COPM). Participants were recruited through eight paediatric rehabilitation centres and randomized between October 2011 and May 2013. The primary outcome measure was the Goal Attainment Scaling and the secondary measure, the COPM performance scale (COPM-P). Data were collected pre- and post-intervention and at the 5-month follow-up. There was no evidence of a difference in mean characteristics at baseline between groups. There was evidence of an increase in mean goal attainment (mean T score) in both groups after intervention (child-goal group: estimated mean difference [EMD] 27.84, 95% CI 22.93-32.76; parent-goal group: EMD 21.42, 95% CI 16.16-26.67). There was no evidence of a difference in the mean T scores post-intervention between the two groups (EMD 6.42, 95% CI -0.80 to 13.65). These results were sustained at the 5-month follow-up. Children's self-identified goals are achievable to the same extent as parent-identified goals and remain stable over time. Thus children can be trusted to identify their own goals for intervention, thereby influencing their involvement in their intervention programmes. © 2015 Mac Keith Press.

  13. Molecular Targets Related to Inflammation and Insulin Resistance and Potential Interventions

    Directory of Open Access Journals (Sweden)

    Sandro M. Hirabara

    2012-01-01

    Full Text Available Inflammation and insulin resistance are common in several chronic diseases, such as obesity, type 2 diabetes mellitus, metabolic syndrome, cancer, and cardiovascular diseases. Various studies show a relationship between these two factors, although the mechanisms involved are not completely understood yet. Here, we discuss the molecular basis of insulin resistance and inflammation and the molecular aspects on inflammatory pathways interfering in insulin action. Moreover, we explore interventions based on molecular targets for preventing or treating correlated disorders, advances for a better characterization, and understanding of the mechanisms and mediators involved in the different inflammatory and insulin resistance conditions. Finally, we address biotechnological studies for the development of new potential therapies and interventions.

  14. Identifying water price and population criteria for meeting future urban water demand targets

    Science.gov (United States)

    Ashoori, Negin; Dzombak, David A.; Small, Mitchell J.

    2017-12-01

    Predictive models for urban water demand can help identify the set of factors that must be satisfied in order to meet future targets for water demand. Some of the explanatory variables used in such models, such as service area population and changing temperature and rainfall rates, are outside the immediate control of water planners and managers. Others, such as water pricing and the intensity of voluntary water conservation efforts, are subject to decisions and programs implemented by the water utility. In order to understand this relationship, a multiple regression model fit to 44 years of monthly demand data (1970-2014) for Los Angeles, California was applied to predict possible future demand through 2050 under alternative scenarios for the explanatory variables: population, price, voluntary conservation efforts, and temperature and precipitation outcomes predicted by four global climate models with two CO2 emission scenarios. Future residential water demand in Los Angeles is projected to be largely driven by price and population rather than climate change and conservation. A median projection for the year 2050 indicates that residential water demand in Los Angeles will increase by approximately 36 percent, to a level of 620 million m3 per year. The Monte Carlo simulations of the fitted model for water demand were then used to find the set of conditions in the future for which water demand is predicted to be above or below the Los Angeles Department of Water and Power 2035 goal to reduce residential water demand by 25%. Results indicate that increases in price can not ensure that the 2035 water demand target can be met when population increases. Los Angeles must rely on furthering their conservation initiatives and increasing their use of stormwater capture, recycled water, and expanding their groundwater storage. The forecasting approach developed in this study can be utilized by other cities to understand the future of water demand in water-stressed areas

  15. Social capital interventions targeting older people and their impact on health: a systematic review.

    Science.gov (United States)

    Coll-Planas, Laura; Nyqvist, Fredrica; Puig, Teresa; Urrútia, Gerard; Solà, Ivan; Monteserín, Rosa

    2017-07-01

    Observational studies show that social capital is a protective health factor. Therefore, we aim to assess the currently unclear health impact of social capital interventions targeting older adults. We conducted a systematic review based on a logic model. Studies published between January 1980 and July 2015 were retrieved from MEDLINE, EMBASE, CINAHL, PsycINFO, Cochrane Central Register of Controlled Trials and Web of Science. We included randomised controlled trials targeting participants over 60 years old and focused on social capital or its components (eg, social support and social participation). The comparison group should not promote social capital. We assessed risk of bias and impact on health outcomes and use of health-related resources applying a procedure from the Canadian Agency for Drugs and Technologies in Health (CADTH) based on vote-counting and standardised decision rules. The review protocol was registered in PROSPERO (reference number CRD42014015362). We examined 17 341 abstracts and included 73 papers reporting 36 trials. Trials were clinically and methodologically diverse and reported positive effects in different contexts, populations and interventions across multiple subjective and objective measures. According to sufficiently reported outcomes, social capital interventions showed mixed effects on quality of life, well-being and self-perceived health and were generally ineffective on loneliness, mood and mortality. Eight trials with high quality showed favourable impacts on overall, mental and physical health, mortality and use of health-related resources. Our review highlights the lack of evidence and the diversity among trials, while supporting the potential of social capital interventions to reach comprehensive health effects in older adults. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  16. Systematic Review of Behavioral Interventions Targeting Social Communication Difficulties After Traumatic Brain Injury.

    Science.gov (United States)

    Finch, Emma; Copley, Anna; Cornwell, Petrea; Kelly, Crystal

    2016-08-01

    To determine whether behavioral interventions are beneficial for adults with social communication difficulties after traumatic brain injury (TBI). Electronic databases were searched through October 2013 to find behavioral intervention trials. Keywords used in our search were intervention, therapy, treatment, and program combined with pragmatic disorder, pragmatic impairment, social communication disorder/impairment, conversation disorder/impairment, social disorder/impairment, cognitive-linguistic and cognitive-communication deficit; adult; and traumatic brain injury, head injury, and brain injury. Hand searches of the reference lists of relevant articles were also conducted. To be selected for detailed review, articles found in the initial search were assessed by 2 reviewers and had to meet the following criteria: (1) population (adults with TBI); (2) intervention (behavioral intervention); and (3) outcomes (changes in social communication). Articles needed to describe interventions that were delivered directly to adults with TBI with or without other people (such as significant others) involved. Of the 2181 articles initially identified, 15 were selected for detailed review. Data were independently extracted by members of the research team, then collated and reviewed by the team. Of the 15 publications that met the study criteria, 7 were single-case design studies, 3 were randomized controlled trials, 1 was a nonrandomized controlled trial, and 4 were cohort studies. The methodological qualities of eligible articles were examined using the Physiotherapy Evidence Database and Single-Case Experimental Design rating scales. The interventions described in the studies fell into 2 broad categories: those addressing a specific impairment in social communication, and context-specific interventions with a holistic focus on social communication skills. Studies using context-sensitive approaches had been published more recently and were generally group studies with higher

  17. Identifying Key Drivers of the Impact of an HIV Cure Intervention in Sub-Saharan Africa

    DEFF Research Database (Denmark)

    Phillips, Andrew N; Cambiano, Valentina; Revill, Paul

    2016-01-01

    of introducing an ART-free viral suppression intervention in 2022 using Zimbabwe as an example country. We assumed that the intervention (cost: $500) would be accessible for 90% of the population, be given to those receiving effective ART, have sufficient efficacy to allow ART interruption in 95%, with a rate...

  18. Exploring the Gaps in Practical Ethical Guidance for Animal Welfare Considerations of Field Interventions and Innovations Targeting Dogs and Cats

    Science.gov (United States)

    Tasker, Louisa; Getty, Susan F.; Briggs, Joyce R.; Benka, Valerie A.W.

    2018-01-01

    Simple Summary Large populations of domestic dogs and cats are found living, or in close association with humans. They are often targeted by field interventions or innovations to enhance their welfare or to reduce conflict with communities or wildlife. Ethical review is a cornerstone of responsible engagement that aims to promote animal and human wellbeing. For the review process to be robust, identifying and understanding the ethical dilemmas that may be encountered when working with dogs and cats in field contexts, together with their human communities and in multi-stakeholder partnerships would be advantageous. We explored existing guidance from other disciplines (regulated animal research, veterinary and human clinical trials, and research conducted on wildlife) and identified gaps in ethical frameworks that do not adequately address the specific and practical needs of nongovernmental or intergovernmental organizations, government agencies or independent researchers working with dogs and cats in field contexts. Navigating practical ethical concerns in complex, highly variable field contexts necessitates the development of additional resources that can better inform reliable ethical review processes, and subsequently enhance the humaneness and effectiveness of future interventions and innovations. Abstract Domestic dogs (Canis lupus familiaris) and cats (Felis silvestris catus) are common species targeted by nongovernmental or intergovernmental organizations, veterinarians and government agencies worldwide, for field interventions (e.g., population management, rabies vaccination programs) or innovations (e.g., development of technologies or pharmaceuticals to improve animal welfare). We have a moral responsibility to ensure that the conduct of this work is humane for dogs or cats, and to consider the human communities in which the animals live. Ethical review is widely accepted as being integral to responsible practice, and it is fundamental to good science that

  19. Efficient Isothermal Titration Calorimetry Technique Identifies Direct Interaction of Small Molecule Inhibitors with the Target Protein.

    Science.gov (United States)

    Gal, Maayan; Bloch, Itai; Shechter, Nelia; Romanenko, Olga; Shir, Ofer M

    2016-01-01

    Protein-protein interactions (PPI) play a critical role in regulating many cellular processes. Finding novel PPI inhibitors that interfere with specific binding of two proteins is considered a great challenge, mainly due to the complexity involved in characterizing multi-molecular systems and limited understanding of the physical principles governing PPIs. Here we show that the combination of virtual screening techniques, which are capable of filtering a large library of potential small molecule inhibitors, and a unique secondary screening by isothermal titration calorimetry, a label-free method capable of observing direct interactions, is an efficient tool for finding such an inhibitor. In this study we applied this strategy in a search for a small molecule capable of interfering with the interaction of the tumor-suppressor p53 and the E3-ligase MDM2. We virtually screened a library of 15 million small molecules that were filtered to a final set of 80 virtual hits. Our in vitro experimental assay, designed to validate the activity of mixtures of compounds by isothermal titration calorimetry, was used to identify an active molecule against MDM2. At the end of the process the small molecule (4S,7R)-4-(4-chlorophenyl)-5-hydroxy-2,7-dimethyl-N-(6-methylpyridin-2-yl)-4,6,7,8 tetrahydrIoquinoline-3-carboxamide was found to bind MDM2 with a dissociation constant of ~2 µM. Following the identification of this single bioactive compound, spectroscopic measurements were used to further characterize the interaction of the small molecule with the target protein. 2D NMR spectroscopy was used to map the binding region of the small molecule, and fluorescence polarization measurement confirmed that it indeed competes with p53.

  20. Targeted capture enrichment and sequencing identifies extensive nucleotide variation in the turkey MHC-B.

    Science.gov (United States)

    Reed, Kent M; Mendoza, Kristelle M; Settlage, Robert E

    2016-03-01

    Variation in the major histocompatibility complex (MHC) is increasingly associated with disease susceptibility and resistance in avian species of agricultural importance. This variation includes sequence polymorphisms but also structural differences (gene rearrangement) and copy number variation (CNV). The MHC has now been described for multiple galliform species including the best defined assemblies of the chicken (Gallus gallus) and domestic turkey (Meleagris gallopavo). Using this sequence resource, this study applied high-throughput sequencing to investigate MHC variation in turkeys of North America (NA turkeys). An MHC-specific SureSelect (Agilent) capture array was developed, and libraries were created for 14 turkeys representing domestic (commercial bred), heritage breed, and wild turkeys. In addition, a representative of the Ocellated turkey (M. ocellata) and chicken (G. gallus) was included to test cross-species applicability of the capture array allowing for identification of new species-specific polymorphisms. Libraries were hybridized to ∼12 K cRNA baits and the resulting pools were sequenced. On average, 98% of processed reads mapped to the turkey whole genome sequence and 53% to the MHC target. In addition to the MHC, capture hybridization recovered sequences corresponding to other MHC regions. Sequence alignment and de novo assembly indicated the presence of several additional BG genes in the turkey with evidence for CNV. Variant detection identified an average of 2245 polymorphisms per individual for the NA turkeys, 3012 for the Ocellated turkey, and 462 variants in the chicken (RJF-256). This study provides an extensive sequence resource for examining MHC variation and its relation to health of this agriculturally important group of birds.

  1. Network analysis of translocated Takahe populations to identify disease surveillance targets.

    Science.gov (United States)

    Grange, Zoë L; VAN Andel, Mary; French, Nigel P; Gartrell, Brett D

    2014-04-01

    network in 2011. Likewise, the wild Murchison Mountains population was consistently the sink of the network. Other nodes, such as the offshore islands and the wildlife hospital, varied in importance over time. Common network descriptors and measures of centrality identified key locations for targeting disease surveillance. The visual representation of movements of animals in a population that this technique provides can aid decision makers when they evaluate translocation proposals or attempt to control a disease outbreak. © 2014 Society for Conservation Biology.

  2. Identifying optimal areas for REDD intervention: East Kalimantan, Indonesia as a case study

    International Nuclear Information System (INIS)

    Harris, Nancy L; Petrova, Silvia; Brown, Sandra; Stolle, Fred

    2008-01-01

    International discussions on reducing emissions from deforestation and degradation (REDD) as a greenhouse gas (GHG) abatement strategy are ongoing under the United Nations Framework Convention on Climate Change (UNFCCC). In the light of these discussions, it behooves countries to be able to determine the relative likelihood of deforestation over a landscape and perform a first order estimation of the potential reduction in GHGs associated with various protection scenarios. This would allow countries to plan their interventions accordingly to maximize carbon benefits, alongside other environmental and socioeconomic benefits, because forest protection programs might be chosen in places where the perceived threat of deforestation is high whereas in reality the threat is low. In this case study, we illustrate a method for creating deforestation threat maps and estimating potential reductions in GHGs from eighteen protected areas in East Kalimantan, Indonesia, that would occur if protection of these areas was well enforced. Results from our analysis indicate that a further 230 720 ha of East Kalimantan's forest area would be lost and approximately 305 million t CO 2 would be emitted from existing protected areas between 2003 and 2013 if the historical rate of deforestation continued unabated. In other words, the emission of 305 million t CO 2 into the atmosphere would be avoided during this period if protection of the existing areas was well enforced. At a price of $4 per ton of CO 2 (approximate price on the Chicago Climate Exchange in August 2008), this represents an estimated gross income stream of about $120 million per year. We also identified additional areas with high carbon stocks under high deforestation threat that would be important to protect if the carbon benefits of avoided deforestation activities are to be maximized in this region

  3. Stakeholder engagement analysis - a bioethics dilemma in patient-targeted intervention: patients with temporomandibular joint disorders.

    Science.gov (United States)

    Barkhordarian, Andre; Demerjian, Gary; Jan, Allison; Sama, Nateli; Nguyen, Mia; Du, Angela; Chiappelli, Francesco

    2015-01-20

    Modern health care in the field of Medicine, Dentistry and Nursing is grounded in fundamental philosophy and epistemology of translational science. Recently in the U.S major national initiatives have been implemented in the hope of closing the gaps that sometimes exist between the two fundamental components of translational science, the translational research and translational effectiveness. Subsequent to these initiatives, many improvements have been made; however, important bioethical issues and limitations do still exist that need to be addressed. One such issue is the stakeholder engagement and its assessment and validation. Federal, state and local organizations such as PCORI and AHRQ concur that the key to a better understanding of the relationship between translational research and translational effectiveness is the assessment of the extent to which stakeholders are actively engaged in the translational process of healthcare. The stakeholder engagement analysis identifies who the stakeholders are, maps their contribution and involvement, evaluates their priorities and opinions, and accesses their current knowledge base. This analysis however requires conceptualization and validation from the bioethics standpoint. Here, we examine the bioethical dilemma of stakeholder engagement analysis in the context of the person-environment fit (PE-fit) theoretical model. This model is an approach to quantifying stakeholder engagement analysis for the design of patient-targeted interventions. In our previous studies of Alzheimer patients, we have developed, validated and used a simple instrument based on the PE-fit model that can be adapted and utilized in a much less studied pathology as a clinical model that has a wide range of symptoms and manifestations, the temporomandibular joint disorders (TMD). The temporomandibular joint (TMJ) is the jaw joint endowed with sensory and motor innervations that project from within the central nervous system and its dysfunction can

  4. Frameworks for Proof-of-Concept Clinical Trials of Interventions That Target Fundamental Aging Processes

    Science.gov (United States)

    Justice, Jamie; Miller, Jordan D.; Newman, John C.; Hashmi, Shahrukh K.; Halter, Jeffrey; Austad, Steve N.; Barzilai, Nir

    2016-01-01

    Therapies targeted at fundamental processes of aging may hold great promise for enhancing the health of a wide population by delaying or preventing a range of age-related diseases and conditions—a concept dubbed the “geroscience hypothesis.” Early, proof-of-concept clinical trials will be a key step in the translation of therapies emerging from model organism and preclinical studies into clinical practice. This article summarizes the outcomes of an international meeting partly funded through the NIH R24 Geroscience Network, whose purpose was to generate concepts and frameworks for early, proof-of-concept clinical trials for therapeutic interventions that target fundamental processes of aging. The goals of proof-of-concept trials include generating preliminary signals of efficacy in an aging-related disease or outcome that will reduce the risk of conducting larger trials, contributing data and biological samples to support larger-scale research by strategic networks, and furthering a dialogue with regulatory agencies on appropriate registration indications. We describe three frameworks for proof-of-concept trials that target age-related chronic diseases, geriatric syndromes, or resilience to stressors. We propose strategic infrastructure and shared resources that could accelerate development of therapies that target fundamental aging processes. PMID:27535966

  5. Identifying the content of home-based health behaviour change interventions for frail older people: a systematic review protocol.

    Science.gov (United States)

    Jovicic, Ana; Gardner, Benjamin; Belk, Celia; Kharicha, Kalpa; Iliffe, Steve; Manthorpe, Jill; Goodman, Claire; Drennan, Vari; Walters, Kate

    2015-11-04

    Meeting the needs of the growing number of older people is a challenge for health and social care services. Home-based interventions aiming to modify health-related behaviours of frail older people have the potential to improve functioning and well-being. Previous reviews have focused on whether such interventions are effective, rather than what might make them effective. Recent advances in behavioural science make possible the identification of potential 'active ingredients' of effective interventions, such as component behaviour change techniques (BCTs), and intended intervention functions (IFs; e.g. to educate, to impart skills). This paper reports a protocol for a systematic review that seeks to (a) identify health behaviour change interventions for older frail people, (b) describe the content of these interventions, and (c) explore links between intervention content and effectiveness. The protocol is reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) 2015 guidelines. Studies will be identified through a systematic search of 15 electronic databases, supplemented by citation tracking. Studies will be retained for review where they report randomised controlled trials focusing on home-based health promotion delivered by a health professional for frail older people in community settings, written in English, and either published from 1980 onwards, or, for registered trials only, unpublished but completed with results obtainable from authors. Interventions will be coded for their content (BCTs, IFs) and for evidence of effectiveness (outcome data relating to behavioural and health outcomes). Analyses will describe characteristics of all interventions. Interventions for which effectiveness data are available will be categorised into those showing evidence of effectiveness versus those showing no such evidence. The potential for each intervention characteristic to contribute to change in behaviour or

  6. Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease.

    Directory of Open Access Journals (Sweden)

    Daniel W Neef

    2010-01-01

    Full Text Available Neurodegenerative diseases such as Huntington disease are devastating disorders with no therapeutic approaches to ameliorate the underlying protein misfolding defect inherent to poly-glutamine (polyQ proteins. Given the mounting evidence that elevated levels of protein chaperones suppress polyQ protein misfolding, the master regulator of protein chaperone gene transcription, HSF1, is an attractive target for small molecule intervention. We describe a humanized yeast-based high-throughput screen to identify small molecule activators of human HSF1. This screen is insensitive to previously characterized activators of the heat shock response that have undesirable proteotoxic activity or that inhibit Hsp90, the central chaperone for cellular signaling and proliferation. A molecule identified in this screen, HSF1A, is structurally distinct from other characterized small molecule human HSF1 activators, activates HSF1 in mammalian and fly cells, elevates protein chaperone expression, ameliorates protein misfolding and cell death in polyQ-expressing neuronal precursor cells and protects against cytotoxicity in a fly model of polyQ-mediated neurodegeneration. In addition, we show that HSF1A interacts with components of the TRiC/CCT complex, suggesting a potentially novel regulatory role for this complex in modulating HSF1 activity. These studies describe a novel approach for the identification of new classes of pharmacological interventions for protein misfolding that underlies devastating neurodegenerative disease.

  7. Targeted neural network interventions for auditory hallucinations: Can TMS inform DBS?

    Science.gov (United States)

    Taylor, Joseph J; Krystal, John H; D'Souza, Deepak C; Gerrard, Jason Lee; Corlett, Philip R

    2017-09-29

    The debilitating and refractory nature of auditory hallucinations (AH) in schizophrenia and other psychiatric disorders has stimulated investigations into neuromodulatory interventions that target the aberrant neural networks associated with them. Internal or invasive forms of brain stimulation such as deep brain stimulation (DBS) are currently being explored for treatment-refractory schizophrenia. The process of developing and implementing DBS is limited by symptom clustering within psychiatric constructs as well as a scarcity of causal tools with which to predict response, refine targeting or guide clinical decisions. Transcranial magnetic stimulation (TMS), an external or non-invasive form of brain stimulation, has shown some promise as a therapeutic intervention for AH but remains relatively underutilized as an investigational probe of clinically relevant neural networks. In this editorial, we propose that TMS has the potential to inform DBS by adding individualized causal evidence to an evaluation processes otherwise devoid of it in patients. Although there are significant limitations and safety concerns regarding DBS, the combination of TMS with computational modeling of neuroimaging and neurophysiological data could provide critical insights into more robust and adaptable network modulation. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Gut microbiota: A player in aging and a target for anti-aging intervention.

    Science.gov (United States)

    Vaiserman, Alexander M; Koliada, Alexander K; Marotta, Francesco

    2017-05-01

    Aging-associated alterations in composition, diversity and functional features of intestinal microbiota are well-described in the modern literature. They are suggested to be caused by an age-related decline in immune system functioning (immunosenescence) and a low-grade chronic inflammation (inflammaging), which accompany many aging-associated pathologies. The microbiota-targeted dietary and probiotic interventions have been shown to favorably affect the host health and aging by an enhancement of antioxidant activity, improving immune homeostasis, suppression of chronic inflammation, regulation of fat deposition and metabolism and prevention of insulin resistance. Recently, a high effectiveness and safety of novel therapeutic application such as fecal microbiota transplantation in the prevention and treatment of age-related pathological conditions including atherosclerosis, type 2 diabetes and Parkinson's disease has been demonstrated. In this review, recent research findings are summarized on the role of gut micribiota in aging processes with emphasis on therapeutic potential of microbiome-targeted interventions in anti-aging medicine. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Targeted intervention strategies to optimise diversion of BMW in the Dublin, Ireland region

    International Nuclear Information System (INIS)

    Purcell, M.; Magette, W.L.

    2011-01-01

    Highlights: → Previous research indicates that targeted strategies designed for specific areas should lead to improved diversion. → Survey responses and GIS model predictions from previous research were the basis for goal setting. → Then logic modelling and behavioural research were employed to develop site-specific management intervention strategies. → Waste management initiatives can be tailored to specific needs of areas rather than one size fits all means currently used. - Abstract: Urgent transformation is required in Ireland to divert biodegradable municipal waste (BMW) from landfill and prevent increases in overall waste generation. When BMW is optimally managed, it becomes a resource with value instead of an unwanted by-product requiring disposal. An analysis of survey responses from commercial and residential sectors for the Dublin region in previous research by the authors proved that attitudes towards and behaviour regarding municipal solid waste is spatially variable. This finding indicates that targeted intervention strategies designed for specific geographic areas should lead to improved diversion rates of BMW from landfill, a requirement of the Landfill Directive 1999/31/EC. In the research described in this paper, survey responses and GIS model predictions from previous research were the basis for goal setting, after which logic modelling and behavioural research were employed to develop site-specific waste management intervention strategies. The main strategies devised include (a) roll out of the Brown Bin (Organics) Collection and Community Workshops in Dun Laoghaire Rathdown, (b) initiation of a Community Composting Project in Dublin City (c) implementation of a Waste Promotion and Motivation Scheme in South Dublin (d) development and distribution of a Waste Booklet to promote waste reduction activities in Fingal (e) region wide distribution of a Waste Booklet to the commercial sector and (f) Greening Irish Pubs Initiative. Each of these

  10. Identifying and Overcoming Barriers to Diabetes Management in the Elderly: An Intervention Study

    Science.gov (United States)

    2011-06-01

    Geriatric Depression Scale 8. Assessment of diabetes-related distress with help of a. PAID (Problem Areas In Diabetes) 9. Nutrition assessment a...focused intervention by a geriatric multidisciplinary team with the addition of a geriatric life specialist is superior to usual care (with...diabetes and randomized them to care by either geriatric diabetes intervention team (GDT) or attention control group. Subjects in GDT group had

  11. COSMID: A Web-based Tool for Identifying and Validating CRISPR/Cas Off-target Sites

    Directory of Open Access Journals (Sweden)

    Thomas J Cradick

    2014-01-01

    Full Text Available Precise genome editing using engineered nucleases can significantly facilitate biological studies and disease treatment. In particular, clustered regularly interspaced short palindromic repeats (CRISPR with CRISPR-associated (Cas proteins are a potentially powerful tool for modifying a genome by targeted cleavage of DNA sequences complementary to designed guide strand RNAs. Although CRISPR/Cas systems can have on-target cleavage rates close to the transfection rates, they may also have relatively high off-target cleavage at similar genomic sites that contain one or more base pair mismatches, and insertions or deletions relative to the guide strand. We have developed a bioinformatics-based tool, COSMID (CRISPR Off-target Sites with Mismatches, Insertions, and Deletions that searches genomes for potential off-target sites (http://crispr.bme.gatech.edu. Based on the user-supplied guide strand and input parameters, COSMID identifies potential off-target sites with the specified number of mismatched bases and insertions or deletions when compared with the guide strand. For each site, amplification primers optimal for the chosen application are also given as output. This ranked-list of potential off-target sites assists the choice and evaluation of intended target sites, thus helping the design of CRISPR/Cas systems with minimal off-target effects, as well as the identification and quantification of CRISPR/Cas induced off-target cleavage in cells.

  12. Development of a Targeted Smoking Relapse-Prevention Intervention for Cancer Patients

    Science.gov (United States)

    Meltzer, Lauren R.; Meade, Cathy D.; Diaz, Diana B.; Carrington, Monica S.; Brandon, Thomas H.; Jacobsen, Paul B.; McCaffrey, Judith C.; Haura, Eric B.; Simmons, Vani N.

    2016-01-01

    We describe the series of iterative steps used to develop a smoking relapse-prevention intervention customized to the needs of cancer patients. Informed by relevant literature and a series of preliminary studies, an educational tool (DVD) was developed to target the unique smoking relapse risk factors among cancer patients. Learner verification interviews were conducted with 10 cancer patients who recently quit smoking to elicit feedback and inform the development of the DVD. The DVD was then refined using iterative processes and feedback from the learner verification interviews. Major changes focused on visual appeal, and the inclusion of additional testimonials and graphics to increase comprehension of key points and further emphasize the message that the patient is in control of their ability to maintain their smoking abstinence. Together, these steps resulted in the creation of a DVD titled Surviving Smokefree®, which represents the first smoking relapse-prevention intervention for cancer patients. If found effective, the Surviving Smokefree® DVD is an easily disseminable and low-cost portable intervention which can assist cancer patients in maintaining smoking abstinence. PMID:27476432

  13. Development of a Targeted Smoking Relapse-Prevention Intervention for Cancer Patients.

    Science.gov (United States)

    Meltzer, Lauren R; Meade, Cathy D; Diaz, Diana B; Carrington, Monica S; Brandon, Thomas H; Jacobsen, Paul B; McCaffrey, Judith C; Haura, Eric B; Simmons, Vani N

    2018-04-01

    We describe the series of iterative steps used to develop a smoking relapse-prevention intervention customized to the needs of cancer patients. Informed by relevant literature and a series of preliminary studies, an educational tool (DVD) was developed to target the unique smoking relapse risk factors among cancer patients. Learner verification interviews were conducted with 10 cancer patients who recently quit smoking to elicit feedback and inform the development of the DVD. The DVD was then refined using iterative processes and feedback from the learner verification interviews. Major changes focused on visual appeal, and the inclusion of additional testimonials and graphics to increase comprehension of key points and further emphasize the message that the patient is in control of their ability to maintain their smoking abstinence. Together, these steps resulted in the creation of a DVD titled Surviving Smokefree®, which represents the first smoking relapse-prevention intervention for cancer patients. If found effective, the Surviving Smokefree® DVD is an easily disseminable and low-cost portable intervention which can assist cancer patients in maintaining smoking abstinence.

  14. Psychostimulant and sensory stimulation interventions that target the reading and math deficits of students with ADHD.

    Science.gov (United States)

    Zentall, Sydney S; Tom-Wright, Kinsey; Lee, Jiyeon

    2013-05-01

    The purpose of this review of students with attention deficit hyperactivity disorder (ADHD) was to summarize the following: (1) academic deficits in math and reading, (2) possible theoretical contributors to these deficits, and (3) psychostimulant interventions that target math and reading, as well as, parallel interventions involving sensory stimulation. A comprehensive examination of the literature was conducted on children with ADHD with and without co-occurring disabilities, summarizing their reading and math achievement and the effects of psychostimulant and sensory stimulant interventions on these academic areas. Students without co-occurring disabilities (ADHD-) had fewer deficits in reading than in math and than students with co-occurring disabilities (ADHD+). Furthermore, students with ADHD+ demonstrated greater responsiveness to psychostimulants through improved reading recognition and math calculations, with limited gains in literal reading comprehension. Added sensory stimulation produced differential gains for both groups in reading recognition and comprehension and in math calculations and problem solving. The efficacy of psychostimulants was documented on specific areas of achievement for the ADHD+ group, but this review did not support the administration of psychostimulants for students with ADHD-. For both groups of students, differential gains, losses, and habituation were documented in response to sensory stimulation for both subareas within reading and math, which were interpreted as support for the optimal stimulation theory.

  15. Development and Evaluation of a Learning Intervention Targeting First-Year Resident Defibrillation Skills.

    Science.gov (United States)

    Jeffers, Justin; Eppich, Walter; Trainor, Jennifer; Mobley, Bonnie; Adler, Mark

    2016-04-01

    The aim of the study was to evaluate an educational intervention targeting the acquisition and retention of critical core skills of defibrillation in first-year pediatric residents using simulation-based training and deliberate practice. From January 2011 to April 2012, a total of 23 first-year pediatric residents participated in a pretest-posttest study. An initial survey evaluated previous experience, training, and comfort. The scoring tool was designed and validated using a standard setting procedure and 60% was determined to be the minimum passing score. The 1-hour educational intervention included a brief video describing the defibrillator, 10 to 15 minutes of hands-on time with the defibrillator, and 30 minutes of simulation-based scenarios using deliberate practice with real-time feedback. The number of subjects who achieved competency in defibrillation skills increased from 8 to 16 of 23 (35% vs 70%, P defibrillation (282-189 s, P defibrillation skills by first-year pediatric residents. In the process, we uncovered educational gaps in cardiopulmonary resuscitation and other resuscitation skills that need to be addressed in future educational interventions and training.

  16. Targeted drugs and Psycho-oncological intervention for breast cancer patients.

    Science.gov (United States)

    D'Abramo, Flavio; Goerling, Ute; Guastadisegni, Cecilia

    2016-04-01

    Personalized medicine is a new field based on molecular biology and genomics in which targeted tumor therapies are administered to patients. Psycho-oncology is a complementary approach that considers social and psychological aspects of patients as part of the treatments for cancer patients. The aim of this mini-review is to weigh clinical benefits for breast cancer patients of both treatments and possibly enhance benefits by modulating the use of both interventions. We have compared and evaluated on the one hand the use of anti Vascular Endothelial Growth Factor and, on the other hand, psycho-oncological interventions in metastatic and non-metastatic breast cancer patients.Both treatments did not increase survival of metastatic breast cancer patients, while in a selected study psycho-oncological interventions extended lifespan of non-metastatic breast cancer patients and ameliorate psychological and social factors of metastatic breast cancer patients. Because the two approaches address completely different aspects of cancer patients, if the comparison is limited to the extension of survival, the value of these two treatments cannot be assessed and compared.It is likely that by comparing patients reported outcomes, possibly by using standardized Quality of Life questionnaires, both patients and health care providers can weigh the benefits of the two treatments. It is therefore important to evaluate the use of cancer patients' quality of life measures as a mean to improve their experiences about life and treatment, and possibly to extend their survival.

  17. Hip Hop HEALS: Pilot Study of a Culturally Targeted Calorie Label Intervention to Improve Food Purchases of Children

    Science.gov (United States)

    Williams, Olajide; DeSorbo, Alexandra; Sawyer, Vanessa; Apakama, Donald; Shaffer, Michele; Gerin, William; Noble, James

    2016-01-01

    Objectives: We explored the effect of a culturally targeted calorie label intervention on food purchasing behavior of elementary school students. Method: We used a quasi-experimental design with two intervention schools and one control school to assess food purchases of third through fifth graders at standardized school food sales before and after…

  18. Joint marketing as a framework for targeting men who have sex with men in China: A pilot intervention study

    NARCIS (Netherlands)

    J. Tan (Jingguang); R. Cai (Rui); Z. Lu (Zhongbing); J. Cheng (Jianguo); S.J. de Vlas (Sake); J.H. Richardus (Jan Hendrik)

    2013-01-01

    textabstractTo apply the joint marketing principle as a new intervention approach for targeting men who have sex with men (MSM) who are often difficult to reach in societies with discrimination towards homosexuality and HIV/ AIDS. A pilot intervention according to the principles of joint marketing

  19. A guided self-help intervention targeting psychological distress among head and neck cancer and lung cancer patients: motivation to start, experiences and perceived outcomes.

    Science.gov (United States)

    Krebber, Anne-Marie H; van Uden-Kraan, Cornelia F; Melissant, Heleen C; Cuijpers, Pim; van Straten, Annemieke; Becker-Commissaris, Annemarie; Leemans, C René; Verdonck-de Leeuw, Irma M

    2017-01-01

    Recent results of a randomized clinical trial showed that a guided self-help intervention (based on problem-solving therapy) targeting psychological distress among head and neck cancer and lung cancer patients is effective. This study qualitatively explored motivation to start, experiences with and perceived outcomes of this intervention. Data were collected from semi-structured interviews of 16 patients. All interviews were audio-recorded and transcribed verbatim. Data were analyzed individually by two coders and coded into key issues and themes. Patients participated in the intervention for intrinsic (e.g. to help oneself) and for extrinsic reasons (e.g. being asked by a care professional or to help improve health care). Participants indicated positive and negative experiences with the intervention. Several participants appreciated participating as being a pleasant way to work on oneself, while others described participating as too confrontational. Some expressed their disappointment as they felt the intervention had brought them nothing or indicated that they felt worse temporarily, but most participants perceived positive outcomes of the intervention (e.g. feeling less distressed and having learned what matters in life). Cancer patients have various reasons to start a guided self-help intervention. Participants appreciated the guided self-help as intervention to address psychological distress, but there were also concerns. Most participants reported the intervention to be beneficial. The results suggest the need to identify patients who might benefit most from guided self-help targeting psychological distress and that interventions should be further tailored to individual cancer patients' requirements.

  20. Mechanisms of naturally acquired immunity to P. falciparum and approaches to identify merozoite antigen targets.

    Science.gov (United States)

    Healer, Julie; Chiu, Chris Y; Hansen, Diana S

    2017-11-16

    Malaria is one the most serious infectious diseases with over 200 million clinical cases annually. Most cases of the severe disease are caused by Plasmodium falciparum. The blood stage of Plasmodium parasite is entirely responsible for malaria-associated pathology. The population most susceptible to severe malaria are children under the age of 5, with low levels of immunity. It is only after many years of repeated exposure that individuals living in endemic areas develop clinical immunity. This form of protection prevents clinical episodes by substantially reducing parasite burden. Naturally acquired immunity predominantly targets blood-stage parasites with antibody responses being the main mediators of protection. The targets of clinical immunity are the extracellular merozoite and the infected erythrocyte surface, with the extremely diverse PfEMP1 proteins the main target here. This observation provides a strong rationale that an effective anti-malaria vaccine targeting blood-stage parasites is achievable. Thus the identification of antigenic targets of naturally acquired immunity remains an important step towards the formulation of novel vaccine combinations before testing their efficacy in clinical trials. This review summarizes the main findings to date defining antigenic targets present on the extracellular merozoite associated with naturally acquired immunity to P. falciparum malaria.

  1. Improving food environments and tackling obesity: A realist systematic review of the policy success of regulatory interventions targeting population nutrition.

    Science.gov (United States)

    Sisnowski, Jana; Street, Jackie M; Merlin, Tracy

    2017-01-01

    This systematic review (PROSPERO: CRD42015025276) employs a realist approach to investigate the effect of "real-world" policies targeting different aspects of the food environment that shape individual and collective nutrition. We were interested in assessing intermediate outcomes along the assumed causal pathway to "policy success", in addition to the final outcome of changed consumption patterns. We performed a search of 16 databases through October 2015, with no initial restriction by language. We included all publications that reported the effect of statutory provisions aimed at reducing the consumption of energy-dense foods and beverages in the general population. We allowed all methodological approaches that contained some measure of comparison, including studies of implementation progress. We reviewed included studies using the appraisal tools for pre-post and observational studies developed by the National Heart, Lung, and Blood Institute. Given the considerable heterogeneity in interventions assessed, study designs employed, and outcome measures reported, we opted for a narrative synthesis of results. Results drawn from 36 peer-reviewed articles and grey literature reports demonstrated that isolated regulatory interventions can improve intermediate outcomes, but fail to affect consumption at clinically significant levels. The included literature covered six different types of interventions, with 19 studies reporting on calorie posting on chain restaurant menus. The large majority of the identified interventions were conducted in the US. Early results from recent taxation measures were published after the review cut-off date but these suggested more favorable effects on consumption levels. Nevertheless, the evidence assessed in this review suggests that current policies are generally falling short of anticipated health impacts.

  2. TRP channels as targets for therapeutic intervention in obesity: focus on TRPV1 and TRPM5.

    Science.gov (United States)

    Palmer, R Kyle; Lunn, Charles A

    2013-01-01

    The disease of obesity is one of the greatest healthcare challenges of our time. The increasing urgency for effective treatment is driving an intensive search for new targets for anti-obesity drug discovery. The TRP channel super family represents a class of proteins now recognized to serve many functions in physiology related to maintenance of health and the development of diseases. A few of these might offer new potential for therapeutic intervention in obesity. Among the TRP channels, TRPV1 appears most closely associated with body weight homeostasis through its influence on energy expenditure. TRPM5 has been thoroughly characterized as a critical component of taste signaling and recently has been implicated in insulin release. Because of its role in taste signaling, we argue that drugs designed to modulate TRPM5 could be useful in controlling energy consumption by impacting taste sensory signals. As drug targets for obesity, both TRPV1 and TRPM5 offer the advantage of operating in compartments that could limit drug distribution to the site of action. The potential for other TRP channels as anti-obesity drug targets also is discussed.

  3. The "Robustness" of Vocabulary Intervention in the Public Schools: Targets and Techniques Employed in Speech-Language Therapy

    Science.gov (United States)

    Justice, Laura M.; Schmitt, Mary Beth; Murphy, Kimberly A.; Pratt, Amy; Biancone, Tricia

    2014-01-01

    This study examined vocabulary intervention--in terms of targets and techniques--for children with language impairment receiving speech-language therapy in public schools (i.e., non-fee-paying schools) in the United States. Vocabulary treatments and targets were examined with respect to their alignment with the empirically validated practice of…

  4. Systematic screening of isogenic cancer cells identifies DUSP6 as context-specific synthetic lethal target in melanoma

    DEFF Research Database (Denmark)

    Wittig-Blaich, Stephanie; Wittig, Rainer; Schmidt, Steffen

    2017-01-01

    Next-generation sequencing has dramatically increased genome-wide profiling options and conceptually initiates the possibility for personalized cancer therapy. State-of-the-art sequencing studies yield large candidate gene sets comprising dozens or hundreds of mutated genes. However, few technolo...... to identify new drug targets via the identification of the tumor suppressor DUSP6 as potential synthetic lethal target in melanoma cell lines with BRAF V600E mutations and high DUSP6 expression....

  5. [Progress of methodology for identifying target protein of natural active small molecules].

    Science.gov (United States)

    Tu, Peng-Fei; Zeng, Ke-Wu; Liao, Li-Xi; Song, Xiao-Min

    2016-01-01

    Drug targets are special molecules that can interact with drugs and exert pharmacological functions in human body. The natural active small molecules are the bioactive basis of traditional Chinese medicine, and the mechanism study is a hot topic now, especially for the identification of their target proteins. However, little progress has been made in this field until now. Here, we summarized the recent technologies and methods for the identification of target proteins of natural bioactive small molecules, and introduced the main research methods, principles and successful cases in this field. We also explored the applicability and discussed the advantages and disadvantages among different methods. We hope this review can be used as a reference for the researchers who engaged in natural pharmaceutical chemistry, pharmacology and chemical biology. Copyright© by the Chinese Pharmaceutical Association.

  6. Screening intervention to identify eligible patients and improve accrual to phase II-IV oncology clinical trials.

    Science.gov (United States)

    Chen, Leo; Grant, Janice; Cheung, Winson Y; Kennecke, Hagen F

    2013-07-01

    Low enrolment rates in clinical trials present a barrier to the development of novel cancer therapies. Currently, only 3% of patients with cancer participate, and many studies fail to achieve necessary enrolment. The objective of this study was to evaluate whether a screening intervention to identify potentially eligible patients (PEPs) would increase accrual rates. Over a 4-month intervention period, PEPs for 21 phase II-IV breast, gastrointestinal, genitourinary, gynecology, and lung cancer trials were identified by a screening coordinator. This individual reviewed the electronic medical records of patients attending outpatient clinics and flagged PEPs for 10 medical oncologists at the BC Cancer Agency. Patients who were already documented to be trial eligible by physicians were not flagged. Oncologists were surveyed regarding the helpfulness and accuracy of the intervention. During the intervention period, 73 patients were enrolled, compared with 61 patients enrolled in the 4 months prior and 51 patients in the 4 months after. A total of 2,098 charts were reviewed, and 120 PEPs were identified during the intervention period, resulting in 19 PEPs who enrolled and four PEPs who declined a clinical trial. Relative accrual rates adjusted for oncologist appointments were 0.85 (P = .15) before and 0.70 (P < .005) after, relative to the intervention period. Oncologist-returned surveys indicated that 67% of flags were helpful, and 70% were accurate. In this study, manually screening patient records increased enrolment to specific clinical trials. A screening intervention process, involving a dedicated screening coordinator, should be considered to improve clinical trial accrual.

  7. Identifying target groups for environmentally sustainable transport: assessment of different segmentation approaches

    DEFF Research Database (Denmark)

    Haustein, Sonja; Hunecke, Marcel

    2013-01-01

    Recently, the use of attitude-based market segmentation to promote environmentally sustainable transport has significantly increased. The segmentation of the population into meaningful groups sharing similar attitudes and preferences provides valuable information about how green measures should...... and behavioural segmentations are compared regarding marketing criteria. Although none of the different approaches can claim absolute superiority, attitudinal approaches show advantages in providing startingpoints for interventions to reduce car use....

  8. Evaluation of early weight loss thresholds for identifying nonresponders to an intensive lifestyle intervention

    Science.gov (United States)

    Objective: Weight losses in lifestyle interventions are variable, yet prediction of long-term success is difficult. The utility of using various weight loss thresholds in the first 2 months of treatment for predicting 1-year outcomes was examined. Methods: Participants included 2,327 adults with t...

  9. Empowering Preschool Teachers to Identify Mental Health Problems: A Task-Sharing Intervention in Ethiopia

    Science.gov (United States)

    Desta, Menelik; Deyessa, Negussie; Fish, Irving; Maxwell, Benjamin; Zerihun, Tigist; Levine, Saul; Fox, Claire; Giedd, Jay; Zelleke, Tesfaye G.; Alem, Atalay; Garland, Ann F.

    2017-01-01

    In Ethiopia there is a severe shortage of child mental health professionals. Identification and intervention for young children's mental health problems is crucial to improve developmental trajectories and reduce the severity of emotional and behavioral disorders. Teachers can play an important role in early problem detection. This role is…

  10. Identifying interventions to help rural Kenyan mothers cope with food insecurity: results of a focused ethnographic study

    OpenAIRE

    Pelto, Gretel H.; Armar?Klemesu, Margaret

    2016-01-01

    Abstract An ethnographic study was conducted in two areas in southern and western Kenya to identify potential interventions to improve the quality, availability and affordability of foods consumed by infants and young children. A cultural?ecological model of determinants of nutrition identified the sectors of information for data collection related to infant and young child (IYC) diet and feeding?related behaviours, and the focused ethnographic study manual was used to guide the research. The...

  11. Identifying targets for topical RNAi therapeutics in psoriasis: assessment of a new in vitro psoriasis model

    NARCIS (Netherlands)

    Bracke, S.; Desmet, E.; Guerrero-Aspizua, S.; Tjabringa, S.; Schalkwijk, J.; Gele, M. Van; Carretero, M.; Lambert, J.

    2013-01-01

    Diseases of the skin are amenable to RNAi-based therapies and targeting key components in the pathophysiology of psoriasis using RNAi may represent a successful new therapeutic strategy. We aimed to develop a straightforward and highly reproducible in vitro psoriasis model useful to study the

  12. Targeted prevention of common mental health disorders in university students: randomised controlled trial of a transdiagnostic trait-focused web-based intervention.

    Science.gov (United States)

    Musiat, Peter; Conrod, Patricia; Treasure, Janet; Tylee, Andre; Williams, Chris; Schmidt, Ulrike

    2014-01-01

    A large proportion of university students show symptoms of common mental disorders, such as depression, anxiety, substance use disorders and eating disorders. Novel interventions are required that target underlying factors of multiple disorders. To evaluate the efficacy of a transdiagnostic trait-focused web-based intervention aimed at reducing symptoms of common mental disorders in university students. Students were recruited online (n=1047, age: M=21.8, SD=4.2) and categorised into being at high or low risk for mental disorders based on their personality traits. Participants were allocated to a cognitive-behavioural trait-focused (n=519) or a control intervention (n=528) using computerised simple randomisation. Both interventions were fully automated and delivered online (trial registration: ISRCTN14342225). Participants were blinded and outcomes were self-assessed at baseline, at 6 weeks and at 12 weeks after registration. Primary outcomes were current depression and anxiety, assessed on the Patient Health Questionnaire (PHQ9) and Generalised Anxiety Disorder Scale (GAD7). Secondary outcome measures focused on alcohol use, disordered eating, and other outcomes. Students at high risk were successfully identified using personality indicators and reported poorer mental health. A total of 520 students completed the 6-week follow-up and 401 students completed the 12-week follow-up. Attrition was high across intervention groups, but comparable to other web-based interventions. Mixed effects analyses revealed that at 12-week follow up the trait-focused intervention reduced depression scores by 3.58 (pstudents at high risk. In high-risk students, between group effect sizes were 0.58 (depression) and 0.42 (anxiety). In addition, self-esteem was improved. No changes were observed regarding the use of alcohol or disordered eating. This study suggests that a transdiagnostic web-based intervention for university students targeting underlying personality risk factors may be a

  13. Diabetes Device Use in Adults With Type 1 Diabetes: Barriers to Uptake and Potential Intervention Targets.

    Science.gov (United States)

    Tanenbaum, Molly L; Hanes, Sarah J; Miller, Kellee M; Naranjo, Diana; Bensen, Rachel; Hood, Korey K

    2017-02-01

    Diabetes devices (insulin pumps, continuous glucose monitors [CGMs]) are associated with benefits for glycemic control, yet uptake of these devices continues to be low. Some barriers to device uptake may be modifiable through psychosocial intervention, but little is known about which barriers and which patients to target. We surveyed 1,503 adult T1D Exchange participants (mean age 35.3 [SD 14.8] years, mean diagnosis duration 20.4 [SD 12.5] years) to investigate barriers to device uptake, understand profiles of device users versus nonusers, and explore differences by age and sex. Scales used were the Diabetes Distress Scale, Technology Use Attitudes (General and Diabetes-Specific), and Barriers to Device Use and Reasons for Discontinuing Devices. Most commonly endorsed modifiable barriers were related to the hassle of wearing devices (47%) and disliking devices on one's body (35%). CGM users (37%) were older than nonusers (mean 38.3 vs. 33.5 years), had diabetes for longer (22.9 vs. 18.8 years), had more positive technology attitudes (22.6-26.0 vs. 21.4-24.8), and reported fewer barriers to using diabetes technology than nonusers (3.3 vs. 4.3). The youngest age-group (18-25 years) had the lowest CGM (26% vs. 40-48%) and insulin pump (64% vs. 69-77%) uptake, highest diabetes distress (2.2 vs. 1.8-2.1), and highest HbA 1c levels (8.3% [67 mmol/mol] vs. 7.2-7.4% [55-57 mmol/mol]). Efforts to increase device use need to target physical barriers to wearing devices. Because young adults had the lowest device uptake rates, highest distress, and highest HbA 1c compared with older age-groups, they should be the focus of future interventions to increase device use. © 2017 by the American Diabetes Association.

  14. Community empowerment and involvement of female sex workers in targeted sexual and reproductive health interventions in Africa: a systematic review

    Science.gov (United States)

    2014-01-01

    Background Female sex workers (FSWs) experience high levels of sexual and reproductive health (SRH) morbidity, violence and discrimination. Successful SRH interventions for FSWs in India and elsewhere have long prioritised community mobilisation and structural interventions, yet little is known about similar approaches in African settings. We systematically reviewed community empowerment processes within FSW SRH projects in Africa, and assessed them using a framework developed by Ashodaya, an Indian sex worker organisation. Methods In November 2012 we searched Medline and Web of Science for studies of FSW health services in Africa, and consulted experts and websites of international organisations. Titles and abstracts were screened to identify studies describing relevant services, using a broad definition of empowerment. Data were extracted on service-delivery models and degree of FSW involvement, and analysed with reference to a four-stage framework developed by Ashodaya. This conceptualises community empowerment as progressing from (1) initial engagement with the sex worker community, to (2) community involvement in targeted activities, to (3) ownership, and finally, (4) sustainability of action beyond the community. Results Of 5413 articles screened, 129 were included, describing 42 projects. Targeted services in FSW ‘hotspots’ were generally isolated and limited in coverage and scope, mostly offering only free condoms and STI treatment. Many services were provided as part of research activities and offered via a clinic with associated community outreach. Empowerment processes were usually limited to peer-education (stage 2 of framework). Community mobilisation as an activity in its own right was rarely documented and while most projects successfully engaged communities, few progressed to involvement, community ownership or sustainability. Only a few interventions had evolved to facilitate collective action through formal democratic structures (stage 3

  15. Community empowerment and involvement of female sex workers in targeted sexual and reproductive health interventions in Africa: a systematic review.

    Science.gov (United States)

    Moore, Lizzie; Chersich, Matthew F; Steen, Richard; Reza-Paul, Sushena; Dhana, Ashar; Vuylsteke, Bea; Lafort, Yves; Scorgie, Fiona

    2014-06-10

    Female sex workers (FSWs) experience high levels of sexual and reproductive health (SRH) morbidity, violence and discrimination. Successful SRH interventions for FSWs in India and elsewhere have long prioritised community mobilisation and structural interventions, yet little is known about similar approaches in African settings. We systematically reviewed community empowerment processes within FSW SRH projects in Africa, and assessed them using a framework developed by Ashodaya, an Indian sex worker organisation. In November 2012 we searched Medline and Web of Science for studies of FSW health services in Africa, and consulted experts and websites of international organisations. Titles and abstracts were screened to identify studies describing relevant services, using a broad definition of empowerment. Data were extracted on service-delivery models and degree of FSW involvement, and analysed with reference to a four-stage framework developed by Ashodaya. This conceptualises community empowerment as progressing from (1) initial engagement with the sex worker community, to (2) community involvement in targeted activities, to (3) ownership, and finally, (4) sustainability of action beyond the community. Of 5413 articles screened, 129 were included, describing 42 projects. Targeted services in FSW 'hotspots' were generally isolated and limited in coverage and scope, mostly offering only free condoms and STI treatment. Many services were provided as part of research activities and offered via a clinic with associated community outreach. Empowerment processes were usually limited to peer-education (stage 2 of framework). Community mobilisation as an activity in its own right was rarely documented and while most projects successfully engaged communities, few progressed to involvement, community ownership or sustainability. Only a few interventions had evolved to facilitate collective action through formal democratic structures (stage 3). These reported improved sexual

  16. Healthy weight regulation and eating disorder prevention in high school students: a universal and targeted Web-based intervention.

    Science.gov (United States)

    Jones, Megan; Taylor Lynch, Katherine; Kass, Andrea E; Burrows, Amanda; Williams, Joanne; Wilfley, Denise E; Taylor, C Barr

    2014-02-27

    Given the rising rates of obesity in children and adolescents, developing evidence-based weight loss or weight maintenance interventions that can be widely disseminated, well implemented, and are highly scalable is a public health necessity. Such interventions should ensure that adolescents establish healthy weight regulation practices while also reducing eating disorder risk. This study describes an online program, StayingFit, which has two tracks for universal and targeted delivery and was designed to enhance healthy living skills, encourage healthy weight regulation, and improve weight/shape concerns among high school adolescents. Ninth grade students in two high schools in the San Francisco Bay area and in St Louis were invited to participate. Students who were overweight (body mass index [BMI] >85th percentile) were offered the weight management track of StayingFit; students who were normal weight were offered the healthy habits track. The 12-session program included a monitored discussion group and interactive self-monitoring logs. Measures completed pre- and post-intervention included self-report height and weight, used to calculate BMI percentile for age and sex and standardized BMI (zBMI), Youth Risk Behavior Survey (YRBS) nutrition data, the Weight Concerns Scale, and the Center for Epidemiological Studies Depression Scale. A total of 336 students provided informed consent and were included in the analyses. The racial breakdown of the sample was as follows: 46.7% (157/336) multiracial/other, 31.0% (104/336) Caucasian, 16.7% (56/336) African American, and 5.7% (19/336) did not specify; 43.5% (146/336) of students identified as Hispanic/Latino. BMI percentile and zBMI significantly decreased among students in the weight management track. BMI percentile and zBMI did not significantly change among students in the healthy habits track, demonstrating that these students maintained their weight. Weight/shape concerns significantly decreased among participants in

  17. Interventions targeting child undernutrition in developing countries may be undermined by dietary exposure to aflatoxin.

    Science.gov (United States)

    Watson, Sinead; Gong, Yun Yun; Routledge, Michael

    2017-06-13

    Child undernutrition, a form of malnutrition, is a major public health burden in developing countries. Supplementation interventions targeting the major micronutrient deficiencies have only reduced the burden of child undernutrition to a certain extent, indicating that there are other underlying determinants that need to be addressed. Aflatoxin exposure, which is also highly prevalent in developing countries, may be considered an aggravating factor for child undernutrition. Increasing evidence suggests that aflatoxin exposure can occur in any stage of life, including in utero through a trans-placental pathway and in early childhood (through contaminated weaning food and family food). Early life exposure to aflatoxin is associated with adverse effects on low birth weight, stunting, immune suppression, and the liver function damage. The mechanisms underlying impaired growth and aflatoxin exposure are still unclear but intestinal function damage, reduced immune function, and alteration in the insulin-like growth factor axis caused by the liver damage are the suggested hypotheses. Given the fact that both aflatoxin and child undernutrition are common in sub-Saharan Africa, effective interventions aimed at reducing undernutrition cannot be satisfactorily achieved until the interactive relationship between aflatoxin and child undernutrition is clearly understood, and an aflatoxin mitigation strategy takes effect in those vulnerable mothers and children.

  18. Targeting relational aggression in veterans: the Strength at Home Friends and Family intervention.

    Science.gov (United States)

    Hayes, Maureen A; Gallagher, Matthew W; Gilbert, Karina Stavitsky; Creech, Suzannah K; DeCandia, Carmela J; Beach, Corey A; Taft, Casey T

    2015-06-01

    We evaluated the effectiveness of Strength at Home Friends and Families (SAH-F), a dyadic group intervention to prevent relational aggression and its negative consequences, in a community-based sample of service members/veterans and significant others who reported relational difficulties. Participants included 70 veterans and their loved ones. Recruitment was conducted from October 2010 through March 2012. Participants completed an initial assessment that included measures of relational aggression and functioning, depressive symptoms, and posttraumatic stress disorder (PTSD) symptoms. Participants were enrolled in the 10-week SAH-F targeting social information-processing mechanisms hypothesized to underlie the relationship between trauma and aggression and were reassessed at program completion and 3 months after intervention. Significant reductions in psychological aggression were seen both at program completion and at 3-month follow-up for both veterans (standardized mean gain effect size [ESsg] = -0.45, P aggression remained low after pretreatment and did not increase. Relationship adjustment reported by significant others, but not veterans, indicated a significant improvement from pretreatment to program completion (ESsg = 0.33, P relational aggression in military member/significant other dyads and enhancing relationship quality and mental health. © Copyright 2015 Physicians Postgraduate Press, Inc.

  19. Spatial and population drivers of persistent cholera transmission in rural Bangladesh: Implications for vaccine and intervention targeting.

    Science.gov (United States)

    Nazia, Nushrat; Ali, Mohammad; Jakariya, Md; Nahar, Quamrun; Yunus, Mohammad; Emch, Michael

    2018-02-01

    We identify high risk clusters and measure their persistence in time and analyze spatial and population drivers of small area incidence over time. The geographically linked population and cholera surveillance data in Matlab, Bangladesh for a 10-year period were used. Individual level data were aggregated by local 250 × 250 m communities. A retrospective space-time scan statistic was applied to detect high risk clusters. Generalized estimating equations were used to identify risk factors for cholera. We identified 10 high risk clusters, the largest of which was in the southern part of the study area where a smaller river flows into a large river. There is persistence of local spatial patterns of cholera and the patterns are related to both the population composition and ongoing spatial diffusion from nearby areas over time. This information suggests that targeting interventions to high risk areas would help eliminate locally persistent endemic areas. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Development and Refinement of a Targeted Sexual Risk Reduction Intervention for Women With a History of Childhood Sexual Abuse.

    Science.gov (United States)

    Senn, Theresa E; Braksmajer, Amy; Hutchins, Heidi; Carey, Michael P

    2017-11-01

    Childhood sexual abuse (CSA) is associated with sexual risk behavior in adulthood. Traditional sexual risk reduction interventions do not meet the unique needs of women who have been sexually abused. In the current paper, we describe the four-stage process we followed to develop and refine a targeted sexual risk reduction intervention for this population. First, initial quantitative work revealed that the intervention should address how maladaptive thoughts related to traumatic sexualization, trust, powerlessness, and guilt/shame (traumagenic dynamics constructs) influence current sexual behavior. Second, qualitative interviews with 10 women who reported a history of CSA ( M age = 34 years; 90% African American) as well as current sexual risk behavior provided support for targeting maladaptive thoughts associated with these traumagenic dynamics constructs. Third, based on the qualitative and quantitative results, we developed a 5-session, group-delivered intervention to address the maladaptive thoughts that occurred as a result of CSA, as well as the cognitive-behavioral determinants of sexual risk behavior. This intervention drew heavily on cognitive behavioral techniques to address cognitions associated with CSA and the links between these cognitions and current sexual risk behavior. Techniques from trauma-based therapies, as well as motivational techniques, were also incorporated into the intervention. Finally, we refined the intervention with 24 women ( M age = 33 years; 79% African American), and assessed feasibility and acceptability. These women reported high levels of satisfaction with the intervention. The resultant intervention is currently being evaluated in a small, randomized controlled trial.

  1. HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention

    Science.gov (United States)

    Irving, Stephen L.; Brown, David G.; Anderson, Marie; Bazin, Richard; Cao, Joan; Ciaramella, Giuseppe; Isaacson, Jason; Jackson, Lynn; Hunt, Rachael; Kjerrstrom, Anne; Nieman, James A.; Patick, Amy K.; Perros, Manos; Scott, Andrew D.; Whitby, Kevin; Wu, Hua; Butler, Scott L.

    2010-01-01

    Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy. PMID:21170360

  2. Understanding the Progression of Bone Metastases to Identify Novel Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    Annie Schmid-Alliana

    2018-01-01

    Full Text Available Bone is one of the most preferential target site for cancer metastases, particularly for prostate, breast, kidney, lung and thyroid primary tumours. Indeed, numerous chemical signals and growth factors produced by the bone microenvironment constitute factors promoting cancer cell invasion and aggression. After reviewing the different theories proposed to provide mechanism for metastatic progression, we report on the gene expression profile of bone-seeking cancer cells. We also discuss the cross-talk between the bone microenvironment and invading cells, which impacts on the tumour actions on surrounding bone tissue. Lastly, we detail therapies for bone metastases. Due to poor prognosis for patients, the strategies mainly aim at reducing the impact of skeletal-related events on patients’ quality of life. However, recent advances have led to a better understanding of molecular mechanisms underlying bone metastases progression, and therefore of novel therapeutic targets.

  3. IDENTIFYING AND TARGETING TUMOR-INITIATING CELLS IN THE TREATMENT OF BREAST CANCER

    Science.gov (United States)

    Wei, Wei; Lewis, Michael T.

    2015-01-01

    Breast cancer is the most common cancer in women (exclusive of skin cancer), and is the second leading cause of cancer-related deaths. Although conventional and targeted therapies have improved survival rates, there are still considerable challenges in treating breast cancer, including treatment resistance, disease recurrence, and metastasis. Treatment resistance can be either de novo - due to traits that tumor cells possess prior to treatment, or acquired, - due to traits that tumor cells gain in response to treatment. A recently proposed mechanism of de novo resistance invokes existence of a specialized subset of cancer cells defined as tumor-initiating cells (TICs), or cancer stem cells (CSC). TICs have the capacity to self-renew and regenerate new tumors that consist of all clonally-derived cell types present in the parental tumor. There are data to suggest that TICs are resistant to many conventional cancer therapies, and survive treatment in spite of dramatic shrinkage of the tumor. Residual TICs can then eventually regrow resulting in disease relapse. It is also hypothesized that TIC may be responsible for metastatic disease. If these hypotheses are correct, targeting TICs may be imperative to achieve cure. In this review, we discuss evidence for breast TICs and their apparent resistance to conventional chemotherapy and radiotherapy, as well as to various targeted therapies. We also address the potential impact of breast TIC plasticity and metastatic potential on therapeutic strategies. Finally, we describe several genes and signaling pathways that appear important for TIC function that may represent promising therapeutic targets. PMID:25876646

  4. Role of n-3 Polyunsaturated Fatty Acids and Exercise in Breast Cancer Prevention: Identifying Common Targets

    OpenAIRE

    Salma A. Abdelmagid; Jessica L. MacKinnon; Sarah M. Janssen; David W.L. Ma

    2016-01-01

    Diet and exercise are recognized as important lifestyle factors that significantly influence breast cancer risk. In particular, dietary n-3 polyunsaturated fatty acids (PUFAs) have been shown to play an important role in breast cancer prevention. Growing evidence also demonstrates a role for exercise in cancer and chronic disease prevention. However, the potential synergistic effect of n-3 PUFA intake and exercise is yet to be determined. This review explores targets for breast cancer prevent...

  5. Biologic targets identified from dynamic 18FDG-PET and implications for image-guided therapy

    International Nuclear Information System (INIS)

    Rusten, Espen; Malinen, Eirik; Roedal, Jan; Bruland, Oeyvind S.

    2013-01-01

    Purpose: The outcome of biologic image-guided radiotherapy depends on the definition of the biologic target. The purpose of the current work was to extract hyper perfused and hypermetabolic regions from dynamic positron emission tomography (D-PET) images, to dose escalate either region and to discuss implications of such image guided strategies. Methods: Eleven patients with soft tissue sarcomas were investigated with D-PET. The images were analyzed using a two-compartment model producing parametric maps of perfusion and metabolic rate. The two image series were segmented and exported to a treatment planning system, and biological target volumes BTV per and BTV met (perfusion and metabolism, respectively) were generated. Dice's similarity coefficient was used to compare the two biologic targets. Intensity-modulated radiation therapy (IMRT) plans were generated for a dose painting by contours regime, where planning target volume (PTV) was planned to 60 Gy and BTV to 70 Gy. Thus, two separate plans were created for each patient with dose escalation of either BTV per or BTV met . Results: BTV per was somewhat smaller than BTV met (209 ±170 cm 3 against 243 ±143 cm 3 , respectively; population-based mean and s.d.). Dice's coefficient depended on the applied margin, and was 0.72 ±0.10 for a margin of 10 mm. Boosting BTV per resulted in mean dose of 69 ±1.0 Gy to this region, while BTV met received 67 ±3.2 Gy. Boosting BTV met gave smaller dose differences between the respective non-boost DVHs (such as D 98 ). Conclusions: Dose escalation of one of the BTVs results in a partial dose escalation of the other BTV as well. If tumor aggressiveness is equally pronounced in hyper perfused and hypermetabolic regions, this should be taken into account in the treatment planning

  6. Spiroindolines identify the vesicular acetylcholine transporter as a novel target for insecticide action.

    Directory of Open Access Journals (Sweden)

    Ann Sluder

    Full Text Available The efficacy of all major insecticide classes continues to be eroded by the development of resistance mediated, in part, by selection of alleles encoding insecticide insensitive target proteins. The discovery of new insecticide classes acting at novel protein binding sites is therefore important for the continued protection of the food supply from insect predators, and of human and animal health from insect borne disease. Here we describe a novel class of insecticides (Spiroindolines encompassing molecules that combine excellent activity against major agricultural pest species with low mammalian toxicity. We confidently assign the vesicular acetylcholine transporter as the molecular target of Spiroindolines through the combination of molecular genetics in model organisms with a pharmacological approach in insect tissues. The vesicular acetylcholine transporter can now be added to the list of validated insecticide targets in the acetylcholine signalling pathway and we anticipate that this will lead to the discovery of novel molecules useful in sustaining agriculture. In addition to their potential as insecticides and nematocides, Spiroindolines represent the only other class of chemical ligands for the vesicular acetylcholine transporter since those based on the discovery of vesamicol over 40 years ago, and as such, have potential to provide more selective tools for PET imaging in the diagnosis of neurodegenerative disease. They also provide novel biochemical tools for studies of the function of this protein family.

  7. Perivascular adipose tissue as a regulator of vascular disease pathogenesis: identifying novel therapeutic targets.

    Science.gov (United States)

    Akoumianakis, Ioannis; Tarun, Akansha; Antoniades, Charalambos

    2017-10-01

    Adipose tissue (AT) is an active endocrine organ with the ability to dynamically secrete a wide range of adipocytokines. Importantly, its secretory profile is altered in various cardiovascular disease states. AT surrounding vessels, or perivascular AT (PVAT), is recognized in particular as an important local regulator of vascular function and dysfunction. Specifically, PVAT has the ability to sense vascular paracrine signals and respond by secreting a variety of vasoactive adipocytokines. Due to the crucial role of PVAT in regulating many aspects of vascular biology, it may constitute a novel therapeutic target for the prevention and treatment of vascular disease pathogenesis. Signalling pathways in PVAT, such as those using adiponectin, H 2 S, glucagon-like peptide 1 or pro-inflammatory cytokines, are among the potential novel pharmacological therapeutic targets of PVAT. This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc. © 2016 The British Pharmacological Society.

  8. Sustainable Transportation Attitudes and Health Behavior Change: Evaluation of a Brief Stage-Targeted Video Intervention

    Science.gov (United States)

    Mundorf, Norbert; Redding, Colleen A.; Paiva, Andrea L.

    2018-01-01

    Promoting physical activity and sustainable transportation is essential in the face of rising health care costs, obesity rates, and other public health threats resulting from lack of physical activity. Targeted communications can encourage distinct population segments to adopt active and sustainable transportation modes. Our work is designed to promote the health, social, and environmental benefits of sustainable/active transportation (ST) using the Transtheoretical Model of Change (TTM), which has been successfully applied to a range of health, and more recently, sustainability behaviors. Earlier, measurement development confirmed both the structure of ST pros and cons and efficacy measures as well as the relationship between these constructs and ST stages of change, replicating results found for many other behaviors. The present paper discusses a brief pre-post video pilot intervention study designed for precontemplators and contemplators (N = 604) that was well received, effective in moving respondents towards increased readiness for ST behavior change, and improving some ST attitudes, significantly reducing the cons of ST. This research program shows that a brief stage-targeted behavior change video can increase readiness and reduce the cons for healthy transportation choices. PMID:29346314

  9. Sustainable Transportation Attitudes and Health Behavior Change: Evaluation of a Brief Stage-Targeted Video Intervention

    Directory of Open Access Journals (Sweden)

    Norbert Mundorf

    2018-01-01

    Full Text Available Promoting physical activity and sustainable transportation is essential in the face of rising health care costs, obesity rates, and other public health threats resulting from lack of physical activity. Targeted communications can encourage distinct population segments to adopt active and sustainable transportation modes. Our work is designed to promote the health, social, and environmental benefits of sustainable/active transportation (ST using the Transtheoretical Model of Change (TTM, which has been successfully applied to a range of health, and more recently, sustainability behaviors. Earlier, measurement development confirmed both the structure of ST pros and cons and efficacy measures as well as the relationship between these constructs and ST stages of change, replicating results found for many other behaviors. The present paper discusses a brief pre-post video pilot intervention study designed for precontemplators and contemplators (N = 604 that was well received, effective in moving respondents towards increased readiness for ST behavior change, and improving some ST attitudes, significantly reducing the cons of ST. This research program shows that a brief stage-targeted behavior change video can increase readiness and reduce the cons for healthy transportation choices.

  10. Sustainable Transportation Attitudes and Health Behavior Change: Evaluation of a Brief Stage-Targeted Video Intervention.

    Science.gov (United States)

    Mundorf, Norbert; Redding, Colleen A; Paiva, Andrea L

    2018-01-18

    Promoting physical activity and sustainable transportation is essential in the face of rising health care costs, obesity rates, and other public health threats resulting from lack of physical activity. Targeted communications can encourage distinct population segments to adopt active and sustainable transportation modes. Our work is designed to promote the health, social, and environmental benefits of sustainable/active transportation (ST) using the Transtheoretical Model of Change (TTM), which has been successfully applied to a range of health, and more recently, sustainability behaviors. Earlier, measurement development confirmed both the structure of ST pros and cons and efficacy measures as well as the relationship between these constructs and ST stages of change, replicating results found for many other behaviors. The present paper discusses a brief pre-post video pilot intervention study designed for precontemplators and contemplators (N = 604) that was well received, effective in moving respondents towards increased readiness for ST behavior change, and improving some ST attitudes, significantly reducing the cons of ST. This research program shows that a brief stage-targeted behavior change video can increase readiness and reduce the cons for healthy transportation choices.

  11. Risks for depression onset in primary care elderly patients: potential targets for preventive interventions.

    Science.gov (United States)

    Lyness, Jeffrey M; Yu, Qin; Tang, Wan; Tu, Xin; Conwell, Yeates

    2009-12-01

    Prevention of late-life depression, a common, disabling condition with often poor outcomes in primary care, requires identification of seniors at highest risk of incident episodes. The authors examined a broad range of clinical, functional, and psychosocial predictors of incident depressive episodes in a well-characterized cohort of older primary care patients. In this observational cohort study, patients age >/=65 years without current major depression, recruited from practices in general internal medicine, geriatrics, and family medicine, received annual follow-up assessments over a period of 1 to 4 years. Of 617 enrolled subjects, 405 completed the 1-year follow-up evaluation. The Structured Clinical Interview for DSM-IV (SCID) determined incident major depressive episodes. Each risk indicator's predictive utility was examined by calculating the risk exposure rate, incident risk ratio, and population attributable fraction, leading to determination of the number needed to treat in order to prevent incident depression. A combination of risks, including minor or subsyndromal depression, impaired functional status, and history of major or minor depression, identified a group in which fully effective treatment of five individuals would prevent one new case of incident depression. Indicators routinely assessed in primary care identified a group at very high risk for onset of major depressive episodes. Such markers may inform current clinical care by fostering the early detection and intervention critical to improving patient outcomes and may serve as the basis for future studies refining the recommendations for screening and determining the effectiveness of preventive interventions.

  12. CRISPRseek: a bioconductor package to identify target-specific guide RNAs for CRISPR-Cas9 genome-editing systems.

    Directory of Open Access Journals (Sweden)

    Lihua J Zhu

    Full Text Available CRISPR-Cas systems are a diverse family of RNA-protein complexes in bacteria that target foreign DNA sequences for cleavage. Derivatives of these complexes have been engineered to cleave specific target sequences depending on the sequence of a CRISPR-derived guide RNA (gRNA and the source of the Cas9 protein. Important considerations for the design of gRNAs are to maximize aimed activity at the desired target site while minimizing off-target cleavage. Because of the rapid advances in the understanding of existing CRISPR-Cas9-derived RNA-guided nucleases and the development of novel RNA-guided nuclease systems, it is critical to have computational tools that can accommodate a wide range of different parameters for the design of target-specific RNA-guided nuclease systems. We have developed CRISPRseek, a highly flexible, open source software package to identify gRNAs that target a given input sequence while minimizing off-target cleavage at other sites within any selected genome. CRISPRseek will identify potential gRNAs that target a sequence of interest for CRISPR-Cas9 systems from different bacterial species and generate a cleavage score for potential off-target sequences utilizing published or user-supplied weight matrices with position-specific mismatch penalty scores. Identified gRNAs may be further filtered to only include those that occur in paired orientations for increased specificity and/or those that overlap restriction enzyme sites. For applications where gRNAs are desired to discriminate between two related sequences, CRISPRseek can rank gRNAs based on the difference between predicted cleavage scores in each input sequence. CRISPRseek is implemented as a Bioconductor package within the R statistical programming environment, allowing it to be incorporated into computational pipelines to automate the design of gRNAs for target sequences identified in a wide variety of genome-wide analyses. CRISPRseek is available under the GNU General

  13. A Functional Genomics Approach to Identify Novel Breast Cancer Gene Targets in Yeast

    National Research Council Canada - National Science Library

    Bennett, Craig B

    2005-01-01

    .... We identified conserved components of the CCR4 damage response network and many of these genes, including CCR4, DHHl, DEFi, HCMl, SPT4, SPT5, SUBi, YAF9, YAP3 and numerous components of the nuclear...

  14. An Integrated Approach to Change the Outcome Part II: Targeted Neuromuscular Training Techniques to Reduce Identified ACL Injury Risk Factors

    Science.gov (United States)

    Myer, Gregory D.; Ford, Kevin R.; Brent, Jensen L.; Hewett, Timothy E.

    2014-01-01

    Prior reports indicate that female athletes who demonstrate high knee abduction moments (KAMs) during landing are more responsive to neuromuscular training designed to reduce KAM. Identification of female athletes who demonstrate high KAM, which accurately identifies those at risk for noncontact anterior cruciate ligament (ACL) injury, may be ideal for targeted neuromuscular training. Specific neuromuscular training targeted to the underlying biomechanical components that increase KAM may provide the most efficient and effective training strategy to reduce noncontact ACL injury risk. The purpose of the current commentary is to provide an integrative approach to identify and target mechanistic underpinnings to increased ACL injury in female athletes. Specific neuromuscular training techniques will be presented that address individual algorithm components related to high knee load landing patterns. If these integrated techniques are employed on a widespread basis, prevention strategies for noncontact ACL injury among young female athletes may prove both more effective and efficient. PMID:22580980

  15. An integrated structure- and system-based framework to identify new targets of metabolites and known drugs

    KAUST Repository

    Naveed, Hammad

    2015-08-18

    Motivation: The inherent promiscuity of small molecules towards protein targets impedes our understanding of healthy versus diseased metabolism. This promiscuity also poses a challenge for the pharmaceutical industry as identifying all protein targets is important to assess (side) effects and repositioning opportunities for a drug. Results: Here, we present a novel integrated structure- and system-based approach of drug-target prediction (iDTP) to enable the large-scale discovery of new targets for small molecules, such as pharmaceutical drugs, co-factors and metabolites (collectively called ‘drugs’). For a given drug, our method uses sequence order–independent structure alignment, hierarchical clustering, and probabilistic sequence similarity to construct a probabilistic pocket ensemble (PPE) that captures promiscuous structural features of different binding sites on known targets. A drug’s PPE is combined with an approximation of its delivery profile to reduce false positives. In our cross-validation study, we use iDTP to predict the known targets of eleven drugs, with 63% sensitivity and 81% specificity. We then predicted novel targets for these drugs—two that are of high pharmacological interest, the nuclear receptor PPARγ and the oncogene Bcl-2, were successfully validated through in vitro binding experiments. Our method is broadly applicable for the prediction of protein-small molecule interactions with several novel applications to biological research and drug development.

  16. Identifying Neurofibromin Specific Regulatory Nodes for Therapeutic Targeting in NF1

    Science.gov (United States)

    2017-10-01

    leads to up-regulation of specific receptors. We hope that we will be able to find news of up-regulating neurofibromin in cells in which one allele is...generated using CRISPR/Cas9 with a sgRNA targeting exon 2 of NF1 and exon 1 of Spred1. Following antibiotic selection clones were screened by Western blot...2016. 18 Impact Nothing to report Changes/Problems While the Aims of the project remain unchanged, we will use new technologies to

  17. Identifying Medication Targets for Psychostimulant Addiction: Unraveling the Dopamine D3 Receptor Hypothesis

    Science.gov (United States)

    2016-01-01

    The dopamine D3 receptor (D3R) is a target for developing medications to treat substance use disorders. D3R-selective compounds with high affinity and varying efficacies have been discovered, providing critical research tools for cell-based studies that have been translated to in vivo models of drug abuse. D3R antagonists and partial agonists have shown especially promising results in rodent models of relapse-like behavior, including stress-, drug-, and cue-induced reinstatement of drug seeking. However, to date, translation to human studies has been limited. Herein, we present an overview and illustrate some of the pitfalls and challenges of developing novel D3R-selective compounds toward clinical utility, especially for treatment of cocaine abuse. Future research and development of D3R-selective antagonists and partial agonists for substance abuse remains critically important but will also require further evaluation and development of translational animal models to determine the best time in the addiction cycle to target D3Rs for optimal therapeutic efficacy. PMID:25826710

  18. Analysis of Sequenced Genomes of Xanthomonas perforans Identifies Candidate Targets for Resistance Breeding in Tomato.

    Science.gov (United States)

    Timilsina, Sujan; Abrahamian, Peter; Potnis, Neha; Minsavage, Gerald V; White, Frank F; Staskawicz, Brian J; Jones, Jeffrey B; Vallad, Gary E; Goss, Erica M

    2016-10-01

    Bacterial disease management is a challenge for modern agriculture due to rapid changes in pathogen populations. Genome sequences for hosts and pathogens provide detailed information that facilitates effector-based breeding strategies. Tomato genotypes have gene-for-gene resistance to the bacterial spot pathogen Xanthomonas perforans. The bacterial spot populations in Florida shifted from tomato race 3 to 4, such that the corresponding tomato resistance gene no longer recognizes the effector protein AvrXv3. Genome sequencing showed variation in effector profiles among race 4 strains collected in 2006 and 2012 and compared with a race 3 strain collected in 1991. We examined variation in putative targets of resistance among Florida strains of X. perforans collected from 1991 to 2006. Consistent with race change, avrXv3 was present in race 3 strains but nonfunctional in race 4 strains due to multiple independent mutations. Effectors xopJ4 and avrBs2 were unchanged in all strains. The effector avrBsT was absent in race 3 strains collected in the 1990s but present in race 3 strains collected in 2006 and nearly all race 4 strains. These changes in effector profiles suggest that xopJ4 and avrBsT are currently the best targets for resistance breeding against bacterial spot in tomato.

  19. MEDICI: Mining Essentiality Data to Identify Critical Interactions for Cancer Drug Target Discovery and Development.

    Science.gov (United States)

    Harati, Sahar; Cooper, Lee A D; Moran, Josue D; Giuste, Felipe O; Du, Yuhong; Ivanov, Andrei A; Johns, Margaret A; Khuri, Fadlo R; Fu, Haian; Moreno, Carlos S

    2017-01-01

    Protein-protein interactions (PPIs) mediate the transmission and regulation of oncogenic signals that are essential to cellular proliferation and survival, and thus represent potential targets for anti-cancer therapeutic discovery. Despite their significance, there is no method to experimentally disrupt and interrogate the essentiality of individual endogenous PPIs. The ability to computationally predict or infer PPI essentiality would help prioritize PPIs for drug discovery and help advance understanding of cancer biology. Here we introduce a computational method (MEDICI) to predict PPI essentiality by combining gene knockdown studies with network models of protein interaction pathways in an analytic framework. Our method uses network topology to model how gene silencing can disrupt PPIs, relating the unknown essentialities of individual PPIs to experimentally observed protein essentialities. This model is then deconvolved to recover the unknown essentialities of individual PPIs. We demonstrate the validity of our approach via prediction of sensitivities to compounds based on PPI essentiality and differences in essentiality based on genetic mutations. We further show that lung cancer patients have improved overall survival when specific PPIs are no longer present, suggesting that these PPIs may be potentially new targets for therapeutic development. Software is freely available at https://github.com/cooperlab/MEDICI. Datasets are available at https://ctd2.nci.nih.gov/dataPortal.

  20. Identifying High Potential Well Targets with 3D Seismic and Mineralogy

    Energy Technology Data Exchange (ETDEWEB)

    Mellors, R. J. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2015-10-30

    Seismic reflection the primary tool used in petroleum exploration and production, but use in geothermal exploration is less standard, in part due to cost but also due to the challenges in identifying the highly-permeable zones essential for economic hydrothermal systems [e.g. Louie et al., 2011; Majer, 2003]. Newer technology, such as wireless sensors and low-cost high performance computing, has helped reduce the cost and effort needed to conduct 3D surveys. The second difficulty, identifying permeable zones, has been less tractable so far. Here we report on the use of seismic attributes from a 3D seismic survey to identify and map permeable zones in a hydrothermal area.

  1. A cluster randomised controlled trial of a pharmacist-led collaborative intervention to improve statin prescribing and attainment of cholesterol targets in primary care.

    Directory of Open Access Journals (Sweden)

    Richard Lowrie

    Full Text Available Small trials with short term follow up suggest pharmacists' interventions targeted at healthcare professionals can improve prescribing. In comparison with clinical guidance, contemporary statin prescribing is sub-optimal and achievement of cholesterol targets falls short of accepted standards, for patients with atherosclerotic vascular disease who are at highest absolute risk and who stand to obtain greatest benefit. We hypothesised that a pharmacist-led complex intervention delivered to doctors and nurses in primary care, would improve statin prescribing and achievement of cholesterol targets for incident and prevalent patients with vascular disease, beyond one year.We allocated general practices to a 12-month Statin Outreach Support (SOS intervention or usual care. SOS was delivered by one of 11 pharmacists who had received additional training. SOS comprised academic detailing and practical support to identify patients with vascular disease who were not prescribed a statin at optimal dose or did not have cholesterol at target, followed by individualised recommendations for changes to management. The primary outcome was the proportion of patients achieving cholesterol targets. Secondary outcomes were: the proportion of patients prescribed simvastatin 40 mg with target cholesterol achieved; cholesterol levels; prescribing of simvastatin 40 mg; prescribing of any statin and the proportion of patients with cholesterol tested. Outcomes were assessed after an average of 1.7 years (range 1.4-2.2 years, and practice level simvastatin 40 mg prescribing was assessed after 10 years.We randomised 31 practices (72 General Practitioners (GPs, 40 nurses. Prior to randomisation a subset of eligible patients were identified to characterise practices; 40% had cholesterol levels below the target threshold. Improvements in data collection procedures allowed identification of all eligible patients (n = 7586 at follow up. Patients in practices allocated to SOS were

  2. Kinase Screening in Pichia pastoris Identified Promising Targets Involved in Cell Growth and Alcohol Oxidase 1 Promoter (PAOX1 Regulation.

    Directory of Open Access Journals (Sweden)

    Wei Shen

    Full Text Available As one of the most commonly used eukaryotic recombinant protein expression systems, P. pastoris relies heavily on the AOX1 promoter (PAOX1, which is strongly induced by methanol but strictly repressed by glycerol and glucose. However, the complicated signaling pathways involved in PAOX1 regulation when supplemented with different carbon sources are poorly understood. Here we constructed a kinase deletion library in P. pastoris and identified 27 mutants which showed peculiar phenotypes in cell growth or PAOX1 regulation. We analyzed both annotations and possible functions of these 27 targets, and then focused on the MAP kinase Hog1. In order to locate its potential downstream components, we performed the phosphoproteome analysis on glycerol cultured WT and Δhog1 strains and identified 157 differentially phosphorylated proteins. Our results identified important kinases involved in P. pastoris cell growth and PAOX1 regulation, which could serve as valuable targets for further mechanistic studies.

  3. The effects of interventions targeting multiple health behaviors on smoking cessation outcomes: a rapid realist review protocol.

    Science.gov (United States)

    Minian, Nadia; deRuiter, Wayne K; Lingam, Mathangee; Corrin, Tricia; Dragonetti, Rosa; Manson, Heather; Taylor, Valerie H; Zawertailo, Laurie; Ebnahmady, Arezoo; Melamed, Osnat C; Rodak, Terri; Hahn, Margaret; Selby, Peter

    2018-03-01

    Health behaviors directly impact the health of individuals, and populations. Since individuals tend to engage in multiple unhealthy behaviors such as smoking, excessive alcohol use, physical inactivity, and eating an unhealthy diet simultaneously, many large community-based interventions have been implemented to reduce the burden of disease through the modification of multiple health behaviors. Smoking cessation can be particularly challenging as the odds of becoming dependent on nicotine increase with every unhealthy behavior a smoker exhibits. This paper presents a protocol for a rapid realist review which aims to identify factors associated with effectively changing tobacco use and target two or more additional unhealthy behaviors. An electronic literature search will be conducted using the following bibliographic databases: MEDLINE, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), The Cochrane Library, Social Science Abstracts, Social Work Abstracts, and Web of Science. Two reviewers will screen titles and abstracts for relevant research, and the selected full papers will be used to extract data and assess the quality of evidence. Throughout this process, the rapid realist approach proposed by Saul et al., 2013 will be used to refine our initial program theory and identify contextual factors and mechanisms that are associated with successful multiple health behavior change. This review will provide evidence-based research on the context and mechanisms that may drive the success or failure of interventions designed to support multiple health behavior change. This information will be used to guide curriculum and program development for a government funded project on improving smoking cessation by addressing multiple health behaviors in people in Canada. PROSPERO CRD42017064430.

  4. Application of Latent Class Analysis to Identify Behavioral Patterns of Response to Behavioral Lifestyle Interventions in Overweight and Obese Adults.

    Science.gov (United States)

    Fitzpatrick, Stephanie L; Coughlin, Janelle W; Appel, Lawrence J; Tyson, Crystal; Stevens, Victor J; Jerome, Gerald J; Dalcin, Arlene; Brantley, Phillip J; Hill-Briggs, Felicia

    2015-08-01

    Examining responders and non-responders to behavioral lifestyle interventions among overweight/obese adults with additional comorbidities may aid in refining and tailoring obesity treatment. The purpose of this study is to demonstrate the use of latent class analysis to identify patterns of response to behavioral lifestyle interventions based on adherence to diet and exercise recommendations. Repeated measures latent class analysis was applied to two clinical trial datasets, combination of two active interventions in the PREMIER Trial (n = 501) and phase 1 of the Weight Loss Maintenance Trial (WLM; n = 1685), to identify patterns of response to behavioral lifestyle interventions. Treatment response was based on adherence to daily recommendations for fruit/vegetable, fat, saturated fat, sodium, and exercise at baseline and 6 months. In PREMIER, three distinct latent classes emerged: responders (45.9%), non-responders (23.6%), and early adherers (30.5%). Responders and Early Adherers had greater weight loss at 6 and 18 months and were more likely to meet behavioral recommendations at 18 months than Non-responders. For WLM, there were four latent classes: partial responders (16%), non-responders (40%), early adherers (2%), and fruit/veggie only responders (41%). Non-responders in WLM had significantly less weight loss at 6 months compared to that of the other three latent classes. Latent class analysis is a useful method to apply to clinical trial data to identify distinct patterns of response to behavioral interventions. Overweight/ obese participants who respond to behavioral lifestyle treatment (i.e., meet behavioral recommendations) have significantly greater weight loss than that of participants who do not make behavioral changes.

  5. Use of the nursing intervention classification for identifying the workload of a nursing team in a surgical center

    Directory of Open Access Journals (Sweden)

    João Francisco Possari

    2015-10-01

    Full Text Available Objective: to analyze the distribution of nursing professionals' workloads, according to the Nursing Intervention Classification (NIC, during the transoperative period at a surgical center specializing in oncology.Methods: this was an observational and descriptive cross-sectional study. The sample consisted of 11 nurses, 25 nursing technicians who performed a variety of roles within the operating room, 16 nursing technicians who worked with the surgical instrumentation and two nursing technicians from patient reception who worked in the surgical center during the transoperative period. An instrument was developed to collect data and the interventions were validated according to NIC taxonomy.Results: a total of 266 activities were identified and mapped into 49 nursing interventions, seven domains and 20 classes of the NIC. The most representative domains were Physiological-Complex (61.68% and Health System (22.12%, while the most frequent interventions were Surgical Care (30.62% and Documentation (11.47%, respectively. The productivity of the nursing team reached 95.34%.Conclusions: use of the Nursing Intervention Classification contributes towards the discussion regarding adequate, professional nursing staffing levels, because it shows the distribution of the work load.

  6. Role of n-3 Polyunsaturated Fatty Acids and Exercise in Breast Cancer Prevention: Identifying Common Targets

    Directory of Open Access Journals (Sweden)

    Salma A. Abdelmagid

    2016-01-01

    Full Text Available Diet and exercise are recognized as important lifestyle factors that significantly influence breast cancer risk. In particular, dietary n-3 polyunsaturated fatty acids (PUFAs have been shown to play an important role in breast cancer prevention. Growing evidence also demonstrates a role for exercise in cancer and chronic disease prevention. However, the potential synergistic effect of n-3 PUFA intake and exercise is yet to be determined. This review explores targets for breast cancer prevention that are common between n-3 PUFA intake and exercise and that may be important study outcomes for future research investigating the combined effect of n-3 PUFA intake and exercise. These lines of evidence highlight potential new avenues for research and strategies for breast cancer prevention.

  7. Novel targets of sulforaphane in primary cardiomyocytes identified by proteomic analysis.

    Science.gov (United States)

    Angeloni, Cristina; Turroni, Silvia; Bianchi, Laura; Fabbri, Daniele; Motori, Elisa; Malaguti, Marco; Leoncini, Emanuela; Maraldi, Tullia; Bini, Luca; Brigidi, Patrizia; Hrelia, Silvana

    2013-01-01

    Cardiovascular diseases represent the main cause of mortality in the industrialized world and the identification of effective preventive strategies is of fundamental importance. Sulforaphane, an isothiocyanate from cruciferous vegetables, has been shown to up-regulate phase II enzymes in cardiomyocytes and counteract oxidative stress-induced apoptosis. Aim of the present study was the identification and characterization of novel sulforaphane targets in cardiomyocytes applying a proteomic approach. Two-dimensional gel electrophoresis and mass spectrometry were used to generate protein profiles of primary neonatal rat cardiomyocytes treated and untreated with 5 µM sulforaphane for 1-48 h. According to image analysis, 64 protein spots were found as differentially expressed and their functional correlations were investigated using the MetaCore program. We mainly focused on 3 proteins: macrophage migration inhibitory factor (MIF), CLP36 or Elfin, and glyoxalase 1, due to their possible involvement in cardioprotection. Validation of the time-dependent differential expression of these proteins was performed by western blotting. In particular, to gain insight into the cardioprotective role of the modulation of glyoxalase 1 by sulforaphane, further experiments were performed using methylglyoxal to mimic glycative stress. Sulforaphane was able to counteract methylglyoxal-induced apoptosis, ROS production, and glycative stress, likely through glyoxalase 1 up-regulation. In this study, we reported for the first time new molecular targets of sulforaphane, such as MIF, CLP36 and glyoxalase 1. In particular, we gave new insights into the anti-glycative role of sulforaphane in cardiomyocytes, confirming its pleiotropic behavior in counteracting cardiovascular diseases.

  8. General Approach to Identifying Potential Targets for Cancer Imaging by Integrated Bioinformatics Analysis of Publicly Available Genomic Profiles

    Directory of Open Access Journals (Sweden)

    Yongliang Yang

    2011-03-01

    Full Text Available Molecular imaging has moved to the forefront of drug development and biomedical research. The identification of appropriate imaging targets has become the touchstone for the accurate diagnosis and prognosis of human cancer. Particularly, cell surface- or membrane-bound proteins are attractive imaging targets for their aberrant expression, easily accessible location, and unique biochemical functions in tumor cells. Previously, we published a literature mining of potential targets for our in-house enzyme-mediated cancer imaging and therapy technology. Here we present a simple and integrated bioinformatics analysis approach that assembles a public cancer microarray database with a pathway knowledge base for ascertaining and prioritizing upregulated genes encoding cell surface- or membrane-bound proteins, which could serve imaging targets. As examples, we obtained lists of potential hits for six common and lethal human tumors in the prostate, breast, lung, colon, ovary, and pancreas. As control tests, a number of well-known cancer imaging targets were detected and confirmed by our study. Further, by consulting gene-disease and protein-disease databases, we suggest a number of significantly upregulated genes as promising imaging targets, including cell surface-associated mucin-1, prostate-specific membrane antigen, hepsin, urokinase plasminogen activator receptor, and folate receptors. By integrating pathway analysis, we are able to organize and map “focused” interaction networks derived from significantly dysregulated entity pairs to reflect important cellular functions in disease processes. We provide herein an example of identifying a tumor cell growth and proliferation subnetwork for prostate cancer. This systematic mining approach can be broadly applied to identify imaging or therapeutic targets for other human diseases.

  9. The Use of the Target Cancellation Task to Identify Eloquent Visuospatial Regions in Awake Craniotomies: Technical Note.

    Science.gov (United States)

    Conner, Andrew K; Glenn, Chad; Burks, Joshua D; McCoy, Tressie; Bonney, Phillip A; Chema, Ahmed A; Case, Justin L; Brunner, Scott; Baker, Cordell; Sughrue, Michael

    2016-11-17

    The success of awake craniotomies relies on the patient's performance of function-specific tasks that are simple, quick, and reproducible. Intraoperative identification of visuospatial function through cortical and subcortical mapping has utilized a variety of intraoperative tests, each with its own benefits and drawbacks. In light of this, we developed a simple software program that aids in preventing neglect by simulating a target-cancellation task on a portable electronic device. In this report, we describe the interactive target cancellation task and have reviewed seven consecutive patients who underwent awake craniotomy for parietal and/or posterior temporal infiltrating brain tumors of the non-dominant hemisphere. Each of these patients performed target cancellation and line bisection tasks intraoperatively. The outcomes of each patient and testing scenario are described. Positive intraoperative cortical and subcortical sites involved with visuospatial processing were identified in three of the seven patients using the target cancellation and confirmed utilizing the line-bisection task. No identification of visuospatial function was accomplished utilizing the line-bisection task alone. Complete visuospatial function mapping was completed in less than 10 minutes in all patients. No patients had preoperative or postoperative hemineglect. Our findings highlight the feasibility of the target cancellation technique for use during awake craniotomy to aid in avoiding postoperative hemineglect. Target cancellation may offer an alternative method of cortical and subcortical visuospatial mapping in patients unable to perform other commonly used modalities.

  10. α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy.

    Science.gov (United States)

    Ettle, Benjamin; Kerman, Bilal E; Valera, Elvira; Gillmann, Clarissa; Schlachetzki, Johannes C M; Reiprich, Simone; Büttner, Christian; Ekici, Arif B; Reis, André; Wegner, Michael; Bäuerle, Tobias; Riemenschneider, Markus J; Masliah, Eliezer; Gage, Fred H; Winkler, Jürgen

    2016-07-01

    Multiple system atrophy (MSA) is a rare atypical parkinsonian disorder characterized by a rapidly progressing clinical course and at present without any efficient therapy. Neuropathologically, myelin loss and neurodegeneration are associated with α-synuclein accumulation in oligodendrocytes, but underlying pathomechanisms are poorly understood. Here, we analyzed the impact of oligodendrocytic α-synuclein on the formation of myelin sheaths to define a potential interventional target for MSA. Post-mortem analyses of MSA patients and controls were performed to quantify myelin and oligodendrocyte numbers. As pre-clinical models, we used transgenic MSA mice, a myelinating stem cell-derived oligodendrocyte-neuron co-culture, and primary oligodendrocytes to determine functional consequences of oligodendrocytic α-synuclein overexpression on myelination. We detected myelin loss accompanied by preserved or even increased numbers of oligodendrocytes in post-mortem MSA brains or transgenic mouse forebrains, respectively, indicating an oligodendrocytic dysfunction in myelin formation. Corroborating this observation, overexpression of α-synuclein in primary and stem cell-derived oligodendrocytes severely impaired myelin formation, defining a novel α-synuclein-linked pathomechanism in MSA. We used the pro-myelinating activity of the muscarinic acetylcholine receptor antagonist benztropine to analyze the reversibility of the myelination deficit. Transcriptome profiling of primary pre-myelinating oligodendrocytes demonstrated that benztropine readjusts myelination-related processes such as cholesterol and membrane biogenesis, being compromised by oligodendrocytic α-synuclein. Additionally, benztropine restored the α-synuclein-induced myelination deficit of stem cell-derived oligodendrocytes. Strikingly, benztropine also ameliorated the myelin deficit in transgenic MSA mice, resulting in a prevention of neuronal cell loss. In conclusion, this study defines the

  11. Use of a bacteriophage lysin to identify a novel target for antimicrobial development.

    Directory of Open Access Journals (Sweden)

    Raymond Schuch

    Full Text Available We identified an essential cell wall biosynthetic enzyme in Bacillus anthracis and an inhibitor thereof to which the organism did not spontaneously evolve measurable resistance. This work is based on the exquisite binding specificity of bacteriophage-encoded cell wall-hydrolytic lysins, which have evolved to recognize critical receptors within the bacterial cell wall. Focusing on the B. anthracis-specific PlyG lysin, we first identified its unique cell wall receptor and cognate biosynthetic pathway. Within this pathway, one biosynthetic enzyme, 2-epimerase, was required for both PlyG receptor expression and bacterial growth. The 2-epimerase was used to design a small-molecule inhibitor, epimerox. Epimerox prevented growth of several Gram-positive pathogens and rescued mice challenged with lethal doses of B. anthracis. Importantly, resistance to epimerox was not detected (<10(-11 frequency in B. anthracis and S. aureus. These results describe the use of phage lysins to identify promising lead molecules with reduced resistance potential for antimicrobial development.

  12. A cross sectional evaluation of an alcohol intervention targeting young university students.

    Science.gov (United States)

    Burns, Sharyn; Jancey, Jonine; Crawford, Gemma; Hallett, Jonathan; Portsmouth, Linda; Longo, Janelle

    2016-07-20

    Hazardous drinking has been found to be higher among young university students compared to their non-university peers. Although young university students are exposed to new and exciting experiences, including greater availability and emphasis on social functions involving alcohol there are few multi strategy comprehensive interventions aimed at reducing alcohol-related harms. Random cross sectional online surveys were administered to 18-24 year old students studying at the main campus of a large metropolitan university in Perth, Western Australia. Prior to the completion of the second survey an alcohol intervention was implemented on campus. Completed surveys were received from 2465 (Baseline; T1) and 2422 (Post Year 1: T2) students. Students who consumed alcohol in the past 12 months were categorised as low risk or hazardous drinkers using the Alcohol Use Disorders Identification Test (AUDIT). Due to the cross sectional nature of the two samples two-tailed two-proportion z-test and two sample t-tests were employed to determine statistical significance between the two time periods for categorical and continuous variables respectively. At T1 and T2 89.1 % and 87.2 % of the total sample reported drinking alcohol in the past month respectively. Hazardous levels of alcohol consumption reduced slightly between T1 (39.7 %) and T2 (38 %). In both time periods hazardous drinkers reported significantly higher mean scores for experienced harm, second-hand harm and witnessed harm scores compared to low risk drinkers (p alcohol consumption and to report more positive alcohol expectations than low risk drinkers at both time periods (p students who report hazardous drinking are of concern and efforts should be made to ensure integrated and targeted strategies reach higher risk students and focus on specific issues such as driving while intoxicated and alcohol related unplanned sexual activity. However there is also a need for universal strategies targeting all students and

  13. Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT--relationship to newly identified mitochondrial pyruvate carrier proteins.

    Directory of Open Access Journals (Sweden)

    Jerry R Colca

    Full Text Available Thiazolidinedione (TZD insulin sensitizers have the potential to effectively treat a number of human diseases, however the currently available agents have dose-limiting side effects that are mediated via activation of the transcription factor PPARγ. We have recently shown PPARγ-independent actions of TZD insulin sensitizers, but the molecular target of these molecules remained to be identified. Here we use a photo-catalyzable drug analog probe and mass spectrometry-based proteomics to identify a previously uncharacterized mitochondrial complex that specifically recognizes TZDs. These studies identify two well-conserved proteins previously known as brain protein 44 (BRP44 and BRP44 Like (BRP44L, which recently have been renamed Mpc2 and Mpc1 to signify their function as a mitochondrial pyruvate carrier complex. Knockdown of Mpc1 or Mpc2 in Drosophila melanogaster or pre-incubation with UK5099, an inhibitor of pyruvate transport, blocks the crosslinking of mitochondrial membranes by the TZD probe. Knockdown of these proteins in Drosophila also led to increased hemolymph glucose and blocked drug action. In isolated brown adipose tissue (BAT cells, MSDC-0602, a PPARγ-sparing TZD, altered the incorporation of (13C-labeled carbon from glucose into acetyl CoA. These results identify Mpc1 and Mpc2 as components of the mitochondrial target of TZDs (mTOT and suggest that understanding the modulation of this complex, which appears to regulate pyruvate entry into the mitochondria, may provide a viable target for insulin sensitizing pharmacology.

  14. Targeted next-generation sequencing of 22 mismatch repair genes identifies Lynch syndrome families.

    Science.gov (United States)

    Talseth-Palmer, Bente A; Bauer, Denis C; Sjursen, Wenche; Evans, Tiffany J; McPhillips, Mary; Proietto, Anthony; Otton, Geoffrey; Spigelman, Allan D; Scott, Rodney J

    2016-05-01

    Causative germline mutations in mismatch repair (MMR) genes can only be identified in ~50% of families with a clinical diagnosis of the inherited colorectal cancer (CRC) syndrome hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome (LS). Identification of these patients are critical as they are at substantially increased risk of developing multiple primary tumors, mainly colorectal and endometrial cancer (EC), occurring at a young age. This demonstrates the need to develop new and/or more thorough mutation detection approaches. Next-generation sequencing (NGS) was used to screen 22 genes involved in the DNA MMR pathway in constitutional DNA from 14 HNPCC and 12 sporadic EC patients, plus 2 positive controls. Several softwares were used for analysis and functional annotation. We identified 5 exonic indel variants, 42 exonic nonsynonymous single-nucleotide variants (SNVs) and 1 intronic variant of significance. Three of these variants were class 5 (pathogenic) or class 4 (likely pathogenic), 5 were class 3 (uncertain clinical relevance) and 40 were classified as variants of unknown clinical significance. In conclusion, we have identified two LS families from the sporadic EC patients, one without a family history of cancer, supporting the notion for universal MMR screening of EC patients. In addition, we have detected three novel class 3 variants in EC cases. We have, in addition discovered a polygenic interaction which is the most likely cause of cancer development in a HNPCC patient that could explain previous inconsistent results reported on an intronic EXO1 variant. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  15. Diversity-oriented natural product platform identifies plant constituents targeting Plasmodium falciparum.

    Science.gov (United States)

    Zhang, Jin; Bowling, John J; Smithson, David; Clark, Julie; Jacob, Melissa R; Khan, Shabana I; Tekwani, Babu L; Connelly, Michele; Samoylenko, Vladimir; Ibrahim, Mohamed A; Zaki, Mohamed A; Wang, Mei; Hester, John P; Tu, Ying; Jeffries, Cynthia; Twarog, Nathaniel; Shelat, Anang A; Walker, Larry A; Muhammad, Ilias; Guy, R Kiplin

    2016-05-10

    A diverse library of pre-fractionated plant extracts, generated by an automated high-throughput system, was tested using an in vitro anti-malarial screening platform to identify known or new natural products for lead development. The platform identifies hits on the basis of in vitro growth inhibition of Plasmodium falciparum and counter-screens for cytotoxicity to human foreskin fibroblast or embryonic kidney cell lines. The physical library was supplemented by early-stage collection of analytical data for each fraction to aid rapid identification of the active components within each screening hit. A total of 16,177 fractions from 1300 plants were screened, identifying several P. falciparum inhibitory fractions from 35 plants. Although individual fractions were screened for bioactivity to ensure adequate signal in the analytical characterizations, fractions containing less than 2.0 mg of dry weight were combined to produce combined fractions (COMBIs). Fractions of active COMBIs had EC50 values of 0.21-50.28 and 0.08-20.04 µg/mL against chloroquine-sensitive and -resistant strains, respectively. In Berberis thunbergii, eight known alkaloids were dereplicated quickly from its COMBIs, but berberine was the most-active constituent against P. falciparum. The triterpenoids α-betulinic acid and β-betulinic acid of Eugenia rigida were also isolated as hits. Validation of the anti-malarial discovery platform was confirmed by these scaled isolations from B. thunbergii and E. rigida. These results demonstrate the value of curating and exploring a library of natural products for small molecule drug discovery. Attention given to the diversity of plant species represented in the library, focus on practical analytical data collection, and the use of counter-screens all facilitate the identification of anti-malarial compounds for lead development or new tools for chemical biology.

  16. A network analysis of the human T-cell activation gene network identifies JAGGED1 as a therapeutic target for autoimmune diseases.

    Directory of Open Access Journals (Sweden)

    Ricardo Palacios

    2007-11-01

    Full Text Available Understanding complex diseases will benefit the recognition of the properties of the gene networks that control biological functions. Here, we set out to model the gene network that controls T-cell activation in humans, which is critical for the development of autoimmune diseases such as Multiple Sclerosis (MS. The network was established on the basis of the quantitative expression from 104 individuals of 20 genes of the immune system, as well as on biological information from the Ingenuity database and Bayesian inference. Of the 31 links (gene interactions identified in the network, 18 were identified in the Ingenuity database and 13 were new and we validated 7 of 8 interactions experimentally. In the MS patients network, we found an increase in the weight of gene interactions related to Th1 function and a decrease in those related to Treg and Th2 function. Indeed, we found that IFN-ss therapy induces changes in gene interactions related to T cell proliferation and adhesion, although these gene interactions were not restored to levels similar to controls. Finally, we identify JAG1 as a new therapeutic target whose differential behaviour in the MS network was not modified by immunomodulatory therapy. In vitro treatment with a Jagged1 agonist peptide modulated the T-cell activation network in PBMCs from patients with MS. Moreover, treatment of mice with experimental autoimmune encephalomyelitis with the Jagged1 agonist ameliorated the disease course, and modulated Th2, Th1 and Treg function. This study illustrates how network analysis can predict therapeutic targets for immune intervention and identified the immunomodulatory properties of Jagged1 making it a new therapeutic target for MS and other autoimmune diseases.

  17. African American Young Adult Smoking Initiation: Identifying Intervention Points and Prevention Opportunities

    Science.gov (United States)

    Cheney, Marshall K.; Mansker, Jacqueline

    2014-01-01

    Background: African Americans have one of the lowest smoking rates as teens yet have one of the highest smoking rates as adults. Approximately 40% of African Americans who have ever smoked started smoking between the ages of 18 and 21. Purpose: This study aimed to identify why African American young adults began smoking in young adulthood and what…

  18. Hip Hop HEALS: Pilot Study of a Culturally Targeted Calorie Label Intervention to Improve Food Purchases of Children.

    Science.gov (United States)

    Williams, Olajide; DeSorbo, Alexandra; Sawyer, Vanessa; Apakama, Donald; Shaffer, Michele; Gerin, William; Noble, James

    2016-02-01

    We explored the effect of a culturally targeted calorie label intervention on food purchasing behavior of elementary school students. We used a quasi-experimental design with two intervention schools and one control school to assess food purchases of third through fifth graders at standardized school food sales before and after the intervention (immediate and delayed) in schools. The intervention comprised three 1-hour assembly-style hip-hop-themed multimedia classes. A mean total of 225 children participated in two baseline preintervention sales with and without calorie labels; 149 children participated in immediate postintervention food sales, while 133 children participated in the delayed sales. No significant change in purchased calories was observed in response to labels alone before the intervention. However, a mean decline in purchased calories of 20% (p < .01) and unhealthy foods (p < .01) was seen in immediately following the intervention compared to baseline purchases, and this persisted without significant decay after 7 days and 12 days. A 3-hour culturally targeted calorie label intervention may improve food-purchasing behavior of children. © 2015 Society for Public Health Education.

  19. Validated adherence scales used in a measurement-guided medication management approach to target and tailor a medication adherence intervention: a randomised controlled trial.

    Science.gov (United States)

    Nguyen, Thi-My-Uyen; La Caze, Adam; Cottrell, Neil

    2016-11-30

    To determine if a targeted and tailored intervention based on a discussion informed by validated adherence scales will improve medication adherence. Prospective randomised trial. 2 community pharmacies in Brisbane, Australia. Patients recently initiated on a cardiovascular or oral hypoglycaemic medication within the past 4-12 weeks were recruited from two community pharmacies. Participants identified as non-adherent using the Medication Adherence Questionnaire (MAQ) were randomised into the intervention or control group. The intervention group received a tailored intervention based on a discussion informed by responses to the MAQ, Beliefs about Medicines Questionnaire-Specific and Brief Illness Perception Questionnaire. Adherence was measured using the MAQ at 3 and 6 months following the intervention. A total of 408 patients were assessed for eligibility, from which 152 participants were enrolled into the study. 120 participants were identified as non-adherent using the MAQ and randomised to the 'intervention' or 'control' group. The mean MAQ score at baseline in the intervention and control were similar (1.58: 95% CI (1.38 to 1.78) and 1.60: 95% CI (1.43 to 1.77), respectively). There was a statistically significant improvement in adherence in the intervention group compared to control at 3 months (mean MAQ score 0.42: 95% CI (0.27 to 0.57) vs 1.58: 95% CI (1.42 to 1.75); p<0.001). The significant improvement in MAQ score in the intervention group compared to control was sustained at 6 months (0.48: 95% CI (0.31 to 0.65) vs 1.48: 95% CI (1.27 to 1.69); p<0.001). An intervention that targeted non-adherent participants and tailored to participant-specific reasons for non-adherence was successful at improving medication adherence. ACTRN12613000162718; Results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  20. Characterizing Active Ingredients of eHealth Interventions Targeting Persons With Poorly Controlled Type 2 Diabetes Mellitus Using the Behavior Change Techniques Taxonomy: Scoping Review.

    Science.gov (United States)

    Kebede, Mihiretu M; Liedtke, Tatjana P; Möllers, Tobias; Pischke, Claudia R

    2017-10-12

    The behavior change technique taxonomy v1 (BCTTv1; Michie and colleagues, 2013) is a comprehensive tool to characterize active ingredients of interventions and includes 93 labels that are hierarchically clustered into 16 hierarchical clusters. The aim of this study was to identify the active ingredients in electronic health (eHealth) interventions targeting patients with poorly controlled type 2 diabetes mellitus (T2DM) and relevant outcomes. We conducted a scoping review using the BCTTv1. Randomized controlled trials (RCTs), studies with or pre-post-test designs, and quasi-experimental studies examining efficacy and effectiveness of eHealth interventions for disease management or the promotion of relevant health behaviors were identified by searching PubMed, Web of Science, and PsycINFO. Reviewers independently screened titles and abstracts for eligibility using predetermined eligibility criteria. Data were extracted following a data extraction sheet. The BCTTv1 was used to characterize active ingredients of the interventions reported in the included studies. Of the 1404 unique records screened, 32 studies fulfilled the inclusion criteria and reported results on the efficacy and or or effectiveness of interventions. Of the included 32 studies, 18 (56%) were Web-based interventions delivered via personal digital assistant (PDA), tablet, computer, and/or mobile phones; 7 (22%) were telehealth interventions delivered via landline; 6 (19%) made use of text messaging (short service message, SMS); and 1 employed videoconferencing (3%). Of the 16 hierarchical clusters of the BCTTv1, 11 were identified in interventions included in this review. Of the 93 individual behavior change techniques (BCTs), 31 were identified as active ingredients of the interventions. The most common BCTs identified were instruction on how to perform behavior, adding objects to the environment, information about health consequences, self-monitoring of the outcomes and/or and prefers to be

  1. The role of macrophage polarization on bipolar disorder: Identifying new therapeutic targets.

    Science.gov (United States)

    Ascoli, Bruna M; Géa, Luiza P; Colombo, Rafael; Barbé-Tuana, Florência M; Kapczinski, Flávio; Rosa, Adriane Ribeiro

    2016-07-01

    Bipolar disorder is a chronic, severe and disabling disease; however, its pathophysiology remains poorly understood. Recent evidence has suggested that inflammation and immune dysregulation play a significant role in the pathophysiology of bipolar disorder. This review is aimed to highlight the importance of systemic inflammation in modulating the inflammatory response of microglia and hence its potential involvement with bipolar disorder. We also discuss novel therapeutic strategies that emerge from this new research. This article presents a theoretical synthesis of the effects of systemic inflammation on the immune response of the central nervous system in bipolar disorder. The complex relationship between stress, pro-inflammatory cytokines and microglial dysfunction is summarized, emphasizing the role of the kynurenine pathway in this process and, consequently, their effects on neuronal plasticity. Bipolar patients demonstrate increased serum levels of pro-inflammatory cytokines (interleukin-1β, interleukin-6 and tumor necrosis factor-α) and lower hypothalamic-pituitary-adrenal axis sensitivity. This imbalance in the immune system promotes a change in blood-brain barrier permeability, leading to an inflammatory signal spread in the central nervous system from the periphery, through macrophages activation (M1 polarization). Chronic microglial activation can result in neuronal apoptosis, neurogenesis inhibition, hippocampal volume reduction, lower neurotransmitters synthesis and cytotoxicity, by increasing glutamate production and kynurenine metabolism. This review provides an overview of the mechanisms involved in the immune system imbalance and its potential involvement in the pathophysiology of bipolar disorder. Consequently, new strategies that normalize the immune-inflammatory pathways may provide a valuable therapeutic target for the treatment of these disorders. © The Royal Australian and New Zealand College of Psychiatrists 2016.

  2. Analysis in the joint time-frequency domain of the identifying signatures of submerged targets insonified by dolphin clicks

    Science.gov (United States)

    Strifors, Hans C.; Gaunaurd, Guillermo C.; Moore, Patrick W.

    1997-06-01

    We study the scattering interaction of dolphin-emitted acoustic pulses ('clicks') with various elastic shells located, underwater, in front of the animal in a large test site in Kaneohe Bay, Hawaii. A carefully instrumented analog- to-digital system continuously captured the emitted clicks and also the returned, backscattered echoes. Using standard conditioning techniques and food reinforcers, the dolphin is taught to push an underwater paddle when the 'correct' target -- the one he has been trained to identify -- is presented to him. He communicates to us his consistently correct identifying choices in this manner. By means of several time- frequency distributions (TFD) of the Wigner-type, or Cohen class, we examine echoes returned by three types of cylindrical shells. The time-frequency distributions we compare in this survey are the pseudo-Wigner distribution (PWD), the Choi-Williams distribution (CWD), the adaptive spectrogram (AS), the cone-shaped distribution (CSD), the Gabor spectrogram (GS), and the spectrogram (SPEC). To be satisfactory for target identification purposes, a time- frequency representation of the echoes should display a sufficient amount of distinguishing features, and still be robust enough to suppress the interference of noise contained in the received signals. Both these properties in a time- frequency distribution depend on the distribution's capability of concentrating the featuers in time and frequency and of handling cross-term interference. With some time-frequency distributions there is a trade-off between the concentration of features and the suppression of cross-term interference. The results of our investigation serve the twofold purposes of (1) advancing the understanding of the amazing target identification capability of dolphins, and (2) to assist in assessing the possibility of identifying submerged targets using active sonar and a classifier based on target signatures in the combined time-frequency domain.

  3. Systolic Blood Pressure Intervention Trial (SPRINT) and Target Systolic Blood Pressure in Future Hypertension Guidelines.

    Science.gov (United States)

    Egan, Brent M; Li, Jiexiang; Wagner, C Shaun

    2016-08-01

    The Systolic Blood Pressure (SBP, mm Hg) Intervention Trial (SPRINT) showed that targeting SBP hypertension guidelines: (1) standard therapy controlled SBP similarly to that in adults with treated hypertension and (2) intensive therapy produced a lower mean SBP than in adults with treated hypertension and SBP hypertension: group 1 consisted of SPRINT-like participants aged ≥50 years; group 2 consisted of participants all aged ≥18 years; and group 3 consisted of participants aged ≥18 years excluding group 1 but otherwise similar to SPRINT-like participants except high cardiovascular risk. Mean SBPs in groups 1, 2, and 3 were 133.0, 130.1, and 124.6, with 66.2%, 72.2%, and 81.9%, respectively, controlled to SBP hypertension, (1) the SPRINT-like group had higher mean SBP than comparison groups, yet lower than SPRINT standard treatment group and (2) among groups 1 to 3 with SBP <140, SBP values were within <3 mm Hg of SPRINT intensive treatment. SPRINT results suggest that treatment should be continued and not reduced when treated SBP is <130, especially for the SPRINT-like subset. Furthermore, increasing the percentage of treated adults with SBP <140 could approximate SPRINT intensive treatment SBP without lowering treatment goals. © 2016 American Heart Association, Inc.

  4. EDITORIAL Neuroglia as a Central Element of Neurological Diseases: An Underappreciated Target for Therapeutic Intervention

    Science.gov (United States)

    Peng, Liang; Parpura, Vladimir; Verkhratsky, Alexei

    2014-01-01

    Neuroglia of the central nervous system (CNS), represented by cells of neural (astrocytes, oligodendrocytes and NG2 glial cells) and myeloid (microglia) origins are fundamental for homeostasis of the nervous tissue. Astrocytes are critical for the development of the CNS, they are indispensable for synaptogenesis, and they define structural organisation of the nervous tissue, as well as the generation and maintenance of CNS-blood and cerebrospinal fluid-blood barriers. Astroglial cells control homeostasis of ions and neurotransmitters and provide neurones with metabolic support. Oligodendrocytes, through the process of myelination, as well as by homoeostatic support of axons provide for interneuronal connectivity. The NG2 cells receive direct synaptic inputs, and might be important elements of adult remyelination. Microglial cells, which originate from foetal macrophages invading the brain early in embryogenesis, shape the synaptic connections through removing of redundant synapses and phagocyting apoptotic neurones. Neuroglia also form the defensive system of the CNS through complex and context-specific programmes of activation, known as reactive gliosis. Many neurological diseases are associated with neurogliopathologies represented by asthenic and atrophic changes in glial cells that, through the loss or diminution of their homeostatic and defensive functions, assist evolution of pathology. Conceptually, neurological and psychiatric disorders can be regarded as failures of neuroglial homeostatic/ defensive responses, and, hence, glia represent a (much underappreciated) target for therapeutic intervention. PMID:25342938

  5. Combining phenotypic and proteomic approaches to identify membrane targets in a ‘triple negative’ breast cancer cell type

    Directory of Open Access Journals (Sweden)

    Rust Steven

    2013-02-01

    Full Text Available Abstract Background The continued discovery of therapeutic antibodies, which address unmet medical needs, requires the continued discovery of tractable antibody targets. Multiple protein-level target discovery approaches are available and these can be used in combination to extensively survey relevant cell membranomes. In this study, the MDA-MB-231 cell line was selected for membranome survey as it is a ‘triple negative’ breast cancer cell line, which represents a cancer subtype that is aggressive and has few treatment options. Methods The MDA-MB-231 breast carcinoma cell line was used to explore three membranome target discovery approaches, which were used in parallel to cross-validate the significance of identified antigens. A proteomic approach, which used membrane protein enrichment followed by protein identification by mass spectrometry, was used alongside two phenotypic antibody screening approaches. The first phenotypic screening approach was based on hybridoma technology and the second was based on phage display technology. Antibodies isolated by the phenotypic approaches were tested for cell specificity as well as internalisation and the targets identified were compared to each other as well as those identified by the proteomic approach. An anti-CD73 antibody derived from the phage display-based phenotypic approach was tested for binding to other ‘triple negative’ breast cancer cell lines and tested for tumour growth inhibitory activity in a MDA-MB-231 xenograft model. Results All of the approaches identified multiple cell surface markers, including integrins, CD44, EGFR, CD71, galectin-3, CD73 and BCAM, some of which had been previously confirmed as being tractable to antibody therapy. In total, 40 cell surface markers were identified for further study. In addition to cell surface marker identification, the phenotypic antibody screening approaches provided reagent antibodies for target validation studies. This is illustrated

  6. Phosphotyrosine enrichment identifies focal adhesion kinase and other tyrosine kinases for targeting in canine hemangiosarcoma.

    Science.gov (United States)

    Marley, K; Maier, C S; Helfand, S C

    2012-09-01

    Canine hemangiosarcoma (HSA) is an endothelial cell malignancy driven, in part, by activating mutations in receptor and non-receptor tyrosine kinases. Proteomics, Western blots and a tyrosine kinase inhibitor were used to elucidate activating mechanisms in HSA cell lines. Phosphotyrosine peptides from focal adhesion kinase (FAK) STAT3, Lyn, Fyn and other signal transduction kinases were identified by mass spectrometry. FAK was constitutively activated at tyrosine 397, the autophosphorylation site, and this was reversible with high concentrations of a FAK inhibitor. FAK inhibitor-14 suppressed migration and phosphorylation of FAK tyrosine 397 and tyrosines 576/577 and was cytotoxic to HSA cells suggesting FAK signalling may be an important contributor to canine HSA survival. © 2012 Blackwell Publishing Ltd.

  7. Identifying Innovative Interventions to Promote Healthy Eating Using Consumption-Oriented Food Supply Chain Analysis.

    Science.gov (United States)

    Hawkes, Corinna

    2009-07-01

    The mapping and analysis of supply chains is a technique increasingly used to address problems in the food system. Yet such supply chain management has not yet been applied as a means of encouraging healthier diets. Moreover, most policies recommended to promote healthy eating focus on the consumer end of the chain. This article proposes a consumption-oriented food supply chain analysis to identify the changes needed in the food supply chain to create a healthier food environment, measured in terms of food availability, prices, and marketing. Along with established forms of supply chain analysis, the method is informed by a historical overview of how food supply chains have changed over time. The method posits that the actors and actions in the chain are affected by organizational, financial, technological, and policy incentives and disincentives, which can in turn be levered for change. It presents a preliminary example of the supply of Coca-Cola beverages into school vending machines and identifies further potential applications. These include fruit and vegetable supply chains, local food chains, supply chains for health-promoting versions of food products, and identifying financial incentives in supply chains for healthier eating.

  8. Targeting N-glycan cryptic sugar moieties for broad-spectrum virus neutralization: progress in identifying conserved molecular targets in viruses of distinct phylogenetic origins.

    Science.gov (United States)

    Wang, Denong; Tang, Jin; Tang, Jiulai; Wang, Lai-Xi

    2015-03-12

    Identifying molecular targets for eliciting broadly virus-neutralizing antibodies is one of the key steps toward development of vaccines against emerging viral pathogens. Owing to genomic and somatic diversities among viral species, identifying protein targets for broad-spectrum virus neutralization is highly challenging even for the same virus, such as HIV-1. However, viruses rely on host glycosylation machineries to synthesize and express glycans and, thereby, may display common carbohydrate moieties. Thus, exploring glycan-binding profiles of broad-spectrum virus-neutralizing agents may provide key information to uncover the carbohydrate-based virus-neutralizing epitopes. In this study, we characterized two broadly HIV-neutralizing agents, human monoclonal antibody 2G12 and Galanthus nivalis lectin (GNA), for their viral targeting activities. Although these agents were known to be specific for oligomannosyl antigens, they differ strikingly in virus-binding activities. The former is HIV-1 specific; the latter is broadly reactive and is able to neutralize viruses of distinct phylogenetic origins, such as HIV-1, severe acute respiratory syndrome coronavirus (SARS-CoV), and human cytomegalovirus (HCMV). In carbohydrate microarray analyses, we explored the molecular basis underlying the striking differences in the spectrum of anti-virus activities of the two probes. Unlike 2G12, which is strictly specific for the high-density Man9GlcNAc2Asn (Man9)-clusters, GNA recognizes a number of N-glycan cryptic sugar moieties. These include not only the known oligomannosyl antigens but also previously unrecognized tri-antennary or multi-valent GlcNAc-terminating N-glycan epitopes (Tri/m-Gn). These findings highlight the potential of N-glycan cryptic sugar moieties as conserved targets for broad-spectrum virus neutralization and suggest the GNA-model of glycan-binding warrants focused investigation.

  9. Targeting N-Glycan Cryptic Sugar Moieties for Broad-Spectrum Virus Neutralization: Progress in Identifying Conserved Molecular Targets in Viruses of Distinct Phylogenetic Origins

    Directory of Open Access Journals (Sweden)

    Denong Wang

    2015-03-01

    Full Text Available Identifying molecular targets for eliciting broadly virus-neutralizing antibodies is one of the key steps toward development of vaccines against emerging viral pathogens. Owing to genomic and somatic diversities among viral species, identifying protein targets for broad-spectrum virus neutralization is highly challenging even for the same virus, such as HIV-1. However, viruses rely on host glycosylation machineries to synthesize and express glycans and, thereby, may display common carbohydrate moieties. Thus, exploring glycan-binding profiles of broad-spectrum virus-neutralizing agents may provide key information to uncover the carbohydrate-based virus-neutralizing epitopes. In this study, we characterized two broadly HIV-neutralizing agents, human monoclonal antibody 2G12 and Galanthus nivalis lectin (GNA, for their viral targeting activities. Although these agents were known to be specific for oligomannosyl antigens, they differ strikingly in virus-binding activities. The former is HIV-1 specific; the latter is broadly reactive and is able to neutralize viruses of distinct phylogenetic origins, such as HIV-1, severe acute respiratory syndrome coronavirus (SARS-CoV, and human cytomegalovirus (HCMV. In carbohydrate microarray analyses, we explored the molecular basis underlying the striking differences in the spectrum of anti-virus activities of the two probes. Unlike 2G12, which is strictly specific for the high-density Man9GlcNAc2Asn (Man9-clusters, GNA recognizes a number of N-glycan cryptic sugar moieties. These include not only the known oligomannosyl antigens but also previously unrecognized tri-antennary or multi-valent GlcNAc-terminating N-glycan epitopes (Tri/m-Gn. These findings highlight the potential of N-glycan cryptic sugar moieties as conserved targets for broad-spectrum virus neutralization and suggest the GNA-model of glycan-binding warrants focused investigation.

  10. Small-molecule screen identifies modulators of EWS/FLI1 target gene expression and cell survival in Ewing's sarcoma.

    Science.gov (United States)

    Boro, Aleksandar; Prêtre, Kathya; Rechfeld, Florian; Thalhammer, Verena; Oesch, Susanne; Wachtel, Marco; Schäfer, Beat W; Niggli, Felix K

    2012-11-01

    Ewing's sarcoma family of tumors (EFT) is characterized by the presence of chromosomal translocations leading to the expression of oncogenic transcription factors such as, in the majority of cases, EWS/FLI1. Because of its key role in Ewing's sarcoma development and maintenance, EWS/FLI1 represents an attractive therapeutic target. Here, we characterize PHLDA1 as a novel direct target gene whose expression is repressed by EWS/FLI1. Using this gene and additional specific well-characterized target genes such as NROB1, NKX2.2 and CAV1, all activated by EWS/FLI1, as a read-out system, we screened a small-molecule compound library enriched for FDA-approved drugs that modulated the expression of EWS/FLI1 target genes. Among a hit-list of nine well-known drugs such as camptothecin, fenretinide, etoposide and doxorubicin, we also identified the kinase inhibitor midostaurin (PKC412). Subsequent experiments demonstrated that midostaurin is able to induce apoptosis in a panel of six Ewing's sarcoma cell lines in vitro and can significantly suppress xenograft tumor growth in vivo. These results suggest that midostaurin might be a novel drug that is active against Ewing's cells, which might act by modulating the expression of EWS/FLI1 target genes. Copyright © 2012 UICC.

  11. Identifying the Learning Curve for Uterine Artery Embolisation in an Interventional Radiological Training Unit

    Energy Technology Data Exchange (ETDEWEB)

    Das, Raj, E-mail: rajdas@nhs.net, E-mail: raj.das@stgeorges.nhs.uk; Lucatelli, Pierleone, E-mail: pierleone.lucatelli@gmail.com; Wang, Haofan, E-mail: wwhhff123@gmail.com; Belli, Anna-Maria, E-mail: anna.belli@stgeorges.nhs.uk [St George’s Hospital, Department of Radiology (United Kingdom)

    2015-08-15

    AimA clear understanding of operator experience is important in improving technical success whilst minimising patient risk undergoing endovascular procedures, and there is the need to ensure that trainees have the appropriate skills as primary operators. The aim of the study is to retrospectively analyse uterine artery embolisation (UAE) procedures performed by interventional radiology (IR) trainees at an IR training unit analysing fluoroscopy times and radiation dose as surrogate markers of technical skill.MethodsTen IR fellows were primary operator in 200 UAE procedures over a 5-year period. We compared fluoroscopy times, radiation dose and complications, after having them categorised according to three groups: Group 1, initial five, Group 2, >5 procedures and Group 3, penultimate five UAE procedures. We documented factors that may affect screening time (number of vials employed and use of microcatheters).ResultsMean fluoroscopy time was 18.4 (±8.1), 17.3 (±9.0), 16.3 (±8.4) min in Groups 1, 2 and 3, respectively. There was no statistically significant difference between these groups (p > 0.05) with respect to fluoroscopy time or radiation dose. Analysis after correction for confounding factors showed no statistical significance (p > 0.05). All procedures were technically successful, and total complication rate was 4 %.ConclusionUAE was chosen as a highly standardised procedure followed by IR practitioners. Although there is a non-significant trend for shorter screening times with experience, technical success and safety were not compromised with appropriate Consultant supervision, which illustrates a safe construct for IR training. This is important and reassuring information for patients undergoing a procedure in a training unit.

  12. Using an International Clinical Registry of Regional Anesthesia to Identify Targets for Quality Improvement

    Science.gov (United States)

    Sites, Brian D.; Barrington, Michael J.; Davis, Matthew

    2014-01-01

    Background Despite the widespread use of regional anesthesia, limited information on clinical performance exists. Institutions, therefore, have little knowledge of how they are performing in regards to both safety and effectiveness. In this study, we demonstrate how a medical institution (or physician/physician group) may use data from a multi-center clinical registry of regional anesthesia to inform quality improvement strategies. Methods We analyzed data from the International Registry of Regional Anesthesia that includes prospective data on peripheral regional anesthesia procedures from 19 centers located around the world. Using data from the clinical registry, we present summary statistics of the overall safety and effectiveness of regional anesthesia. Furthermore, we demonstrate, using a variety of performance measures, how these data can be used by hospitals to identify areas for quality improvement. To do so, we compare the performance of one member institution (a United States medical center in New Hampshire) to that of the other 18 member institutions of the clinical registry. Results The clinical registry contained information on 23,271 blocks that were performed between June 1, 2011, and May 1, 2014, on 16,725 patients. The overall success rate was 96.7%, immediate complication rate was 2.2%, and the all-cause 60-day rate of neurological sequelae was 8.3 (95% CI, 7.2–9.7) per 10,000. Registry wide major hospital events included 7 wrong site blocks, 3 seizures, 1 complete heart block, 1 retroperitoneal hematoma, and 3 pneumothoraces. For our reference medical center, we identified areas meriting quality improvement. Specifically, after accounting for differences in the age, sex, and health status of patient populations, the reference medical center appeared to rely more heavily on opioids for post procedure management, had higher patient pain scores, and experienced delayed discharge when compared with other member institutions. Conclusions To our

  13. Transcriptome Analysis Identifies the Dysregulation of Ultraviolet Target Genes in Human Skin Cancers.

    Directory of Open Access Journals (Sweden)

    Yao Shen

    Full Text Available Exposure to ultraviolet radiation (UVR is a major risk factor for both melanoma and non-melanoma skin cancers. In addition to its mutagenic effect, UVR can also induce substantial transcriptional instability in skin cells affecting thousands of genes, including many cancer genes, suggesting that transcriptional instability may be another important etiological factor in skin photocarcinogenesis. In this study, we performed detailed transcriptomic profiling studies to characterize the kinetic changes in global gene expression in human keratinocytes exposed to different UVR conditions. We identified a subset of UV-responsive genes as UV signature genes (UVSGs based on 1 conserved UV-responsiveness of this subset of genes among different keratinocyte lines; and 2 UV-induced persistent changes in their mRNA levels long after exposure. Interestingly, 11 of the UVSGs were shown to be critical to skin cancer cell proliferation and survival. Through computational Gene Set Enrichment Analysis, we demonstrated that a significant portion of the UVSGs were dysregulated in human skin squamous cell carcinomas, but not in other human malignancies. This highlights the potential and specificity of the UVSGs in clinical diagnosis of UV damage and stratification of skin cancer risk.

  14. The spxB gene as a target to identify Lactobacillus casei group species in cheese.

    Science.gov (United States)

    Savo Sardaro, Maria Luisa; Levante, Alessia; Bernini, Valentina; Gatti, Monica; Neviani, Erasmo; Lazzi, Camilla

    2016-10-01

    This study focused on the spxB gene, which encodes for pyruvate oxidase. The presence of spxB in the genome and its transcription could be a way to produce energy and allow bacterial growth during carbohydrate starvation. In addition, the activity of pyruvate oxidase, which produces hydrogen peroxide, could be a mechanism for interspecies competition. Because this gene seems to provide advantages for the encoding species for adaptation in complex ecosystems, we studied spxB in a large set of cheese isolates belonging to the Lactobacillus casei group. Through this study, we demonstrated that this gene is widely found in the genomes of members of the L. casei group and shows variability useful for taxonomic studies. In particular, the HRM analysis method allowed for a specific discrimination between Lactobacillus rhamnosus, Lactobacillus paracasei and L. casei. Regarding the coding region, the spxB functionality in cheese was shown for the first time by real-time PCR, and by exploiting the heterogeneity between the L. casei group species, we identified the bacterial communities encoding the spxB gene in this ecosystem. This study allowed for monitoring of the active bacterial community involved in different stages of ripening by following the POX pathway. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Building Social Competence in Preschool: The Effects of a Social Skills Intervention Targeting Children Enrolled in Head Start

    Science.gov (United States)

    Stanton-Chapman, Tina L.; Walker, Virginia; Jamison, Kristen R.

    2014-01-01

    The current study evaluated the peer-to-peer interactions of at-risk children enrolled in Head Start who participated in a social pragmatic intervention targeting skills such as initiations, responses, name use, proximity, and turn-taking skills. Eight Head Start classroom teams received two workshops and two coaching sessions and were taught to…

  16. Internet-Delivered Targeted Group Intervention for Body Dissatisfaction and Disordered Eating in Adolescent Girls: A Randomized Controlled Trial

    Science.gov (United States)

    Heinicke, Brooke E.; Paxton, Susan J.; McLean, Sian A.; Wertheim, Eleanor H.

    2007-01-01

    This study evaluated a targeted intervention designed to alleviate body image and eating problems in adolescent girls that was delivered over the internet so as to increase access to the program. The program consisted of six, 90-minute weekly small group, synchronous on-line sessions and was facilitated by a therapist and manual. Participants were…

  17. Targeted pathologic evaluation of bone marrow donors identifies previously undiagnosed marrow abnormalities.

    Science.gov (United States)

    Tilson, Matthew P; Jones, Richard J; Sexauer, Amy; Griffin, C A; Morsberger, Laura A; Batista, Denise A S; Small, Donald; Burns, Kathleen H; Gocke, Christopher D; Vuica-Ross, Milena; Borowitz, Michael J; Duffield, Amy S

    2013-08-01

    Potential bone marrow donors are screened to ensure the safety of both the donor and recipient. At our institution, potential donors with abnormal peripheral blood cell counts, a personal history of malignancy, or age >60 years are evaluated to ensure that they are viable candidates for donation. Evaluation of the marrow includes morphologic, flow cytometric, and cytogenetic studies. A total of 122 potential donors were screened between the years of 2001 and 2011, encompassing approximately 10% of all donors. Of the screened potential donors, the mean age was 59 years and there were 59 men and 63 women. The donors were screened because of age >60 years (n = 33), anemia (n = 22), cytopenias other than anemia (n = 27), elevated peripheral blood counts without a concurrent cytopenia (n = 20), elevated peripheral blood counts with a concurrent cytopenia (n = 10), history of malignancy (n = 4), abnormal peripheral blood differential (n = 3), prior graft failure (n = 1), history of treatment with chemotherapy (n = 1), and body habitus (n = 1). Marrow abnormalities were detected in 9% (11 of 122) of donors. These donors were screened because of anemia (5 of 22, 23%), age >60 years (2 of 33, 6%), history of malignancy (2 of 4, 50%), elevated peripheral blood counts (1 of 20, 5%), and body habitus (1 of 1, 100%). Abnormalities included plasma cell dyscrasia (n = 3), abnormal marrow cellularity (n = 3), clonal cytogenetic abnormalities (n = 2), low-grade myelodysplastic syndrome (1), a mutated JAK2 V617F allele (n = 1), and monoclonal B cell lymphocytosis (n = 1). Our experience indicates that extended screening of potential donors identifies a significant number of donors with previously undiagnosed marrow abnormalities. Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  18. A concerted kinase interplay identifies PPARgamma as a molecular target of ghrelin signaling in macrophages.

    Directory of Open Access Journals (Sweden)

    Annie Demers

    2009-11-01

    Full Text Available The peroxisome proliferator-activator receptor PPARgamma plays an essential role in vascular biology, modulating macrophage function and atherosclerosis progression. Recently, we have described the beneficial effect of combined activation of the ghrelin/GHS-R1a receptor and the scavenger receptor CD36 to induce macrophage cholesterol release through transcriptional activation of PPARgamma. Although the interplay between CD36 and PPARgamma in atherogenesis is well recognized, the contribution of the ghrelin receptor to regulate PPARgamma remains unknown. Here, we demonstrate that ghrelin triggers PPARgamma activation through a concerted signaling cascade involving Erk1/2 and Akt kinases, resulting in enhanced expression of downstream effectors LXRalpha and ABC sterol transporters in human macrophages. These effects were associated with enhanced PPARgamma phosphorylation independently of the inhibitory conserved serine-84. Src tyrosine kinase Fyn was identified as being recruited to GHS-R1a in response to ghrelin, but failure of activated Fyn to enhance PPARgamma Ser-84 specific phosphorylation relied on the concomitant recruitment of docking protein Dok-1, which prevented optimal activation of the Erk1/2 pathway. Also, substitution of Ser-84 preserved the ghrelin-induced PPARgamma activity and responsiveness to Src inhibition, supporting a mechanism independent of Ser-84 in PPARgamma response to ghrelin. Consistent with this, we found that ghrelin promoted the PI3-K/Akt pathway in a Galphaq-dependent manner, resulting in Akt recruitment to PPARgamma, enhanced PPARgamma phosphorylation and activation independently of Ser-84, and increased expression of LXRalpha and ABCA1/G1. Collectively, these results illustrate a complex interplay involving Fyn/Dok-1/Erk and Galphaq/PI3-K/Akt pathways to transduce in a concerted manner responsiveness of PPARgamma to ghrelin in macrophages.

  19. Gene expression profiling identifies molecular pathways associated with collagen VI deficiency and provides novel therapeutic targets.

    Directory of Open Access Journals (Sweden)

    Sonia Paco

    Full Text Available Ullrich congenital muscular dystrophy (UCMD, caused by collagen VI deficiency, is a common congenital muscular dystrophy. At present, the role of collagen VI in muscle and the mechanism of disease are not fully understood. To address this we have applied microarrays to analyse the transcriptome of UCMD muscle and compare it to healthy muscle and other muscular dystrophies. We identified 389 genes which are differentially regulated in UCMD relative to controls. In addition, there were 718 genes differentially expressed between UCMD and dystrophin deficient muscle. In contrast, only 29 genes were altered relative to other congenital muscular dystrophies. Changes in gene expression were confirmed by real-time PCR. The set of regulated genes was analysed by Gene Ontology, KEGG pathways and Ingenuity Pathway analysis to reveal the molecular functions and gene networks associated with collagen VI defects. The most significantly regulated pathways were those involved in muscle regeneration, extracellular matrix remodelling and inflammation. We characterised the immune response in UCMD biopsies as being mainly mediated via M2 macrophages and the complement pathway indicating that anti-inflammatory treatment may be beneficial to UCMD as for other dystrophies. We studied the immunolocalisation of ECM components and found that biglycan, a collagen VI interacting proteoglycan, was reduced in the basal lamina of UCMD patients. We propose that biglycan reduction is secondary to collagen VI loss and that it may be contributing towards UCMD pathophysiology. Consequently, strategies aimed at over-expressing biglycan and restore the link between the muscle cell surface and the extracellular matrix should be considered.

  20. Hombres Sanos: exposure and response to a social marketing HIV prevention campaign targeting heterosexually identified Latino men who have sex with men and women.

    Science.gov (United States)

    Martínez-Donate, Ana P; Zellner, Jennifer A; Fernández-Cerdeño, Araceli; Sañudo, Fernando; Hovell, Melbourne F; Sipan, Carol L; Engelberg, Moshe; Ji, Ming

    2009-10-01

    This study examined the reach and impact of a social marketing intervention to reduce HIV risk among heterosexually identified (HI) Latino men who have sex with men and women (MSMW). Repeated cross-sectional intercept surveys were conducted in selected community venues during and after the campaign with 1,137 HI Latino men. Of them, 6% were classified as HI Latino MSMW. On average, 85.9% of the heterosexual respondents and 86.8% of the HI MSMW subsample reported exposure to the campaign. Responses to the campaign included having made an appointment for a male health exam that included HIV testing and using condoms. Campaign exposure was significantly associated with HIV testing behavior and intentions and with knowledge of where to get tested. The campaign reached its underserved target audience and stimulated preventive behaviors. Social marketing represents a promising approach for HIV prevention among HI Latinos, in general, and HI Latino MSMW, in particular.

  1. Joint marketing as a framework for targeting men who have sex with men in China: a pilot intervention study.

    Science.gov (United States)

    Tan, Jingguang; Cai, Rui; Lu, Zuxun; Cheng, Jinquan; de Vlas, Sake J; Richardus, Jan Hendrik

    2013-04-01

    To apply the joint marketing principle as a new intervention approach for targeting men who have sex with men (MSM) who are often difficult to reach in societies with discrimination towards homosexuality and HIV/AIDS. A pilot intervention according to the principles of joint marketing was carried out by the CDC in Shenzhen, China, in MSM social venues. A self-designed questionnaire of HIV knowledge, condom use, and access to HIV-related services was used before and after the pilot intervention to evaluate its effectiveness. The CDC supported gatekeepers of MSM social venues in running their business and thereby increasing their respectability and income. In return, the gatekeepers cooperated with the CDC in reaching the MSM at the venues with health promotion messages and materials. Thus a win-win situation was created, bringing together two noncompetitive parties in reaching out to a shared customer, the MSM. The pilot intervention succeeded in demonstrating acceptability and feasibility of the joint marketing approach targeting MSM. HIV knowledge, the rate of condom use, and access to HIV-related services of participants in the pilot intervention increased significantly. The joint marketing intervention is an innovative way to create synergies between the gatekeepers of MSM social venues and public health officials for reaching and potentially changing HIV high-risk behaviors among MSM.

  2. Kinase Gene Expression Profiling of Metastatic Clear Cell Renal Cell Carcinoma Tissue Identifies Potential New Therapeutic Targets.

    Directory of Open Access Journals (Sweden)

    Pooja Ghatalia

    Full Text Available Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR and mammalian target of rapamycin (mTOR improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC, but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T, matched normal kidney (N and metastatic tumor tissue (M may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79 compared to those that did not develop metastasis for at least 2 years (n = 187. Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Of 10 kinase genes overexpressed in metastases compared to primary tumor in the discovery cohort, 9 genes were also differentially expressed in TCGA primary tumors with metastasis at baseline compared to primary tumors without metastasis for at least 2 years: EPHB2, AURKA, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7 and MAP3K8; p<0.001. The top pathways overexpressed in M tissue were pyridoxal 5'-phosphate salvage, salvage pathways of pyrimidine ribonucleotides, NF-kB signaling, NGF signaling and cell cycle control of chromosomal replication. The 9 kinase genes validated to be over-expressed in metastatic ccRCC may represent currently unrecognized but potentially actionable therapeutic targets that warrant functional validation.

  3. Systems Biology-Based Investigation of Cellular Antiviral Drug Targets Identified by Gene-Trap Insertional Mutagenesis.

    Directory of Open Access Journals (Sweden)

    Feixiong Cheng

    2016-09-01

    Full Text Available Viruses require host cellular factors for successful replication. A comprehensive systems-level investigation of the virus-host interactome is critical for understanding the roles of host factors with the end goal of discovering new druggable antiviral targets. Gene-trap insertional mutagenesis is a high-throughput forward genetics approach to randomly disrupt (trap host genes and discover host genes that are essential for viral replication, but not for host cell survival. In this study, we used libraries of randomly mutagenized cells to discover cellular genes that are essential for the replication of 10 distinct cytotoxic mammalian viruses, 1 gram-negative bacterium, and 5 toxins. We herein reported 712 candidate cellular genes, characterizing distinct topological network and evolutionary signatures, and occupying central hubs in the human interactome. Cell cycle phase-specific network analysis showed that host cell cycle programs played critical roles during viral replication (e.g. MYC and TAF4 regulating G0/1 phase. Moreover, the viral perturbation of host cellular networks reflected disease etiology in that host genes (e.g. CTCF, RHOA, and CDKN1B identified were frequently essential and significantly associated with Mendelian and orphan diseases, or somatic mutations in cancer. Computational drug repositioning framework via incorporating drug-gene signatures from the Connectivity Map into the virus-host interactome identified 110 putative druggable antiviral targets and prioritized several existing drugs (e.g. ajmaline that may be potential for antiviral indication (e.g. anti-Ebola. In summary, this work provides a powerful methodology with a tight integration of gene-trap insertional mutagenesis testing and systems biology to identify new antiviral targets and drugs for the development of broadly acting and targeted clinical antiviral therapeutics.

  4. Solution scanning as a key policy tool: identifying management interventions to help maintain and enhance regulating ecosystem services

    Directory of Open Access Journals (Sweden)

    William J. Sutherland

    2014-06-01

    Full Text Available The major task of policy makers and practitioners when confronted with a resource management problem is to decide on the potential solution(s to adopt from a range of available options. However, this process is unlikely to be successful and cost effective without access to an independently verified and comprehensive available list of options. There is currently burgeoning interest in ecosystem services and quantitative assessments of their importance and value. Recognition of the value of ecosystem services to human well-being represents an increasingly important argument for protecting and restoring the natural environment, alongside the moral and ethical justifications for conservation. As well as understanding the benefits of ecosystem services, it is also important to synthesize the practical interventions that are capable of maintaining and/or enhancing these services. Apart from pest regulation, pollination, and global climate regulation, this type of exercise has attracted relatively little attention. Through a systematic consultation exercise, we identify a candidate list of 296 possible interventions across the main regulating services of air quality regulation, climate regulation, water flow regulation, erosion regulation, water purification and waste treatment, disease regulation, pest regulation, pollination and natural hazard regulation. The range of interventions differs greatly between habitats and services depending upon the ease of manipulation and the level of research intensity. Some interventions have the potential to deliver benefits across a range of regulating services, especially those that reduce soil loss and maintain forest cover. Synthesis and applications: Solution scanning is important for questioning existing knowledge and identifying the range of options available to researchers and practitioners, as well as serving as the necessary basis for assessing cost effectiveness and guiding implementation strategies. We

  5. Toward the identification of adaptive functioning intervention targets for intellectually-able, transition-aged youth with autism: An examination of caregiver responses on the Vineland-II.

    Science.gov (United States)

    Matthews, Nicole L; Malligo, Amanda; Smith, Christopher J

    2017-12-01

    Little is known about specific adaptive functioning impairments in intellectually-able individuals with autism spectrum disorder. In adolescents (n = 22) and young adults (n = 22) matched on composite IQ scores, this study examined profiles of cognitive and adaptive functioning, and caregiver responses on individual Vineland-II items. Adaptive functioning standard scores were significantly lower than IQ scores, and the adult group had significantly lower adaptive functioning standard scores than the adolescent group. Examination of caregiver responses to individual Vineland-II items identified more than 100 potential intervention targets. Differences favoring the adult group were observed on only 16 items across all three adaptive functioning domains, suggesting that little skill development is occurring during the transition to adulthood. Future research will examine the relevance of identified intervention targets to optimal outcomes. Autism Res 2017, 10: 2023-2036. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Adolescents and young adults with autism spectrum disorder (ASD) without intellectual disability demonstrated impaired adaptive functioning skills (i.e., age appropriate skills necessary for independent living). Development of adaptive functioning skills appears to slow with age among individuals without intellectual disability. Findings clarify the specific adaptive functioning skills that transition-aged youth with ASD have difficulty completing independently and will inform the development of interventions to increase the likelihood of independent living in adulthood. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

  6. The transcriptome analysis of Strongyloides stercoralis L3i larvae reveals targets for intervention in a neglected disease.

    Directory of Open Access Journals (Sweden)

    Antonio Marcilla

    Full Text Available BACKGROUND: Strongyloidiasis is one of the most neglected diseases distributed worldwide with endemic areas in developed countries, where chronic infections are life threatening. Despite its impact, very little is known about the molecular biology of the parasite involved and its interplay with its hosts. Next generation sequencing technologies now provide unique opportunities to rapidly address these questions. PRINCIPAL FINDINGS: Here we present the first transcriptome of the third larval stage of S. stercoralis using 454 sequencing coupled with semi-automated bioinformatic analyses. 253,266 raw sequence reads were assembled into 11,250 contiguous sequences, most of which were novel. 8037 putative proteins were characterized based on homology, gene ontology and/or biochemical pathways. Comparison of the transcriptome of S. strongyloides with those of other nematodes, including S. ratti, revealed similarities in transcription of molecules inferred to have key roles in parasite-host interactions. Enzymatic proteins, like kinases and proteases, were abundant. 1213 putative excretory/secretory proteins were compiled using a new pipeline which included non-classical secretory proteins. Potential drug targets were also identified. CONCLUSIONS: Overall, the present dataset should provide a solid foundation for future fundamental genomic, proteomic and metabolomic explorations of S. stercoralis, as well as a basis for applied outcomes, such as the development of novel methods of intervention against this neglected parasite.

  7. Familial risk factors in social anxiety disorder: calling for a family-oriented approach for targeted prevention and early intervention.

    Science.gov (United States)

    Knappe, Susanne; Beesdo-Baum, Katja; Wittchen, Hans-Ulrich

    2010-12-01

    Within the last decade, social anxiety disorder (SAD) has been identified as a highly prevalent and burdensome disorder. Both the characterization of its symptomatology and effective treatment options are widely documented. Studies particularly indicate that SAD aggregates in families and has its onset in early adolescence. Given the family as an important context for children's cognitive, emotional and behavioural development, familial risk factors could be expected to significantly contribute to the reliable detection of populations at risk for SAD. Reviewing studies on familial risk factors for SAD argues for the importance of parental psychopathology and unfavourable family environment, but also denotes to several shortcomings such as cross-sectional designs, short follow-up periods, diverging methodologies and the focus on isolated factors. Using a prospective longitudinal study that covers the high-risk period for SAD, including a broader spectrum of putative risk factors may help to overcome many of the methodological limitations. This review sets out to develop a more family-oriented approach for predicting the onset and maintenance of SAD that may be fruitful to derive targeted prevention and early intervention in SAD.

  8. Endoglin: a novel target for therapeutic intervention in acute leukemias revealed in xenograft mouse models.

    Science.gov (United States)

    Dourado, Keina M C; Baik, June; Oliveira, Vanessa K P; Beltrame, Miriam; Yamamoto, Ami; Theuer, Charles P; Figueiredo, Camila A V; Verneris, Michael R; Perlingeiro, Rita C R

    2017-05-04

    Endoglin (CD105), a receptor of the transforming growth factor-β superfamily, has been reported to identify functional long-term repopulating hematopoietic stem cells, and has been detected in certain subtypes of acute leukemias. Whether this receptor plays a functional role in leukemogenesis remains unknown. We identified endoglin expression on the majority of blasts from patients with acute myeloid leukemia (AML) and acute B-lymphoblastic leukemia (B-ALL). Using a xenograft model, we find that CD105 + blasts are endowed with superior leukemogenic activity compared with the CD105 - population. We test the effect of targeting this receptor using the monoclonal antibody TRC105, and find that in AML, TRC105 prevented the engraftment of primary AML blasts and inhibited leukemia progression following disease establishment, but in B-ALL, TRC105 alone was ineffective due to the shedding of soluble CD105. However, in both B-ALL and AML, TRC105 synergized with reduced intensity myeloablation to inhibit leukemogenesis, indicating that TRC105 may represent a novel therapeutic option for B-ALL and AML. © 2017 by The American Society of Hematology.

  9. The potential impact of case-area targeted interventions in response to cholera outbreaks: A modeling study.

    Science.gov (United States)

    Finger, Flavio; Bertuzzo, Enrico; Luquero, Francisco J; Naibei, Nathan; Touré, Brahima; Allan, Maya; Porten, Klaudia; Lessler, Justin; Rinaldo, Andrea; Azman, Andrew S

    2018-02-01

    Cholera prevention and control interventions targeted to neighbors of cholera cases (case-area targeted interventions [CATIs]), including improved water, sanitation, and hygiene, oral cholera vaccine (OCV), and prophylactic antibiotics, may be able to efficiently avert cholera cases and deaths while saving scarce resources during epidemics. Efforts to quickly target interventions to neighbors of cases have been made in recent outbreaks, but little empirical evidence related to the effectiveness, efficiency, or ideal design of this approach exists. Here, we aim to provide practical guidance on how CATIs might be used by exploring key determinants of intervention impact, including the mix of interventions, "ring" size, and timing, in simulated cholera epidemics fit to data from an urban cholera epidemic in Africa. We developed a micro-simulation model and calibrated it to both the epidemic curve and the small-scale spatiotemporal clustering pattern of case households from a large 2011 cholera outbreak in N'Djamena, Chad (4,352 reported cases over 232 days), and explored the potential impact of CATIs in simulated epidemics. CATIs were implemented with realistic logistical delays after cases presented for care using different combinations of prophylactic antibiotics, OCV, and/or point-of-use water treatment (POUWT) starting at different points during the epidemics and targeting rings of various radii around incident case households. Our findings suggest that CATIs shorten the duration of epidemics and are more resource-efficient than mass campaigns. OCV was predicted to be the most effective single intervention, followed by POUWT and antibiotics. CATIs with OCV started early in an epidemic focusing on a 100-m radius around case households were estimated to shorten epidemics by 68% (IQR 62% to 72%), with an 81% (IQR 69% to 87%) reduction in cases compared to uncontrolled epidemics. These same targeted interventions with OCV led to a 44-fold (IQR 27 to 78) reduction in

  10. Targeting Interventions: Moderators of the Effects of Expressive Writing and Assertiveness Training on the Adjustment of International University Students.

    Science.gov (United States)

    Hijazi, Alaa M; Tavakoli, Shedeh; Slavin-Spenny, Olga M; Lumley, Mark A

    2011-06-01

    Acculturative stress is a common experience for international students and is associated with psychological and physical problems. In a previous study, the authors reported that two stress reduction interventions-expressive writing (EW) and assertiveness training (AT)-had limited overall benefits among international students at an American University. The current analyses of data from that study investigated whether individual differences moderated the effects of EW and AT. Results indicate that greater acculturative stress at baseline predicted greater improvement from both interventions, compared with control. Women benefited more from AT than EW, except that EW improved women's physical symptoms. Men benefited more from EW than AT. Students with limited emotional awareness and expression tended to benefit from both interventions, relative to control. Finally, nation of origin cultural differences generally did not predict outcomes. It is concluded that the benefits of EW and AT and can be enhanced by targeting these interventions to specific subgroups of international students.

  11. Frameshift mutational target gene analysis identifies similarities and differences in constitutional mismatch repair-deficiency and Lynch syndrome.

    Science.gov (United States)

    Maletzki, Claudia; Huehns, Maja; Bauer, Ingrid; Ripperger, Tim; Mork, Maureen M; Vilar, Eduardo; Klöcking, Sabine; Zettl, Heike; Prall, Friedrich; Linnebacher, Michael

    2017-07-01

    Mismatch-repair deficient (MMR-D) malignancies include Lynch Syndrome (LS), which is secondary to germline mutations in one of the MMR genes, and the rare childhood-form of constitutional mismatch repair-deficiency (CMMR-D); caused by bi-allelic MMR gene mutations. A hallmark of LS-associated cancers is microsatellite instability (MSI), characterized by coding frameshift mutations (cFSM) in target genes. By contrast, tumors arising in CMMR-D patients are thought to display a somatic mutation pattern differing from LS. This study has the main goal to identify cFSM in MSI target genes relevant in CMMR-D and to compare the spectrum of common somatic mutations, including alterations in DNA polymerases POLE and D1 between LS and CMMR-D. CMMR-D-associated tumors harbored more somatic mutations compared to LS cases, especially in the TP53 gene and in POLE and POLD1, where novel mutations were additionally identified. Strikingly, MSI in classical mononucleotide markers BAT40 and CAT25 was frequent in CMMR-D cases. MSI-target gene analysis revealed mutations in CMMR-D-associated tumors, some of them known to be frequently hit in LS, such as RNaseT2, HT001, and TGFβR2. Our results imply a general role for these cFSM as potential new drivers of MMR-D tumorigenesis. © 2017 Wiley Periodicals, Inc.

  12. Identifying the unmet health needs of patients with congenital hypogonadotropic hypogonadism using a web-based needs assessment: implications for online interventions and peer-to-peer support.

    Science.gov (United States)

    Dwyer, Andrew A; Quinton, Richard; Morin, Diane; Pitteloud, Nelly

    2014-06-11

    Patients with rare diseases such as congenital hypogonadotropic hypogonadism (CHH) are dispersed, often challenged to find specialized care and face other health disparities. The internet has the potential to reach a wide audience of rare disease patients and can help connect patients and specialists. Therefore, this study aimed to: (i) determine if web-based platforms could be effectively used to conduct an online needs assessment of dispersed CHH patients; (ii) identify the unmet health and informational needs of CHH patients and (iii) assess patient acceptability regarding patient-centered, web-based interventions to bridge shortfalls in care. A sequential mixed-methods design was used: first, an online survey was conducted to evaluate health promoting behavior and identify unmet health and informational needs of CHH men. Subsequently, patient focus groups were held to explore specific patient-identified targets for care and to examine the acceptability of possible online interventions. Descriptive statistics and thematic qualitative analyses were used. 105 male participants completed the online survey (mean age 37 ± 11, range 19-66 years) representing a spectrum of patients across a broad socioeconomic range and all but one subject had adequate healthcare literacy. The survey revealed periods of non-adherence to treatment (34/93, 37%) and gaps in healthcare (36/87, 41%) exceeding one year. Patient focus groups identified lasting psychological effects related to feelings of isolation, shame and body-image concerns. Survey respondents were active internet users, nearly all had sought CHH information online (101/105, 96%), and they rated the internet, healthcare providers, and online community as equally important CHH information sources. Focus group participants were overwhelmingly positive regarding online interventions/support with links to reach expert healthcare providers and for peer-to-peer support. The web-based needs assessment was an effective way

  13. A retrospective population-based cohort study identifying target areas for prevention of acute lower respiratory infections in children

    Directory of Open Access Journals (Sweden)

    Richmond Peter

    2010-12-01

    Full Text Available Abstract Background Acute lower respiratory infections (ALRI are a major cause of hospitalisation in young children. Many factors can lead to increased risk of ALRI in children and predispose a child to hospitalisation, but population attributable fractions for different risk factors and how these fractions differ between Indigenous and non-Indigenous children is unknown. This study investigates population attributable fractions of known infant and maternal risk factors for ALRI to inform prevention strategies that target high-risk groups or particular risk factors. Methods A retrospective population-based data linkage study of 245,249 singleton births in Western Australia. Population attributable fractions of known maternal and infant risk factors for hospitalisation with ALRI between 1996 and 2005 were calculated using multiple logistic regression. Results The overall ALRI hospitalisation rate was 16.1/1,000 person-years for non-Aboriginal children and 93.0/1,000 for Aboriginal children. Male gender, being born in autumn, gestational age Conclusions The population attributable fractions estimated in this study should help in guiding public health interventions to prevent ALRI. A key risk factor for all children is maternal smoking during pregnancy, and multiple previous pregnancies and autumnal births are important high-risk groups. Specific key target areas are reducing elective caesareans in non-Aboriginal women and reducing teenage pregnancies and improving access to services and living conditions for the Aboriginal population.

  14. A new screening method to identify inhibitors of the Lol (localization of lipoproteins) system, a novel antibacterial target.

    Science.gov (United States)

    Ito, Hideaki; Ura, Atsushi; Oyamada, Yoshihiro; Yoshida, Hiroaki; Yamagishi, Jun-Ichi; Narita, Shin-Ichiro; Matsuyama, Shin-Ichi; Tokuda, Hajime

    2007-01-01

    As the Lol system, which is involved in localization of lipoproteins, is essential for Escherichia coli growth and widely conserved among gram-negative bacteria, it is considered to be a promising target for the development of anti-gram-negative bacterial agents. However, no high-throughput screening method has so far been developed to screen for Lol system inhibitors. By combining three assay systems (anucleate cell blue assay, Lpp assay, and LolA-dependent release inhibition assay) and a drug susceptibility test, we have successfully developed a new screening method for identification of compounds that inhibit the Lol system. Using this new screening method, we screened 23,600 in-house chemical compounds and found 2 Lol system inhibitors. We therefore conclude that our new screening method can efficiently identify new antibacterial agents that target the Lol system.

  15. Impact of a longitudinal community HIV intervention targeting injecting drug users' stage of change for condom and bleach use.

    Science.gov (United States)

    Jamner, M S; Wolitski, R J; Corby, N H

    1997-01-01

    To evaluate the impact of the Long Beach AIDS Community Demonstration Project, a community-based HIV-prevention intervention incorporating principles from the Transtheoretical model in its design and evaluation. Repeated cross-sectional sampling with matched intervention and comparison communities. Neighborhoods in Long Beach, California, having a high prevalence of drug abuse and prostitution. 3081 injecting drug users who were sexually active and/or shared injection equipment. Trained peer volunteers distributed fliers featuring role model stories targeted to the population's stage of change. Fliers were packaged with bleaching kits and/or condoms. Primary outcome measures were exposure to the intervention, condom carrying, and stage of change for disinfecting injection equipment with bleach and for using condoms with main and other partners. Toward the end of the study, 77% of injection drug users in the intervention area reported being exposed to the intervention. In the intervention area, rates of condom carrying increased from 10 to 27% (p project exposure had higher stage-of-change scores for using condoms with a main partner (p Project intervention for reaching injecting drug users in the community and for motivating the adoption of risk-reducing practices.

  16. Body image and self-esteem among adolescents undergoing an intervention targeting dietary and physical activity behaviors.

    Science.gov (United States)

    Huang, Jeannie S; Norman, Gregory J; Zabinski, Marion F; Calfas, Karen; Patrick, Kevin

    2007-03-01

    To determine the effect of a one-year intervention targeting physical activity, sedentary, and diet behaviors among adolescents on self-reported body image and self-esteem. Health promotion interventions can lead to awareness of health risk and subsequent adoption of beneficial changes in behavior. However, it is possible that interventions targeting behaviors associated with childhood obesity may also increase the likelihood of unhealthy eating and physical activity obsessions and behaviors. Body image and self-esteem were assessed for adolescents participating in the PACE+ study, a randomized controlled trial of a 1-year behavioral intervention targeting physical activity, sedentary, and dietary behaviors. The Body Dissatisfaction subscale of the Eating Disorder Inventory and Rosenberg Self-Esteem scale were used to assess body image and self-esteem, respectively, and measurements were performed at baseline, and at 6 and 12 months. Demographic characteristics and weight status of participants were also ascertained. Analysis of responses was performed via both between-group and within-group repeated measure analyses. There were 657 adolescents who completed all measurements. Body image differences were found for age, gender, and weight status at baseline, whereas self-esteem differences were demonstrated for gender, ethnicity, and weight status. There were no intervention effects on body image or self-esteem for either girls or boys. Self-esteem and body satisfaction did not worsen as a result of participating in the PACE+ intervention for either boys or girls whether or not they lost or maintained their weight or gained weight. Girls assigned to the PACE intervention who experienced weight reduction or weight maintenance at either 6 or 12 months reported improvements in body image satisfaction (p = .02) over time compared with subjects who had experienced weight gain during the 12-month study period. Adverse effects on body satisfaction and self-esteem were not

  17. Identifying mRNA targets of microRNA dysregulated in cancer: with application to clear cell Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Liou Louis S

    2010-04-01

    Full Text Available Abstract Background MicroRNA regulate mRNA levels in a tissue specific way, either by inducing degradation of the transcript or by inhibiting translation or transcription. Putative mRNA targets of microRNA identified from seed sequence matches are available in many databases. However, such matches have a high false positive rate and cannot identify tissue specificity of regulation. Results We describe a simple method to identify direct mRNA targets of microRNA dysregulated in cancers from expression level measurements in patient matched tumor/normal samples. The word "direct" is used here in a strict sense to: a represent mRNA which have an exact seed sequence match to the microRNA in their 3'UTR, b the seed sequence match is strictly conserved across mouse, human, rat and dog genomes, c the mRNA and microRNA expression levels can distinguish tumor from normal with high significance and d the microRNA/mRNA expression levels are strongly and significantly anti-correlated in tumor and/or normal samples. We apply and validate the method using clear cell Renal Cell Carcinoma (ccRCC and matched normal kidney samples, limiting our analysis to mRNA targets which undergo degradation of the mRNA transcript because of a perfect seed sequence match. Dysregulated microRNA and mRNA are first identified by comparing their expression levels in tumor vs normal samples. Putative dysregulated microRNA/mRNA pairs are identified from these using seed sequence matches, requiring that the seed sequence be conserved in human/dog/rat/mouse genomes. These are further pruned by requiring a strong anti-correlation signature in tumor and/or normal samples. The method revealed many new regulations in ccRCC. For instance, loss of miR-149, miR-200c and mir-141 causes gain of function of oncogenes (KCNMA1, LOX, VEGFA and SEMA6A respectively and increased levels of miR-142-3p, miR-185, mir-34a, miR-224, miR-21 cause loss of function of tumor suppressors LRRC2, PTPN13, SFRP1

  18. A Multicomponent Schoolyard Intervention Targeting Children's Recess Physical Activity and Sedentary Behavior: Effects After 1 Year.

    Science.gov (United States)

    Van Kann, Dave H H; de Vries, Sanne I; Schipperijn, Jasper; de Vries, Nanne K; Jansen, Maria W J; Kremers, Stef P J

    2017-11-01

    The aim of the study was to test the 12-month effects of a multicomponent physical activity (PA) intervention at schoolyards on morning recess PA levels of sixth- and seventh-grade children in primary schools, using accelerometry and additional global positioning system data. A quasi-experimental study design was used with 20 paired intervention and control schools. Global positioning system confirmatory analyses were applied to validate attendance at schoolyards during recess. Accelerometer data from 376 children from 7 pairs of schools were included in the final analyses. Pooled intervention effectiveness was tested by multilevel linear regression analyses, whereas effectiveness of intervention components was tested by multivariate linear regression analyses. Children exposed to the multicomponent intervention increased their time spent in light PA (+5.9%) during recess. No pooled effects on moderate to vigorous PA were found. In-depth analyses of intervention components showed that physical schoolyard interventions particularly predicted a decrease in time spent in sedentary behavior during recess at follow-up. Intervention intensity and the school's commitment to the project strengthened this effect. The multicomponent schoolyard PA intervention was effective in making children spend a larger proportion of recess time in light PA, which was most likely the result of a shift from sedentary behavior to light PA.

  19. A Multicomponent Schoolyard Intervention Targeting Children's Recess Physical Activity and Sedentary Behavior: Effects After One Year.

    Science.gov (United States)

    Van Kann, Dave H H; de Vries, S I; Schipperijn, J; de Vries, N K; Jansen, M W J; Kremers, S P J

    2016-10-24

    Background Aim of the study was to test the 12-month effects of a multicomponent physical activity (PA) intervention at schoolyards on recess PA levels of 6th and 7th grade children in primary schools, combining Global Positioning System (GPS) and accelerometry data. Methods A quasi-experimental study design was used with 20 paired intervention and control schools. GPS confirmatory analyses were applied to validate attendance at schoolyards during recess. Data from 376 children from 7 pairs of schools were included in the final analyses. Pooled intervention effectiveness was tested by multilevel linear regression analyses, whereas effectiveness of intervention components was tested by multivariate linear regression analyses. Results Children exposed to the multicomponent intervention increased their time spent in light PA (+5.9%) during recess. No pooled effects on Moderate-to-Vigorous PA were found. In depth-analyses on intervention components showed that physical schoolyard interventions particularly predicted a decrease in time spent in sedentary behavior during recess at follow-up. Intervention intensity and school's commitment to the project strengthened this effect. Conclusions The multicomponent schoolyard PA intervention was effective in making children spend a larger proportion of recess time in light PA, which was most likely the result of a shift from sedentary behavior to light PA.

  20. Identifying interventions to help rural Kenyan mothers cope with food insecurity: results of a focused ethnographic study.

    Science.gov (United States)

    Pelto, Gretel H; Armar-Klemesu, Margaret

    2015-12-01

    An ethnographic study was conducted in two areas in southern and western Kenya to identify potential interventions to improve the quality, availability and affordability of foods consumed by infants and young children. A cultural-ecological model of determinants of nutrition identified the sectors of information for data collection related to infant and young child (IYC) diet and feeding-related behaviours, and the focused ethnographic study manual was used to guide the research. The results provide qualitative evidence about facilitators and constraints to IYC nutrition in the two geographical areas and document their inter-connections. We conclude with suggestions to consider 13 potential nutrition-sensitive interventions. The studies provide empirical ethnographic support for arguments concerning the importance of combining nutrition-specific and nutrition-sensitive interventions through a multi-sectoral, integrated approach to improve the nutrition of infants and young children in low-income, resource-constrained populations. They also document the value of ethnography as a component of landscape analysis in nutrition programme and policy planning. Key messages In addition to constraints on infant and young child diet that originate in environmental and technological conditions in both agro-ecological zones, other factors that affect feeding practices include features of social organisation, household access to social support, caregivers income-earning activities and their own health. The results of the ethnographies, which highlight the importance of obtaining the knowledge and perspectives of caregivers of infants and young children, reveal the interactions of the multiple factors that affect child nutrition and the need for simultaneous nutrition-sensitive interventions to complement nutrition-specific intervention actions. Most caregivers in both areas not only understood the importance of diet and food quality for child survival, they also regarded it as

  1. Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment.

    Directory of Open Access Journals (Sweden)

    Adam A Friedman

    Full Text Available A newer generation of anti-cancer drugs targeting underlying somatic genetic driver events have resulted in high single-agent or single-pathway response rates in selected patients, but few patients achieve complete responses and a sizeable fraction of patients relapse within a year. Thus, there is a pressing need for identification of combinations of targeted agents which induce more complete responses and prevent disease progression. We describe the results of a combination screen of an unprecedented scale in mammalian cells performed using a collection of targeted, clinically tractable agents across a large panel of melanoma cell lines. We find that even the most synergistic drug pairs are effective only in a discrete number of cell lines, underlying a strong context dependency for synergy, with strong, widespread synergies often corresponding to non-specific or off-target drug effects such as multidrug resistance protein 1 (MDR1 transporter inhibition. We identified drugs sensitizing cell lines that are BRAFV600E mutant but intrinsically resistant to BRAF inhibitor PLX4720, including the vascular endothelial growth factor receptor/kinase insert domain receptor (VEGFR/KDR and platelet derived growth factor receptor (PDGFR family inhibitor cediranib. The combination of cediranib and PLX4720 induced apoptosis in vitro and tumor regression in animal models. This synergistic interaction is likely due to engagement of multiple receptor tyrosine kinases (RTKs, demonstrating the potential of drug- rather than gene-specific combination discovery approaches. Patients with elevated biopsy KDR expression showed decreased progression free survival in trials of mitogen-activated protein kinase (MAPK kinase pathway inhibitors. Thus, high-throughput unbiased screening of targeted drug combinations, with appropriate library selection and mechanistic follow-up, can yield clinically-actionable drug combinations.

  2. Global tyrosine kinome profiling of human thyroid tumors identifies Src as a promising target for invasive cancers

    International Nuclear Information System (INIS)

    Cho, Nancy L.; Lin, Chi-Iou; Du, Jinyan; Whang, Edward E.; Ito, Hiromichi; Moore, Francis D.; Ruan, Daniel T.

    2012-01-01

    Highlights: ► Kinome profiling is a novel technique for identifying activated kinases in human cancers. ► Src activity is increased in invasive thyroid cancers. ► Inhibition of Src activity decreased proliferation and invasion in vitro. ► Further investigation of Src targeted therapies in thyroid cancer is warranted. -- Abstract: Background: Novel therapies are needed for the treatment of invasive thyroid cancers. Aberrant activation of tyrosine kinases plays an important role in thyroid oncogenesis. Because current targeted therapies are biased toward a small subset of tyrosine kinases, we conducted a study to reveal novel therapeutic targets for thyroid cancer using a bead-based, high-throughput system. Methods: Thyroid tumors and matched normal tissues were harvested from twenty-six patients in the operating room. Protein lysates were analyzed using the Luminex immunosandwich, a bead-based kinase phosphorylation assay. Data was analyzed using GenePattern 3.0 software and clustered according to histology, demographic factors, and tumor status regarding capsular invasion, size, lymphovascular invasion, and extrathyroidal extension. Survival and invasion assays were performed to determine the effect of Src inhibition in papillary thyroid cancer (PTC) cells. Results: Tyrosine kinome profiling demonstrated upregulation of nine tyrosine kinases in tumors relative to matched normal thyroid tissue: EGFR, PTK6, BTK, HCK, ABL1, TNK1, GRB2, ERK, and SRC. Supervised clustering of well-differentiated tumors by histology, gender, age, or size did not reveal significant differences in tyrosine kinase activity. However, supervised clustering by the presence of invasive disease showed increased Src activity in invasive tumors relative to non-invasive tumors (60% v. 0%, p < 0.05). In vitro, we found that Src inhibition in PTC cells decreased cell invasion and proliferation. Conclusion: Global kinome analysis enables the discovery of novel targets for thyroid cancer

  3. Stroke outreach in an inner city market: A platform for identifying African American males for stroke prevention interventions

    Directory of Open Access Journals (Sweden)

    Anjail Zarinah Sharrief

    2015-06-01

    Full Text Available AbstractBackground: There are significant racial disparities in stroke incidence and mortality. Health fairs and outreach programs can be used to increase stroke literacy, but they often fail to reach those at highest risk, including African American males. Methods: We conducted a stroke outreach and screening program at an inner city market in order to attract a high-risk group for a stroke education intervention. A modified Framingham risk tool was used to estimate stroke risk and a 10-item quiz was developed to assess stroke literacy among 80 participants. We report results of the demographic and stroke risk analyses and stroke knowledge assessment. Results: The program attracted a majority male (70% and African American (95% group of participants. Self-reported hypertension (57.5%, tobacco use (40%, and diabetes (23.8% were prevalent. Knowledge of stroke warning signs, risk factors, and appropriate action to take for stroke symptoms was not poor when compared to the literature. Conclusions: Stroke outreach and screening in an inner city public market may be an effective way to target a high-risk population for stroke prevention interventions. Stroke risk among participants was high despite adequate stroke knowledge.

  4. Stroke Outreach in an Inner City Market: A Platform for Identifying African American Males for Stroke Prevention Interventions.

    Science.gov (United States)

    Sharrief, Anjail Zarinah; Johnson, Brenda; Urrutia, Victor Cruz

    2015-01-01

    There are significant racial disparities in stroke incidence and mortality. Health fairs and outreach programs can be used to increase stroke literacy, but they often fail to reach those at highest risk, including African American males. We conducted a stroke outreach and screening program at an inner city market in order to attract a high-risk group for a stroke education intervention. A modified Framingham risk tool was used to estimate stroke risk and a 10-item quiz was developed to assess stroke literacy among 80 participants. We report results of the demographic and stroke risk analyses and stroke knowledge assessment. The program attracted a majority male (70%) and African American (95%) group of participants. Self-reported hypertension (57.5%), tobacco use (40%), and diabetes (23.8%) were prevalent. Knowledge of stroke warning signs, risk factors, and appropriate action to take for stroke symptoms was not poor when compared to the literature. Stroke outreach and screening in an inner city public market may be an effective way to target a high-risk population for stroke prevention interventions. Stroke risk among participants was high despite adequate stroke knowledge.

  5. Understanding the echo clues used by dolphins to remotely identify the target characteristics of submerged elastic shells

    Science.gov (United States)

    Gaunaurd, Guillermo C.; Brill, Donald; Huang, H.; Moore, Patrick W.; Strifors, Hans C.

    1996-05-01

    We have examined a large set of dolphin-emitted acoustic pulses (`echolocation clicks') which were reflected from various elastic shells that were suspended, underwater, 4.5 m in front of the animal in a large test site in Kaneohe Bay. A carefully instrumented analog-to-digital system continuously captured the emitted clicks and also the returned, backscattered, echoes (A/D conversion at 500 kHz). Using standard conditioning techniques and food reinforces, the dolphin is taught to push an underwater paddle when the `correct' target--the one he has been trained to identify--is presented to him. He communicates to us his consistently correct identifying choices in this manner. We have examined many echoes returned by three types of cylindrical shells in both the time and frequency domains. We will show exactly how specific features observable in these displays are directly related to the physical characteristics of the shells. Our processing uses certain fundamental resonance principles to show which echo- features contain information about the size, shape, wall-thickness, and material composition of both the shell and its filler substance. In the same fashion that these resonance features give us the identifying characteristics of each shell, we believe they also give them to the dolphin. These echo features may tell him the target properties without any need for computations. We claim that this may be the fundamental physical explanation of the dolphin's amazing target-ID feats, upon which they base their recognition choices. Our claim may be substantiated by the detailed analysis of many typical echoes returned by various shells, when they are interrogated by several dolphins. Thus far, this analysis of many echoes from many shells has only been carried out for a single dolphin.

  6. Comparative proteomic approach identifies PKM2 and cofilin-1 as potential diagnostic, prognostic and therapeutic targets for pulmonary adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Xing-chen Peng

    Full Text Available Lung cancer is the leading cause of cancer-related death in the world. Non-small cell lung carcinomas (Non-SCLC account for almost 80% of lung cancers, of which 40% were adenocarcinomas. For a better understanding of the molecular mechanisms behind the development and progression of lung cancer, particularly lung adenocarcinoma, we have used proteomics technology to search for candidate prognostic and therapeutic targets in pulmonary adenocarcinoma. The protein profile changes between human pulmonary adenocarcinoma tissue and paired surrounding normal tissue were analyzed using two-dimensional polyacrylamide gel electrophoresis (2-DE based approach. Differentially expressed protein-spots were identified with ESI-Q-TOF MS/MS instruments. As a result, thirty two differentially expressed proteins (over 2-fold, p<0.05 were identified in pulmonary adenocarcinoma compared to normal tissues. Among them, two proteins (PKM2 and cofilin-1, significantly up-regulated in adenocarcinoma, were selected for detailed analysis. Immunohistochemical examination indicated that enhanced expression of PKM2 and cofilin-1 were correlated with the severity of epithelial dysplasia, as well as a relatively poor prognosis. Knockdown of PKM2 expression by RNA interference led to a significant suppression of cell growth and induction of apoptosis in pulmonary adenocarcinoma SPC-A1 cells in vitro, and tumor growth inhibition in vivo xenograft model (P<0.05. In addition, the shRNA expressing plasmid targeting cofilin-1 significantly inhibited tumor metastases and prolonged survival in LL/2 metastatic model. While additional works are needed to elucidate the biological significance and molecular mechanisms of these altered proteins identified in this study, PKM2 and cofilin-1 may serve as potential diagnostic and prognostic biomarkers, as well as therapeutic targets for pulmonary adenocarcinoma.

  7. The 'robustness' of vocabulary intervention in the public schools: targets and techniques employed in speech-language therapy.

    Science.gov (United States)

    Justice, Laura M; Schmitt, Mary Beth; Murphy, Kimberly A; Pratt, Amy; Biancone, Tricia

    2014-01-01

    This study examined vocabulary intervention-in terms of targets and techniques-for children with language impairment receiving speech-language therapy in public schools (i.e., non-fee-paying schools) in the United States. Vocabulary treatments and targets were examined with respect to their alignment with the empirically validated practice of rich vocabulary intervention. Participants were forty-eight 5-7-year-old children participating in kindergarten or the first-grade year of school, all of whom had vocabulary-specific goals on their individualized education programmes. Two therapy sessions per child were coded to determine what vocabulary words were being directly targeted and what techniques were used for each. Study findings showed that the majority of words directly targeted during therapy were lower-level basic vocabulary words (87%) and very few (1%) were academically relevant. On average, three techniques were used per word to promote deep understanding. Interpreting findings against empirical descriptions of rich vocabulary intervention indicates that children were exposed to some but not all aspects of this empirically supported practice. © 2013 Royal College of Speech and Language Therapists.

  8. Integration of Traditional and Metabolomics Biomarkers Identifies Prognostic Metabolites for Predicting Responsiveness to Nutritional Intervention against Oxidative Stress and Inflammation

    Directory of Open Access Journals (Sweden)

    You Jin Kim

    2017-03-01

    Full Text Available Various statistical approaches can be applied to integrate traditional and omics biomarkers, allowing the discovery of prognostic markers to classify subjects into poor and good prognosis groups in terms of responses to nutritional interventions. Here, we performed a prototype study to identify metabolites that predict responses to an intervention against oxidative stress and inflammation, using a data set from a randomized controlled trial evaluating Korean black raspberry (KBR in sedentary overweight/obese subjects. First, a linear mixed-effects model analysis with multiple testing correction showed that four-week consumption of KBR significantly changed oxidized glutathione (GSSG, q = 0.027 level, the ratio of reduced glutathione (GSH to GSSG (q = 0.039 in erythrocytes, malondialdehyde (MDA, q = 0.006 and interleukin-6 (q = 0.006 levels in plasma, and seventeen NMR metabolites in urine compared with those in the placebo group. A subsequent generalized linear mixed model analysis showed linear correlations between baseline urinary glycine and N-phenylacetylglycine (PAG and changes in the GSH:GSSG ratio (p = 0.008 and 0.004 as well as between baseline urinary adenine and changes in MDA (p = 0.018. Then, receiver operating characteristic analysis revealed that a two-metabolite set (glycine and PAG had the strongest prognostic relevance for future interventions against oxidative stress (the area under the curve (AUC = 0.778. Leave-one-out cross-validation confirmed the accuracy of prediction (AUC = 0.683. The current findings suggest that a higher level of this two-metabolite set at baseline is useful for predicting responders to dietary interventions in subjects with oxidative stress and inflammation, contributing to the emergence of personalized nutrition.

  9. Downregulation of GNA13-ERK network in prefrontal cortex of schizophrenia brain identified by combined focused and targeted quantitative proteomics.

    Science.gov (United States)

    Hirayama-Kurogi, Mio; Takizawa, Yohei; Kunii, Yasuto; Matsumoto, Junya; Wada, Akira; Hino, Mizuki; Akatsu, Hiroyasu; Hashizume, Yoshio; Yamamoto, Sakon; Kondo, Takeshi; Ito, Shingo; Tachikawa, Masanori; Niwa, Shin-Ichi; Yabe, Hirooki; Terasaki, Tetsuya; Setou, Mitsutoshi; Ohtsuki, Sumio

    2017-03-31

    Schizophrenia is a disabling mental illness associated with dysfunction of the prefrontal cortex, which affects cognition and emotion. The purpose of the present study was to identify altered molecular networks in the prefrontal cortex of schizophrenia patients by comparing protein expression levels in autopsied brains of patients and controls, using a combination of targeted and focused quantitative proteomics. We selected 125 molecules possibly related to schizophrenia for quantification by knowledge-based targeted proteomics. Among the quantified molecules, GRIK4 and MAO-B were significantly decreased in plasma membrane and cytosolic fractions, respectively, of prefrontal cortex. Focused quantitative proteomics identified 15 increased and 39 decreased proteins. Network analysis identified "GNA13-ERK1-eIF4G2 signaling" as a downregulated network, and proteins involved in this network were significantly decreased. Furthermore, searching downstream of eIF4G2 revealed that eIF4A1/2 and CYFIP1 were decreased, suggesting that downregulation of the network suppresses expression of CYFIP1, which regulates actin remodeling and is involved in axon outgrowth and spine formation. Downregulation of this signaling seems likely to impair axon formation and synapse plasticity of neuronal cells, and could be associated with development of cognitive impairment in the pathology of schizophrenia. The present study compared the proteome of the prefrontal cortex between schizophrenia patients and healthy controls by means of targeted proteomics and global quantitative proteomics. Targeted proteomics revealed that GRIK4 and MAOB were significantly decreased among 125 putatively schizophrenia-related proteins in prefrontal cortex of schizophrenia patients. Global quantitative proteomics identified 54 differentially expressed proteins in schizophrenia brains. The protein profile indicates attenuation of "GNA13-ERK signaling" in schizophrenia brain. In particular, EIF4G2 and CYFIP1

  10. Bacterial rRNA-Targeted Reverse Transcription-PCR Used To Identify Pathogens Responsible for Fever with Neutropenia▿

    OpenAIRE

    Sakaguchi, Sachi; Saito, Masahiro; Tsuji, Hirokazu; Asahara, Takashi; Takata, Oto; Fujimura, Junya; Nagata, Satoru; Nomoto, Koji; Shimizu, Toshiaki

    2010-01-01

    The purpose of this study was to evaluate the clinical utility of bacterial rRNA-targeted reverse transcription-quantitative PCR (BrRNA RT-qPCR) assays for identifying the bacterial pathogens that cause fever with neutropenia in pediatric cancer patients, by comparing the bacterial detection rate of this technique with that of blood culture. One milliliter of blood was collected from pediatric patients who developed fever with neutropenia following cancer chemotherapy. BrRNA RT-qPCR was perfo...

  11. Targeted prevention of common mental health disorders in university students: randomised controlled trial of a transdiagnostic trait-focused web-based intervention.

    Directory of Open Access Journals (Sweden)

    Peter Musiat

    Full Text Available BACKGROUND: A large proportion of university students show symptoms of common mental disorders, such as depression, anxiety, substance use disorders and eating disorders. Novel interventions are required that target underlying factors of multiple disorders. AIMS: To evaluate the efficacy of a transdiagnostic trait-focused web-based intervention aimed at reducing symptoms of common mental disorders in university students. METHOD: Students were recruited online (n=1047, age: M=21.8, SD=4.2 and categorised into being at high or low risk for mental disorders based on their personality traits. Participants were allocated to a cognitive-behavioural trait-focused (n=519 or a control intervention (n=528 using computerised simple randomisation. Both interventions were fully automated and delivered online (trial registration: ISRCTN14342225. Participants were blinded and outcomes were self-assessed at baseline, at 6 weeks and at 12 weeks after registration. Primary outcomes were current depression and anxiety, assessed on the Patient Health Questionnaire (PHQ9 and Generalised Anxiety Disorder Scale (GAD7. Secondary outcome measures focused on alcohol use, disordered eating, and other outcomes. RESULTS: Students at high risk were successfully identified using personality indicators and reported poorer mental health. A total of 520 students completed the 6-week follow-up and 401 students completed the 12-week follow-up. Attrition was high across intervention groups, but comparable to other web-based interventions. Mixed effects analyses revealed that at 12-week follow up the trait-focused intervention reduced depression scores by 3.58 (p<.001, 95%CI [5.19, 1.98] and anxiety scores by 2.87 (p=.018, 95%CI [1.31, 4.43] in students at high risk. In high-risk students, between group effect sizes were 0.58 (depression and 0.42 (anxiety. In addition, self-esteem was improved. No changes were observed regarding the use of alcohol or disordered eating. CONCLUSIONS

  12. The efficacy of targeted interventions for modifiable psychosocial risk factors of persistent nonspecific low back pain e A systematic review

    DEFF Research Database (Denmark)

    Kent, Peter; Kjær, Per

    2012-01-01

    were randomised controlled trials of targeted psychosocial interventions that used trial designs capable of providing robust information on the efficacy of targeted treatment (treatment effect modification) for the outcomes of pain, activity limitation and psychosocial factors (fear avoidance......, catastrophisation, anxiety and depression). Results and conclusion: Four studies met the inclusion criteria and collectively investigated nine hypotheses about targeted treatment on 28 subgroup/treatment outcomes. There were only two statistically significant results. Graded activity plus Treatment Based...... Classification targeted to people with high movement-related fear was more effective than Treatment Based Classification at reducing movement-related fear at 4 weeks. Active rehabilitation (physical exercise classes with cognitivebehavioural principles) was more effective than usual GP care at reducing activity...

  13. Outcomes of a pilot obesity prevention plus intervention targeting children and parenting practices

    Science.gov (United States)

    Prevention-Plus interventions for primary care offer a venue to intervene with both children and parents for child obesity treatment. Such interventions can promote effective parenting practices that encourage healthy eating, physical activity (PA), and lower TV use among children. Test for feasibil...

  14. A Trial of an iPad™ Intervention Targeting Social Communication Skills in Children with Autism

    Science.gov (United States)

    Fletcher-Watson, Sue; Petrou, Alexandra; Scott-Barrett, Juliet; Dicks, Pamela; Graham, Catherine; O'Hare, Anne; Pain, Helen; McConachie, Helen

    2016-01-01

    This study evaluated a technology-based early intervention for social communication skills in pre-schoolers in a randomised controlled trial. Participants were 54 children aged under 6 years with a diagnosis of autism, assigned to either intervention or control conditions. The app engaged children, who played consistently, regardless of…

  15. Firm Foundations: The Effectiveness of an Educational Psychologist Developed Intervention Targeting Early Numeracy Skills

    Science.gov (United States)

    Somerville, Ros; Ayre, Kate; Tunbridge, Daniel; Cole, Katy; Stollery, Richard; Sanders, Mary

    2015-01-01

    This study evaluates the efficacy of a mathematics intervention devised by Essex Educational Psychology Service (EPS), UK. The intervention was designed to develop understanding and skills across four key domains within arithmetical development, by applying the principles of errorless learning, distributed practice and teaching to mastery. A…

  16. When are they old enough to drink? Outcomes of an Australian social marketing intervention targeting alcohol initiation.

    Science.gov (United States)

    Jones, Sandra C; Andrews, Kelly; Francis, Kate L; Akram, Muhammad

    2018-01-04

    This paper reports on the evaluation of an Australian whole-of-community social marketing intervention targeting social norms, which aimed to reduce inflated perceptions of the prevalence of underage drinking and increase the age at which alcohol initiation is considered acceptable. A community-wide intervention was delivered in a single community over a period of 2 years, targeting adolescents, parents and community members. Pre-and post-intervention computer-assisted telephone interview surveys were conducted in the intervention and a matched comparison (control) community. A total of 417 respondents completed both surveys (215 in the intervention community and 202 in the control community). The intervention community saw an increase of 6 months in the average age at which it is perceived to be acceptable for young people to have a sip/taste of alcohol and 5 months in the average age at which it is perceived to be acceptable to have weak/watered down alcohol. Furthermore, there was a reduction in the perception of the prevalence of alcohol consumption by young people to a level consistent with actual underage drinking rates. In comparison, the control community saw no change in any of these variables. This study provides preliminary evidence that a whole-of-community social marketing intervention can change perceptions of the prevalence, and acceptability, of underage drinking. Given the central role of social norms in decisions regarding alcohol consumption, these changes have the potential to reduce parental supply and thus underage drinking. © 2018 Australasian Professional Society on Alcohol and other Drugs.

  17. Universality properties of school-based preventive intervention targeted at cannabis use.

    Science.gov (United States)

    Miovský, Michal; Voňková, Hana; Gabrhelík, Roman; Šťastná, Lenka

    2015-02-01

    This study aims to examine the effect of school-based preventive intervention on cannabis use in Czech adolescents with different levels of risk factors and provide evidence of its universality. A randomized controlled prevention trial with six waves was conducted over a period of 33 months. We used a two-level logistic random-intercept model for panel data; we first looked at the statistical significance of the effect of the intervention on cannabis use, controlling for the characteristics of the children and time dummies. Then we analyzed the effects of the interactions between the intervention and the characteristics of the children on cannabis use and related it to the definition of universal preventive interventions. The setting for the study was in basic schools in the Czech Republic in the years 2007-2010. A total of 1,874 sixth-graders (mean age 11.82 years) who completed the baseline testing. According to our results, the prevention intervention was effective. We found all the selected characteristics of the children to be relevant in relation to cannabis use, except their relationships with their friends. We showed empirically that the intervention is universal in two dimensions for the selected characteristics of the children. First, all adolescents who undergo the intervention are expected to benefit. Second, with respect to the effect of the intervention on cannabis use, the total level of individual risk of cannabis use is superior to the composition of the risk factors in the individual risk profile. We present indicative evidence that the drug prevention intervention may be considered a true universal preventive intervention.

  18. Identifying diabetes-related important protein targets with few interacting partners with the PageRank algorithm.

    Science.gov (United States)

    Grolmusz, Vince I

    2015-04-01

    Diabetes is a growing concern for the developed nations worldwide. New genomic, metagenomic and gene-technologic approaches may yield considerable results in the next several years in its early diagnosis, or in advances in therapy and management. In this work, we highlight some human proteins that may serve as new targets in the early diagnosis and therapy. With the help of a very successful mathematical tool for network analysis that formed the basis of the early successes of Google(TM), Inc., we analyse the human protein-protein interaction network gained from the IntAct database with a mathematical algorithm. The novelty of our approach is that the new protein targets suggested do not have many interacting partners (so, they are not hubs or super-hubs), so their inhibition or promotion probably will not have serious side effects. We have identified numerous possible protein targets for diabetes therapy and/or management; some of these have been well known for a long time (these validate our method), some of them appeared in the literature in the last 12 months (these show the cutting edge of the algorithm), and the remainder are still unknown to be connected with diabetes, witnessing completely new hits of the method.

  19. High-Resolution Genetics Identifies the Lipid Transfer Protein Sec14p as Target for Antifungal Ergolines.

    Directory of Open Access Journals (Sweden)

    Ireos Filipuzzi

    2016-11-01

    Full Text Available Invasive infections by fungal pathogens cause more deaths than malaria worldwide. We found the ergoline compound NGx04 in an antifungal screen, with selectivity over mammalian cells. High-resolution chemogenomics identified the lipid transfer protein Sec14p as the target of NGx04 and compound-resistant mutations in Sec14p define compound-target interactions in the substrate binding pocket of the protein. Beyond its essential lipid transfer function in a variety of pathogenic fungi, Sec14p is also involved in secretion of virulence determinants essential for the pathogenicity of fungi such as Cryptococcus neoformans, making Sec14p an attractive antifungal target. Consistent with this dual function, we demonstrate that NGx04 inhibits the growth of two clinical isolates of C. neoformans and that NGx04-related compounds have equal and even higher potency against C. neoformans. Furthermore NGx04 analogues showed fungicidal activity against a fluconazole resistant C. neoformans strain. In summary, we present genetic evidence that NGx04 inhibits fungal Sec14p and initial data supporting NGx04 as a novel antifungal starting point.

  20. Integrated microarray and ChIP analysis identifies multiple Foxa2 dependent target genes in the notochord.

    Science.gov (United States)

    Tamplin, Owen J; Cox, Brian J; Rossant, Janet

    2011-12-15

    The node and notochord are key tissues required for patterning of the vertebrate body plan. Understanding the gene regulatory network that drives their formation and function is therefore important. Foxa2 is a key transcription factor at the top of this genetic hierarchy and finding its targets will help us to better understand node and notochord development. We performed an extensive microarray-based gene expression screen using sorted embryonic notochord cells to identify early notochord-enriched genes. We validated their specificity to the node and notochord by whole mount in situ hybridization. This provides the largest available resource of notochord-expressed genes, and therefore candidate Foxa2 target genes in the notochord. Using existing Foxa2 ChIP-seq data from adult liver, we were able to identify a set of genes expressed in the notochord that had associated regions of Foxa2-bound chromatin. Given that Foxa2 is a pioneer transcription factor, we reasoned that these sites might represent notochord-specific enhancers. Candidate Foxa2-bound regions were tested for notochord specific enhancer function in a zebrafish reporter assay and 7 novel notochord enhancers were identified. Importantly, sequence conservation or predictive models could not have readily identified these regions. Mutation of putative Foxa2 binding elements in two of these novel enhancers abrogated reporter expression and confirmed their Foxa2 dependence. The combination of highly specific gene expression profiling and genome-wide ChIP analysis is a powerful means of understanding developmental pathways, even for small cell populations such as the notochord. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. Identification of BIRC6 as a novel intervention target for neuroblastoma therapy

    Directory of Open Access Journals (Sweden)

    Lamers Fieke

    2012-07-01

    Full Text Available Abstract Background Neuroblastoma are pediatric tumors of the sympathetic nervous system with a poor prognosis. Apoptosis is often deregulated in cancer cells, but only a few defects in apoptotic routes have been identified in neuroblastoma. Methods Here we investigated genomic aberrations affecting genes of the intrinsic apoptotic pathway in neuroblastoma. We analyzed DNA profiling data (CGH and SNP arrays and mRNA expression data of 31 genes of the intrinsic apoptotic pathway in a dataset of 88 neuroblastoma tumors using the R2 bioinformatic platform (http://r2.amc.nl. BIRC6 was selected for further analysis as a tumor driving gene. Knockdown experiments were performed using BIRC6 lentiviral shRNA and phenotype responses were analyzed by Western blot and MTT-assays. In addition, DIABLO levels and interactions were investigated with immunofluorescence and co-immunoprecipitation. Results We observed frequent gain of the BIRC6 gene on chromosome 2, which resulted in increased mRNA expression. BIRC6 is an inhibitor of apoptosis protein (IAP, that can bind and degrade the cytoplasmic fraction of the pro-apoptotic protein DIABLO. DIABLO mRNA expression was exceptionally high in neuroblastoma but the protein was only detected in the mitochondria. Upon silencing of BIRC6 by shRNA, DIABLO protein levels increased and cells went into apoptosis. Co-immunoprecipitation confirmed direct interaction between DIABLO and BIRC6 in neuroblastoma cell lines. Conclusion Our findings indicate that BIRC6 may have a potential oncogenic role in neuroblastoma by inactivating cytoplasmic DIABLO. BIRC6 inhibition may therefore provide a means for therapeutic intervention in neuroblastoma.

  2. History of Maltreatment in Childhood and Subsequent Parenting Stress in At-Risk, First-Time Mothers: Identifying Points of Intervention During Home Visiting.

    Science.gov (United States)

    Shenk, Chad E; Ammerman, Robert T; Teeters, Angelique R; Bensman, Heather E; Allen, Elizabeth K; Putnam, Frank W; Van Ginkel, Judith B

    2017-04-01

    Home visiting is an effective preventive intervention that can improve parenting outcomes for at-risk, new mothers, thereby optimizing subsequent child development. A history of maltreatment in childhood is common in mothers participating in home visiting, yet the extent to which such a history is related to parenting outcomes during home visiting is unknown. The current study evaluated whether mothers with a history of maltreatment in childhood respond less favorably to home visiting by examining the direct and indirect pathways to subsequent parenting stress, a key parenting outcome affecting child development. First-time mothers (N = 220; age range = 16-42) participating in one of two home visiting programs, Healthy Families America or Nurse Family Partnership, were evaluated at enrollment and again at 9-and 18-month post-enrollment assessments. Researchers administered measures of maternal history of maltreatment in childhood, depressive symptoms, social support, and parenting stress. Maternal history of maltreatment in childhood predicted worsening parenting stress at the 18-month assessment. Mediation modeling identified two indirect pathways, one involving social support at enrollment and one involving persistent depressive symptoms during home visiting, that explained the relation between a history of maltreatment in childhood and parenting stress at the 18-month assessment. Ways to improve the preventive effects of home visiting for mothers with a history of maltreatment in childhood through the identification of relevant intervention targets and their ideal time of administration are discussed.

  3. Targeted array comparative genomic hybridisation (array CGH) identifies genomic imbalances associated with isolated congenital diaphragmatic hernia (CDH).

    Science.gov (United States)

    Srisupundit, Kasemsri; Brady, Paul D; Devriendt, Koenraad; Fryns, Jean-Pierre; Cruz-Martinez, Rogelio; Gratacos, Eduard; Deprest, Jan A; Vermeesch, Joris R

    2010-12-01

    Congenital diaphragmatic hernia (CDH) is a congenital birth defect affecting around 1/3000 births. We propose that a significant number of isolated CDH cases have an underlying genetic cause, and that a subset of these result from copy number variations (CNVs) identifiable by array CGH. We have designed a custom array targeted at genes and genomic loci associated with CDH. A total of 79 isolated CDH patients were screened using this targeted array. In three patients, we detected genomic imbalances associated with the observed diaphragmatic hernia; a deletion of 8p22-p23.3, 14.2 Mb in size, a 340 kb duplication of Xq13.1 including the ephrin-B1 gene (EFNB1), and mosaicism for trisomy 2. Using this approach, we detected genomic imbalances associated with CDH in 3/79 (4%) isolated CDH patients. Our findings further implicate 8p deletions as being associated with CDH. The duplication of EFNB1 further highlights this gene as a potential candidate involved in diaphragm development. Mosaicism for trisomy 2 is a rare event and unlikely to be a common cause of CDH. Further investigations of isolated CDH patients by array CGH will continue to identify novel submicroscopic loci and refine genomic regions associated with CDH. Copyright © 2010 John Wiley & Sons, Ltd.

  4. A cross-sectional study of individuals seeking information on transient ischemic attack and stroke symptoms online: a target for intervention?

    Directory of Open Access Journals (Sweden)

    Anthony S Kim

    Full Text Available BACKGROUND: Individuals with TIA/stroke symptoms often do not seek urgent medical attention. We assessed the feasibility of identifying individuals searching for information on TIA/stroke symptoms online as a target for future interventions to encourage urgent evaluation and we evaluated the performance of a self-reported risk score to identify subjects with true TIA or stroke. METHODOLOGY/PRINCIPAL FINDINGS: We placed online advertisements to target English-speaking adults in the United States searching for TIA/stroke-related keywords. After completing an online questionnaire, participants were telephoned by a vascular neurologist to assess the likelihood of TIA/stroke. We used logistic regression and the c-statistic to assess associations and model discrimination respectively. Over 122 days, 251 (1% of 25,292 website visitors completed the online questionnaire and 175 were reached by telephone (mean age 58.5 years; 63% women for follow-up. Of these participants, 37 (21% had symptoms within 24 hours, 60 (34% had not had a medical evaluation yet, and 68 (39% had TIA/stroke. Applying a modified ABCD(2 score yielded a c-statistic of 0.66, but 2 of 12 with a zero score had a TIA/stroke. Those with new symptoms were more likely to have TIA/stroke (OR 4.90, 95% CI 2.56-9.09. CONCLUSIONS/SIGNIFICANCE: Individuals with TIA/stroke that are seeking real-time information on symptoms online can be readily identified, in some cases before they have sought formal medical evaluation. Although a simple self-reported risk score was unable to identify a low-risk population in this selected group, this population may still present an attractive target for future interventions designed to encourage urgent medical evaluation.

  5. Targeting children's dietary behaviors in a family intervention: 'Entre familia: reflejos de salud'.

    Science.gov (United States)

    Horton, Lucy A; Parada, Humberto; Slymen, Donald J; Arredondo, Elva; Ibarra, Leticia; Ayala, Guadalupe X

    2013-01-01

    This intervention sought to promote healthy eating with the ultimate goal of reducing childhood obesity risk. Three hundred and sixty-one Latino families living on the US-Mexico border with at least one child between 7-13 years of age were eligible to participate. Families randomly assigned to the four-month intervention received 14 contacts with a promotora (community health worker), consisting of 11 home visits and three telephone calls; the control condition was a delayed treatment intervention. Children reported on their dietary intake at baseline, immediately post-intervention and at the six month follow-up visit. The intervention reduced weekly consumption of fast food (p<0.05). A dose-response relationship was observed such that for every seven hours of promotora contact, monthly variety of fruits (p<0.01) and vegetables (p<0.01) increased by one. No other intervention effects were observed. Family-based interventions can improve children's eating habits, with the amount of contact with the promotora being key to success.

  6. Identifying genomic changes associated with insecticide resistance in the dengue mosquito Aedes aegypti by deep targeted sequencing

    Science.gov (United States)

    Faucon, Frederic; Dusfour, Isabelle; Gaude, Thierry; Navratil, Vincent; Boyer, Frederic; Chandre, Fabrice; Sirisopa, Patcharawan; Thanispong, Kanutcharee; Juntarajumnong, Waraporn; Poupardin, Rodolphe; Chareonviriyaphap, Theeraphap; Girod, Romain; Corbel, Vincent; Reynaud, Stephane; David, Jean-Philippe

    2015-01-01

    The capacity of mosquitoes to resist insecticides threatens the control of diseases such as dengue and malaria. Until alternative control tools are implemented, characterizing resistance mechanisms is crucial for managing resistance in natural populations. Insecticide biodegradation by detoxification enzymes is a common resistance mechanism; however, the genomic changes underlying this mechanism have rarely been identified, precluding individual resistance genotyping. In particular, the role of copy number variations (CNVs) and polymorphisms of detoxification enzymes have never been investigated at the genome level, although they can represent robust markers of metabolic resistance. In this context, we combined target enrichment with high-throughput sequencing for conducting the first comprehensive screening of gene amplifications and polymorphisms associated with insecticide resistance in mosquitoes. More than 760 candidate genes were captured and deep sequenced in several populations of the dengue mosquito Ae. aegypti displaying distinct genetic backgrounds and contrasted resistance levels to the insecticide deltamethrin. CNV analysis identified 41 gene amplifications associated with resistance, most affecting cytochrome P450s overtranscribed in resistant populations. Polymorphism analysis detected more than 30,000 variants and strong selection footprints in specific genomic regions. Combining Bayesian and allele frequency filtering approaches identified 55 nonsynonymous variants strongly associated with resistance. Both CNVs and polymorphisms were conserved within regions but differed across continents, confirming that genomic changes underlying metabolic resistance to insecticides are not universal. By identifying novel DNA markers of insecticide resistance, this study opens the way for tracking down metabolic changes developed by mosquitoes to resist insecticides within and among populations. PMID:26206155

  7. Estimating the Economic Value of Information for Screening in Disseminating and Targeting Effective School-based Preventive Interventions: An Illustrative Example.

    Science.gov (United States)

    Johnston, Stephen S; Salkever, David S; Ialongo, Nicholas S; Slade, Eric P; Stuart, Elizabeth A

    2017-11-01

    When candidates for school-based preventive interventions are heterogeneous in their risk of poor outcomes, an intervention's expected economic net benefits may be maximized by targeting candidates for whom the intervention is most likely to yield benefits, such as those at high risk of poor outcomes. Although increasing amounts of information about candidates may facilitate more accurate targeting, collecting information can be costly. We present an illustrative example to show how cost-benefit analysis results from effective intervention demonstrations can help us to assess whether improved targeting accuracy justifies the cost of collecting additional information needed to make this improvement.

  8. Combining a nontargeted and targeted metabolomics approach to identify metabolic pathways significantly altered in polycystic ovary syndrome.

    Science.gov (United States)

    Chang, Alice Y; Lalia, Antigoni Z; Jenkins, Gregory D; Dutta, Tumpa; Carter, Rickey E; Singh, Ravinder J; Nair, K Sreekumaran

    2017-06-01

    Polycystic ovary syndrome (PCOS) is a condition of androgen excess and chronic anovulation frequently associated with insulin resistance. We combined a nontargeted and targeted metabolomics approach to identify pathways and metabolites that distinguished PCOS from metabolic syndrome (MetS). Twenty obese women with PCOS were compared with 18 obese women without PCOS. Both groups met criteria for MetS but could not have diabetes mellitus or take medications that treat PCOS or affect lipids or insulin sensitivity. Insulin sensitivity was derived from the frequently sampled intravenous glucose tolerance test. A nontargeted metabolomics approach was performed on fasting plasma samples to identify differentially expressed metabolites, which were further evaluated by principal component and pathway enrichment analysis. Quantitative targeted metabolomics was then applied on candidate metabolites. Measured metabolites were tested for associations with PCOS and clinical variables by logistic and linear regression analyses. This multiethnic, obese sample was matched by age (PCOS, 37±6; MetS, 40±6years) and body mass index (BMI) (PCOS, 34.6±5.1; MetS, 33.7±5.2kg/m 2 ). Principal component analysis of the nontargeted metabolomics data showed distinct group separation of PCOS from MetS controls. From the subset of 385 differentially expressed metabolites, 22% were identified by accurate mass, resulting in 19 canonical pathways significantly altered in PCOS, including amino acid, lipid, steroid, carbohydrate, and vitamin D metabolism. Targeted metabolomics identified many essential amino acids, including branched-chain amino acids (BCAA) that were elevated in PCOS compared with MetS. PCOS was most associated with BCAA (P=.02), essential amino acids (P=.03), the essential amino acid lysine (P=.02), and the lysine metabolite α-aminoadipic acid (P=.02) in models adjusted for surrogate variables representing technical variation in metabolites. No significant differences between

  9. Distribution and determinants of risk of teenage motherhood in three British longitudinal studies: implications for targeted prevention interventions

    OpenAIRE

    Kneale, D.; Fletcher, Adam; Wiggins, R.; Bonell, Chris

    2012-01-01

    Purpose: In order to consider the potential contribution of universal versus targeted prevention interventions, the authors examined what is the distribution of established risk variables for teenage motherhood? from where in these distributions do births arise? and how does this distribution/determination of risk vary between studies?\\ud \\ud Methods: Secondary data analysis of three British longitudinal studies.\\ud \\ud Results: For all cohorts and variables, the ‘risk’ category was the least...

  10. A model of gene-gene and gene-environment interactions and its implications for targeting environmental interventions by genotype

    OpenAIRE

    Wallace Helen M

    2006-01-01

    Abstract Background The potential public health benefits of targeting environmental interventions by genotype depend on the environmental and genetic contributions to the variance of common diseases, and the magnitude of any gene-environment interaction. In the absence of prior knowledge of all risk factors, twin, family and environmental data may help to define the potential limits of these benefits in a given population. However, a general methodology to analyze twin data is required becaus...

  11. Economic assessments of small-scale drinking-water interventions in pursuit of MDG target 7C.

    Science.gov (United States)

    Cameron, John; Jagals, Paul; Hunter, Paul R; Pedley, Steve; Pond, Katherine

    2011-12-01

    This paper uses an applied rural case study of a safer water intervention in South Africa to illustrate how three levels of economic assessment can be used to understand the impact of the intervention on people's well-being. It is set in the context of Millennium Development Goal 7 which sets a target (7C) for safe drinking-water provision and the challenges of reaching people in remote rural areas with relatively small-scale schemes. The assessment moves from cost efficiency to cost effectiveness to a full social cost-benefit analysis (SCBA) with an associated sensitivity test. In addition to demonstrating techniques of analysis, the paper brings out many of the challenges in understanding how safer drinking-water impacts on people's livelihoods. The SCBA shows the case study intervention is justified economically, though the sensitivity test suggests 'downside' vulnerability. Copyright © 2011 Elsevier B.V. All rights reserved.

  12. Primary health care-level interventions targeting health literacy and their effect on weight loss: a systematic review.

    Science.gov (United States)

    Faruqi, Nighat; Spooner, Catherine; Joshi, Chandni; Lloyd, Jane; Dennis, Sarah; Stocks, Nigel; Taggart, Jane; Harris, Mark F

    2015-01-01

    Enhancing individual's health literacy for weight loss is important in addressing the increasing burden of chronic disease due to overweight and obesity. We conducted a systematic review and narrative synthesis to determine the effectiveness of lifestyle interventions aimed at improving adults' knowledge and skills for weight loss in primary health care. The literature search included English-language papers published between 1990 and 30 June 2013 reporting research conducted within Organisation for Economic Cooperation and Development member countries. Twelve electronic databases and five journals were searched and this was supplemented by hand searching. The study population included adults (≥18 years old) with a body mass index (BMI) ≥25 kg/m(2) and without chronic disease at baseline. We included intervention studies with a minimum 6 month follow-up. Three reviewers independently extracted data and two reviewers independently assessed study quality by using predefined criteria. The main outcome was a change in measured weight and/or BMI over 6 or 12 months. Thirteen intervention studies, all targeting diet, physical activity and behaviour change to improve individuals' knowledge and/or skills for weight loss, were included with 2,089 participants. Most (9/13) of these studies were of a 'weak' quality. Seven studies provided training to the intervention deliverers. The majority of the studies (11/13) showed significant reduction in weight and/or BMI in at least one follow-up visit. There were no consistent associations in outcomes related to the mode of intervention delivery, the number or type of providers involved or the intensity of the intervention. There was evidence for the effectiveness of interventions that focussed on improving knowledge and skills (health literacy) for weight loss. However, there was insufficient evidence to determine relative effectiveness of individual interventions. The lack of studies measuring socio-economic status needs to

  13. Targeting persons with low socioeconomic status of different ethnic origins with lifestyle interventions

    NARCIS (Netherlands)

    Bukman, A.J.

    2016-01-01

    Lifestyle intervention studies have shown that the development of cardiometabolic diseases can be partly prevented or postponed by the combination of a healthy diet and physical activity. Cardiometabolic diseases and their risk factors are particularly prevalent among individuals with low

  14. Targeting hardcore smokers: The effects of an online tailored intervention, based on motivational interviewing techniques.

    Science.gov (United States)

    Bommelé, Jeroen; Schoenmakers, Tim M; Kleinjan, Marloes; Peters, Gjalt-Jorn Ygram; Dijkstra, Arie; van de Mheen, Dike

    2017-09-01

    Hardcore smokers have smoked for many years and do not intend to quit. They also seem unreceptive to information about smoking cessation. We developed a 30-min, tailored web-based intervention that includes motivational interviewing principles. It aims to increase hardcore smokers' intention to quit and their receptivity to information about smoking cessation. In a two-arm experiment, we compared outcome scores of the experimental intervention (n = 346) with those of a control intervention (n = 411). Our main outcomes were receptivity to information about quitting, intention to quit, quitting self-efficacy, and interest in a subsequent online intervention. Our secondary outcomes were cigarettes smoked per day and quit attempts. All outcomes were measured directly post-experiment (t 1 ), after 2 weeks (t 2 ), and after 2 months (t 3 ). At t 1 , hardcore smokers in the intervention condition were more receptive to information about quitting than controls. At both t 2 and t 3 , those in the experimental group had reduced the number of cigarettes more than those in the control group. At t 2 , but not t 3 , more participants in the experimental group had reduced their cigarette consumption by at least 50% than among controls. We found no significant differences in intention to quit, quitting self-efficacy, interest in a subsequent online quitting intervention, and number of quit attempts. The intervention increased hardcore smokers' receptivity to information about smoking cessation and decreased their cigarette consumption by about 1 cigarette per day. Although the results are positive, the clinical relevance may be limited. We recommend further developing this intervention for practical use in health care settings. Statement of contribution What is already known on this subject? Hardcore smokers have smoked for many years and do not intend to quit. There are currently no online interventions for hardcore smokers. What does this study add? This study tested an

  15. Protocol for the atWork trial: a randomised controlled trial of a workplace intervention targeting subjective health complaints

    Directory of Open Access Journals (Sweden)

    Tone Langjordet Johnsen

    2016-08-01

    Full Text Available Abstract Background Subjective health complaints, such as musculoskeletal and mental health complaints, have a high prevalence in the general population, and account for a large proportion of sick leave in Norway. It may be difficult to prevent the occurrence of subjective health complaints, but it may be possible to influence employees’ perception and management of these complaints, which in turn may have impact on sick leave and return to work after sick leave. Long term sick leave has many negative health and social consequences, and it is important to gain knowledge about effective interventions to prevent and reduce long term sick leave. Methods/Design This study is a cluster randomised controlled trial to evaluate the effect of the modified atWork intervention, targeting non-specific musculoskeletal complaints and mental health complaints. This intervention will be compared to the original atWork intervention targeting only non-specific musculoskeletal complaints. Kindergartens in Norway are invited to participate in the study and will be randomly assigned to one of the two interventions. Estimated sample size is 100 kindergartens, with a total of approximately 1100 employees. Primary outcome is sick leave at unit level, measured using register data from the Norwegian Labour and Welfare Administration. One kindergarten equals one unit, regardless of number of employees. Secondary outcomes will be measured at the individual level and include coping, health, job satisfaction, social support, and workplace inclusion, collected through questionnaires distributed at baseline and at 12 months follow up. All employees in the included kindergartens are eligible for participating in the survey. Discussion The effect evaluation of the modified atWork intervention is a large and comprehensive project, providing evidence-based information on prevention of long-term sick leave, which may be of considerable benefit both from a societal

  16. Protocol for the atWork trial: a randomised controlled trial of a workplace intervention targeting subjective health complaints.

    Science.gov (United States)

    Johnsen, Tone Langjordet; Indahl, Aage; Baste, Valborg; Eriksen, Hege Randi; Tveito, Torill Helene

    2016-08-19

    Subjective health complaints, such as musculoskeletal and mental health complaints, have a high prevalence in the general population, and account for a large proportion of sick leave in Norway. It may be difficult to prevent the occurrence of subjective health complaints, but it may be possible to influence employees' perception and management of these complaints, which in turn may have impact on sick leave and return to work after sick leave. Long term sick leave has many negative health and social consequences, and it is important to gain knowledge about effective interventions to prevent and reduce long term sick leave. This study is a cluster randomised controlled trial to evaluate the effect of the modified atWork intervention, targeting non-specific musculoskeletal complaints and mental health complaints. This intervention will be compared to the original atWork intervention targeting only non-specific musculoskeletal complaints. Kindergartens in Norway are invited to participate in the study and will be randomly assigned to one of the two interventions. Estimated sample size is 100 kindergartens, with a total of approximately 1100 employees. Primary outcome is sick leave at unit level, measured using register data from the Norwegian Labour and Welfare Administration. One kindergarten equals one unit, regardless of number of employees. Secondary outcomes will be measured at the individual level and include coping, health, job satisfaction, social support, and workplace inclusion, collected through questionnaires distributed at baseline and at 12 months follow up. All employees in the included kindergartens are eligible for participating in the survey. The effect evaluation of the modified atWork intervention is a large and comprehensive project, providing evidence-based information on prevention of long-term sick leave, which may be of considerable benefit both from a societal, organisational, and individual perspective. Clinicaltrials.gov: NCT02396797

  17. Synthetic Lethal Screen Identifies NF-κB as a Target for Combination Therapy with Topotecan for patients with Neuroblastoma

    International Nuclear Information System (INIS)

    Tsang, Patricia S; Cheuk, Adam T; Chen, Qing-Rong; Song, Young K; Badgett, Thomas C; Wei, Jun S; Khan, Javed

    2012-01-01

    Despite aggressive multimodal treatments the overall survival of patients with high-risk neuroblastoma remains poor. The aim of this study was to identify novel combination chemotherapy to improve survival rate in patients with high-risk neuroblastoma. We took a synthetic lethal approach using a siRNA library targeting 418 apoptosis-related genes and identified genes and pathways whose inhibition synergized with topotecan. Microarray analyses of cells treated with topotecan were performed to identify if the same genes or pathways were altered by the drug. An inhibitor of this pathway was used in combination with topotecan to confirm synergism by in vitro and in vivo studies. We found that there were nine genes whose suppression synergized with topotecan to enhance cell death, and the NF-κB signaling pathway was significantly enriched. Microarray analysis of cells treated with topotecan revealed a significant enrichment of NF-κB target genes among the differentially altered genes, suggesting that NF-κB pathway was activated in the treated cells. Combination of topotecan and known NF-κB inhibitors (NSC 676914 or bortezomib) significantly reduced cell growth and induced caspase 3 activity in vitro. Furthermore, in a neuroblastoma xenograft mouse model, combined treatment of topotecan and bortezomib significantly delayed tumor formation compared to single-drug treatments. Synthetic lethal screening provides a rational approach for selecting drugs for use in combination therapy and warrants clinical evaluation of the efficacy of the combination of topotecan and bortezomib or other NF-κB inhibitors in patients with high risk neuroblastoma

  18. Composite Sequence-Structure Stability Models as Screening Tools for Identifying Vulnerable Targets for HIV Drug and Vaccine Development.

    Science.gov (United States)

    Manocheewa, Siriphan; Mittler, John E; Samudrala, Ram; Mullins, James I

    2015-11-04

    Rapid evolution and high sequence diversity enable Human Immunodeficiency Virus (HIV) populations to acquire mutations to escape antiretroviral drugs and host immune responses, and thus are major obstacles for the control of the pandemic. One strategy to overcome this problem is to focus drugs and vaccines on regions of the viral genome in which mutations are likely to cripple function through destabilization of viral proteins. Studies relying on sequence conservation alone have had only limited success in determining critically important regions. We tested the ability of two structure-based computational models to assign sites in the HIV-1 capsid protein (CA) that would be refractory to mutational change. The destabilizing mutations predicted by these models were rarely found in a database of 5811 HIV-1 CA coding sequences, with none being present at a frequency greater than 2%. Furthermore, 90% of variants with the low predicted stability (from a set of 184 CA variants whose replication fitness or infectivity has been studied in vitro) had aberrant capsid structures and reduced viral infectivity. Based on the predicted stability, we identified 45 CA sites prone to destabilizing mutations. More than half of these sites are targets of one or more known CA inhibitors. The CA regions enriched with these sites also overlap with peptides shown to induce cellular immune responses associated with lower viral loads in infected individuals. Lastly, a joint scoring metric that takes into account both sequence conservation and protein structure stability performed better at identifying deleterious mutations than sequence conservation or structure stability information alone. The computational sequence-structure stability approach proposed here might therefore be useful for identifying immutable sites in a protein for experimental validation as potential targets for drug and vaccine development.

  19. Synthetic Lethal Screen Identifies NF-κB as a Target for Combination Therapy with Topotecan for patients with Neuroblastoma

    Directory of Open Access Journals (Sweden)

    Tsang Patricia S

    2012-03-01

    Full Text Available Abstract Background Despite aggressive multimodal treatments the overall survival of patients with high-risk neuroblastoma remains poor. The aim of this study was to identify novel combination chemotherapy to improve survival rate in patients with high-risk neuroblastoma. Methods We took a synthetic lethal approach using a siRNA library targeting 418 apoptosis-related genes and identified genes and pathways whose inhibition synergized with topotecan. Microarray analyses of cells treated with topotecan were performed to identify if the same genes or pathways were altered by the drug. An inhibitor of this pathway was used in combination with topotecan to confirm synergism by in vitro and in vivo studies. Results We found that there were nine genes whose suppression synergized with topotecan to enhance cell death, and the NF-κB signaling pathway was significantly enriched. Microarray analysis of cells treated with topotecan revealed a significant enrichment of NF-κB target genes among the differentially altered genes, suggesting that NF-κB pathway was activated in the treated cells. Combination of topotecan and known NF-κB inhibitors (NSC 676914 or bortezomib significantly reduced cell growth and induced caspase 3 activity in vitro. Furthermore, in a neuroblastoma xenograft mouse model, combined treatment of topotecan and bortezomib significantly delayed tumor formation compared to single-drug treatments. Conclusions Synthetic lethal screening provides a rational approach for selecting drugs for use in combination therapy and warrants clinical evaluation of the efficacy of the combination of topotecan and bortezomib or other NF-κB inhibitors in patients with high risk neuroblastoma.

  20. Social Network Analysis and Mining to Monitor and Identify Problems with Large-Scale Information and Communication Technology Interventions.

    Directory of Open Access Journals (Sweden)

    Aleksandra do Socorro da Silva

    Full Text Available The published literature reveals several arguments concerning the strategic importance of information and communication technology (ICT interventions for developing countries where the digital divide is a challenge. Large-scale ICT interventions can be an option for countries whose regions, both urban and rural, present a high number of digitally excluded people. Our goal was to monitor and identify problems in interventions aimed at certification for a large number of participants in different geographical regions. Our case study is the training at the Telecentros.BR, a program created in Brazil to install telecenters and certify individuals to use ICT resources. We propose an approach that applies social network analysis and mining techniques to data collected from Telecentros.BR dataset and from the socioeconomics and telecommunications infrastructure indicators of the participants' municipalities. We found that (i the analysis of interactions in different time periods reflects the objectives of each phase of training, highlighting the increased density in the phase in which participants develop and disseminate their projects; (ii analysis according to the roles of participants (i.e., tutors or community members reveals that the interactions were influenced by the center (or region to which the participant belongs (that is, a community contained mainly members of the same region and always with the presence of tutors, contradicting expectations of the training project, which aimed for intense collaboration of the participants, regardless of the geographic region; (iii the social network of participants influences the success of the training: that is, given evidence that the degree of the community member is in the highest range, the probability of this individual concluding the training is 0.689; (iv the North region presented the lowest probability of participant certification, whereas the Northeast, which served municipalities with similar

  1. Social Network Analysis and Mining to Monitor and Identify Problems with Large-Scale Information and Communication Technology Interventions.

    Science.gov (United States)

    da Silva, Aleksandra do Socorro; de Brito, Silvana Rossy; Vijaykumar, Nandamudi Lankalapalli; da Rocha, Cláudio Alex Jorge; Monteiro, Maurílio de Abreu; Costa, João Crisóstomo Weyl Albuquerque; Francês, Carlos Renato Lisboa

    2016-01-01

    The published literature reveals several arguments concerning the strategic importance of information and communication technology (ICT) interventions for developing countries where the digital divide is a challenge. Large-scale ICT interventions can be an option for countries whose regions, both urban and rural, present a high number of digitally excluded people. Our goal was to monitor and identify problems in interventions aimed at certification for a large number of participants in different geographical regions. Our case study is the training at the Telecentros.BR, a program created in Brazil to install telecenters and certify individuals to use ICT resources. We propose an approach that applies social network analysis and mining techniques to data collected from Telecentros.BR dataset and from the socioeconomics and telecommunications infrastructure indicators of the participants' municipalities. We found that (i) the analysis of interactions in different time periods reflects the objectives of each phase of training, highlighting the increased density in the phase in which participants develop and disseminate their projects; (ii) analysis according to the roles of participants (i.e., tutors or community members) reveals that the interactions were influenced by the center (or region) to which the participant belongs (that is, a community contained mainly members of the same region and always with the presence of tutors, contradicting expectations of the training project, which aimed for intense collaboration of the participants, regardless of the geographic region); (iii) the social network of participants influences the success of the training: that is, given evidence that the degree of the community member is in the highest range, the probability of this individual concluding the training is 0.689; (iv) the North region presented the lowest probability of participant certification, whereas the Northeast, which served municipalities with similar

  2. Choice disability as a target for non-medical HIV intervention.

    Science.gov (United States)

    de Boer, Rebecca; Lutscher, Frithjof

    2018-03-14

    Even though medical intervention measures against HIV transmission are available, the epidemic continues to spread in several sub-Saharan African countries. Empirical studies indicate that many people are unable to implement prevention strategies because of individual factors, such as extreme poverty or lack of education, but also because or relational factors, such as gender-based violence or transactional sex. This phenomenon, known as choice disability, may be such a large obstacle in the effectiveness of medical interventions that several field trials of structural (non-medical) interventions are underway that address these issues. While dynamical-systems models are frequently used to advise management and policy around infectious diseases, they typically assume that individuals are free to make optimal choices. We derive and analyze a novel model where individuals have a certain choice status, based on which they are more or less likely to transmit or receive the infection. Choice status is affected by social interactions. When studying the model in the absence of an infectious disease, we find that structural interventions aimed at raising the status of one group can have the unintended side effect of lowering the status of another group. When combined with an epidemic model, we find that the same structural interventions can even increase the total prevalence of a disease in the population. Our model provides a framework to evaluate the possible effectiveness of structural intervention in an epidemic. Copyright © 2018 Elsevier Inc. All rights reserved.

  3. Do MRI findings identify patients with low back pain or sciatica who respond better to particular interventions? A systematic review.

    Science.gov (United States)

    Steffens, Daniel; Hancock, Mark J; Pereira, Leani S M; Kent, Peter M; Latimer, Jane; Maher, Chris G

    2016-04-01

    Magnetic resonance imaging (MRI) can reveal a range of degenerative findings and anatomical abnormalities; however, the clinical importance of these remains uncertain and controversial. We aimed to investigate if the presence of MRI findings identifies patients with low back pain (LBP) or sciatica who respond better to particular interventions. MEDLINE, EMBASE and CENTRAL databases were searched. We included RCTs investigating MRI findings as treatment effect modifiers for patients with LBP or sciatica. We excluded studies with specific diseases as the cause of LBP. Risk of bias was assessed using the criteria of the Cochrane Back Review Group. Each MRI finding was examined for its individual capacity for effect modification. Eight published trials met the inclusion criteria. The methodological quality of trials was inconsistent. Substantial variability in MRI findings, treatments and outcomes across the eight trials prevented pooling of data. Patients with Modic type 1 when compared with patients with Modic type 2 had greater improvements in function when treated by Diprospan (steroid) injection, compared with saline. Patients with central disc herniation when compared with patients without central disc herniation had greater improvements in pain when treated by surgery, compared with rehabilitation. Although individual trials suggested that some MRI findings might be effect modifiers for specific interventions, none of these interactions were investigated in more than a single trial. High quality, adequately powered trials investigating MRI findings as effect modifiers are essential to determine the clinical importance of MRI findings in LBP and sciatica ( CRD42013006571).

  4. Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality.

    Directory of Open Access Journals (Sweden)

    Johannes Raffler

    2015-09-01

    Full Text Available Genome-wide association studies with metabolic traits (mGWAS uncovered many genetic variants that influence human metabolism. These genetically influenced metabotypes (GIMs contribute to our metabolic individuality, our capacity to respond to environmental challenges, and our susceptibility to specific diseases. While metabolic homeostasis in blood is a well investigated topic in large mGWAS with over 150 known loci, metabolic detoxification through urinary excretion has only been addressed by few small mGWAS with only 11 associated loci so far. Here we report the largest mGWAS to date, combining targeted and non-targeted 1H NMR analysis of urine samples from 3,861 participants of the SHIP-0 cohort and 1,691 subjects of the KORA F4 cohort. We identified and replicated 22 loci with significant associations with urinary traits, 15 of which are new (HIBCH, CPS1, AGXT, XYLB, TKT, ETNPPL, SLC6A19, DMGDH, SLC36A2, GLDC, SLC6A13, ACSM3, SLC5A11, PNMT, SLC13A3. Two-thirds of the urinary loci also have a metabolite association in blood. For all but one of the 6 loci where significant associations target the same metabolite in blood and urine, the genetic effects have the same direction in both fluids. In contrast, for the SLC5A11 locus, we found increased levels of myo-inositol in urine whereas mGWAS in blood reported decreased levels for the same genetic variant. This might indicate less effective re-absorption of myo-inositol in the kidneys of carriers. In summary, our study more than doubles the number of known loci that influence urinary phenotypes. It thus allows novel insights into the relationship between blood homeostasis and its regulation through excretion. The newly discovered loci also include variants previously linked to chronic kidney disease (CPS1, SLC6A13, pulmonary hypertension (CPS1, and ischemic stroke (XYLB. By establishing connections from gene to disease via metabolic traits our results provide novel hypotheses about molecular

  5. A pharmacologically-based array to identify targets of cyclosporine A-induced toxicity in cultured renal proximal tubule cells

    Energy Technology Data Exchange (ETDEWEB)

    Sarró, Eduard, E-mail: eduard.sarro@vhir.org [Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra (Barcelona) (Spain); Renal Physiopathology, CIBBIM-Nanomedicine, Vall d' Hebron Research Institute (VHIR), 08035 Barcelona (Spain); Jacobs-Cachá, Conxita, E-mail: conxita.jacobs@vhir.org [Renal Physiopathology, CIBBIM-Nanomedicine, Vall d' Hebron Research Institute (VHIR), 08035 Barcelona (Spain); Itarte, Emilio, E-mail: emili.itarte@uab.es [Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra (Barcelona) (Spain); Meseguer, Anna, E-mail: ana.meseguer@vhir.org [Renal Physiopathology, CIBBIM-Nanomedicine, Vall d' Hebron Research Institute (VHIR), 08035 Barcelona (Spain); Departament de Bioquimica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra (Barcelona) (Spain)

    2012-01-15

    Mechanisms of cyclosporine A (CsA)-induced nephrotoxicity were generally thought to be hemodynamic in origin; however, there is now accumulating evidence of a direct tubular effect. Although genomic and proteomic experiments by our group and others provided overall information on genes and proteins up- or down-regulated by CsA in proximal tubule cells (PTC), a comprehensive view of events occurring after CsA exposure remains to be described. For this purpose, we applied a pharmacologic approach based on the use of known activities of a large panel of potentially protective compounds and evaluated their efficacy in preventing CsA toxicity in cultured mouse PTC. Our results show that compounds that blocked protein synthesis and apoptosis, together with the CK2 inhibitor DMAT and the PI3K inhibitor apigenin, were the most efficient in preventing CsA toxicity. We also identified GSK3, MMPs and PKC pathways as potential targets to prevent CsA damage. Additionally, heparinase-I and MAPK inhibitors afforded partial but significant protection. Interestingly, antioxidants and calcium metabolism-related compounds were unable to ameliorate CsA-induced cytotoxicity. Subsequent experiments allowed us to clarify the hierarchical relationship of targeted pathways after CsA treatment, with ER stress identified as an early effector of CsA toxicity, which leads to ROS generation, phenotypical changes and cell death. In summary, this work presents a novel experimental approach to characterizing cellular responses to cytotoxics while pointing to new targets to prevent CsA-induced toxicity in proximal tubule cells. Highlights: ► We used a novel pharmacological approach to elucidate cyclosporine (CsA) toxicity. ► The ability of a broad range of compounds to prevent CsA toxicity was evaluated. ► CsA toxicity was monitored using LDH release assay and PARP cleavage. ► Protein synthesis, PI3K, GSK3, MMP, PKC and caspase inhibitors prevented CsA toxicity. ► We also identified ER

  6. A pharmacologically-based array to identify targets of cyclosporine A-induced toxicity in cultured renal proximal tubule cells

    International Nuclear Information System (INIS)

    Sarró, Eduard; Jacobs-Cachá, Conxita; Itarte, Emilio; Meseguer, Anna

    2012-01-01

    Mechanisms of cyclosporine A (CsA)-induced nephrotoxicity were generally thought to be hemodynamic in origin; however, there is now accumulating evidence of a direct tubular effect. Although genomic and proteomic experiments by our group and others provided overall information on genes and proteins up- or down-regulated by CsA in proximal tubule cells (PTC), a comprehensive view of events occurring after CsA exposure remains to be described. For this purpose, we applied a pharmacologic approach based on the use of known activities of a large panel of potentially protective compounds and evaluated their efficacy in preventing CsA toxicity in cultured mouse PTC. Our results show that compounds that blocked protein synthesis and apoptosis, together with the CK2 inhibitor DMAT and the PI3K inhibitor apigenin, were the most efficient in preventing CsA toxicity. We also identified GSK3, MMPs and PKC pathways as potential targets to prevent CsA damage. Additionally, heparinase-I and MAPK inhibitors afforded partial but significant protection. Interestingly, antioxidants and calcium metabolism-related compounds were unable to ameliorate CsA-induced cytotoxicity. Subsequent experiments allowed us to clarify the hierarchical relationship of targeted pathways after CsA treatment, with ER stress identified as an early effector of CsA toxicity, which leads to ROS generation, phenotypical changes and cell death. In summary, this work presents a novel experimental approach to characterizing cellular responses to cytotoxics while pointing to new targets to prevent CsA-induced toxicity in proximal tubule cells. Highlights: ► We used a novel pharmacological approach to elucidate cyclosporine (CsA) toxicity. ► The ability of a broad range of compounds to prevent CsA toxicity was evaluated. ► CsA toxicity was monitored using LDH release assay and PARP cleavage. ► Protein synthesis, PI3K, GSK3, MMP, PKC and caspase inhibitors prevented CsA toxicity. ► We also identified ER

  7. Pharmacophore modeling and structure-based virtual screening to identify potent inhibitors targeting LuxP of Vibrio harveyi.

    Science.gov (United States)

    Rajamanikandan, Sundaraj; Srinivasan, Pappu

    2016-12-01

    The main aim of the study is to identify molecules that can disrupt quorum sensing (QS) system of Vibrio harveyi and therefore perhaps the production of toxins. Recently, a novel class of dioxazaborocane derivatives has been found to block AI-2 QS by targeting LuxPQ, but the mechanism of protein inhibition is still unclear. In order to investigate the possible binding modes, all the derivatives were docked into the binding site of LuxP using induced fit docking (IFD). The computed binding affinity is in good agreement with the experimental data. Resultant protein-ligand complexes were simulated using Desmond module and the result revealed better binding of ligands in the binding site of LuxP. Both pharmacophore- and structure-based virtual screening was performed to identify novel hits against LuxP. A filtering protocol, including lipinski filters, number of rotatable bonds and three levels of docking precisions were used for the selection of hits with specific properties. The virtual screening results were then combined and analyzed, which retrieved six hits with significant Glide score, binding affinity toward LuxP. The pharmacokinetic properties of the retrieved hits are in the acceptable range. Enrichment calculation was performed to validate the final hits, to discriminate the active compounds from the inactive compounds. The identified hits could serve as a base for further drug development against LuxP of Vibrio harveyi.

  8. Early T Cell Recognition of B Cells following Epstein-Barr Virus Infection: Identifying Potential Targets for Prophylactic Vaccination.

    Directory of Open Access Journals (Sweden)

    Jill M Brooks

    2016-04-01

    Full Text Available Epstein-Barr virus, a B-lymphotropic herpesvirus, is the cause of infectious mononucleosis, has strong aetiologic links with several malignancies and has been implicated in certain autoimmune diseases. Efforts to develop a prophylactic vaccine to prevent or reduce EBV-associated disease have, to date, focused on the induction of neutralising antibody responses. However, such vaccines might be further improved by inducing T cell responses capable of recognising and killing recently-infected B cells. In that context, EBNA2, EBNA-LP and BHRF1 are the first viral antigens expressed during the initial stage of B cell growth transformation, yet have been poorly characterised as CD8+ T cell targets. Here we describe CD8+ T cell responses against each of these three "first wave" proteins, identifying target epitopes and HLA restricting alleles. While EBNA-LP and BHRF1 each contained one strong CD8 epitope, epitopes within EBNA2 induced immunodominant responses through several less common HLA class I alleles (e.g. B*3801 and B*5501, as well as subdominant responses through common class I alleles (e.g. B7 and C*0304. Importantly, such EBNA2-specific CD8+ T cells recognised B cells within the first day post-infection, prior to CD8+ T cells against well-characterised latent target antigens such as EBNA3B or LMP2, and effectively inhibited outgrowth of EBV-transformed B cell lines. We infer that "first wave" antigens of the growth-transforming infection, especially EBNA2, constitute potential CD8+ T cell immunogens for inclusion in prophylactic EBV vaccine design.

  9. FUNCTIONAL GENOMICS IDENTIFIES TIS21-DEPENDENT MECHANISMS AND PUTATIVE CANCER DRUG TARGETS UNDERLYING MEDULLOBLASTOMA SHH-TYPE DEVELOPMENT

    Directory of Open Access Journals (Sweden)

    Giulia Gentile

    2016-11-01

    Full Text Available We have recently generated a novel medulloblastoma (MB mouse model with activation of the Shh pathway and lacking the MB suppressor Tis21 (Patched1+-Tis21KO.ts main phenotype is a defect of migration of the cerebellar granule precursor cells (GCPs. By genomic analysis of GCPs in vivo, we identified as drug target and major responsible of this defect the down-regulation of the promigratory chemokine Cxcl3. Consequently, the GCPs remain longer in the cerebellum proliferative area, and the MB frequency is enhanced. Here, we further analyzed the genes deregulated in a Tis21-dependent manner (Patched1+-is21 wild-type versus Ptch1+-Tis21 knockout, among which are a number of down-regulated tumor inhibitors and up-regulated tumor facilitators, focusing on pathways potentially involved in the tumorigenesis and on putative new drug targets.The data analysis using bioinformatic tools revealed: i a link between the Shh signaling and the Tis21-dependent impairment of the GCPs migration, through a Shh-dependent deregulation of the clathrin-mediated chemotaxis operating in the primary cilium through the Cxcl3-Cxcr2 axis; ii a possible lineage shift of Shh-type GCPs toward retinal precursor phenotype the neural cell type involved in group 3 MB; iii the identification of a subset of putative drug targets for MB, involved, among the others, in the regulation of Hippo signaling and centrosome assembly. Finally, our findings define also the role of Tis21 in the regulation of gene expression, through epigenetic and RNA processing mechanisms, influencing the fate of the GCPs.

  10. Office-based intervention to reduce bottle use among toddlers: TARGet Kids! Pragmatic, randomized trial.

    Science.gov (United States)

    Maguire, Jonathon L; Birken, Catherine S; Jacobson, Sheila; Peer, Michael; Taylor, Carolyn; Khambalia, Amina; Mekky, Magda; Thorpe, Kevin E; Parkin, Patricia

    2010-08-01

    The goal was to determine whether an office-based, educational intervention for parents of 9-month-old children could reduce bottle use and iron depletion at 2 years of age. Between January 2006 and 2007, 251 healthy, 9-month-old infants attending a routine health maintenance visit were assigned randomly to intervention or control groups. Parents in the intervention group were introduced to a 1-week protocol to wean their children from the bottle. Iron depletion (ferritin levels of milk consumption of >16 oz (16 [16%] of 102 children vs 17 [17%] of 99 children; P = .7) were not significantly different between the 2 groups at 2 years of age. However, children in the intervention group started using a cup 3 months earlier (9 vs 12 months; P = .001), were weaned from the bottle 4 months earlier (12 vs 16 months; P = .004), and were more than one-half as likely to be using a bottle at 2 years of age (15 [15%] of 102 children vs 39 [40%] of 99 children; P = .0004). This simple intervention administered during a health maintenance visit did not result in a decrease in iron depletion at 2 years of age but did result in a 60% reduction in prolonged bottle use.

  11. Neuroplasticity of ascending and descending pathways after somatosensory system injury: reviewing knowledge to identify neuropathic pain therapeutic targets.

    Science.gov (United States)

    Boadas-Vaello, P; Castany, S; Homs, J; Álvarez-Pérez, B; Deulofeu, M; Verdú, E

    2016-05-01

    This is a narrative review of the literature. This review aims to be useful in identifying therapeutic targets. It focuses on the molecular and biochemical neuroplasticity changes that occur in the somatosensory system, including ascending and descending pathways, during the development of neuropathic pain. Furthermore, it highlights the latest experimental strategies, based on the changes reported in the damaged nociceptive neurons during neuropathic pain states. This study was conducted in Girona, Catalonia, Spain. A MEDLINE search was performed using the following terms: descending pain pathways; ascending pain pathways; central sensitization; molecular pain; and neuropathic pain pharmacological treatment. Neuropathic pain triggered by traumatic lesions leads to sensitization and hyperexcitability of nociceptors and projection neurons of the dorsal horn, a strengthening in the descendent excitatory pathway and an inhibition of the descending inhibitory pathway of pain. These functional events are associated with molecular plastic changes such as overexpression of voltage-gated ion channels, algogen-sensitive receptors and synthesis of several neurotransmitters. Molecular studies on the plastic changes in the nociceptive somatosensory system enable the development of new pharmacological treatments against neuropathic pain, with higher specificity and effectiveness than classical drug treatments. Although research efforts have already focused on these aspects, additional research may be necessary to further explore the potential therapeutic targets in neuropathic pain involved in the neuroplasticity changes of neuropathological pathways from the injured somatosensory system.

  12. Expression and function analysis of mitotic checkpoint genes identifies TTK as a potential therapeutic target for human hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Xiao-Dong Liang

    Full Text Available The mitotic spindle checkpoint (SAC genes have been considered targets of anticancer therapies. Here, we sought to identify the attractive mitotic spindle checkpoint genes appropriate for human hepatocellular carcinoma (HCC therapies. Through expression profile analysis of 137 selected mitotic spindle checkpoint genes in the publicly available microarray datasets, we showed that 13 genes were dramatically up-regulated in HCC tissues compared to normal livers and adjacent non-tumor tissues. A role of the 13 genes in proliferation was evaluated by knocking them down via small interfering RNA (siRNA in HCC cells. As a result, several mitotic spindle checkpoint genes were required for maintaining the proliferation of HCC cells, demonstrated by cell viability assay and soft agar colony formation assay. Then we established sorafenib-resistant sublines of HCC cell lines Huh7 and HepG2. Intriguingly, increased TTK expression was significantly associated with acquired sorafenib-resistance in Huh7, HepG2 cells. More importantly, TTK was observably up-regulated in 46 (86.8% of 53 HCC specimens. A series of in vitro and in vivo functional experiment assays showed that TTK overexpression promoted cell proliferation, anchor-dependent colony formation and resistance to sorafenib of HCC cells; TTK knockdown restrained cell growth, soft agar colony formation and resistance to sorafenib of HCC cells. Collectively, TTK plays an important role in proliferation and sorafenib resistance and could act as a potential therapeutic target for human hepatocellular carcinoma.

  13. Novel noncontiguous duplications identified with a comprehensive mutation analysis in the DMD gene by DMD gene-targeted sequencing.

    Science.gov (United States)

    Xu, Yan; Wang, Huanhuan; Xiao, Bing; Wei, Wei; Liu, Yu; Ye, Hui; Ying, Xiaomin; Chen, Yingwei; Liu, Xiaoqing; Ji, Xing; Sun, Yu

    2018-03-01

    Genomic rearrangements, such as intragenic deletions and duplications, are the most prevalent types of mutation in the DMD gene, and DMD mutations underlie Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Using multiplex ligation dependent probe amplification (MLPA) and DMD gene-targeted sequencing, we performed a molecular characterization of two cases of complex noncontiguous duplication rearrangements that involved inverted duplications. The breakpoint sequences were analyzed to investigate the mechanisms of the rearrangement. The two cases shared the same duplication events (Dup-nml-Dup/inv), and both involved microhomology and small insertions at the breakpoints. Additionally, in case 1, SNP sequencing results indicated that the de novo duplication mutation arose in the allele that originated from the grandfather. This study has identified a novel type of DMD complex rearrangement and provides insight into the molecular basis of this genomic rearrangement. Copyright © 2017. Published by Elsevier B.V.

  14. Comprehensive Metabolomic, Lipidomic and Microscopic Profiling of Yarrowia lipolytica during Lipid Accumulation Identifies Targets for Increased Lipogenesis.

    Directory of Open Access Journals (Sweden)

    Kyle R Pomraning

    Full Text Available Yarrowia lipolytica is an oleaginous ascomycete yeast that accumulates large amounts of lipids and has potential as a biofuel producing organism. Despite a growing scientific literature focused on lipid production by Y. lipolytica, there remain significant knowledge gaps regarding the key biological processes involved. We applied a combination of metabolomic and lipidomic profiling approaches as well as microscopic techniques to identify and characterize the key pathways involved in de novo lipid accumulation from glucose in batch cultured, wild-type Y. lipolytica. We found that lipids accumulated rapidly and peaked at 48 hours during the five day experiment, concurrent with a shift in amino acid metabolism. We also report that exhaustion of extracellular sugars coincided with thickening of the cell wall, suggesting that genes involved in cell wall biogenesis may be a useful target for improving the efficiency of lipid producing yeast strains.

  15. Comprehensive Metabolomic, Lipidomic and Microscopic Profiling of Yarrowia lipolytica during Lipid Accumulation Identifies Targets for Increased Lipogenesis

    Science.gov (United States)

    Pomraning, Kyle R.; Wei, Siwei; Karagiosis, Sue A.; Kim, Young-Mo; Dohnalkova, Alice C.; Arey, Bruce W.; Bredeweg, Erin L.; Orr, Galya; Metz, Thomas O.; Baker, Scott E.

    2015-01-01

    Yarrowia lipolytica is an oleaginous ascomycete yeast that accumulates large amounts of lipids and has potential as a biofuel producing organism. Despite a growing scientific literature focused on lipid production by Y. lipolytica, there remain significant knowledge gaps regarding the key biological processes involved. We applied a combination of metabolomic and lipidomic profiling approaches as well as microscopic techniques to identify and characterize the key pathways involved in de novo lipid accumulation from glucose in batch cultured, wild-type Y. lipolytica. We found that lipids accumulated rapidly and peaked at 48 hours during the five day experiment, concurrent with a shift in amino acid metabolism. We also report that exhaustion of extracellular sugars coincided with thickening of the cell wall, suggesting that genes involved in cell wall biogenesis may be a useful target for improving the efficiency of lipid producing yeast strains. PMID:25905710

  16. Expression profiling of Dexamethasone-treated primary chondrocytes identifies targets of glucocorticoid signalling in endochondral bone development

    Directory of Open Access Journals (Sweden)

    Beier Frank

    2007-07-01

    Full Text Available Abstract Background Glucocorticoids (GCs are widely used anti-inflammatory drugs. While useful in clinical practice, patients taking GCs often suffer from skeletal side effects including growth retardation in children and adolescents, and decreased bone quality in adults. On a physiological level, GCs have been implicated in the regulation of chondrogenesis and osteoblast differentiation, as well as maintaining homeostasis in cartilage and bone. We identified the glucocorticoid receptor (GR as a potential regulator of chondrocyte hypertrophy in a microarray screen of primary limb bud mesenchyme micromass cultures. Some targets of GC regulation in chondrogenesis are known, but the global effects of pharmacological GC doses on chondrocyte gene expression have not been comprehensively evaluated. Results This study systematically identifies a spectrum of GC target genes in embryonic growth plate chondrocytes treated with a synthetic GR agonist, dexamethasone (DEX, at 6 and 24 hrs. Conventional analysis of this data set and gene set enrichment analysis (GSEA was performed. Transcripts associated with metabolism were enriched in the DEX condition along with extracellular matrix genes. In contrast, a subset of growth factors and cytokines were negatively correlated with DEX treatment. Comparing DEX-induced gene expression data to developmental changes in gene expression in micromass cultures revealed an additional layer of complexity in which DEX maintains the expression of certain chondrocyte marker genes while inhibiting factors that promote vascularization and ultimately ossification of the cartilaginous template. Conclusion Together, these results provide insight into the mechanisms and major molecular classes functioning downstream of DEX in primary chondrocytes. In addition, comparison of our data with microarray studies of DEX treatment in other cell types demonstrated that the majority of DEX effects are tissue-specific. This study provides

  17. A comparative analysis of the ubiquitination kinetics of multiple degrons to identify an ideal targeting sequence for a proteasome reporter.

    Directory of Open Access Journals (Sweden)

    Adam T Melvin

    Full Text Available The ubiquitin proteasome system (UPS is the primary pathway responsible for the recognition and degradation of misfolded, damaged, or tightly regulated proteins. The conjugation of a polyubiquitin chain, or polyubiquitination, to a target protein requires an increasingly diverse cascade of enzymes culminating with the E3 ubiquitin ligases. Protein recognition by an E3 ligase occurs through a specific sequence of amino acids, termed a degradation sequence or degron. Recently, degrons have been incorporated into novel reporters to monitor proteasome activity; however only a limited few degrons have successfully been incorporated into such reporters. The goal of this work was to evaluate the ubiquitination kinetics of a small library of portable degrons that could eventually be incorporated into novel single cell reporters to assess proteasome activity. After an intensive literary search, eight degrons were identified from proteins recognized by a variety of E3 ubiquitin ligases and incorporated into a four component degron-based substrate to comparatively calculate ubiquitination kinetics. The mechanism of placement of multiple ubiquitins on the different degron-based substrates was assessed by comparing the data to computational models incorporating first order reaction kinetics using either multi-monoubiquitination or polyubiquitination of the degron-based substrates. A subset of three degrons was further characterized to determine the importance of the location and proximity of the ubiquitination site lysine with respect to the degron. Ultimately, this work identified three candidate portable degrons that exhibit a higher rate of ubiquitination compared to peptidase-dependent degradation, a desired trait for a proteasomal targeting motif.

  18. Black mother's intention to vaccinate daughters against HPV: A mixed methods approach to identify opportunities for targeted communication.

    Science.gov (United States)

    Cunningham-Erves, Jennifer; Forbes, Laura; Ivankova, Nataliya; Mayo-Gamble, Tilicia; Kelly-Taylor, Kendria; Deakings, Jason

    2018-03-24

    The cervical cancer disparity continues to exist and has widened between Black and non-Hispanic White women. Human Papillomavirus (HPV) vaccines could potentially reduce this disparity, yet remain underused among Black female adolescents. We investigated psychosocial and cultural factors associated with Black mothers' intentions to vaccinate their daughters against HPV, and explored views toward a HPV vaccine mandate. In this quantitative dominant, mixed methods study, cross sectional surveys (n=237) and follow-up semi-structured interviews (n=9) were conducted with Black mothers of daughters. A 2-step logistic regression determined factors associated with Black mothers' intention. Thematic content analysis determined emerging themes. Perceived susceptibility (p=.044), perceived barriers (pHPV vaccination intentions. Follow-up interviews provided insight into factors influencing mothers' intentions. Mothers with low intentions did not perceive their daughter to be currently sexually active or in near future, thus, not at HPV risk. Pediatricians were identified as the most influential person on maternal decision-making if there was a pre-existing relationship. However, many mothers had not received a pediatricians' recommendation for their daughters. Barriers influencing mother's decision-making include knowledge, daughters' age, and mistrust in pharmaceutical companies and physicians. Mothers were not in favor of the HPV vaccine mandate. Findings demonstrate the need to develop and evaluate physician-led interventions on HPV and vaccine importance, and engage these mothers in intervention development to build trust between physicians, researchers, and Black mothers to improve HPV vaccine uptake in Black female adolescents. Published by Elsevier Inc.

  19. Screening and brief intervention targeting risky drinkers in Danish general practice - a pragmatic controlled trial

    DEFF Research Database (Denmark)

    Beich, A.; Gannik, D.; Saelan, H.

    2007-01-01

    general practice performed on the basis of systematic questionnaire screening may fall short of theoretical expectations. When applied to non-selected groups in everyday general practice SBI may have little effect and engender diverse outcome. Women may be more susceptible to defensive reactions than men...... findings, we observed an indiscriminate absolute risk reduction (ARR = 0.08 (95% CI: -0.02; 0.18)) in male binge drinking, but adverse intervention effects for women on the secondary outcomes (binge drinking ARR = -0.30 (95% CI: -0.47; -0.09)). CONCLUSIONS: The results of brief interventions in everyday...

  20. Promoting Parent and Child Physical Activity Together: Elicitation of Potential Intervention Targets and Preferences

    Science.gov (United States)

    Rhodes, Ryan E.; Lim, Clarise

    2018-01-01

    Promoting physical activities that involve both parents and their children would be very useful to the improved health and well-being of families, yet coactivity interventions have been particularly unsuccessful in past research. The purpose of this study was to elicit the salient parental beliefs about coactivity framed through theory of planned…

  1. Improving Behavior by Using Multicomponent Self-Monitoring within a Targeted Reading Intervention

    Science.gov (United States)

    Bruhn, Allison; Watt, Sarah

    2012-01-01

    Many researchers have documented the interrelatedness of reading and behavior (McIntosh, Sadler, & Brown, 2012). Thus, research examining the best way to intervene with students who exhibit problems in both skill sets is merited. Recently, taking an integrated approach to reading and behavioral intervention has been suggested (Mooney, Ryan, Uhing,…

  2. Targeting hardcore smokers : The effects of an online tailored intervention, based on motivational interviewing techniques

    NARCIS (Netherlands)

    Bommelé, Jeroen; Schoenmakers, Tim M.; Kleinjan, Marloes; Peters, Gjalt-Jorn Ygram; Dijkstra, Arie; van de Mheen, Dike

    OBJECTIVES: Hardcore smokers have smoked for many years and do not intend to quit. They also seem unreceptive to information about smoking cessation. We developed a 30-min, tailored web-based intervention that includes motivational interviewing principles. It aims to increase hardcore smokers'

  3. Targeting hardcore smokers : The effects of an online tailored intervention, based on motivational interviewing techniques

    NARCIS (Netherlands)

    Bommelé, J.; Schoenmakers, T.M.; Kleinjan, M.; Peters, G.J.Y.; Dijkstra, A.; van de Mheen, D.

    Hardcore smokers have smoked for many years and do not intend to quit. They also seem unreceptive to information about smoking cessation. We developed a 30-min, tailored web-based intervention that includes motivational interviewing principles. It aims to increase hardcore smokers' intention to quit

  4. Coping and Depressive Symptoms in Adolescents with a Chronic Medical Condition: A Search for Intervention Targets

    Science.gov (United States)

    Kraaij, Vivian; Garnefski, Nadia

    2012-01-01

    The aim of the present study was to find relevant coping factors for the development of psychological intervention programs for adolescents with a chronic medical condition. A wide range of coping techniques were studied, including cognitive coping, behavioral coping and goal adjustment coping. A total of 176 adolescents participated. They were…

  5. Efficacy of Cognitive-Behavioral Interventions Targeting Personality Risk Factors for Youth Alcohol Misuse

    Science.gov (United States)

    Conrod, Patricia J.; Stewart, Sherry H.; Comeau, Nancy; Maclean, A. Michael

    2006-01-01

    Sensation seeking, anxiety sensitivity, and hopelessness are personality risk factors for alcohol use disorders, each associated with specific risky drinking motives in adolescents. We developed a set of interventions and manuals that were designed to intervene at the level of personality risk and associated maladaptive coping strategies,…

  6. Employment Programmes and Interventions Targeting Adults with Autism Spectrum Disorder: A Systematic Review of the Literature

    Science.gov (United States)

    Hedley, Darren; Uljarevic, Mirko; Cameron, Lauren; Halder, Santoshi; Richdale, Amanda; Dissanayake, Cheryl

    2017-01-01

    Individuals with autism spectrum disorder face significant challenges entering the workforce; yet research in this area is limited and the issues are poorly understood. In this systematic review, empirical peer-reviewed studies on employment programmes, interventions and employment-related outcomes in individuals with autism spectrum disorder over…

  7. Targeting persons with low socioeconomic status of different ethnic origins with lifestyle interventions

    NARCIS (Netherlands)

    Bukman, A.J.

    2016-01-01

    Lifestyle intervention studies have shown that the development of cardiometabolic diseases can be partly prevented or postponed by the combination of a healthy diet and physical activity. Cardiometabolic diseases and their risk factors are particularly prevalent among individuals with low

  8. Docking and QSAR Studies of Aryl-valproic Acid Derivatives to Identify Antiproliferative Agents Targeting the HDAC8.

    Science.gov (United States)

    Martínez-Pacheco, Heidy; Ramírez-Galicia, Guillermo; Vergara-Arias, Midalia; Gertsch, Jurg; Fragoso-Vazquez, Jonathan Manuel; Mendez-Luna, David; Abujamra, A L; Cristina, Cabrera-Perez Laura; Cecilia, Rosales-Hernandez Martha; Mendoza-Lujambio, I; Correa-Basurto, Jose

    2017-01-01

    Histone deacetylase 8 (HDAC8) is a plausible target for the development of novel anticancer drugs using a metal-chelating group and hydrophobic moieties as pharmacophores. It is known that valproic acid (administered as its salt, sodium valproate; VPANa+) is an HDAC8 inhibitor characterized by its hydrophobic chains. Nevertheless, VPA is hepatotoxic and VPA analogues might be explored for less hepatotoxic antiproliferative compounds. In this work, docking and QSAR studies of 500 aryl-VPA derivatives as possible HDAC8 inhibitors were performed in order to explore and select potential anti-proliferative compounds. Docking results identified π-π, hydrogen bonds as the most important noncovalent interactions between HDAC8 (PDB: 3F07) and the ligands tested, whereas Belm4 was the best QSAR descriptor and classified as a 2D-BCUT descriptor. Based on theoretical studies, compound DAVP042 was synthesized and evaluated in vitro for its antiproliferative activities on several cancer cell lines (A549-lung, MCF-7-breast, HCT116-colon and U937- lymphoid tissue) in comparison to VPA, as well as for its inhibitory activity on HDAC8 using in vitro models. DAVP042 demonstrated to have antiproliferative activity on all cancer cell lines employed, not only suggesting that this compound should be further studied, but also demonstrating that the methodology herein employed is appropriated to identify new therapeutic candidates. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. Using cluster analysis of anxiety-depression to identify subgroups of prostate cancer patients for targeted treatment planning.

    Science.gov (United States)

    Sharpley, Christopher F; Bitsika, Vicki; Warren, Amelia K; Christie, David R H

    2017-11-01

    To explore any possible subgroupings of prostate cancer (PCa) patients based upon their combined anxiety-depression symptoms for the purposes of informing targeted treatments. A sample of 119 PCa patients completed the GAD7 (anxiety) and PHQ9 (depression), plus a background questionnaire, by mail survey. Data on the GAD7 and PHQ9 were used in a cluster analysis procedure to identify and define any cohesive subgroupings of patients within the sample. Three distinct clusters of patients were identified and were found to be significantly different in the severity of their GAD7 and PHQ9 responses, and also by the profile of symptoms that they exhibited. The presence of these 3 clusters of PCa patients indicates that there is a need to extend assessment of anxiety and depression in these men beyond simple total score results. By applying the clustering profiles to samples of PCa patients, more focussed treatment might be provided to them, hopefully improving outcome efficacy. Copyright © 2017 John Wiley & Sons, Ltd.

  10. Genome expression analysis by suppression subtractive hybridization identified overexpression of Humanin, a target gene in gastric cancer chemoresistance.

    Science.gov (United States)

    Mottaghi-Dastjerdi, Negar; Soltany-Rezaee-Rad, Mohammad; Sepehrizadeh, Zargham; Roshandel, Gholamreza; Ebrahimifard, Farzaneh; Setayesh, Neda

    2014-01-08

    In cancer cells, apoptosis is an important mechanism that influences the outcome of chemotherapy and the development of chemoresistance. To find the genes involved in chemoresistance and the development of gastric cancer, we used the suppression subtractive hybridization method to identify the genes that are overexpressed in gastric cancer tissues compared to normal gastric tissues. In the suppression subtractive hybridization library we constructed, the most highly overexpressed genes were humanin isoforms. Humanin is a recently identified endogenous peptide that has anti-apoptotic activity and has been selected for further study due to its potential role in the chemoresistance of gastric cancer. Upregulation of humanin isoforms was also observed in clinical samples by using quantitative real-time PCR. Among the studied isoforms, humanin isoform 3, with an expression level of 4.166 ± 1.44 fold, was the most overexpressed isoform in GC. The overexpression of humanin in gastric cancer suggests a role for chemoresistance and provides new insight into the biology of gastric cancer. We propose that humanin isoforms are novel targets for combating chemoresistance in gastric cancer.

  11. Dropouts and Compliance in Exercise Interventions Targeting Bone Mineral Density in Adults: A Meta-Analysis of Randomized Controlled Trials

    Directory of Open Access Journals (Sweden)

    George A. Kelley

    2013-01-01

    Full Text Available Background. Dropouts and compliance to exercise interventions targeting bone mineral density (BMD in adults are not well established. The purpose of this study was to address that gap. Methods. Meta-analysis of randomized controlled exercise intervention trials in adults ≥18 years of age. The primary outcomes were dropouts in the exercise and control groups as well as compliance to the exercise interventions. A random-effects model was used to pool results. Moderator analyses were conducted using mixed-effects ANOVA-like models and metaregression. Statistical significance was set at . Results. Thirty-six studies representing 3,297 participants (1,855 exercise, 1,442 control were included. Dropout rates in the exercise and control groups averaged 20.9% (95% CI 16.7%–25.9% and 15.9% (11.8%–21.1% while compliance to exercise was 76.3% (71.7%–80.3%. For both exercise and control groups, greater dropout rates were associated with studies conducted in the USA versus other countries, females versus males, premenopausal versus postmenopausal women, younger versus older participants, longer studies (controls only, and high- versus moderate-intensity training (exercisers only. Greater compliance to exercise was associated with being female, home- or facility-based exercise versus both, and shorter studies. Conclusion. These findings provide important information for researchers and practitioners with respect to exercise programs targeting BMD in adults.

  12. Contributions of Qualitative Research in Informing HIV/AIDS Interventions Targeting Black MSM in the United States.

    Science.gov (United States)

    Wilson, Patrick A; Valera, Pamela; Martos, Alexander J; Wittlin, Natalie M; Muñoz-Laboy, Miguel A; Parker, Richard G

    2016-01-01

    This article presents a systematic review of qualitative studies focusing on human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) among Black men who have sex with men (BMSM) in the United States. We reviewed studies that were published between 1980 and 2014. Qualitative methods employed in the studies reviewed include in-depth interviews, focus groups, participant observation, and ethnography. We searched several databases (PubMed, PsychINFO, JSTOR, ERIC, Sociological Abstracts, and Google Scholar) for relevant articles using the following broad terms: "Black men" "Black gay/bisexual" or "Black men who have sex with men," and "qualitative" and/or "ethnography." We include 70 studies in this review. The key themes observed across studies were (1) heterogeneity, (2) layered stigma and intersectionality, (3) risk behaviors, (4) mental health, (5) resilience, and (6) community engagement. The review suggests that sexual behavior and HIV-status disclosure, sexual risk taking, substance use, and psychological well-being were contextually situated. Interventions occurring at multiple levels and within multiple contexts are needed to reduce stigma within the Black community. Similarly, structural interventions targeting religious groups, schools, and health care systems are needed to improve the health outcomes among BMSM. Community engagement and using community-based participatory research methods may facilitate the development and implementation of culturally appropriate HIV/AIDS interventions targeting BMSM.

  13. Integration of targeted health interventions into health systems: a conceptual framework for analysis.

    Science.gov (United States)

    Atun, Rifat; de Jongh, Thyra; Secci, Federica; Ohiri, Kelechi; Adeyi, Olusoji

    2010-03-01

    The benefits of integrating programmes that emphasize specific interventions into health systems to improve health outcomes have been widely debated. This debate has been driven by narrow binary considerations of integrated (horizontal) versus non-integrated (vertical) programmes, and characterized by polarization of views with protagonists for and against integration arguing the relative merits of each approach. The presence of both integrated and non-integrated programmes in many countries suggests benefits to each approach. While the terms 'vertical' and 'integrated' are widely used, they each describe a range of phenomena. In practice the dichotomy between vertical and horizontal is not rigid and the extent of verticality or integration varies between programmes. However, systematic analysis of the relative merits of integration in various contexts and for different interventions is complicated as there is no commonly accepted definition of 'integration'-a term loosely used to describe a variety of organizational arrangements for a range of programmes in different settings. We present an analytical framework which enables deconstruction of the term integration into multiple facets, each corresponding to a critical health system function. Our conceptual framework builds on theoretical propositions and empirical research in innovation studies, and in particular adoption and diffusion of innovations within health systems, and builds on our own earlier empirical research. It brings together the critical elements that affect adoption, diffusion and assimilation of a health intervention, and in doing so enables systematic and holistic exploration of the extent to which different interventions are integrated in varied settings and the reasons for the variation. The conceptual framework and the analytical approach we propose are intended to facilitate analysis in evaluative and formative studies of-and policies on-integration, for use in systematically comparing and

  14. Cost-benefit of infection control interventions targeting methicillin-resistant Staphylococcus aureus in hospitals: systematic review.

    Science.gov (United States)

    Farbman, L; Avni, T; Rubinovitch, B; Leibovici, L; Paul, M

    2013-12-01

    Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) incur significant costs. We aimed to examine the cost and cost-benefit of infection control interventions against MRSA and to examine factors affecting economic estimates. We performed a systematic review of studies assessing infection control interventions aimed at preventing spread of MRSA in hospitals and reporting intervention costs, savings, cost-benefit or cost-effectiveness. We searched PubMed and references of included studies with no language restrictions up to January 2012. We used the Quality of Health Economic Studies tool to assess study quality. We report cost and savings per month in 2011 US$. We calculated the median save/cost ratio and the save-cost difference with interquartile range (IQR) range. We examined the effects of MRSA endemicity, intervention duration and hospital size on results. Thirty-six studies published between 1987 and 2011 fulfilled inclusion criteria. Fifteen of the 18 studies reporting both costs and savings reported a save/cost ratio >1. The median save/cost ratio across all 18 studies was 7.16 (IQR 1.37-16). The median cost across all studies reporting intervention costs (n = 31) was 8648 (IQR 2025-19 170) US$ per month; median savings were 38 751 (IQR 14 206-75 842) US$ per month (23 studies). Higher save/cost ratios were observed in the intermediate to high endemicity setting compared with the low endemicity setting, in hospitals with 6 months. Infection control intervention to reduce spread of MRSA in acute-care hospitals showed a favourable cost/benefit ratio. This was true also for high MRSA endemicity settings. Unresolved economic issues include rapid screening using molecular techniques and universal versus targeted screening. © 2013 The Authors Clinical Microbiology and Infection © 2013 European Society of Clinical Microbiology and Infectious Diseases.

  15. Multifactorial assessment and targeted intervention in nutritional status among the older adults: a randomized controlled trial: the Octabaix study.

    Science.gov (United States)

    Badia, Teresa; Formiga, Francesc; Ferrer, Assumpta; Sanz, Héctor; Hurtos, Laura; Pujol, Ramón

    2015-04-11

    Malnutrition is frequent among older people and is associated with morbi-mortality. The aim of the study is to assess the effectiveness of a multifactorial and multidisciplinary intervention in the nutritional status among the elderly. Randomized, single-blind, parallel-group, clinical trial conducted from January 2009 to December 2010 in seven primary health care centers in Baix Llobregat (Barcelona). Of 696 referred people, born in 1924, 328 subjects were randomized to an intervention group or a control group. The intervention model used an algorithm and was multifaceted for both the patients and their primary care providers. The main outcome was improvement in nutritional status assessed by Mini Nutritional Assessment (MNA). Data analyses were done by intention-to-treat. Two-year assessment was completed for 127 patients (77.4%) in the intervention group and 98 patients (59.7%) in the control group. In the adjusted linear mixed models for MNA, intervention showed no significant effect during all follow-up period with -0.21 (CI: - 0.96; 0.26). In subjects with nutritional risk (MNA ≤ 23.5/30) existed a tendency towards improvement in MNA score 1.13 (95% CI -0.48; 2.74) after 2 years. A universal multifactorial assessment and target intervention over a two year period in subjects at nutritional risk showed a tendency to improve nutrition but not in the rest of community-dwelling studied subjects. Cognitive impairment was an independent factor strongly associated with a decline in nutritional status. The clinical trial is registered as part of a US National Institutes of Health Clinical Trial: NCT01141166.

  16. Screen-time Weight-loss Intervention Targeting Children at Home (SWITCH: A randomized controlled trial study protocol

    Directory of Open Access Journals (Sweden)

    Tsai Midi

    2011-06-01

    Full Text Available Abstract Background Approximately one third of New Zealand children and young people are overweight or obese. A similar proportion (33% do not meet recommendations for physical activity, and 70% do not meet recommendations for screen time. Increased time being sedentary is positively associated with being overweight. There are few family-based interventions aimed at reducing sedentary behavior in children. The aim of this trial is to determine the effects of a 24 week home-based, family oriented intervention to reduce sedentary screen time on children's body composition, sedentary behavior, physical activity, and diet. Methods/Design The study design is a pragmatic two-arm parallel randomized controlled trial. Two hundred and seventy overweight children aged 9-12 years and primary caregivers are being recruited. Participants are randomized to intervention (family-based screen time intervention or control (no change. At the end of the study, the control group is offered the intervention content. Data collection is undertaken at baseline and 24 weeks. The primary trial outcome is child body mass index (BMI and standardized body mass index (zBMI. Secondary outcomes are change from baseline to 24 weeks in child percentage body fat; waist circumference; self-reported average daily time spent in physical and sedentary activities; dietary intake; and enjoyment of physical activity and sedentary behavior. Secondary outcomes for the primary caregiver include change in BMI and self-reported physical activity. Discussion This study provides an excellent example of a theory-based, pragmatic, community-based trial targeting sedentary behavior in overweight children. The study has been specifically designed to allow for estimation of the consistency of effects on body composition for Māori (indigenous, Pacific and non-Māori/non-Pacific ethnic groups. If effective, this intervention is imminently scalable and could be integrated within existing weight

  17. Systematic review of universal resilience interventions targeting child and adolescent mental health in the school setting: review protocol.

    Science.gov (United States)

    Dray, Julia; Bowman, Jenny; Wolfenden, Luke; Campbell, Elizabeth; Freund, Megan; Hodder, Rebecca; Wiggers, John

    2015-12-29

    The mental health of children and adolescents is a key area of health concern internationally. Previous empirical studies suggest that resilience may act as a protective mechanism towards the development of mental health problems. Resilience refers to the ability to employ a collection of protective factors to return to or maintain positive mental health following disadvantage or adversity. Schools represent a potential setting within which protective factors of all children and adolescents may be fostered through resilience-focussed interventions. Despite this potential, limited research has investigated the effectiveness of universal school-based resilience-focussed interventions on mental health outcomes in children and adolescents. The objective of the present review is to assess the effects of universal school-based resilience-focussed interventions, relative to a comparison group, on mental health outcomes in children and adolescents. Eligible studies will be randomised (including cluster-randomised) controlled trials of universal interventions explicitly described as resilience-focussed or comprising strategies to strengthen a minimum of three internal protective factors, targeting children aged 5 to 18 years, implemented within schools, and reporting a mental health outcome. Screening for studies will be conducted across six electronic databases: MEDLINE, PsycINFO, Educational Resources Information Center (ERIC), Excerpta Medica database (EMBASE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), and the Cochrane Central Register of Controlled Trials (CENTRAL). Two reviewers will retrieve eligible articles, assess risk of bias, and extract data. Where studies are sufficiently homogenous and reported outcomes are amenable for pooled synthesis, meta-analysis will be performed. Narrative description will be used to synthesise trial outcome data where data cannot be combined or heterogeneity exists. This review will aid in building an evidence

  18. A Comparison of Recruitment Methods for an mHealth Intervention Targeting Mothers: Lessons from the Growing Healthy Program.

    Science.gov (United States)

    Laws, Rachel A; Litterbach, Eloise-Kate V; Denney-Wilson, Elizabeth A; Russell, Catherine G; Taki, Sarah; Ong, Kok-Leong; Elliott, Rosalind M; Lymer, Sharyn J; Campbell, Karen J

    2016-09-15

    Mobile health (mHealth) programs hold great promise for increasing the reach of public health interventions. However, mHealth is a relatively new field of research, presenting unique challenges for researchers. A key challenge is understanding the relative effectiveness and cost of various methods of recruitment to mHealth programs. The objectives of this study were to (1) compare the effectiveness of various methods of recruitment to an mHealth intervention targeting healthy infant feeding practices, and (2) explore factors influencing practitioner referral to the intervention. The Growing healthy study used a quasi-experimental design with an mHealth intervention group and a concurrent nonrandomized comparison group. Eligibility criteria included: expectant parents (>30 weeks of gestation) or parents with an infant mobile phone, ≥18 years old, and living in Australia. Recruitment to the mHealth program consisted of: (1) practitioner-led recruitment through Maternal and Child Health nurses, midwives, and nurses in general practice; (2) face-to-face recruitment by researchers; and (3) online recruitment. Participants' baseline surveys provided information regarding how participants heard about the study, and their sociodemographic details. Costs per participant recruited were calculated by taking into account direct advertising costs and researcher time/travel costs. Practitioner feedback relating to the recruitment process was obtained through a follow-up survey and qualitative interviews. A total of 300 participants were recruited to the mHealth intervention. The cost per participant recruited was lowest for online recruitment (AUD $14) and highest for practice nurse recruitment (AUD $586). Just over half of the intervention group (50.3%, 151/300) were recruited online over a 22-week period compared to practitioner recruitment (29.3%, 88/300 over 46 weeks) and face-to-face recruitment by researchers (7.3%, 22/300 over 18 weeks). No significant differences were

  19. Short message service (SMS)-based intervention targeting alcohol consumption among university students: study protocol of a randomized controlled trial.

    Science.gov (United States)

    Thomas, Kristin; Bendtsen, Marcus; Linderoth, Catharina; Karlsson, Nadine; Bendtsen, Preben; Müssener, Ulrika

    2017-04-04

    Despite significant health risks, heavy drinking of alcohol among university students is a widespread problem; excessive drinking is part of the social norm. A growing number of studies indicate that short message service (SMS)-based interventions are cost-effective, accessible, require limited effort by users, and can enable continuous, real-time, brief support in real-world settings. Although there is emerging evidence for the effect of SMS-based interventions in reducing alcohol consumption, more research is needed. This study aims to test the effectiveness of a newly developed SMS-based intervention targeting excessive alcohol consumption among university and college students in Sweden. The study is a two-arm randomized controlled trial with an intervention (SMS programme) and a control (treatment as usual) group. Outcome measures will be investigated at baseline and at 3-month follow up. The primary outcome is total weekly alcohol consumption. Secondary outcomes are frequency of heavy episodic drinking, highest estimated blood alcohol concentration and number of negative consequences due to excessive drinking. This study contributes knowledge on the effect of automatized SMS support to reduce excessive drinking among students compared with existing support such as Student Health Centres. ISRCTN.com, ISRCTN95054707 . Registered on 31 August 2016.

  20. Intraoperative near-infrared fluorescence imaging targeting folate receptors identifies lung cancer in a large-animal model.

    Science.gov (United States)

    Keating, Jane J; Runge, Jeffrey J; Singhal, Sunil; Nims, Sarah; Venegas, Ollin; Durham, Amy C; Swain, Gary; Nie, Shuming; Low, Philip S; Holt, David E

    2017-05-15

    Complete tumor resection is the most important predictor of patient survival with non-small cell lung cancer. Methods for intraoperative margin assessment after lung cancer excision are lacking. This study evaluated near-infrared (NIR) intraoperative imaging with a folate-targeted molecular contrast agent (OTL0038) for the localization of primary lung adenocarcinomas, lymph node sampling, and margin assessment. Ten dogs with lung cancer underwent either video-assisted thoracoscopic surgery or open thoracotomy and tumor excision after an intravenous injection of OTL0038. Lungs were imaged with an NIR imaging device both in vivo and ex vivo. The wound bed was re-imaged for retained fluorescence suspicious for positive tumor margins. The tumor signal-to-background ratio (SBR) was measured in all cases. Next, 3 human patients were enrolled in a proof-of-principle study. Tumor fluorescence was measured both in situ and ex vivo. All canine tumors fluoresced in situ (mean Fluoptics SBR, 5.2 [range, 2.7-8.1]; mean Karl Storz SBR 1.9 [range, 1.4-2.6]). In addition, the fluorescence was consistent with tumor margins on pathology. Three positive lymph nodes were discovered with NIR imaging. Also, a positive retained tumor margin was discovered upon NIR imaging of the wound bed. Human pulmonary adenocarcinomas were also fluorescent both in situ and ex vivo (mean SBR, > 2.0). NIR imaging can identify lung cancer in a large-animal model. In addition, NIR imaging can discriminate lymph nodes harboring cancer cells and also bring attention to a positive tumor margin. In humans, pulmonary adenocarcinomas fluoresce after the injection of the targeted contrast agent. Cancer 2017;123:1051-60. © 2016 American Cancer Society. © 2016 American Cancer Society.

  1. How much behaviour change should we expect from health promotion campaigns targeting cognitions? An approach to pre-intervention assessment.

    Science.gov (United States)

    Fife-Schaw, Chris; Abraham, Charles

    2009-09-01

    For those planning interventions based on social cognition models, it is usually not clear what impact on behaviour will follow from attempts to change the cognitions specified in these models. We describe a statistical simulation technique to assess the likely impact of health promotion targeting Theory of Reasoned Action (TRA)-based predictors of condom use. We apply regression-based simulation techniques to data from the SHARE project (n = 756 Scottish adolescents) to assess the potential impact of changes in cognitions on condom use. Results support the predictive utility of TRA-based models of psychological antecedents of condom use but also provide a cautionary warning about the magnitude of behaviour change likely to be achieved by interventions based on such models.

  2. Target intervention against multiple-risk markers to reduce cardiovascular disease in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Gaede, Peter; Pedersen, Oluf

    2004-01-01

    The risk of cardiovascular disease is markedly increased in patients with type 2 diabetes with a prevalence twice as high compared to the background population. With the recognition of multiple concomitant risk factors for both microvascular as well as cardiovascular disease in type 2 diabetic...... patients, treatment strategies have changed during recent years. This review focuses on the many recent drug trials that have set the course for an effective multifactorial treatment of the disease. Thus, the Steno-2 Study has shown that an intensified multifactorial intervention targeting several risk...... factors for cardiovascular disease is capable of reducing the risk for a combined endpoint of cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, coronary interventions, revascularisation to legs, and amputations by 50%....

  3. Targeting, out-scaling and prioritising climate-smart interventions in agricultural systems: Lessons from applying a generic framework to the livestock sector in sub-Saharan Africa.

    Science.gov (United States)

    Notenbaert, An; Pfeifer, Catherine; Silvestri, Silvia; Herrero, Mario

    2017-02-01

    As a result of population growth, urbanization and climate change, agricultural systems around the world face enormous pressure on the use of resources. There is a pressing need for wide-scale innovation leading to development that improves the livelihoods and food security of the world's population while at the same time addressing climate change adaptation and mitigation. A variety of promising climate-smart interventions have been identified. However, what remains is the prioritization of interventions for investment and broad dissemination. The suitability and adoption of interventions depends on a variety of bio-physical and socio-economic factors. Also their impacts, when adopted and out-scaled, are likely to be highly heterogeneous. This heterogeneity expresses itself not only spatially and temporally but also in terms of the stakeholders affected, some might win and some might lose. A mechanism that can facilitate a systematic, holistic assessment of the likely spread and consequential impact of potential interventions is one way of improving the selection and targeting of such options. In this paper we provide climate smart agriculture (CSA) planners and implementers at all levels with a generic framework for evaluating and prioritising potential interventions. This entails an iterative process of mapping out recommendation domains, assessing adoption potential and estimating impacts. Through examples, related to livestock production in sub-Saharan Africa, we demonstrate each of the steps and how they are interlinked. The framework is applicable in many different forms, scales and settings. It has a wide applicability beyond the examples presented and we hope to stimulate readers to integrate the concepts in the planning process for climate-smart agriculture, which invariably involves multi-stakeholder, multi-scale and multi-objective decision-making.

  4. Indicators of the maximum radiation dose to the skin during percutaneous coronary intervention in different target vessels.

    Science.gov (United States)

    Chida, Koichi; Saito, Haruo; Kagaya, Yutaka; Kohzuki, Masahiro; Takai, Yoshihiro; Takahashi, Shoki; Yamada, Shogo; Zuguchi, Masayuki

    2006-08-01

    To evaluate whether the maximum radiation dose to the patient's skin (MSD) can be estimated during percutaneous coronary intervention (PCI) procedures, we investigated the relationship between the MSD and fluoroscopic time, dose-area product (DAP), and body weight, separately analyzing the relationships for different target vessels. Many cases of skin injury caused by excessive radiation exposure during cardiac intervention procedures have been reported. However, real-time maximum-dose monitoring of the skin is unavailable for many cardiac intervention procedures. We studied 197 consecutive PCI procedures that involved a single target vessel and were conducted. The DAP was measured, and the MSD was calculated by a skin-dose mapping software program (Caregraph). The target vessels of the PCI procedures were divided into four groups based on the AHA classification system: AHA 5-10, left anterior descending artery domain (LAD), AHA 11-15, left circumflex artery domain (LCx), AHA 1-3 = R 1-3, and AHA 4 = R 4. The correlation coefficient (r) between the MSD and fluoroscopic time was higher for the right coronary artery (RCA) vessels (R 1-3, 0.852; R 4, 0.715) than for the left coronary artery (LCA) vessels (LAD, 0.527; LCx, 0.646), and the r value between the MSD and DAP was higher for the RCA vessels (R 1-3, 0.871; R 4, 0.898) than for the LCA vessels (LAD, 0.628; LCx, 0.694). Similarly, the correlation coefficient between the MSD and weight x fluoroscopic time (WFP) was higher for the RCA vessels (R 1-3, 0.874; R 4, 0.807) than for the LCA vessels (LAD, 0.551; LCx, 0.735). The DAP and WFP can be used to estimate the MSD during PCI in the RCA but not in the LCA, especially the LAD.

  5. Speech-language pathologists' practices regarding assessment, analysis, target selection, intervention, and service delivery for children with speech sound disorders.

    Science.gov (United States)

    Mcleod, Sharynne; Baker, Elise

    2014-01-01

    A survey of 231 Australian speech-language pathologists (SLPs) was undertaken to describe practices regarding assessment, analysis, target selection, intervention, and service delivery for children with speech sound disorders (SSD). The participants typically worked in private practice, education, or community health settings and 67.6% had a waiting list for services. For each child, most of the SLPs spent 10-40 min in pre-assessment activities, 30-60 min undertaking face-to-face assessments, and 30-60 min completing paperwork after assessments. During an assessment SLPs typically conducted a parent interview, single-word speech sampling, collected a connected speech sample, and used informal tests. They also determined children's stimulability and estimated intelligibility. With multilingual children, informal assessment procedures and English-only tests were commonly used and SLPs relied on family members or interpreters to assist. Common analysis techniques included determination of phonological processes, substitutions-omissions-distortions-additions (SODA), and phonetic inventory. Participants placed high priority on selecting target sounds that were stimulable, early developing, and in error across all word positions and 60.3% felt very confident or confident selecting an appropriate intervention approach. Eight intervention approaches were frequently used: auditory discrimination, minimal pairs, cued articulation, phonological awareness, traditional articulation therapy, auditory bombardment, Nuffield Centre Dyspraxia Programme, and core vocabulary. Children typically received individual therapy with an SLP in a clinic setting. Parents often observed and participated in sessions and SLPs typically included siblings and grandparents in intervention sessions. Parent training and home programs were more frequently used than the group therapy. Two-thirds kept up-to-date by reading journal articles monthly or every 6 months. There were many similarities with

  6. Impact of a targeted direct marketing price promotion intervention (Buywell) on food-purchasing behaviour by low income consumers: a randomised controlled trial.

    Science.gov (United States)

    Stead, M; MacKintosh, A M; Findlay, A; Sparks, L; Anderson, A S; Barton, K; Eadie, D

    2017-08-01

    Price promotions are a promising intervention for encouraging healthier food purchasing. We aimed to assess the impact of a targeted direct marketing price promotion combined with healthy eating advice and recipe suggestions on the purchase of selected healthier foods by low income consumers. We conducted a randomised controlled trial (n = 53 367) of a direct marketing price promotion (Buywell) combined with healthy eating advice and recipe suggestions for low income consumers identified as 'less healthy' shoppers. Impact was assessed using electronic point of sale data for UK low income shoppers before, during and after the promotion. The proportion of customers buying promoted products in the intervention month increased by between 1.4% and 2.8% for four of the five products. There was significantly higher uptake in the promotion month (P marketing price promotions combined with healthy eating advice and recipe suggestions targeted at low income consumers are feasible and can have a modest impact on short-term food-purchasing behaviour, although further approaches are needed to help sustain these changes. © 2017 The British Dietetic Association Ltd.

  7. Adolescent Bystander Behavior in the School and Online Environments and the Implications for Interventions Targeting Cyberbullying

    Science.gov (United States)

    Patterson, Lisa J.; Allan, Alfred; Cross, Donna

    2017-01-01

    The aim of this study was to add to the emerging knowledge about the role of bystanders in cyberbullying. To differentiate online versus offline bystander behaviors, 292 Australian children (mean age = 15.2; female = 54.4%) reviewed hypothetical scenarios experimentally manipulated by bystander sex, relationship to target and perpetrator, and…

  8. Identifying new lignin bioengineering targets: 1. Monolignol-substitute impacts on lignin formation and cell wall fermentability

    Directory of Open Access Journals (Sweden)

    Lu Fachuang

    2010-06-01

    Full Text Available Abstract Background Recent discoveries highlighting the metabolic malleability of plant lignification indicate that lignin can be engineered to dramatically alter its composition and properties. Current plant biotechnology efforts are primarily aimed at manipulating the biosynthesis of normal monolignols, but in the future apoplastic targeting of phenolics from other metabolic pathways may provide new approaches for designing lignins that are less inhibitory toward the enzymatic hydrolysis of structural polysaccharides, both with and without biomass pretreatment. To identify promising new avenues for lignin bioengineering, we artificially lignified cell walls from maize cell suspensions with various combinations of normal monolignols (coniferyl and sinapyl alcohols plus a variety of phenolic monolignol substitutes. Cell walls were then incubated in vitro with anaerobic rumen microflora to assess the potential impact of lignin modifications on the enzymatic degradability of fibrous crops used for ruminant livestock or biofuel production. Results In the absence of anatomical constraints to digestion, lignification with normal monolignols hindered both the rate and extent of cell wall hydrolysis by rumen microflora. Inclusion of methyl caffeate, caffeoylquinic acid, or feruloylquinic acid with monolignols considerably depressed lignin formation and strikingly improved the degradability of cell walls. In contrast, dihydroconiferyl alcohol, guaiacyl glycerol, epicatechin, epigallocatechin, and epigallocatechin gallate readily formed copolymer-lignins with normal monolignols; cell wall degradability was moderately enhanced by greater hydroxylation or 1,2,3-triol functionality. Mono- or diferuloyl esters with various aliphatic or polyol groups readily copolymerized with monolignols, but in some cases they accelerated inactivation of wall-bound peroxidase and reduced lignification; cell wall degradability was influenced by lignin content and the degree

  9. Can We Identify the Active Ingredients of Behaviour Change Interventions for Coronary Heart Disease Patients? A Systematic Review and Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Laura Goodwin

    Full Text Available The main behaviour change intervention available for coronary heart disease (CHD patients is cardiac rehabilitation. There is little recognition of what the active ingredients of behavioural interventions for CHD might be. Using a behaviour change technique (BCT framework to code existing interventions may help to identify this. The objectives of this systematic review are to determine the effectiveness of CHD behaviour change interventions and how this may be explained by BCT content and structure.A systematic search of Medline, EMBASE and PsycInfo electronic databases was conducted over a twelve year period (2003-2015 to identify studies which reported on behaviour change interventions for CHD patients. The content of the behaviour change interventions was coded using the Coventry Aberdeen and London-Refined (CALO-RE taxonomy. Meta-regression analyses examined the BCT content as a predictor of mortality. Twenty two papers met the criteria for this review, reporting data on 16,766 participants. The most commonly included BCTs were providing information, and goal setting. There was a small but significant effect of the interventions on smoking (risk ratio (RR = 0.89, 95% CI 0.81-0.97. The interventions did not reduce the risk of CHD events (RR = 0.86, 95% CI 0.68, 1.09, but significantly reduced the risk of mortality (RR = 0.82, 95% CI 0.69, 0.97. Sensitivity analyses did not find that any of the BCT variables predicted mortality and the number of BCTs included in an intervention was not associated with mortality (β = -0.02, 95% CI -0.06-0.03.Behaviour change interventions for CHD patients appear to have a positive impact on a number of outcomes. Using an existing BCT taxonomy to code the interventions helped us to understand which were the most commonly used techniques, providing information and goal setting, but not the active components of these complex interventions.

  10. Can We Identify the Active Ingredients of Behaviour Change Interventions for Coronary Heart Disease Patients? A Systematic Review and Meta-Analysis.

    Science.gov (United States)

    Goodwin, Laura; Ostuzzi, Giovanni; Khan, Nadia; Hotopf, Matthew H; Moss-Morris, Rona

    2016-01-01

    The main behaviour change intervention available for coronary heart disease (CHD) patients is cardiac rehabilitation. There is little recognition of what the active ingredients of behavioural interventions for CHD might be. Using a behaviour change technique (BCT) framework to code existing interventions may help to identify this. The objectives of this systematic review are to determine the effectiveness of CHD behaviour change interventions and how this may be explained by BCT content and structure. A systematic search of Medline, EMBASE and PsycInfo electronic databases was conducted over a twelve year period (2003-2015) to identify studies which reported on behaviour change interventions for CHD patients. The content of the behaviour change interventions was coded using the Coventry Aberdeen and London-Refined (CALO-RE) taxonomy. Meta-regression analyses examined the BCT content as a predictor of mortality. Twenty two papers met the criteria for this review, reporting data on 16,766 participants. The most commonly included BCTs were providing information, and goal setting. There was a small but significant effect of the interventions on smoking (risk ratio (RR) = 0.89, 95% CI 0.81-0.97). The interventions did not reduce the risk of CHD events (RR = 0.86, 95% CI 0.68, 1.09), but significantly reduced the risk of mortality (RR = 0.82, 95% CI 0.69, 0.97). Sensitivity analyses did not find that any of the BCT variables predicted mortality and the number of BCTs included in an intervention was not associated with mortality (β = -0.02, 95% CI -0.06-0.03). Behaviour change interventions for CHD patients appear to have a positive impact on a number of outcomes. Using an existing BCT taxonomy to code the interventions helped us to understand which were the most commonly used techniques, providing information and goal setting, but not the active components of these complex interventions.

  11. Target intervention against multiple-risk markers to reduce cardiovascular disease in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Gaede, Peter; Pedersen, Oluf

    2004-01-01

    The risk of cardiovascular disease is markedly increased in patients with type 2 diabetes with a prevalence twice as high compared to the background population. With the recognition of multiple concomitant risk factors for both microvascular as well as cardiovascular disease in type 2 diabetic...... patients, treatment strategies have changed during recent years. This review focuses on the many recent drug trials that have set the course for an effective multifactorial treatment of the disease. Thus, the Steno-2 Study has shown that an intensified multifactorial intervention targeting several risk...

  12. Stimulation of oral fibroblast chemokine receptors identifies CCR3 and CCR4 as potential wound healing targets

    Science.gov (United States)

    Buskermolen, Jeroen K.; Roffel, Sanne

    2017-01-01

    The focus of this study was to determine which chemokine receptors are present on oral fibroblasts and whether these receptors influence proliferation, migration, and/or the release of wound healing mediators. This information may provide insight into the superior wound healing characteristics of the oral mucosa. The gingiva fibroblasts expressed 12 different chemokine receptors (CCR3, CCR4, CCR6, CCR9, CCR10, CXCR1, CXCR2, CXCR4, CXCR5, CXCR7, CX3CR1, and XCR1), as analyzed by flow cytometry. Fourteen corresponding chemokines (CCL5, CCL15, CCL20, CCL22, CCL25, CCL27, CCL28, CXCL1, CXCL8, CXCL11, CXCL12, CXCL13, CX3CL1, and XCL1) were used to study the activation of these receptors on gingiva fibroblasts. Twelve of these fourteen chemokines stimulated gingiva fibroblast migration (all except for CXCL8 and CXCL12). Five of the chemokines stimulated proliferation (CCL5/CCR3, CCL15/CCR3, CCL22/CCR4, CCL28/CCR3/CCR10, and XCL1/XCR1). Furthermore, CCL28/CCR3/CCR10 and CCL22/CCR4 stimulation increased IL‐6 secretion and CCL28/CCR3/CCR10 together with CCL27/CCR10 upregulated HGF secretion. Moreover, TIMP‐1 secretion was reduced by CCL15/CCR3. In conclusion, this in‐vitro study identifies chemokine receptor‐ligand pairs which may be used in future targeted wound healing strategies. In particular, we identified the chemokine receptors CCR3 and CCR4, and the mucosa specific chemokine CCL28, as having an predominant role in oral wound healing by increasing human gingiva fibroblast proliferation, migration, and the secretion of IL‐6 and HGF and reducing the secretion of TIMP‐1. PMID:28387445

  13. RNAi Screen for NRF2 Inducers Identifies Targets That Rescue Primary Lung Epithelial Cells from Cigarette Smoke Induced Radical Stress.

    Directory of Open Access Journals (Sweden)

    Frances-Rose Schumacher

    Full Text Available Chronic Obstructive Pulmonary Disease (COPD is a highly prevalent condition characterized by inflammation and progressive obstruction of the airways. At present, there is no treatment that suppresses the chronic inflammation of the disease, and COPD patients often succumb to the condition. Excessive oxidative stress caused by smoke inhalation is a major driving force of the disease. The transcription factor NRF2 is a critical player in the battle against oxidative stress and its function is impaired in COPD. Increasing NRF2 activity may therefore be a viable therapeutic option for COPD treatment. We show that down regulation of KEAP1, a NRF2 inhibitor, protects primary human lung epithelial cells from cigarette-smoke-extract (CSE induced cell death in an established in vitro model of radical stress. To identify new potential drug targets with a similar effect, we performed a siRNA screen of the 'druggable' genome using a NRF2 transcriptional reporter cell line. This screen identified multiple genes that when down regulated increased NRF2 transcriptional activity and provided a survival benefit in the in vitro model. Our results suggest that inhibiting components of the ubiquitin-proteasome system will have the strongest effects on NRF2 transcriptional activity by increasing NRF2 levels. We also find that down regulation of the small GTPase Rab28 or the Estrogen Receptor ESRRA provide a survival benefit. Rab28 knockdown increased NRF2 protein levels, indicating that Rab28 may regulate NRF2 proteolysis. Conversely ESRRA down regulation increased NRF2 transcriptional activity without affecting NRF2 levels, suggesting a proteasome-independent mechanism.

  14. EEG-based motor network biomarkers for identifying target patients with stroke for upper limb rehabilitation and its construct validity.

    Directory of Open Access Journals (Sweden)

    Chun-Chuan Chen

    Full Text Available Rehabilitation is the main therapeutic approach for reducing poststroke functional deficits in the affected upper limb; however, significant between-patient variability in rehabilitation efficacy indicates the need to target patients who are likely to have clinically significant improvement after treatment. Many studies have determined robust predictors of recovery and treatment gains and yielded many great results using linear approachs. Evidence has emerged that the nonlinearity is a crucial aspect to study the inter-areal communication in human brains and abnormality of oscillatory activities in the motor system is linked to the pathological states. In this study, we hypothesized that combinations of linear and nonlinear (cross-frequency network connectivity parameters are favourable biomarkers for stratifying patients for upper limb rehabilitation with increased accuracy. We identified the biomarkers by using 37 prerehabilitation electroencephalogram (EEG datasets during a movement task through effective connectivity and logistic regression analyses. The predictive power of these biomarkers was then tested by using 16 independent datasets (i.e. construct validation. In addition, 14 right handed healthy subjects were also enrolled for comparisons. The result shows that the beta plus gamma or theta network features provided the best classification accuracy of 92%. The predictive value and the sensitivity of these biomarkers were 81.3% and 90.9%, respectively. Subcortical lesion, the time poststroke and initial Wolf Motor Function Test (WMFT score were identified as the most significant clinical variables affecting the classification accuracy of this predictive model. Moreover, 12 of 14 normal controls were classified as having favourable recovery. In conclusion, EEG-based linear and nonlinear motor network biomarkers are robust and can help clinical decision making.

  15. Identifying a compound modifying a cellular response, comprises attaching cells having a reporter system onto solid supports, releasing a library member, screening and identifying target cells

    DEFF Research Database (Denmark)

    2011-01-01

    The present invention relates to methods for identifying compounds capable of modulating a cellular response. The methods involve attaching living cells to solid supports comprising a library of test compounds. Test compounds modulating a cellular response, for example via a cell surface molecule...... may be identified by selecting solid supports comprising cells, wherein the cellular response of interest has been modulated. The cellular response may for example be changes in signal transduction pathways modulated by a cell surface molecule....

  16. An optimized InCell Western screening technique identifies hexachlorophene as a novel potent TDP43 targeting drug.

    Science.gov (United States)

    Narayan, Malathi; Peralta, Diego A; Gibson, Chelsea; Zitnyar, Ashley; Jinwal, Umesh K

    2015-08-10

    TAR DNA binding protein (TDP43) is a DNA- and RNA-binding protein that is implicated in several neurodegenerative disorders termed as "TDP43 proteinopathies" including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and fronto-temporal lobe dementia (FTLD). We have developed an InCell Western (ICW) technique for screening TDP targeting drugs in 96 well plates. We tested 281 compounds and identified a novel compound hexachlorophene (referred to as B10) that showed potent reduction in TDP43 levels. The effect of B10 on TDP protein level was validated in two different cellular models: endogenous TDP43 expressing N9 microglial cells and TDP43-over-expressing HEK293 and HeLa cells. We also analyzed effect of B10 on various pathological forms of TDP such as the C25 cleaved fragment that localizes to the cytosol, insoluble high molecular weight species, and ALS-linked mutants. Our data suggest that B10 effectively reduces all forms of TDP. Overall, our data suggest that B10 could serve as a potential drug molecule for the treatment of AD, ALS and other TDP43 proteinopathies. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Antibody responses to NY-ESO-1 in primary breast cancer identify a subtype target for immunotherapy.

    Science.gov (United States)

    Hamaï, Ahmed; Duperrier-Amouriaux, Karine; Pignon, Pascale; Raimbaud, Isabelle; Memeo, Lorenzo; Colarossi, Cristina; Canzonieri, Vincenzo; Perin, Tiziana; Classe, Jean-Marc; Campone, Mario; Jézéquel, Pascal; Campion, Loïc; Ayyoub, Maha; Valmori, Danila

    2011-01-01

    The highly immunogenic human tumor antigen NY-ESO-1 (ESO) is a target of choice for anti-cancer immune therapy. In this study, we assessed spontaneous antibody (Ab) responses to ESO in a large cohort of patients with primary breast cancer (BC) and addressed the correlation between the presence of anti-ESO Ab, the expression of ESO in the tumors and their characteristics. We found detectable Ab responses to ESO in 1% of the patients. Tumors from patients with circulating Ab to ESO exhibited common characteristics, being mainly hormone receptor (HR)⁻ invasive ductal carcinomas of high grade, including both HER2⁻ and HER2⁺ tumors. In line with these results, we detected ESO expression in 20% of primary HR⁻ BC, including both ESO Ab⁺ and Ab⁻ patients, but not in HR⁺ BC. Interestingly, whereas expression levels in ESO⁺ BC were not significantly different between ESO Ab⁺ and Ab⁻ patients, the former had, in average, significantly higher numbers of tumor-infiltrated lymph nodes, indicating that lymph node invasion may be required for the development of spontaneous anti-tumor immune responses. Thus, the presence of ESO Ab identifies a tumor subtype of HR⁻ (HER2⁻ or HER2⁺) primary BC with frequent ESO expression and, together with the assessment of antigen expression in the tumor, may be instrumental for the selection of patients for whom ESO-based immunotherapy may complement standard therapy.

  18. Targeted next generation sequencing approach identifies eighteen new candidate genes in normosmic hypogonadotropic hypogonadism and Kallmann syndrome.

    Science.gov (United States)

    Quaynor, Samuel D; Bosley, Maggie E; Duckworth, Christina G; Porter, Kelsey R; Kim, Soo-Hyun; Kim, Hyung-Goo; Chorich, Lynn P; Sullivan, Megan E; Choi, Jeong-Hyeon; Cameron, Richard S; Layman, Lawrence C

    2016-12-05

    The genetic basis is unknown for ∼60% of normosmic hypogonadotropic hypogonadism (nHH)/Kallmann syndrome (KS). DNAs from (17 male and 31 female) nHH/KS patients were analyzed by targeted next generation sequencing (NGS) of 261 genes involved in hypothalamic, pituitary, and/or olfactory pathways, or suggested by chromosome rearrangements. Selected variants were subjected to Sanger DNA sequencing, the gold standard. The frequency of Sanger-confirmed variants was determined using the ExAC database. Variants were classified as likely pathogenic (frameshift, nonsense, and splice site) or predicted pathogenic (nonsynonymous missense). Two novel FGFR1 mutations were identified, as were 18 new candidate genes including: AMN1, CCKBR, CRY1, CXCR4, FGF13, GAP43, GLI3, JAG1, NOS1, MASTL, NOTCH1, NRP2, PALM2, PDE3A, PLEKHA5, RD3, and TRAPPC9, and TSPAN11. Digenic and trigenic variants were found in 8/48 (16.7%) and 1/48 (2.1%) patients, respectively. NGS with confirmation by Sanger sequencing resulted in the identification of new causative FGFR1 gene mutations and suggested 18 new candidate genes in nHH/KS. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  19. Accelerating the domestication of a bioenergy crop: identifying and modelling morphological targets for sustainable yield increase in Miscanthus.

    Science.gov (United States)

    Robson, Paul; Jensen, Elaine; Hawkins, Sarah; White, Simon R; Kenobi, Kim; Clifton-Brown, John; Donnison, Iain; Farrar, Kerrie

    2013-11-01

    To accelerate domestication of Miscanthus, an important energy crop, 244 replicated genotypes, including two different species and their hybrids, were analysed for morphological traits and biomass yield over three growing seasons following an establishment phase of 2 years in the largest Miscanthus diversity trial described to date. Stem and leaf traits were selected that contributed both directly and indirectly to total harvested biomass yield, and there was variation in all traits measured. Morphological diversity within the population was correlated with dry matter yield (DMY) both as individual traits and in combination, in order to determine the respective contributions of the traits to biomass accumulation and to identify breeding targets for yield improvement. Predictive morphometric analysis was possible at year 3 within Miscanthus sinensis genotypes but not between M. sinensis, Miscanthus sacchariflorus, and interspecific hybrids. Yield is a complex trait, and no single simple trait explained more than 33% of DMY, which varied from 1 to 5297 g among genotypes within this trial. Associating simple traits increased the power of the morphological data to predict yield to 60%. Trait variety, in combination, enabled multiple ideotypes, thereby increasing the potential diversity of the crop for multiple growth locations and end uses. Both triploids and interspecific hybrids produced the highest mature yields, indicating that there is significant heterosis to be exploited within Miscanthus that might be overlooked in early selection screens within years 1-3. The potential for optimizing biomass yield by selecting on the basis of morphology is discussed.

  20. A person-centered intervention targeting the psychosocial needs of gynecological cancer survivors

    DEFF Research Database (Denmark)

    Olesen, Mette Linnet; Duun-Henriksen, Anne Katrine; Hansson, Eva Helena

    2016-01-01

    , depression, self-esteem, and self-reported ability to monitor and respond to symptoms of recurrence. METHODS: We randomly assigned 165 gynecological cancer survivors to usual care (UC) plus GSD-GYN-C or UC alone. Self-reported QOL-cancer survivor (QOL-CS) total score and subscale scores on physical......PURPOSE: We investigated the effect of a person-centered intervention consisting of two to four nurse-led conversations using guided self-determination tailored to gynecologic cancer (GSD-GYN-C) on gynecological cancer survivors' quality of life (QOL), impact of cancer, distress, anxiety...

  1. XIAP as a Molecular Target for Therapeutic Intervention in Prostate Cancer

    Science.gov (United States)

    2007-10-01

    control of the apoptotic threshold. Although we learnt that the use of lentivirally manipulated cell lines in xenograft studies results in excessive...effort by many research groups to devise IAP-targeting strategies as a means of devel- oping novel antineoplastic drugs. In this Review, we consider the...very  care - fully regulates this release. Once released into the cytosol, cytochrome c binds directly to  a key cellular component of  the apoptotic

  2. Targeting physical activity and nutrition interventions towards mothers with young children: a review on components that contribute to attendance and effectiveness

    NARCIS (Netherlands)

    Hartman, Marieke A.; Hosper, Karen; Stronks, Karien

    2011-01-01

    To gain insight into intervention components targeted specifically to mothers of young children that may contribute to attendance and effectiveness on physical activity and healthy eating. Systematic literature searches were performed using MEDLINE, Embase and cited references. Articles were

  3. Identifying new lignin bioengineering targets: impact of epicatechin, quercetin glycoside, and gallate derivatives on the lignification and fermentation of maize cell walls

    Science.gov (United States)

    Apoplastic targeting of secondary metabolites compatible with monolignol polymerization may provide new avenues for designing lignins that are less inhibitory toward fiber fermentation. To identify suitable monolignol substitutes, we artificially lignified maize cell walls with normal monolignols pl...

  4. New biomarkers of coffee consumption identified by the non-targeted metabolomic profiling of cohort study subjects.

    Directory of Open Access Journals (Sweden)

    Joseph A Rothwell

    Full Text Available Coffee contains various bioactives implicated with human health and disease risk. To accurately assess the effects of overall consumption upon health and disease, individual intake must be measured in large epidemiological studies. Metabolomics has emerged as a powerful approach to discover biomarkers of intake for a large range of foods. Here we report the profiling of the urinary metabolome of cohort study subjects to search for new biomarkers of coffee intake. Using repeated 24-hour dietary records and a food frequency questionnaire, 20 high coffee consumers (183-540 mL/d and 19 low consumers were selected from the French SU.VI.MAX2 cohort. Morning spot urine samples from each subject were profiled by high-resolution mass spectrometry. Partial least-square discriminant analysis of multidimensional liquid chromatography-mass spectrometry data clearly distinguished high consumers from low via 132 significant (p-value<0.05 discriminating features. Ion clusters whose intensities were most elevated in the high consumers were annotated using online and in-house databases and their identities checked using commercial standards and MS-MS fragmentation. The best discriminants, and thus potential markers of coffee consumption, were the glucuronide of the diterpenoid atractyligenin, the diketopiperazine cyclo(isoleucyl-prolyl, and the alkaloid trigonelline. Some caffeine metabolites, such as 1-methylxanthine, were also among the discriminants, however caffeine may be consumed from other sources and its metabolism is subject to inter-individual variation. Receiver operating characteristics curve analysis showed that the biomarkers identified could be used effectively in combination for increased sensitivity and specificity. Once validated in other cohorts or intervention studies, these specific single or combined biomarkers will become a valuable alternative to assessment of coffee intake by dietary survey and finally lead to a better understanding of

  5. Systemic Response to Microgravity: Utilizing GeneLab Datasets to Identify Molecular Targets for Future Hypotheses-Driven Spaceflight Studies

    Science.gov (United States)

    Beheshti, Afshin; Ray, Shayoni; Fogle, Homer; Berrios, Daniel C.; Costes, Sylvain V.

    2017-01-01

    subsequent impact on health, a theoretical health risk score was calculated. The genes and miRNAs identified from our analyses can be targeted for future research involving efficient countermeasure design. Our study thus exemplifies the utility of GeneLab data repository to aid in the process of performing novel hypothesis based spaceflight research aimed at elucidating the global impact of environmental stressors at multiple biological scales.

  6. Quality of Care at Hospitals Identified as Outliers in Publicly Reported Mortality Statistics for Percutaneous Coronary Intervention.

    Science.gov (United States)

    Waldo, Stephen W; McCabe, James M; Kennedy, Kevin F; Zigler, Corwin M; Pinto, Duane S; Yeh, Robert W

    2017-05-16

    Public reporting of percutaneous coronary intervention (PCI) outcomes may create disincentives for physicians to provide care for critically ill patients, particularly at institutions with worse clinical outcomes. We thus sought to evaluate the procedural management and in-hospital outcomes of patients treated for acute myocardial infarction before and after a hospital had been publicly identified as a negative outlier. Using state reports, we identified hospitals that were recognized as negative PCI outliers in 2 states (Massachusetts and New York) from 2002 to 2012. State hospitalization files were used to identify all patients with an acute myocardial infarction within these states. Procedural management and in-hospital outcomes were compared among patients treated at outlier hospitals before and after public report of outlier status. Patients at nonoutlier institutions were used to control for temporal trends. Among 86 hospitals, 31 were reported as outliers for excess mortality. Outlier facilities were larger, treating more patients with acute myocardial infarction and performing more PCIs than nonoutlier hospitals ( P fashion (interaction P =0.50) after public report of outlier status. The likelihood of in-hospital mortality decreased at outlier institutions (RR, 0.83; 95% CI, 0.81-0.85) after public report, and to a lesser degree at nonoutlier institutions (RR, 0.90; 95% CI, 0.87-0.92; interaction P <0.001). Among patients that underwent PCI, in-hospital mortality decreased at outlier institutions after public recognition of outlier status in comparison with prior (RR, 0.72; 9% CI, 0.66-0.79), a decline that exceeded the reduction at nonoutlier institutions (RR, 0.87; 95% CI, 0.80-0.96; interaction P <0.001). Large hospitals with higher clinical volume are more likely to be designated as negative outliers. The rates of percutaneous revascularization increased similarly at outlier and nonoutlier institutions after report of outlier status. After outlier

  7. Using target population specification, effect size, and reach to estimate and compare the population impact of two PTSD preventive interventions.

    Science.gov (United States)

    Zatzick, Douglas F; Koepsell, Thomas; Rivara, Frederick P

    2009-01-01

    The population impact of a preventive intervention depends on two factors: what proportion of the full population at risk receives the intervention and how large a reduction in risk occurs among those who receive it. We sought to illustrate how information from a cognitive behavioral psychotherapy (CBT) trial and stepped collaborative care (CC) trial could be used to estimate the population impact of two contrasting approaches to PTSD prevention. We first specified trauma center target populations represented by participants in each trial. Patient characteristics were compared, as were effect size and reach indices and population-level reductions in PTSD incidence. The CBT trial demonstrated a larger effect size (50% PTSD prevention), but minimal reach (27/10,000), while the CC trial demonstrated a smaller effect size (7% PTSD prevention) but greater reach (1762/10,000). Modeling of the population impact suggested that a 9.5-fold greater cumulative reduction in the incidence of PTSD would result from the dissemination of the CC broad reach prevention strategy. A reciprocal relationship between effect size and reach was evident in these two trials. By specifying a target population, effect size and reach could be combined to project the overall population impact of each PTSD prevention approach.

  8. Can a lifestyle intervention be offered through NHS breast cancer screening? Challenges and opportunities identified in a qualitative study of women attending screening

    Directory of Open Access Journals (Sweden)

    Ellie Conway

    2016-08-01

    . The concept of focussing on small lifestyle changes, which were personalised, supported socially and appropriate to age and ability were welcomed. Conclusions Offering access to a lifestyle programme through breast screening appears acceptable. Explaining the relevance of the target behaviours for breast cancer health, endorsing and utilising consistent messages and identifying personalised, mutually agreed, behaviour change goals provides a framework for programme development.

  9. Inequities in utilization of maternal health interventions in Namibia: implications for progress towards MDG 5 targets

    Directory of Open Access Journals (Sweden)

    Kirigia Joses

    2010-06-01

    Full Text Available Abstract Background Inequities in the utilization of maternal health services impede progress towards the MDG 5 target of reducing the maternal mortality ratio by three quarters, between 1990 and 2015. In Namibia, despite increasing investments in the health sector, the maternal mortality ratio has increased from 271 per 100,000 live births in the period 1991-2000 to 449 per 100,000 live births in 1998-2007. Monitoring equity in the use of maternal health services is important to target scarce resources to those with more need and expedite the progress towards the MDG 5 target. The objective of this study is to measure socio-economic inequalities in access to maternal health services and propose recommendations relevant for policy and planning. Methods Data from the Namibia Demographic and Health Survey 2006-07 are analyzed for inequities in the utilization of maternal health. In measuring the inequities, rate-ratios, concentration curves and concentration indices are used. Results Regions with relatively high human development index have the highest rates of delivery by skilled health service providers. The rate of caesarean section in women with post secondary education is about seven times that of women with no education. Women in urban areas are delivered by skilled providers 30% more than their rural counterparts. The rich use the public health facilities 30% more than the poor for child delivery. Conclusion Most of the indicators such as delivery by trained health providers, delivery by caesarean section and postnatal care show inequities favoring the most educated, urban areas, regions with high human development indices and the wealthy. In the presence of inequities, it is difficult to achieve a significant reduction in the maternal mortality ratio needed to realize the MDG 5 targets so long as a large segment of society has inadequate access to essential maternal health services and other basic social services. Addressing inequities in

  10. Variation in Veteran Identity as a Factor in Veteran-Targeted Interventions.

    Science.gov (United States)

    Hack, Samantha M; DeForge, Bruce R; Lucksted, Alicia

    2017-07-01

    The sociocultural identities that people self-assign or accept influence their interpersonal interactions and decision making. Identity-based interventions attempt to influence individuals by associating healthy behaviors with in-group membership. Outreach and educational efforts aimed at veterans may rely on "typical" veteran identity stereotypes. However, as discussed in this Open Forum, there is evidence that veteran identity is not monolithic but rather fluctuates on the basis of personal characteristics and individual military service experiences. Overall, the impact of veteran identity on veterans' health behaviors and use of health care is not known and has been understudied. A major limiting factor is the lack of a standardized measure of veteran identity that can assess variations in salience, prominence, and emotional valence.

  11. Maternal over-nutrition and offspring obesity predisposition: targets for preventative interventions.

    Science.gov (United States)

    Rooney,